{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-07-11", "results": { "skip": 0, "limit": 10, "total": 1626 } }, "results": [ { "spl_product_data_elements": [ "SIMVASTATIN SIMVASTATIN ASCORBIC ACID BUTYLATED HYDROXYANISOLE CELLULOSE, MICROCRYSTALLINE CITRIC ACID MONOHYDRATE FERROSOFERRIC OXIDE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSES LACTOSE MONOHYDRATE MAGNESIUM STEARATE STARCH, CORN TALC TITANIUM DIOXIDE SIMVASTATIN SIMVASTATIN brick red biconvex LL;C04" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Simvastatin tablets USP are indicated: To reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Simvastatin tablets USP are an HMG-CoA reductase inhibitor indicated: To reduce the risk of total mortality by reducing risk of coronary heart disease death, non-fatal myocardial infarction and stroke, and the need for coronary and non-coronary revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or diabetes, who are at high risk of coronary heart disease events. As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C): In adults with primary hyperlipidemia. In adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Information : ( 1 ) Take simvastatin tablets USP orally once daily in the evening. Maximum recommended dosage is simvastatin tablets USP 40 mg once daily. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating, and adjust the dosage if necessary. Adults : Recommended dosage is 20 mg to 40 mg once daily. ( 2.2 ) Pediatric Patients Aged 10 Years and Older with HeFH : Recommended dosage is 10 mg to 40 mg once daily. ( 2.3 ) Patients with Severe Renal Impairment : Recommended starting dosage is simvastatin 5 mg once daily. ( 2.4 , 8.6 ) See full prescribing information for simvastatin tablets USP dosage modifications due to drug interactions. ( 2.5 ) 2.1 Important Dosage and Administration Information Take simvastatin tablets USP orally once daily in the evening. The maximum recommended dosage is simvastatin tablets USP 40 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.2 , 2.3 )]. An 80 mg daily dosage of simvastatin tablets USP is restricted to patients who have been taking simvastatin tablets USP 80 mg daily chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see WARNINGS AND PRECAUTIONS ( 5.1 )]. If as dose is missed, take the missed dose as soon as possible. Do not double the next dose. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving simvastatin tablets USP 40 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating simvastatin tablets USP, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended dosage range of simvastatin tablets USP is 20 mg to 40 mg once daily 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended dosage range of simvastatin tablets USP is 10 mg to 40 mg daily. 2.4 Recommended Dosage in Patients with Renal Impairment For patients with severe renal impairment [creatinine clearance (CLcr) 15 – 29 mL/min], the recommended starting dosage of simvastatin is 5 mg once daily [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND USE IN SPECIFIC POPULATIONS ( 8.6 )]. Use another simvastatin product to initiate dosing in such patients [see DOSAGE AND ADMINISTRATION ( 2.1 )]. There are no dosage adjustment recommendations for patients with mild or moderate renal impairment. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of simvastatin tablets USP with the following drugs requires dosage modification of simvastatin tablets USP [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND DRUG INTERACTIONS ( 7.1 )]. Patients taking Lomitapide Reduce the dosage of simvastatin tablets USP by 50%. Do not exceed simvastatin tablets USP 20 mg once daily (or 40 mg once daily for patients who have previously taken an 80 mg daily dosage of simvastatin tablets USP chronically while taking lomitapide) [see DOSAGE AND ADMINISTRATION (2.1)]. Patients taking Verapamil, Diltiazem, or Dronedarone Do not exceed simvastatin tablets USP 10 mg once daily. Patients taking Amiodarone, Amlodipine, or Ranolazine Do not exceed simvastatin tablets USP 20 mg once daily." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Simvastatin tablets 5 mg are tan colored, round, biconvex, film-coated tablets debossed with 'LL' on one side and 'C01' on the other side. Simvastatin tablets 10 mg are peach colored, oval shaped, biconvex, film-coated tablets debossed with 'LL' on one side and 'C02' on the other side. Simvastatin tablets 20 mg are tan colored, oval shaped, biconvex, film-coated tablets debossed with 'LL' on one side and 'C03' on the other side. Simvastatin tablets 40 mg are brick red colored, round shaped, biconvex, film-coated tablets debossed with 'LL' on one side and 'C04' on the other side. Simvastatin tablets 80 mg are brick red colored, capsule shaped, biconvex, film-coated tablets debossed with 'LL' on one side and 'C05' on the other side. Tablets: 5 mg, 10 mg; 20 mg; 40 mg; 80 mg" ], "contraindications": [ "4 CONTRAINDICATIONS Simvastatin is contraindicated in the following conditions: Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) [see DRUG INTERACTIONS ( 7.1 )]. Concomitant use of cyclosporine, danazol or gemfibrozil [see DRUG INTERACTIONS ( 7.1 )]. Acute liver failure or decompensated cirrhosis [see WARNINGS AND PRECAUTIONS ( 5.3 )] Hypersensitivity to simvastatin or any excipients in simvastatin tablets USP. Hypersensitivity reactions, including anaphylaxis, angioedema and Stevens-Johnson syndrome, have been reported [see ADVERSE REACTIONS ( 6.2 )] Concomitant use of strong CYP3A4 inhibitors (select azole anti-fungals, macrolide antibiotics, anti-viral medications, and nefazodone) ( 4 , 7.1 ) Concomitant use of cyclosporine, danazol or gemfibrozil ( 4 , 7.1 ) Acute liver failure or decompensated cirrhosis ( 4 , 5.3 ) Hypersensitivity to simvastatin or any excipient in simvastatin tablets USP ( 4 , 6.2 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher simvastatin dosage. Chinese patients may be at higher risk for myopathy. Discontinue simvastatin if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue simvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing simvastatin dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 , 7.1 , 8.5 , 8.6 , 8.8 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue simvastatin if IMNM is suspected. ( 5.2 ) Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzyme before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue simvastatin. ( 4 , 5.3 , 8.7 ) 5.1 Myopathy and Rhabdomyolysis Simvastatin may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including simvastatin. In clinical studies of 24,747 simvastatin -treated patients with a median follow-up of 4 years, the incidence of myopathy, defined as unexplained muscle weakness, pain, or tenderness accompanied by creatinine kinase (CK) increases greater than ten times the upper limit of normal (10xULN), were approximately 0.03%, 0.08%, and 0.61% in patients treated with simvastatin 20 mg, 40 mg, and 80 mg daily, respectively. In another clinical study of 12,064 simvastatin -treated patients (with a history of myocardial infarction) with a mean follow-up of 6.7 years, the incidences of myopathy in patients taking simvastatin 20 mg and 80 mg daily were approximately 0.02% and 0.9%, respectively. The incidences of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients taking simvastatin 20 mg and 80 mg daily were approximately 0% and 0.4%, respectively [see ADVERSE REACTIONS ( 6.1 )]. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher simvastatin dosage; Chinese patients on simvastatin may be at higher risk for myopathy [see CONTRAINDICATIONS ( 4 ), DRUG INTERACTIONS ( 7.1 ), AND USE IN SPECIFIC POPULATIONS ( 8.8 )]. The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking simvastatin 80 mg daily compared with patients taking lower simvastatin dosages and compared with patients using other statins with similar or greater LDL-C-lowering efficacy [see ADVERSE REACTIONS ( 6.1 )]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis The concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend simvastatin during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of simvastatin with gemfibrozil, cyclosporine, or danazol is also contraindicated [see CONTRAINDICATIONS ( 4 ) AND DRUG INTERACTIONS ( 7.1 )]. Simvastatin dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine [see DOSAGE AND ADMINISTRATION ( 2.5 )]. Simvastatin use should be temporarily suspended in patients taking daptomycin. Lipid modifying doses (≥1 gram/day) of niacin, fibrates, colchicine, and grapefruit juice may also increase the risk of myopathy and rhabdomyolysis [see DRUG INTERACTIONS ( 7.1 )]. Use the 80 mg daily dosage of simvastatin only in patients who have been taking simvastatin 80 mg daily chronically without evidence of muscle toxicity [see DOSAGE AND ADMINISTRATION ( 2.1 )] . If patients treated with an 80 mg daily dosage of simvastatin tablet USP are prescribed an interacting drug that increases the risk for myopathy and rhabdomyolysis, switch to an alternate statin [SEE DRUG INTERACTIONS ( 7.1 )]. Discontinue simvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if simvastatin is discontinued. Temporarily discontinue simvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the simvastatin dosage and advise patients receiving an 80 mg daily dosage of simvastatin tablet USP of the increased risk of myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue simvastatin if IMNM is suspected 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of simvastatin [see ADVERSE REACTIONS ( 6.1 )] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with simvastatin. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before simvastatin initiation and when clinically indicated thereafter. Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue simvastatin. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including simvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see WARNINGS AND PRECAUTIONS ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see WARNINGS AND PRECAUTIONS ( 5.2 )] Hepatic Dysfunction [see WARNINGS AND PRECAUTIONS ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see WARNINGS AND PRECAUTIONS ( 5.4 )] Most common adverse reactions (incidence ≥5%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In clinical studies, 2,423 adult patients were exposed to simvastatin with a median duration of follow-up of approximately 18 months. The most commonly reported adverse reactions (incidence ≥5%) in these simvastatin clinical studies were: upper respiratory infections (9%), headache (7%), abdominal pain (7%), constipation (7%), and nausea (5%). Overall, 1.4% of patients discontinued simvastatin due to adverse reactions. The most common adverse reactions that led to discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). In a Cardiovascular Outcomes Study (the Scandinavian Simvastatin Survival Study [Study 4S]), adult patients (age range 35-71 years, 19% women, 100% Caucasians) were treated with 20-40 mg per day of simvastatin or placebo over a median of 5.4 years [see CLINICAL STUDIES ( 14 )] ; adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 1. Table 1 : Adverse Reactions Reported ≥2% of Patients Treated with Simvastatin and Greater than Placebo in Study 4S % Placebo (N = 2,223) % Simvastatin (N = 2,221) Bronchitis 6.3 6.6 Abdominal pain 5.8 5.9 Atrial fibrillation 5.1 5.7 Gastritis 3.9 4.9 Eczema 3.0 4.5 Vertigo 4.2 4.5 Diabetes mellitus 3.6 4.2 Insomnia 3.8 4.0 Myalgia 3.2 3.7 Urinary tract infection 3.1 3.2 Edema/swelling 2.3 2.7 Headache 2.1 2.5 Sinusitis 1.8 2.3 Constipation 1.6 2.2 Myopathy/Rhabdomyolysis In clinical studies with a median follow-up of at least 4 years, in which 24,747 patients received simvastatin, the incidence of myopathy (defined as unexplained muscle weakness, pain, or tenderness accompanied by CK increases greater than 10xULN) was approximately 0.03%, 0.08%, and 0.61% for the simvastatin 20 mg, 40 mg, and 80 mg daily groups, respectively. In a clinical outcomes study in which 12,064 adult patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10x [1200 U/L] ULN) in patients taking simvastatin 20 mg and 80 mg daily was approximately 0.02% and 0.9%, respectively. The incidence of rhabdomyolysis (defined as myopathy with a CK >40xULN) in patients on simvastatin 20 mg and 80 mg daily was approximately 0% and 0.4%, respectively. The incidence of myopathy and rhabdomyolysis were highest during the first year and then decreased during the subsequent years of treatment. In another clinical outcomes study in which 10,269 adult patients were treated with simvastatin 40 mg per day (mean follow-up of 5 years), the incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin. Elevations in Liver Enzyme Tests Moderate (less than 3xULN) elevations of serum transaminases have been reported with use of simvastatin. Persistent increases to more than 3xULN in serum transaminases have occurred in approximately 1% of patients receiving simvastatin in clinical studies. Marked persistent increases of hepatic transaminases have occurred with simvastatin. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. In Study 4S, with a median follow-up of 5.4 years, 1,986 adult patients were treated with simvastatin 20 mg once daily, of whom 37% titrated to 40 mg once daily. The percentage of patients with one or more occurrences of transaminase elevations to >3xULN was 0.7% in patients taking simvastatin compared with 0.6% in patients taking placebo. Elevated transaminases leading to discontinuation of study treatment occurred in 0.4% of patients taking simvastatin and 0.2% of patients taking placebo. The majority of elevated transaminases leading to treatment discontinuation occurred within in the first year. Adverse Reactions in Pediatric Patients with Heterozygous Familial Hypercholesterolemia In a 48-week clinical study in pediatric patients 10 years of age and older (43% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with HeFH (n=175), treated with placebo or simvastatin (10 - 40 mg daily), the most common adverse reactions were upper respiratory infection, headache, abdominal pain, and nausea [see USE IN SPECIFIC POPULATIONS (8.4) AND CLINICAL STUDIES ( 14 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of simvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as whole fever, chills, malaise, asthenia Blood and Lymphatic System Disorders anemia, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia Gastrointestinal Disorders pancreatitis, vomiting Hepatic and Pancreatic Disorders hepatitis/jaundice, fatal and non-fatal hepatic failure Immune System Disorders hypersensitivity syndrome including: anaphylaxis, angioedema, lupus erythematous-like syndrome, dermatomyositis, vasculitis Musculoskeletal and Connective Tissue Disorders muscle cramps, immune-mediated necrotizing myopathy, polymyalgia rheumatica, arthritis Nervous System Disorders dizziness, depression, paresthesia, peripheral neuropathy. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Skin and Subcutaneous Tissue Disorders pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), purpura, lichen planus, urticaria, photosensitivity, flushing, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome Respiratory and Thoracic interstitial lung disease, dyspnea Reproductive System Disorders erectile dysfunction" ], "adverse_reactions_table": [ "
Table 1 : Adverse Reactions Reported ≥2% of Patients Treated with Simvastatin and Greater than Placebo in Study 4S
% Placebo (N = 2,223) % Simvastatin (N = 2,221)
Bronchitis 6.3 6.6
Abdominal pain 5.8 5.9
Atrial fibrillation 5.1 5.7
Gastritis 3.9 4.9
Eczema 3.0 4.5
Vertigo 4.2 4.5
Diabetes mellitus 3.6 4.2
Insomnia 3.8 4.0
Myalgia 3.2 3.7
Urinary tract infection 3.1 3.2
Edema/swelling 2.3 2.7
Headache 2.1 2.5
Sinusitis 1.8 2.3
Constipation 1.6 2.2
" ], "drug_interactions": [ "7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of simvastatin with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. ( 2.5 , 7.1 ) Coumarin Anticoagulants: Obtain INR before simvastatin initiation and monitor INR during simvastatin dosage initiation or adjustment. ( 7.2 ) Digoxin: During simvastatin initiation, monitor digoxin levels. ( 7.2 ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Simvastatin is a substrate of CYP3A4 and of the transport protein OATP1B1. Simvastatin exposure can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1. Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with simvastatin and instructions for preventing or managing them [see WARNINGS AND PRECAUTIONS ( 5.1 ) AND CLINICAL PHARMACOLOGY ( 12.3 )] . Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with simvastatin increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher simvastatin dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with Simvastatin is contraindicated [see CONTRAINDICATIONS ( 4 )] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend simvastatin during the course of strong CYP3A4 inhibitor treatment. Examples: Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin is contraindicated [see CONTRAINDICATIONS ( 4 )] . Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with simvastatin. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily [see DOSAGE AND ADMINISTRATION ( 2.5 )] . Lomitapide Clinical Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased. Intervention: Reduce the dose of simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin chronically) while taking lomitapide [see DOSAGE AND ADMINISTRATION ( 2.1 , 2.5 )] . Daptomycin Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending simvastatin during the course of daptomycin treatment. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with simvastatin. The risk of myopathy is greater in Chinese patients. In a clinical study (median follow-up 3.9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin. Intervention: Concomitant use of simvastatin with lipid-modifying dosages of niacin is not recommended in Chinese patients [see USE IN SPECIFIC POPULATIONS ( 8.8 )]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with simvastatin. Intervention : Consider if the benefit of using fibrates concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with simvastatin. Intervention: Consider if the benefit of using colchicine concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking simvastatin. 7.2 Simvastatin Effects on Other Drugs Table 3 presents Simvastatin's effect on other drugs and instructions for preventing or managing them. Table 3: Simvastatin Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: Simvastatin may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. Digoxin Clinical Impact: Concomitant use of digoxin with simvastatin may result in elevated plasma digoxin concentrations [ see CLINICAL PHARMACOLOGY ( 12.3 ) ]. Intervention: Monitor digoxin levels in patients taking digoxin when simvastatin is initiated." ], "drug_interactions_table": [ "
Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Simvastatin
Strong CYP3A4 inhibitors
Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with simvastatin increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher simvastatin dosages.
Intervention: Concomitant use of strong CYP3A4 inhibitors with Simvastatin is contraindicated [see CONTRAINDICATIONS ( 4)] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend simvastatin during the course of strong CYP3A4 inhibitor treatment.
Examples: Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone.
Cyclosporine, Danazol, or Gemfibrozil
Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin. Gemfibrozil may cause myopathy when given alone.
Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with simvastatin is contraindicated [see CONTRAINDICATIONS ( 4)] .
Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers
Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with simvastatin.
Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed simvastatin 10 mg daily. For patients taking amiodarone, amlodipine, or ranolazine, do not exceed simvastatin 20 mg daily [see DOSAGE AND ADMINISTRATION ( 2.5)] .
Lomitapide
Clinical Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased.
Intervention: Reduce the dose of simvastatin by 50% if initiating lomitapide. Do not exceed simvastatin 20 mg daily (or simvastatin 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin chronically) while taking lomitapide [see DOSAGE AND ADMINISTRATION ( 2.1, 2.5)] .
Daptomycin
Clinical Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both simvastatin and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration.
Intervention: If treatment with daptomycin is required, consider temporarily suspending simvastatin during the course of daptomycin treatment.
Niacin
Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with simvastatin. The risk of myopathy is greater in Chinese patients. In a clinical study (median follow-up 3.9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin.
Intervention: Concomitant use of simvastatin with lipid-modifying dosages of niacin is not recommended in Chinese patients [see USE IN SPECIFIC POPULATIONS ( 8.8)]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with simvastatin.
Intervention: Consider if the benefit of using fibrates concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with simvastatin.
Intervention: Consider if the benefit of using colchicine concomitantly with simvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention: Avoid grapefruit juice when taking simvastatin.
", "
Table 3: Simvastatin Effects on Other Drugs
Coumarin Anticoagulants
Clinical Impact: Simvastatin may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin.
Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting simvastatin and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.
Digoxin
Clinical Impact: Concomitant use of digoxin with simvastatin may result in elevated plasma digoxin concentrations [ see CLINICAL PHARMACOLOGY ( 12.3) ].
Intervention: Monitor digoxin levels in patients taking digoxin when simvastatin is initiated.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with simvastatin. ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see CLINICAL PHARMACOLOGY ( 12.1 )] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with simvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m 2 ) (see DATA) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data: A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data: Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta. 8.2 Lactation Risk Summary There is no information about the presence of simvastatin in human or animal milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Statins, including simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with simvastatin [see USE IN SPECIFIC POPULATIONS (8.1), CLINICAL PHARMACOLOGY ( 12.1 )]. 8.4 Pediatric Use The safety and effectiveness of simvastatin as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of simvastatin for this indication is based on a double-blind, placebo-controlled clinical study in 175 pediatric patients (99 boys and 76 girls at least 1 year post-menarche) 10 years of age and older with HeFH. In this limited controlled study, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of simvastatin have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use Of the total number of simvastatin-treated patients in clinical studies 1,021 (23%) patients, 5,366 (52%) patients, and 363 (15%) patients were ≥65 years old, respectively. In Study HPS, 615 (6%) patients were ≥75 years old [see CLINICAL STUDIES ( 14 )] . In a clinical study of patients treated with simvastatin 80 mg daily, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70-78 years of age compared with patients between 18-30 years of age [see CLINICAL PHARMACOLOGY ( 12.3 )] . 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment (CLcr 15 – 29 mL/min), the recommended starting dosage is simvastatin 5 mg once daily [see DOSAGE AND ADMINISTRATION ( 2.4 ), WARNINGS AND PRECAUTIONS ( 5.1 )] . Simvastatin is not available in a 5 mg strength. Use another simvastatin product to initiate dosing in such patients. 8.7 Hepatic Impairment Simvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.3 )] . 8.8 Chinese Patients In a clinical study in which patients at high risk of CVD were treated with simvastatin 40 mg/day (median follow-up 3.9 years), the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). In this study, the incidence of myopathy for Chinese patients on simvastatin 40 mg/day or ezetimibe/simvastatin 10/40 mg/day coadministered with extended-release niacin 2 g/day was 1.24%. Chinese patients may be at higher risk for myopathy, monitor these patients appropriately. Coadministration of simvastatin with lipid-modifying doses of niacin-containing products (≥1 g/day niacin) is not recommended in Chinese patients [see WARNINGS AND PRECAUTIONS (5.1), DRUG INTERACTIONS ( 7.1 )]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Discontinue simvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Simvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, simvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see CLINICAL PHARMACOLOGY ( 12.1 )] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with simvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered simvastatin during the period of organogenesis at doses that resulted in 2.5 and 2 times, respectively, the human exposure at the maximum recommended human dosage of 80 mg/day, based on body surface area (mg/m 2 ) (see DATA) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data: A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data: Simvastatin was given to pregnant rats at doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) from gestation days 6-17 and to pregnant rabbits from gestation days 6-18 at doses of 2.5, 5, and 10 mg/kg/day (0.5 times, 1 times, and 2 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area). For both species, there was no evidence of maternal toxicity or embryolethality. In rats, mean fetal body weights in the 25 mg/kg/day group were decreased 5.4%. Similar fetal body weight effects were not observed in rabbits. Simvastatin doses of 6.25, 12.5 and 25 mg/kg/day (0.6 times, 1.3 times, and 2.5 times, respectively, the maximum recommended dosage of 80 mg/day when normalized to body surface area) were given to pregnant rats from gestation day 15 to lactation day 21. Slight decreases in maternal body weight gain and pup postnatal day 0 weight were observed in the 25 mg/kg/day dose group. Mean body weight gain of pups during lactation was slightly decreased at doses ≥12.5 mg/kg/day. Post weaning weight, behavior, reproductive performance and fertility of the offspring were not affected at any dose tested. Placental transfer of simvastatin was not evaluated in rats or rabbits. However, it has been shown that other drugs in this class cross the placenta." ], "geriatric_use": [ "8.5 Geriatric Use Of the total number of simvastatin-treated patients in clinical studies 1,021 (23%) patients, 5,366 (52%) patients, and 363 (15%) patients were ≥65 years old, respectively. In Study HPS, 615 (6%) patients were ≥75 years old [see CLINICAL STUDIES ( 14 )] . In a clinical study of patients treated with simvastatin 80 mg daily, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. A pharmacokinetic study with simvastatin use showed the mean plasma level of total inhibitors to be approximately 45% higher in geriatric patients between 70-78 years of age compared with patients between 18-30 years of age [see CLINICAL PHARMACOLOGY ( 12.3 )] ." ], "overdosage": [ "10 OVERDOSAGE No specific antidotes for simvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations." ], "description": [ "11 DESCRIPTION Simvastatin is a prodrug of 3-hydoroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is derived synthetically from a fermentation product of Aspergillus terreus . Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S* ,4 S* ),-8aβ]]. The empirical formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Its structural formula is: Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin tablets USP are available for oral administration in strength of 5 mg, 10 mg, 20 mg, 40 mg or 80 mg. Each tablet contains following inactive ingredients: ascorbic acid, citric acid, hydroxy propyl cellulose, hypromellose, iron oxides, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch, talc and titanium dioxide. Butylated hydroxyanisole is added as a preservative. Image" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. 12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that 12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base. Absorption Following an oral dose of 14 C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors –time curve, was apparently linear with doses up to 120 mg Effect of Food: The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal. Distribution Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Elimination Metabolism: Simvastatin is metabolized by CYP3A4. The major active metabolites of simvastatin present in human plasma are simvastatin acid and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Excretion : Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces. Specific Populations Geriatric Patients: In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18-30 years of age [see USE IN SPECIFIC POPULATIONS ( 8.5 )]. Drug Interaction Studies Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid. Cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see DRUG INTERACTIONS ( 7 )] . Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see DRUG INTERACTIONS ( 7 )] . Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. & Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect = 1.00 AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 12 15 simvastatin 8.9 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 13.1 simvastatin 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 7.3 10.3 9.2 9.4 200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 8.5 10.6 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓ from 33.6 to 21.1 ng·eq/mL Simvastatin's Effect on the Pharmacokinetics of Other Drugs: In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. Simvastatin is not an inhibitor of CYP3A4 and is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL [see DRUG INTERACTIONS ( 7.2 )] ." ], "clinical_pharmacology_table": [ "
Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
* Results based on a chemical assay except results with propranolol as indicated.
†Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
&Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with / without coadministered drug) No Effect = 1.00
AUC C max
Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 12 15
simvastatin 8.9 5.3
Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡
simvastatin 6 6.2
Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 13.1
simvastatin 13.1
Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 7.3 10.3 9.2 9.4
200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 8.5 10.6 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91
Grapefruit Juice § (high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice § (low dose) 8 oz (about 237mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7
Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓ from 33.6 to 21.1 ng·eq/mL
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base. Absorption Following an oral dose of 14 C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors –time curve, was apparently linear with doses up to 120 mg Effect of Food: The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal. Distribution Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Elimination Metabolism: Simvastatin is metabolized by CYP3A4. The major active metabolites of simvastatin present in human plasma are simvastatin acid and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Excretion : Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces. Specific Populations Geriatric Patients: In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18-30 years of age [see USE IN SPECIFIC POPULATIONS ( 8.5 )]. Drug Interaction Studies Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid. Cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see DRUG INTERACTIONS ( 7 )] . Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see DRUG INTERACTIONS ( 7 )] . Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. & Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect = 1.00 AUC C max Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 12 15 simvastatin 8.9 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 13.1 simvastatin 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 7.3 10.3 9.2 9.4 200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 8.5 10.6 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓ from 33.6 to 21.1 ng·eq/mL Simvastatin's Effect on the Pharmacokinetics of Other Drugs: In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. Simvastatin is not an inhibitor of CYP3A4 and is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL [see DRUG INTERACTIONS ( 7.2 )] ." ], "pharmacokinetics_table": [ "
Table 4: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
* Results based on a chemical assay except results with propranolol as indicated.
†Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
&Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with / without coadministered drug) No Effect = 1.00
AUC C max
Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 12 15
simvastatin 8.9 5.3
Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡
simvastatin 6 6.2
Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ 13.1
simvastatin 13.1
Posaconazole 100 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 7.3 10.3 9.2 9.4
200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid simvastatin 8.5 10.6 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91
Grapefruit Juice § (high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice § (low dose) 8 oz (about 237mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7
Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-release 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓ from 33.6 to 21.1 ng·eq/mL
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear." ], "clinical_studies": [ "14 CLINICAL STUDIES Adults at High Risk of Coronary Heart Disease Events In a randomized, double-blind, placebo-controlled, multi-centered study [the Scandinavian Simvastatin Survival Study (Study 4S)], the effect of therapy with simvastatin on total mortality was assessed in 4,444 adult patients with CHD (history of angina and/or a previous myocardial infarction) and baseline total cholesterol (total-C) between 212 and 309 mg/dL who were on a lipid-lowering diet. In Study 4S, patients were treated with standard care, including lipid-lowering diet, and randomized to either simvastatin 20-40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 deaths in the simvastatin group vs 189 deaths in the placebo group). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly reduced the risk for the secondary composite endpoint (time to first occurrence of CHD death, definite or probable hospital verified non-fatal MI, silent MI verified by ECG, or resuscitated cardiac arrest) by 34% (p<0.00001, 431 vs 622 patients with one or more events). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p< 0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and triglycerides (TG) of 25%, 35%, and 10%, respectively, and a mean increase in high-density lipoprotein cholesterol (HDL-C) of 8%. In contrast, treatment with placebo led to increases in total-C, LDL-C and TG of 1%, 1%, and 7%, respectively. Because there were only 53 female deaths (approximately 18% of the study population was female), the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly reduced the risk of having major coronary events in women by 34% (60 vs 91 women with one or more event). Simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in geriatric patients (≥65 years) compared with younger adults. The Heart Protection Study (Study HPS) was randomized, placebo-controlled, double-blind, multi-centered study with a mean duration of 5 years conducted in 10,269 patients on simvastatin 40 mg and 10,267 on placebo).Patients had a mean age of 64 years (range 40 to 80 years old), were 97% were white and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vascular disease (33%), or they were males ≥65 years with hypertension in (6%). At baseline: 3,421 patients (17%) had LDL-C levels below 100 mg/dL, including 953 (5%) below 80 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL. Patients were randomized to simvastatin or placebo using a covariate adaptive method which considered the distribution of 10 important baseline characteristics of patients already enrolled. The Study HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; and non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 5). Table 5: CHD Mortality and Cardiovascular Events in Adult Patients with High Risk of Developing a Major Coronary Event in Study HPS * n = number of patients with indicated event Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%) (95% CI) p-Value Primary Mortality 1,328 (12.9%) 1,507 (14.7%) 13 (6 to 19%) p=0.0003 CHD mortality 587 (5.7%) 707 (6.9%) 18 (8 to 26%) p=0.0005 Secondary Non-fatal MI 357 (3.5%) 574 (5.6%) 38 (30 to 46%) p<0.0001 Stroke 444 (4.3%) 585 (5.7%) 25 (15 to 34%) p<0.0001 Tertiary Coronary revascularization 513 (5%) 725 (7.1%) 30 (22 to 38%) p<0.0001 Peripheral and other non-coronary revascularization 450 (4.4%) 532 (5.2%) 16 (5 to 26%) p=0.006 Two composite endpoints were defined in order to have enough events to assess relative risk reductions across a range of baseline characteristics: Major coronary events (MCE) was comprised of CHD mortality and non-fatal MI. Analyzed by time-to-first event; 898 patients (8.7%) treated with simvastatin had events and 1,212 patients (11.8%) treated with placebo had events. Major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures Analyzed by time-to-first event; 2,033 patients (19.8%) treated with simvastatin had events and 2,585 patients (25.2%) on placebo had events. Simvastatin use led to significant relative risk reductions for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001) and for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, baseline levels of LDL-C, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, or obesity. Patients with diabetes showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity. Primary Hyperlipidemia in Adults The effects of simvastatin on total-C and LDL-C were assessed in controlled clinical studies in adult patients with heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. simvastatin significantly decreased total-C, LDL-C, and TG, and increased HDL-C (see Table 6). Maximal to near maximal response was generally achieved within 4-6 weeks and maintained during chronic therapy. Table 6:Mean Changes in Lipid Levels in Adult Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks) * median percent change † mean baseline LDL-C =244 mg/dL and median baseline TG =168 mg/dL ‡ mean baseline LDL-C =188 mg/dL and median baseline TG =128 mg/dL § mean baseline LDL-C =226 mg/dL and median baseline TG =156 mg/dL ¶ 21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded & mean baseline LDL-C =156 mg/dL and median baseline TG =391 mg/dL TREATMENT N TOTAL-C LDL-C HDL-C TG* Lower Dose Comparative Study † (Mean % Change at Week 6) Simvastatin 5 mg at night. 109 -19% -26% +10 -12% Simvastatin 10 mg at night. 110 -23% -30% +12 -15% Scandinavian Simvastatin Survival Study ‡ (Mean % Change at Week 6) Placebo 2223 -1% -1% 0 -2% Simvastatin 20 mg at night. 2221 -28% -38% +8 -19% Upper Dose Comparative Study § (Mean % Change Averaged at Weeks 18 and 24) Simvastatin 40 mg at night. 433 -31% -41% +9 -18% Simvastatin 80 mg at night. ¶ 664 -36% -47% +8 -24% Combined Hyperlipidemia Study # (Mean % Change at Week 6) Placebo 125 1% 2% +3 -4% Simvastatin 40 mg at night. 123 -25% -29% +13 -28% Simvastatin 80 mg at night. 124 -31% -36% +16 -33% Hypertriglyceridemia in Adults The results of a subgroup analysis in 74 patients with hypertriglyceridemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in TABLE 6 for the Combined Hyperlipidemia Study. Simvastatin decreased TC, LDL-C, and TG in these patients. Dysbetalipoproteinemia in Adults The results of a subgroup analysis in 7 adult patients with dysbetalipoproteinemia (apo E2/2) (very-low-density lipoprotein cholesterol [VLDL-C]/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7. Simvastatin decreased total-C, LDL-C + intermediate[1]density lipoprotein (IDL), VLDL-C + IDL, and TG compared to placebo. Table 7:Lipid Effects in Adult Patients with Dysbetalipoproteinemia Over Six Weeks [Median Percent Change (min, max) from Baseline] * * The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291 TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C Placebo 7 -8% (-24, +34) -8% (-27, +23) -2% (-21, +16) +4% (-22, +90) -4% (-28, +78) -8% (-26, -39) Simvastatin 40 mg/day 7 -50% (-66, -39) -50% (-60, -31) +7% (-8, +23) -41% (-74, -16) -58% (-90, -37) -57% (-72, -44) Simvastatin 80 mg/day 7 -52% (-55, -41) -51% (-57, -28) +7% (-5, +29) -38% (-58, +2) -60% (-72, -39) -59% (-61, -46) Homozygous Familial Hypercholesterolemia In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia (HoFH) received simvastatin 40 mg/day in a single dose or 80 mg/day in 3 divided doses. In 12 patients the mean LDL-C changes at 9 weeks for the 40- and 80-mg doses were -13.7% (range -22.5% to -4.9%) and -24.6% (range -37.3% to -11.9%), respectively. Pediatric Patients 10 Years of Age and Older with HeFH In a double-blind, placebo-controlled study, 175 pediatric patients (99 boys and 76 post-menarchal girls) 10 years of age and older (mean age 14 years old) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). To be included in the study, patients were required to have a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24 week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo. Simvastatin significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (ApoB) (see Table 8) in the HeFH study. Results from the extension at 48 weeks were comparable to the results at Week 24. The safety and effectiveness of dosages above 40 mg daily have not been studied in pediatric patients with HeFH. The long-term efficacy of simvastatin therapy in pediatric patients to reduce morbidity and mortality in adulthood has not been established. Table 8 :Lipid Effects in Pediatric Patients 10 Years of Age and Older with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline) Dosage Duration N Total-C LDL-C HDL-C TG median percent change Apo B Placebo 24 Weeks 67 % Change from Baseline (95% CI) +1.6% (-2.2, 5.3) +1.1% (-3.4, 5.5) +3.6% (-0.7, 8.0) -3.2% (-11.8, 5.4) -0.5 (-4.7, 3.6) Mean baseline, mg/dL (SD) 279 (52) 212 (49) 47 (12) 90 (51) 186 (38) Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5% (-29.6, -23.3) -36.8 (-40.5, -33.0) +8.3% (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4% (-35.9, -29.0) Mean baseline, mg/dL (SD) 270 (44) 204 (42) 48 (9) 78 (46) 180 (34)" ], "clinical_studies_table": [ "
Table 5: CHD Mortality and Cardiovascular Events in Adult Patients with High Risk of Developing a Major Coronary Event in Study HPS
* n = number of patients with indicated event
Endpoint Simvastatin (N=10,269) n (%)* Placebo (N=10,267) n (%)* Risk Reduction (%) (95% CI) p-Value
Primary
Mortality 1,328 (12.9%) 1,507 (14.7%) 13 (6 to 19%) p=0.0003
CHD mortality 587 (5.7%) 707 (6.9%) 18 (8 to 26%) p=0.0005
Secondary
Non-fatal MI 357 (3.5%) 574 (5.6%) 38 (30 to 46%) p<0.0001
Stroke 444 (4.3%) 585 (5.7%) 25 (15 to 34%) p<0.0001
Tertiary
Coronary revascularization 513 (5%) 725 (7.1%) 30 (22 to 38%) p<0.0001
Peripheral and other non-coronary revascularization 450 (4.4%) 532 (5.2%) 16 (5 to 26%) p=0.006
", "
Table 6:Mean Changes in Lipid Levels in Adult Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)
* median percent change
† mean baseline LDL-C =244 mg/dL and median baseline TG =168 mg/dL
‡ mean baseline LDL-C =188 mg/dL and median baseline TG =128 mg/dL
§ mean baseline LDL-C =226 mg/dL and median baseline TG =156 mg/dL
21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded
&mean baseline LDL-C =156 mg/dL and median baseline TG =391 mg/dL
TREATMENT N TOTAL-C LDL-C HDL-C TG*
Lower Dose Comparative Study † (Mean % Change at Week 6)
Simvastatin5 mg at night. 109 -19% -26% +10 -12%
Simvastatin10 mg at night. 110 -23% -30% +12 -15%
Scandinavian Simvastatin Survival Study ‡ (Mean % Change at Week 6)
Placebo 2223 -1% -1% 0 -2%
Simvastatin20 mg at night. 2221 -28% -38% +8 -19%
Upper Dose Comparative Study § (Mean % Change Averaged at Weeks 18 and 24)
Simvastatin40 mg at night. 433 -31% -41% +9 -18%
Simvastatin80 mg at night. 664 -36% -47% +8 -24%
Combined Hyperlipidemia Study # (Mean % Change at Week 6)
Placebo 125 1% 2% +3 -4%
Simvastatin40 mg at night. 123 -25% -29% +13 -28%
Simvastatin80 mg at night. 124 -31% -36% +16 -33%
", "
Table 7:Lipid Effects in Adult Patients with Dysbetalipoproteinemia Over Six Weeks [Median Percent Change (min, max) from Baseline] *
* The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291
TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C
Placebo 7 -8% (-24, +34) -8% (-27, +23) -2% (-21, +16) +4% (-22, +90) -4% (-28, +78) -8% (-26, -39)
Simvastatin 40 mg/day 7 -50% (-66, -39) -50% (-60, -31) +7% (-8, +23) -41% (-74, -16) -58% (-90, -37) -57% (-72, -44)
Simvastatin 80 mg/day 7 -52% (-55, -41) -51% (-57, -28) +7% (-5, +29) -38% (-58, +2) -60% (-72, -39) -59% (-61, -46)
", "
Table 8 :Lipid Effects in Pediatric Patients 10 Years of Age and Older with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
Dosage Duration N Total-C LDL-C HDL-C TG median percent change Apo B
Placebo 24 Weeks 67 % Change from Baseline (95% CI) +1.6% (-2.2, 5.3) +1.1% (-3.4, 5.5) +3.6% (-0.7, 8.0) -3.2% (-11.8, 5.4) -0.5 (-4.7, 3.6)
Mean baseline, mg/dL (SD) 279 (52) 212 (49) 47 (12) 90 (51) 186 (38)
Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5% (-29.6, -23.3) -36.8 (-40.5, -33.0) +8.3% (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4% (-35.9, -29.0)
Mean baseline, mg/dL (SD) 270 (44) 204 (42) 48 (9) 78 (46) 180 (34)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Simvastatin Tablets USP, 40 mg are brick red colored, round shaped, biconvex, film-coated tablets, debossed with 'LL' on one side and 'C04' on the other side. They are supplied as follows: NDC 72789-304-30 Bottles of 30 NDC 72789-304-90 Bottles of 90 Storage Store between 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Preserve in tight container as defined in USP." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that simvastatin may cause myopathy and rhabdomyolysis. Inform patients taking an 80 mg daily dose of simvastatin that they are at an increased risk. Inform patients that the risk is also increased when taking certain types of medication or consuming grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see CONTRAINDICATIONS ( 4 ), WARNINGS AND PRECAUTIONS ( 5.1 ), AND DRUG INTERACTIONS ( 7.1 )]. Hepatic Dysfunction Inform patients that simvastatin may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see WARNINGS AND PRECAUTIONS ( 5.3 )] . Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with simvastatin. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see WARNINGS AND PRECAUTIONS ( 5.4 )] . Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if simvastatin should be discontinued [see USE IN SPECIFIC POPULATIONS ( 8.1 )] . Lactation Advise patients that breastfeeding is not recommended during treatment with simvastatin [see USE IN SPECIFIC POPULATIONS ( 8.2 )] . Missed Dose Instruct patients to take simvastatin tablets only as prescribed. If a dose is missed, it should be taken as soon as possible. Advise patients not to double their next dose. LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc. Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States MADE IN INDIA. June 2024 Image" ], "spl_patient_package_insert": [ "SPL PATIENT PACKAGE INSERT PATIENT INFORMATION Simvastatin (SIM-va-stat-in) tablets, for oral use Rx Only Read this Patient Information before you start taking simvastatin tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What are simvastatin tablets? Simvastatin tablets are a prescription medicine that contains the cholesterol lowering medicine, simvastatin. Simvastatin tablets are used to lower: the risk of death by lowering the risk of heart disease death. the risk of heart attacks and strokes. the need for certain types of heart and blood vessel procedures to improve blood flow called arterial revascularization in people with known heart, cerebrovascular disease (conditions that affect blood flow and the blood vessels in the brain), peripheral vascular disease (a blood circulation disorder that causes the blood vessels outside of your heart and brain to narrow, block, or spasm), and diabetes, who are at high risk for heart disease problems. Simvastatin tablets are used along with diet to: lower the level of low-density lipoprotein (LDL) cholesterol or \"bad\" cholesterol in adults with hyperlipidemia (high levels of fat in the blood), and in adults and children 10 years of age and older with heterozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL). treat adults with a type of high cholesterol called primary dysbetalipoproteinemia. lower the level of triglycerides (type of fat in the blood) in adults. Simvastatin tablets are used along with other cholesterol lowering treatments to lower the level of low-density lipoprotein (LDL) in adults with a type of high cholesterol called homozygous familial hypercholesterolemia (an inherited condition that causes high levels of LDL). The safety and effectiveness of simvastatin tablet has not been established in children younger than 10 years of age with heterozygous familial hypercholesterolemia (HeFH) or other types of hyperlipidemia (high levels of fat in the blood). Do not take simvastatin tablets if you: take certain medicines called CYP3A4 inhibitors such as: о certain antifungal medicines (such as itraconazole, ketoconazole, posaconazole, voriconazole). о certain antibiotics (including erythromycin, clarithromycin). о HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir, and darunavir / ritonavir) and cobicistat containing products such as (elvitegravir / cobicistat / emtricitabine/tenofovir disoproxil fumarate). о certain hepatitis C virus protease inhibitors (such as boceprevir or telaprevir). о the antidepressant nefazodone. take medicines called cyclosporine, danazol, or gemfibrozil. have liver problems. are allergic to simvastatin or any of the ingredients in simvastatin tablets. See the end of this Patient Information leaflet for a complete list of ingredients in simvastatin tablets. Ask your healthcare provider or pharmacist if you are not sure if your medicine is listed above. Before you take simvastatin tablets, tell your healthcare provider about all of your medical conditions, including if you: have unexplained muscle aches or weakness. have or have had myasthenia gravis (a disease causing general muscle weakness including in some cases muscles used for breathing), ocular myasthenia (a disease causing eye muscle weakness). have kidney problems. have liver problems or drink more than 2 glasses of alcohol daily. have thyroid problems. are 65 years of age or older. are of Chinese descent. are pregnant or plan to become pregnant. If you become pregnant while taking simvastatin tablets, call your healthcare provider right away to discuss stopping simvastatin tablets. are breastfeeding or plan to breastfeed. It is not known if simvastatin passes into your breast milk. Do not breastfeed while taking simvastatin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Talk to your healthcare provider before you start taking any new medicines. Tell your healthcare provider who prescribes simvastatin tablets if another healthcare provider increases the dose of another medicine you are taking. Simvastatin tablets may affect the way other medicines work, and other medicines may affect how simvastatin tablets works. Especially tell your healthcare provider if you take: digoxin (a drug used to treat irregular heartbeat). coumarin anticoagulants (drugs that prevent blood clots, such as warfarin). Taking simvastatin tablets with certain substances can also increase the risk of muscle problems. Especially tell your healthcare provider if you take: amiodarone or dronedarone (medicines used to treat an irregular heartbeat). verapamil, diltiazem, amlodipine, or ranolazine (medicines used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions). lomitapide (a medicine used to treat a serious and rare genetic cholesterol condition). daptomycin (a drug used to treat complicated skin and bloodstream infections). large doses of niacin or nicotinic acid, especially if you are of Chinese descent. fibric acid derivatives (such as fenofibrate). colchicine (a medicine used to treat gout). grapefruit juice. Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take simvastatin tablets? Take simvastatin tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking simvastatin tablets without talking to your healthcare provider. Take simvastatin tablets 1 time each day in the evening. If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take 2 doses of simvastatin tablets at the same time. Talk with your healthcare provider if you have questions about a missed dose. While taking simvastatin tablets, continue to follow your cholesterol-lowering diet and to exercise as your healthcare provider told you to. Your healthcare provider may do blood tests to check your cholesterol while you take simvastatin tablets. Your healthcare provider may change your dose of simvastatin tablets if needed. In case of overdose, get medical help or contact a live Poison Center expert right away at 1-800-222-1222. Advice is also available online at poisonhelp.org What are the possible side effects of simvastatin tablets? Simvastatin tablets may cause serious side effects including: Muscle pain, tenderness, and weakness (myopathy) . Muscle problems, including muscle breakdown, can be serious in some people and rarely cause kidney damage that can lead to death. Tell your healthcare provider right away if: о you have unexplained muscle pain, tenderness, or weakness, especially if you have a fever or feel more tired than usual, while you take simvastatin tablets. о you have muscle problems that do not go away even after your healthcare provider has advised you to stop taking simvastatin tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: о are taking certain other medicines while you take simvastatin tablets. о are 65 years of age or older. о are female. о have thyroid problems (hypothyroidism) that are not controlled. о have kidney problems. о are taking higher doses of simvastatin tablets. о are Chinese. Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking simvastatin tablets and if you have any symptoms of liver problems while you take simvastatin tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feeling tired or weak loss of appetite right-sided upper belly pain dark urine yellowing of your skin or the whites of your eyes Increase in blood sugar (glucose) levels). Simvastatin tablets may cause an increase in your blood sugar levels. The most common side effects of simvastatin tablets include: upper respiratory infection headache stomach (abdominal) pain constipation nausea Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of simvastatin tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store simvastatin tablets? Store simvastatin tablets between 41°F to 86°F (5°C to 30°C). Keep simvastatin tablets and all medicines out of the reach of children. General information about safe and effective use of simvastatin tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use simvastatin tablets for a condition for which it was not prescribed. Do not give simvastatin tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about simvastatin tablets that is written for health professionals. What are the ingredients in simvastatin tablets? Active ingredient: simvastatin. Inactive ingredients: ascorbic acid, citric acid, hydroxy propyl cellulose, hypromellose, iron oxides, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch, talc and titanium dioxide. Butylated hydroxyanisole is added as a preservative. LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc. Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: June 2024 ID#: 275725 Image" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Simvastatin Tablets USP 40 mg Rx only 72789304 Label" ], "set_id": "00896fff-081d-4553-be8c-1999a8a73dda", "id": "4bbbb5c9-6c29-bc3b-e063-6294a90a6cce", "effective_time": "20260226", "version": "23", "openfda": { "application_number": [ "ANDA078103" ], "brand_name": [ "SIMVASTATIN" ], "generic_name": [ "SIMVASTATIN" ], "manufacturer_name": [ "PD-Rx Pharmaceuticals, Inc." ], "product_ndc": [ "72789-304" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "SIMVASTATIN" ], "rxcui": [ "198211" ], "spl_id": [ "4bbbb5c9-6c29-bc3b-e063-6294a90a6cce" ], "spl_set_id": [ "00896fff-081d-4553-be8c-1999a8a73dda" ], "package_ndc": [ "72789-304-30", "72789-304-90" ], "original_packager_product_ndc": [ "68180-464" ], "upc": [ "0372789304908" ], "nui": [ "N0000175589", "N0000000121" ], "pharm_class_epc": [ "HMG-CoA Reductase Inhibitor [EPC]" ], "pharm_class_moa": [ "Hydroxymethylglutaryl-CoA Reductase Inhibitors [MoA]" ], "unii": [ "AGG2FN16EV" ] } }, { "effective_time": "20171107", "recent_major_changes": [ "" ], "drug_interactions": [ "7 DRUG INTERACTIONS The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3) ] . Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin ( 7 ). Digoxin: Patients should be monitored appropriately ( 7.8 ). Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased ( 7.9 ). Rifampin should be simultaneously co-administered with atorvastatin ( 7.7 ). 7.1 Strong Inhibitors of Cytochrome P450 3A4:Clarithromycin Combination of Protease Inhibitors Itraconazole Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. Clarithromycin Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)] . Combination of Protease Inhibitors Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin alone [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6)] . In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin should not exceed 40 mg and close clinical monitoring is recommended. Itraconazole Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3) ] . Therefore, in patients taking itraconazole, caution should be used when the atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1 ) and D osage and Administration (2.6)] . 7.2 Grapefruit Juice Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day). 7.3 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin alone [see Clinical Pharmacology (12.3) ] . The co-administration of atorvastatin with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1) ] . 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin with gemfibrozil should be avoided [see Warnings and Precautions (5.1) ] . 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) ] . 7.6 Niacin The risk of skeletal muscle effects may be enhanced when atorvastatin is used in combination with niacin; a reduction in atorvastatin dosage should be considered in this setting [see Warnings and Precautions (5.1) ] . 7.7 Rifampin or other Inducers of Cytochrome P450 3A4 Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 7.8 Digoxin When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 7.9 Oral Contraceptives Co-administration of atorvastatin and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ] . These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin. 7.10 Warfarin Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. 7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine." ], "spl_unclassified_section_table": [ "
Manufactured By Manufactured For
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada, M9L 1T9 33326
" ], "geriatric_use": [ "8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly." ], "references": [ "15 REFERENCES 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents, Pediatrics . 89(3):495-501. 1992." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ] ." ], "description": [ "11 DESCRIPTION Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. The drug substance used in atorvastatin calcium tablets is atorvastatin calcium in the form of propylene glycol solvate. The chemical name for atorvastatin calcium propylene glycol solvate is calcium bis((3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate) propylene glycol solvate. The empirical formula of atorvastatin calcium propylene glycol solvate is C 66 H 68 CaF 2 N 4 O 10 * C 3 H 8 O 2 and its molecular weight is 1231.46. Its structural formula is: Atorvastatin calcium is a white to off-white solid that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol. Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium acetate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, magnesium stearate (vegetable source), microcrystalline cellulose, polyethylene glycol, sodium carbonate, and titanium dioxide." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro , atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli , the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years." ], "warnings_and_cautions_table": [ "
Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations
*Use with caution and with the lowest dose necessary (12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS White, oval, biconvex, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium. Atorvastatin calcium tablets 10 mg, 20 mg, 40 mg, and 80 mg tablets ( 3 )." ], "clinical_pharmacology_table": [ "
TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen Atorvastatin
Dose (mg) Change in AUC& Change in Cmax&
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold
#Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold
#, ‡Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold
#Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold
#Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20%
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold
#Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold
#Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold
#Grapefruit Juice, 240 mL QD * 40 mg, SD ↑ 37% ↑ 16%
Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change
Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38%
Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 %
Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11%
Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26%**
Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34%
Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1%
#Rifampin 600 mg QD, 7 days (co-administered) † 40 mg SD ↑ 30% ↑ 2.7 fold
#Rifampin 600 mg QD, 5 days (doses separated) † 40 mg SD ↓ 80% ↓ 40%
#Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1%
#Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2%
Boceprevir 800 mg TID, 7 days 40 mg SD ↑2.30 fold ↑2.66 fold
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.
", "
TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Change in AUC Change in Cmax
80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11%
80 mg QD for 14 days #Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 %
40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1mg - ethinyl estradiol 35mcg ↑ 28% ↑ 19% ↑ 23% ↑ 30%
10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change
10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18%
10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change
# See Section 7 for clinical significance.
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s). A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined." ], "information_for_patients_table": [ "
Manufactured By Manufactured For
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada, M9L 1T9 33326
" ], "pharmacokinetics_table": [ "
TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen Atorvastatin
Dose (mg) Change in AUC& Change in Cmax&
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold
#Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold
#, ‡Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold
#Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold
#Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20%
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold
#Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold
#Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold
#Grapefruit Juice, 240 mL QD * 40 mg, SD ↑ 37% ↑ 16%
Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change
Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38%
Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 %
Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11%
Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26%**
Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34%
Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1%
#Rifampin 600 mg QD, 7 days (co-administered) † 40 mg SD ↑ 30% ↑ 2.7 fold
#Rifampin 600 mg QD, 5 days (doses separated) † 40 mg SD ↓ 80% ↓ 40%
#Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1%
#Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2%
Boceprevir 800 mg TID, 7 days 40 mg SD ↑2.30 fold ↑2.66 fold
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (up to 2.5 fold) and/or Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.
", "
TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Change in AUC Change in Cmax
80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11%
80 mg QD for 14 days #Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 %
40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1mg - ethinyl estradiol 35mcg ↑ 28% ↑ 19% ↑ 23% ↑ 30%
10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change
10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18%
10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change
# See Section 7 for clinical significance.
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ] . Distribution Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ] . Metabolism Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ] . Pediatric Pharmacokinetic data in the pediatric population are not available. Gender Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5) , Warnings and Precautions, Skeletal Muscle (5.1) ] . Hemodialysis While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ] . TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin Dose (mg) Change in AUC & Change in Cmax & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold # Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold # Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold #, ‡ Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold # Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold # Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold # Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20% # Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold # Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold # Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold # Grapefruit Juice, 240 mL QD * 40 mg, SD ↑ 37% ↑ 16% Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38% Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 % Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11% Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26% ** Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34% Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1% # Rifampin 600 mg QD, 7 days (co-administered) † 40 mg SD ↑ 30% ↑ 2.7 fold # Rifampin 600 mg QD, 5 days (doses separated) † 40 mg SD ↓ 80% ↓ 40% # Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1% # Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2% Boceprevir 800 mg TID, 7 days 40 mg SD ↑2.30 fold ↑2.66 fold & Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (up to 2.5 fold) and/or C max (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Change in AUC Change in Cmax 80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11% 80 mg QD for 14 days # Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 % 40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1mg - ethinyl estradiol 35mcg ↑ 28% ↑ 19% ↑ 23% ↑ 30% 10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change 10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18% 10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change # See Section 7 for clinical significance." ], "clinical_studies_table": [ "
TABLE 5. Overview of Efficacy Results in TNT
Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HRa (95%CI)
PRIMARY ENDPOINT n (%) n (%)
First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89)
Components of the Primary Endpoint
CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93)
Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67)
Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96)
SECONDARY ENDPOINTS *
First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94)
First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedureb 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80)
First documented angina endpointb 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99)
All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19)
Components of All-Cause Mortality
Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03)
Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57)
Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55)
Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00)
Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82)
a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
", "
Dose N TC LDL-C Apo B TG HDL-C Non-HDL- C/ HDL-C
Placebo 21 4 4 3 10 -3 7
10 22 -29 -39 -32 -19 6 -34
20 20 -33 -43 -35 -26 9 -41
40 21 -37 -50 -42 -29 6 -45
80 23 -45 -60 -50 -37 5 -53
a Results are pooled from 2 dose-response studies.
", "
Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C
Study 1
Atorvastatin 10 mg 707 -27a -36 a -28 a -17 a +7 -37 a
Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28
95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 -11.1, -7.1
Study 2
Atorvastatin 10 mg 222 -25b -35 b -27 b -17 b +6 -36 b
Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28
95% CI for Diff1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1
Study 3
Atorvastatin 10 mg 132 -29c -37 c -34 c -23 c +7 -39 c
Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33
95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9
1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p ≤0.05 b Significantly different from pravastatin, ANCOVA, p ≤0.05 c Significantly different from simvastatin, ANCOVA, p ≤0.05
", "
Placebo (N=12) Atorvastatin 10 mg (N=37) Atorvastatin 20 mg (N=13) Atorvastatin 80 mg (N=14)
Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3)
Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8)
LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8)
HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2)
VLDL-C -1.0 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62.0 (-88.2, 37.6)
non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3)
", "
Median (min, max) at Baseline (mg/dL) Median % Change (min, max)
Atorvastatin 10 mg Atorvastatin 80 mg
Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
", "
DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B
Placebo 47 -1.5 -0.4 -1.9 1.0 0.7
Atorvastatin Calcium Tablets 140 -31.4 -39.6 2.8 -12.0 -34.0
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablets are an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk factors ( 1.1 ). Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors ( 1.1 ). Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD ( 1.1 ). Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( 1.2 ). Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia ( 1.2 ). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) ( 1.2 ). Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy ( 1.2 ). Limitations of Use Atorvastatin calcium has not been studied in Fredrickson Types I and V dyslipidemias. 1.1 Prevention of Cardiovascular Disease In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina 1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190 mg/dL or b. LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons ( Fredrickson Types I and V)." ], "set_id": "00966aac-118a-4ee5-9230-a53a3ce5142e", "id": "a0350885-4191-4403-bc5d-b59bdbdbb873", "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6) ; Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ] . Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5) ] ." ], "contraindications": [ "4 CONTRAINDICATIONS Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels ( 4.1 ). Women who are pregnant or may become pregnant ( 4.3 ). Nursing mothers ( 4.4 ). Hypersensitivity to any component of this medication ( 4.2 ). 4.1 Active Liver Disease which may include Unexplained Persistent Elevations of Hepatic Transaminase Levels 4.2 Hypersensitivity to any Component of this Medication 4.3 Pregnancy Women who are pregnant or may become pregnant. Atorvastatin may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. ATORVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] . 4.4 Nursing Mothers It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require atorvastatin treatment should not breastfeed their infants [see Use in Specific Populations (8.3) ] ." ], "drug_interactions_table": [ "
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily
" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category X Atorvastatin calcium is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m 2 ) [see Contraindications, Pregnancy (4.3) ] . In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin treatment should be advised not to nurse their infants [see Contraindications (4) ] ." ], "spl_product_data_elements": [ "ATORVASTATIN CALCIUM ATORVASTATIN CALCIUM ATORVASTATIN CALCIUM ATORVASTATIN CALCIUM ACETATE CROSCARMELLOSE SODIUM SODIUM CARBONATE MICROCRYSTALLINE CELLULOSE MAGNESIUM STEARATE SILICON DIOXIDE HYPROMELLOSE, UNSPECIFIED HYDROXYPROPYL CELLULOSE (1200000 MW) POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE APO;ATV80 Figure-01 Figure-02 Figure-03 chemical-structure" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected ( 5.1 , 8.5 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.2 ). A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo ( 5.5 ). 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin. Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs [see Drug Interactions (7) ] . Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 1 [ see also Dosage and Administration (2.6) , Drug Interactions (7) , Clinical Pharmacology (12.3) ] . Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations *Use with caution and with the lowest dose necessary (12.3) Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11) ] . Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). 5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin. It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin. Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin [see Contraindications (4.1) ] . 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. 5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1) ] ." ], "adverse_reactions_table": [ "
Table 2. Clinical adverse reactions occurring in ≥ 2% in patents treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients).
Adverse Reaction* Any dose N=8755 10 mg N=3908 20 mg N=188 40 mg N=604 80 mg N=4055 Placebo N=7311
Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2
Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5
Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3
Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9
Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6
Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3
Nausea 4.0 3.7 3.7 7.1 3.8 3.5
Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6
Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0
Myalgia 3.5 3.6 5.9 8.4 2.7 3.1
Insomnia 3.0 2.8 1.1 5.3 2.8 2.9
Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1
* Adverse Reaction ≥ 2% in any dose greater than placebo
" ], "openfda": {}, "version": "6", "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Dose range: 10 to 80 mg once daily ( 2.1 ). Recommended start dose: 10 or 20 mg once daily ( 2.1 ). Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily ( 2.1 ). Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily ( 2.2 ). 2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson Types IIa and IIb) The recommended starting dose of atorvastatin calcium tablets are 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets are 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines ). After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. 2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines , Clinical Pharmacology (12) , and Indications and Usage (1.2) ] . Adjustments should be made at intervals of 4 weeks or more. 2.3 Homozygous Familial Hypercholesterolemia The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 2.4 Concomitant Lipid-Lowering Therapy Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) , Drug Interactions (7) ] . 2.5 Dosage in Patients With Renal Impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (5.1) , Clinical Pharmacology, Pharmacokinetics (12.3) ] . 2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed [see Warnings and Precautions , Skeletal Muscle (5.1) , Drug Interactions (7) ] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1) ] Liver enzyme abnormalities [see Warnings and Precautions (5.2) ] The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Adverse Experiences Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%). Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Table 2. Clinical adverse reactions occurring in ≥ 2% in patents treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients). Adverse Reaction* Any dose N=8755 10 mg N=3908 20 mg N=188 40 mg N=604 80 mg N=4055 Placebo N=7311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6.0 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8.0 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6.0 3.3 4.3 Nausea 4.0 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3.0 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3.0 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 * Adverse Reaction ≥ 2% in any dose greater than placebo Other adverse reactions reported in placebo-controlled studies include Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [see Clinical Studies (14.1) ] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with atorvastatin calcium was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up. Collaborative Atorvastatin Diabetes Study (CARDS) In CARDS [see Clinical Studies (14.1) ] involving 2,838 subjects (age range 39 to 77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin calcium 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported. Treating to New Targets Study (TNT) In TNT [see Clinical Studies (14.1) ] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with atorvastatin calcium 10 mg daily (n=5006) or atorvastatin calcium 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%). Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL) In IDEAL [see Clinical Studies (14.1) ] involving 8,888 subjects (age range 26 to 80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin calcium 80 mg/day (n=4439) or simvastatin 20 to 40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5) ] . In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin calcium vs. 2 (4%) placebo]. There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin calcium 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin calcium 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium 80 mg group (5.0%) than in the placebo group (4.0%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions associated with atorvastatin calcium therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, myositis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, pancreatitis and interstitial lung disease. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). 6.3 Pediatric Patients (ages 10 to 17 years) In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20 mg daily was generally similar to that of placebo [see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4) ] ." ], "spl_unclassified_section": [ "PATIENT INFORMATION Atorvastatin Calcium Tablets (a tor″ va stat′ in kal′ see um) Read the Patient Information that comes with atorvastatin calcium tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist. What Are Atorvastatin Calcium Tablets? Atorvastatin calcium tablets are a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C (\"bad\" cholesterol) and triglycerides in your blood. It can raise your HDL-C (\"good\" cholesterol) as well. Atorvastatin calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone. Atorvastatin calcium tablets can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as: age, smoking, high blood pressure, low HDL-C, heart disease in the family. Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: eye problems, kidney problems, smoking, or high blood pressure. Atorvastatin calcium tablets start to work in about 2 weeks. What is Cholesterol? Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family. Who Should Not Take Atorvastatin Calcium Tablets? Do not take atorvastatin calcium tablets if you: are pregnant or think you may be pregnant, or are planning to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you get pregnant, stop taking atorvastatin calcium tablets and call your doctor right away. are breast feeding. Atorvastatin calcium can pass into your breast milk and may harm your baby. have liver problems. are allergic to atorvastatin calcium tablets or any of its ingredients. The active ingredient is atorvastatin. See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets. Atorvastatin calcium tablets have not been studied in children under 10 years of age. Before You Start Atorvastatin Calcium Tablets Tell your doctor if you: have muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have a thyroid problem have kidney problems Some medicines should not be taken with atorvastatin calcium tablets. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for: your immune system cholesterol infections birth control heart failure HIV or AIDS Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist. How Should I Take Atorvastatin Calcium Tablets? Take atorvastatin calcium tablets exactly as prescribed by your doctor. Do not change your dose or stop atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium tablets may be changed based on these blood test results. Take atorvastatin calcium tablets each day at any time of day at about the same time each day. Atorvastatin calcium tablets can be taken with or without food. Don't break atorvastatin calcium tablets before taking. Your doctor should start you on a low-fat diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets. If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take atorvastatin calcium tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of atorvastatin calcium tablets at the same time. If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center right away. Or go to the nearest emergency room. What Should I Avoid While Taking Atorvastatin Calcium Tablets? Talk to your doctor before you start any new medicines. This includes prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects. Do not get pregnant. If you get pregnant, stop taking atorvastatin calcium tablets right away and call your doctor. What are the Possible Side Effects of Atorvastatin Calcium Tablets? Atorvastatin calcium tablets can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or atorvastatin calcium tablets are stopped. These serious side effects include: Muscle problems. Atorvastatin calcium tablets can cause serious muscle problems that can lead to kidney problems, including kidney failure. You have a higher chance for muscle problems if you are taking certain other medicines with atorvastatin calcium tablets. Liver problems. Your doctor should do blood tests to check your liver before you start taking atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your doctor right away if you have the following symptoms of liver problems: feel tired or weak loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Call your doctor right away if you have: muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have a fever or feel more tired than usual. This may be an early sign of a rare muscle problem. muscle problems that do not go away even after your doctor has advised you to stop taking atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away. nausea and vomiting. passing brown or dark-colored urine. you feel more tired than usual your skin and whites of your eyes get yellow. stomach pain. allergic skin reactions. In clinical studies, patients reported the following common side effects while taking atorvastatin calcium tablets: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests. The following additional side effects have been reported with atorvastatin calcium tablets: tiredness, tendon problems, memory loss, and confusion. Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away. These are not all the side effects of atorvastatin calcium tablets. Ask your doctor or pharmacist for a complete list. How do I store Atorvastatin Calcium Tablets Store atorvastatin calcium tablets at room temperature, 68°F to 77°F (20°C to 25°C). Do not keep medicine that is out of date or that you no longer need. Keep atorvastatin calcium tablets and all medicines out of the reach of children. Be sure that if you throw medicine away, it is out of the reach of children. General Information About Atorvastatin Calcium Tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about atorvastatin calcium tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about atorvastatin calcium tablets that is written for health professionals. Or for more information contact Apotex Corp., Drug Safety at 1-800-706-5575. What are the Ingredients In Atorvastatin Calcium Tablets? Active Ingredient: atorvastatin calcium Inactive Ingredients: calcium acetate, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, hypromellose, magnesium stearate (vegetable source), microcrystalline cellulose, polyethylene glycol, sodium carbonate, and titanium dioxide. APOTEX INC. ATORVASTATIN CALCIUM TABLETS 10 mg, 20 mg, 40 mg, and 80 mg Manufactured By Manufactured For Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada, M9L 1T9 33326 Revised: July 2017 Rev. 10" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease ( 12.3 ). 8.1 Pregnancy Pregnancy Category X Atorvastatin calcium is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m 2 ) [see Contraindications, Pregnancy (4.3) ] . In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy. 8.3 Nursing Mothers It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin treatment should be advised not to nurse their infants [see Contraindications (4) ] . 8.4 Pediatric Use Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6) ; Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ] . Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5) ] . 8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly. 8.6 Hepatic Impairment Atorvastatin calcium is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3) ] ." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50436-9983 NDC: 50436-9983-1 30 TABLET, FILM COATED in a BOTTLE" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Patients taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with atorvastatin [ see Warnings and Precautions (5.1) ] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium tablets. 17.1 Muscle Pain All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets and call their healthcare professional. 17.4 Breast-feeding Women who are breastfeeding should be advised to not use atorvastatin calcium tablets. Patients who have a lipid disorder and are breast-feeding, should be advised to discuss the options with their healthcare professional. Maalox TC ® is a registered trademark of Novartis Consumer Health Inc. APOTEX INC. ATORVASTATIN CALCIUM TABLETS 10 mg, 20 mg, 40 mg, and 80 mg Manufactured By Manufactured For Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada, M9L 1T9 33326 Revised: July 2017 Rev. 10" ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive. Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059). Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 5). The overall risk reduction was consistent regardless of age (<65, ≥65) or gender. Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) TABLE 5. Overview of Efficacy Results in TNT Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HR a (95%CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS * First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedure b 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpoint b 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00) Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 5). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 5). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium 80 mg/day was compared to treatment with simvastatin 20 to 40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin calcium and 105, 179, 142, 47, and 132 mg/dL during treatment with 20 to 40 mg of simvastatin. There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin calcium 80 mg/day group vs. 463 (10.4%) in the simvastatin 20 to 40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07. There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin calcium 80 mg/day group vs. 374 (8.4%) in the simvastatin 20 to 40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin calcium 80 mg group and the simvastatin 20 to 40 mg group. 14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson Types IIa and IIb) Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. Atorvastatin calcium is effective in a wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly. In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 6.) TABLE 6. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a Dose N TC LDL-C Apo B TG HDL-C Non-HDL- C/ HDL-C Placebo 21 4 4 3 10 -3 7 10 22 -29 -39 -32 -19 6 -34 20 20 -33 -43 -35 -26 9 -41 40 21 -37 -50 -42 -29 6 -45 80 23 -45 -60 -50 -37 5 -53 a Results are pooled from 2 dose-response studies. In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25 th and 75 th percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C. In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 7). TABLE 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C Study 1 Atorvastatin 10 mg 707 -27 a -36 a -28 a -17 a +7 -37 a Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28 95% CI for Diff 1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 -11.1, -7.1 Study 2 Atorvastatin 10 mg 222 -25 b -35 b -27 b -17 b +6 -36 b Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28 95% CI for Diff 1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1 Study 3 Atorvastatin 10 mg 132 -29 c -37 c -34 c -23 c +7 -39 c Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33 95% CI for Diff 1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p ≤0.05 b Significantly different from pravastatin, ANCOVA, p ≤0.05 c Significantly different from simvastatin, ANCOVA, p ≤0.05 The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is not known. Table 7 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable. 14.3 Hypertriglyceridemia ( Fredrickson Type IV) The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 8). For the atorvastatin calcium -treated patients, median (min, max) baseline TG level was 565 (267 to 1502). TABLE 8. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo (N=12) Atorvastatin 10 mg (N=37) Atorvastatin 20 mg (N=13) Atorvastatin 80 mg (N=14) Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2) VLDL-C -1.0 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62.0 (-88.2, 37.6) non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) 14.4 Dysbetalipoproteinemia ( Fredrickson Type III) The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia ( Fredrickson Type III) are shown in the table below (Table 9). TABLE 9. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia ( Fredrickson Type III) Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Atorvastatin 10 mg Atorvastatin 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) 14.5 Homozygous Familial Hypercholesterolemia In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%. 14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385.0 mg/dL) in the atorvastatin calcium group compared to 230.0 mg/dL (range: 160.0 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 10). TABLE 10. Lipid-altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1.0 0.7 Atorvastatin Calcium Tablets 140 -31.4 -39.6 2.8 -12.0 -34.0 The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0 to 242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0 to 385.0 mg/dL) in the placebo group during the 26-week double-blind phase. The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established." ], "package_label_principal_display_panel": [ "ATORVASTATIN CALCIUM TABLET, FILM COATED Label Image" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s). A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. 12.2 Pharmacodynamics Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ] . 12.3 Pharmacokinetics Absorption Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ] . Distribution Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ] . Metabolism Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ] . Pediatric Pharmacokinetic data in the pediatric population are not available. Gender Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5) , Warnings and Precautions, Skeletal Muscle (5.1) ] . Hemodialysis While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ] . TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin Dose (mg) Change in AUC & Change in Cmax & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold # Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold # Telaprevir 750 mg q8h, 10 days 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold #, ‡ Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold # Clarithromycin 500 mg BID, 9 days 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold # Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold # Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20% # Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold # Fosamprenavir 1400 mg BID, 14 days 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold # Nelfinavir 1250 mg BID, 14 days 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold # Grapefruit Juice, 240 mL QD * 40 mg, SD ↑ 37% ↑ 16% Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38% Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 % Cimetidine 300 mg QID, 2 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11% Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26% ** Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34% Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1% # Rifampin 600 mg QD, 7 days (co-administered) † 40 mg SD ↑ 30% ↑ 2.7 fold # Rifampin 600 mg QD, 5 days (doses separated) † 40 mg SD ↓ 80% ↓ 40% # Gemfibrozil 600mg BID, 7 days 40mg SD ↑ 35% ↓ Less than 1% # Fenofibrate 160mg QD, 7 days 40mg SD ↑ 3% ↑ 2% Boceprevir 800 mg TID, 7 days 40 mg SD ↑2.30 fold ↑2.66 fold & Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (up to 2.5 fold) and/or C max (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Change in AUC Change in Cmax 80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11% 80 mg QD for 14 days # Digoxin 0.25 mg QD, 20 days ↑ 15% ↑ 20 % 40 mg QD for 22 days Oral contraceptive QD, 2 months - norethindrone 1mg - ethinyl estradiol 35mcg ↑ 28% ↑ 19% ↑ 23% ↑ 30% 10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change 10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18% 10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change # See Section 7 for clinical significance." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro , atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli , the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years." ], "overdosage": [ "10 OVERDOSAGE There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance." ] }, { "spl_product_data_elements": [ "Atorvastatin calcium Atorvastatin calcium ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE, UNSPECIFIED LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYSORBATE 80 POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE TALC POLYETHYLENE GLYCOL 3350 CALCIUM CARBONATE MAGNESIUM ALUMINOMETASILICATE TYPE IA LECITHIN, SOYBEAN MA;4 structure atorvastatin-figure-01 atorvastatin-figure-02 atorvastatin-figure-03" ], "recent_major_changes": [ "Contraindications, Pregnancy and Lactation ( 4 ) Removed 12/2022 Warnings and Precautions, CNS Toxicity ( 5.5 ) Removed 12/2022" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Atorvastatin calcium tablets are indicated: To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia Hypertriglyceridemia Atorvastatin calcium tablets are an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. As an adjunct to diet for the treatment of adults with: Primary dysbetaliproteinemia. Hypertriglyceridemia." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take orally once daily with or without food ( 2.1 ). Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( 2.1 ). Adults ( 2.2 ): Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. Patients requiring LDL-C reduction >45% may start at 40 mg once daily. Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3 ). Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4 ). See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage Information Take atorvastatin calcium tablets orally once daily at any time of the day, with or without food. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin calcium tablets are 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended starting dosage of atorvastatin calcium tablets are 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. 2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin calcium tablets are 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of atorvastatin calcium tablets with the following drugs requires dosage modification of atorvastatin calcium tablets [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Anti-Viral Medications In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium tablets 20 mg once daily. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, see Drug Interactions (7.1)." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Atorvastatin calcium tablets, USP: 10 mg of atorvastatin: white coloured, oval shaped, biconvex, film-coated tablets with “MA” on one side and “1” on other side. 20 mg of atorvastatin: white coloured, oval shaped, biconvex, film-coated tablets with “MA” on one side and “2” on other side. 40 mg of atorvastatin: white coloured, oval shaped, biconvex, film-coated tablets with “MA” on one side and “3” on other side. 80 mg of atorvastatin: white coloured, oval shaped, biconvex, film-coated tablets with “MA” on one side and “4” on other side. Tablets: 10 mg; 20 mg; 40 mg; 80 mg of atorvastatin ( 3 )." ], "contraindications": [ "4 CONTRAINDICATIONS Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2) ]. Acute liver failure or decompensated cirrhosis ( 4 ). Hypersensitivity to atorvastatin or any excipient in atorvastatin calcium ( 4 )." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium dosage. Discontinue atorvastatin calcium if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin calcium in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing atorvastatin calcium dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2.5 , 5.1 , 7.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue atorvastatin calcium if IMNM is suspected ( 5.2 ). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Atorvastatin calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher atorvastatin dosage [see Drug Interactions (7.1) and Use in Specific Populations (8.5, 8.6 ) ]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Atorvastatin exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin is not recommended. Atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.5)] . Cases of myopathy/rhabdomyolysis have been reported with atorvastatin coadministered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir. Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1) ]. Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin [see Drug Interactions (7.1) ]. Discontinue atorvastatin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if atorvastatin is discontinued. Temporarily discontinue atorvastatin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the atorvastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue atorvastatin if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of atorvastatin [see Adverse Reactions (6.1) ] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7) ]. Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter. Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) ]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 5.5 Increased Risk of Hemorrhagic Stroke in Patients on Atorvastatin Calcium 80 mg with Recent Hemorrhagic Stroke In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or TIA within the preceding 6 months, were treated with atorvastatin 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1) ]. Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin Calcium- Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled trials include: Body as a whole: malaise, pyrexia Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous system: nightmare Respiratory system: epistaxis Skin and appendages: urticaria Special senses: vision blurred, tinnitus Urogenital system: white blood cells urine positive Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium. Treating to New Targets Study (TNT) In TNT, [see Clinical Studies (14.1)] 10,001 patients (age range 29 to 78 years, 19% women; 94% White, 3% Black, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin calcium 10 mg daily (n=5006) or atorvastatin calcium 80 mg daily (n=4995). In the high-dose atorvastatin calcium group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4 to10 days) occurred in 1.3% of individuals with atorvastatin 80 mg and in 0.2% of individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin group (0.3%) compared to the low-dose atorvastatin group (0.1%). Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4731 subjects (age range 21 to 92 years, 40% women; 93% White, 3% Black, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin group and 3.8% of subjects in the placebo group. In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin calcium vs. 4% placebo). Adverse Reactions from Clinical Studies of Atorvastatin Calcium in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4) and Clinical Studies (14.6)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: pancreatitis General disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune system disorders : anaphylaxis Injury: tendon rupture Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Nervous system disorders: dizziness, peripheral neuropathy. There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Psychiatric disorders: depression Respiratory disorders: interstitial lung disease Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)" ], "adverse_reactions_table": [ "
Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755
Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3
Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9
Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8
Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0
Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7
Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7
Nausea 3.5 3.7 3.7 7.1 3.8 4.0
Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8
Muscle spasms 3.0 4.6 4.8 5.1 2.4 3.6
Myalgia 3.1 3.6 5.9 8.4 2.7 3.5
Insomnia 2.9 2.8 1.1 5.3 2.8 3.0
Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3
" ], "drug_interactions": [ "7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of atorvastatin calcium with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.1 ). Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium ( 7.2 ). Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive (7.3 ). Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3) ]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3) ]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration (2.5) ]. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3) ]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [see Dosage and Administration (2.5) ]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin ( > 1 gram/day niacin) with atorvastatin. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin. 7.2 Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Table 3 presents drug interactions that may decrease exposure to atorvastatin and instructions for preventing or managing them. Table 3: Drug Interactions that may Decrease Exposure to Atorvastatin Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin and rifampin simultaneously. 7.3 Atorvastatin Calcium Effects on Other Drugs Table 4 presents Atorvastatin’s effect on other drugs and instructions for preventing or managing them. Table 4: Atorvastatin Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin. Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3) ]. Intervention: Monitor patients taking digoxin appropriately." ], "drug_interactions_table": [ "
Cyclosporine or Gemfibrozil
Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3)]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin.
Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin is not recommended.
Anti-Viral Medications
Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3)]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin.
Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin 20 mg. In patients taking nelfinavir, do not exceed atorvastatin 40 mg [see Dosage and Administration (2.5)]. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.
Select Azole Antifungals or Macrolide Antibiotics
Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)].
Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [see Dosage and Administration (2.5)]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (>1 gram/day niacin) with atorvastatin.
Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin.
Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin.
Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin.
", "
Rifampin
Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Intervention: Administer atorvastatin and rifampin simultaneously.
", "
Oral Contraceptives
Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)].
Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin.
Digoxin
Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [seeClinical Pharmacology (12.3)].
Intervention: Monitor patients taking digoxin appropriately.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ). Lactation: Breastfeeding not recommended during treatment with atorvastatin calcium ( 8.2 ). 8.1 Pregnancy Risk Summary Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. 8.2 Lactation Risk Summary There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including atorvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with atorvastatin [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) ]. Data Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma). 8.4 Pediatric Use The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14) ]. The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH). 8.5 Geriatric Use Of the total number of atorvastatin calcium -treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (≥65 years) is a risk factor for atorvastatin calcium -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of atorvastatin calcium, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. atorvastatin calcium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Discontinue atorvastatin when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. atorvastatin decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20, 100, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of atorvastatin calcium for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the boys or girls, or on menstrual cycle length in girls. The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14) ]. The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH)." ], "geriatric_use": [ "8.5 Geriatric Use Of the total number of atorvastatin calcium -treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (≥65 years) is a risk factor for atorvastatin calcium -associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]." ], "overdosage": [ "10 OVERDOSAGE No specific antidotes for atorvastatin are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin clearance." ], "description": [ "11 DESCRIPTION Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Atorvastatin calcium USP is (βR, δR)-2-(p-fluorophenyl)-β,δ-dihydroxy-5-isopropyl-3-phenyl-4(phenylcarbamoyl)pyrrole-l-heptanaote (1:2), trihydrate. The molecular formula of atorvastatin calcium USP is C 66 H 68 CaF 2 N 4 O 10 .3H 2 O and its molecular weight is 1209.41. Its structural formula is: Atorvastatin calcium USP is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium USP is soluble to freely soluble in methanol, slightly soluble in alcohol, insoluble to very slightly soluble in distilled water, in pH 7.4 phosphate buffer, and in acetonitrile. Atorvastatin calcium tablets, USP for oral use contain atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg (equivalent to 10.34 mg, 20.68 mg, 41.36 mg, or 82.73 mg atorvastatin calcium anhydrous) and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, magnesium aluminometasilicate, microcrystalline cellulose, polysorbate 80, precipitated calcium carbonate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol and lecithin." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-­methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. 12.2 Pharmacodynamics Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ]. 12.3 Pharmacokinetics Absorption Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration . Distribution Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Elimination Metabolism Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)] . In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin [see Use in Specific Populations (8.6) ]. While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7)]. Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 5 : Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg SD c 7.88 10.60 #,‡ Saquinavir 400 mg BID b / ritonavir 400mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 # Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a, * 40 mg SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74** MaaloxTC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (coadministered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600mg BID b , 7 days 40mg SD c 1.35 1.00 # Fenofibrate 160mg QD a , 7 days 40mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or C max (ratio of C max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL - 1.2 liters per day). ** Ratio based on a single sample taken 8-16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of C max 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months -norethindrone 1 mg -ethinyl estradiol 35 μg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 # See Section 7 for clinical significance. a Once daily b Twice daily c Single dose Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment." ], "clinical_pharmacology_table": [ "
Co-administered drug and dosing regimen Atorvastatin
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDa for 28 days 8.69 10.66
#Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 10 mg SDc 9.36 8.58
#Glecaprevir 400 mg QDa/pibrentasvir 120 mg QDa, 7 days 10 mg QDa for 7 days 8.28 22.00
#Telaprevir 750 mg q8hf, 10 days 20 mg SDc 7.88 10.60
#,‡Saquinavir 400 mg BIDb/ ritonavir 400mg BIDb, 15 days 40 mg QDa for 4 days 3.93 4.31
#Elbasvir 50 mg QDa/grazoprevir 200 mg QDa, 13 days 10 mg SDc 1.94 4.34
#Simeprevir 150 mg QDa, 10 days 40 mg SDc 2.12 1.70
#Clarithromycin 500 mg BIDb, 9 days 80 mg QDa for 8 days 4.54 5.38
#Darunavir 300 mg BIDb/ritonavir 100 mg BIDb, 9 days 10 mg QDa for 4 days 3.45 2.25
#Itraconazole 200 mg QDa, 4 days 40 mg SDc 3.32 1.20
#Letermovir 480 mg QDa, 10 days 20 mg SDc 3.29 2.17
#Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 10 mg QDa for 4 days 2.53 2.84
#Fosamprenavir 1400 mg BIDb, 14 days 10 mg QDa for 4 days 2.30 4.04
#Nelfinavir 1250 mg BIDb, 14 days 10 mg QDa for 28 days 1.74 2.22
#Grapefruit Juice, 240 mL QDa,* 40 mg SDc 1.37 1.16
Diltiazem 240 mg QDa, 28 days 40 mg SDc 1.51 1.00
Erythromycin 500 mg QIDe, 7 days 10 mg SDc 1.33 1.38
Amlodipine 10 mg, single dose 80 mg SDc 1.18 0.91
Cimetidine 300 mg QIDe, 2 weeks 10 mg QDa for 2 weeks 1.00 0.89
Colestipol 10 g BIDb, 24 weeks 40 mg QDa for 8 weeks NA 0.74**
MaaloxTC® 30 mL QIDe, 17 days 10 mg QDa for 15 days 0.66 0.67
Efavirenz 600 mg QDa, 14 days 10 mg for 3 days 0.59 1.01
#Rifampin 600 mg QDa, 7 days (coadministered)† 40 mg SDc 1.12 2.90
#Rifampin 600 mg QDa, 5 days (doses separated) † 40 mg SDc 0.20 0.60
#Gemfibrozil 600mg BID b, 7 days 40mg SDc 1.35 1.00
#Fenofibrate 160mg QDa, 7 days 40mg SDc 1.03 1.02
Boceprevir 800 mg TIDd, 7 days 40 mg SDc 2.32 2.66
", "
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Ratio of AUC Ratio of Cmax
80 mg QDa for 15 days Antipyrine, 600 mg SDc 1.03 0.89
80 mg QDa for 10 days # Digoxin 0.25 mg QDa, 20 days 1.15 1.20
40 mg QDa for 22 days Oral contraceptive QDa, 2 months -norethindrone 1 mg -ethinyl estradiol 35 μg 1.28 1.19 1.23 1.30
10 mg, SDc Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 1.08 0.96
10 mg QDa for 4 days Fosamprenavir 1400 mg BIDb, 14 days 0.73 0.82
10 mg QDa for 4 days Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 0.99 0.94
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-­methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Atorvastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ]." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration . Distribution Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Elimination Metabolism Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)] . In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin [see Use in Specific Populations (8.6) ]. While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7)]. Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 5 : Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg SD c 7.88 10.60 #,‡ Saquinavir 400 mg BID b / ritonavir 400mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 # Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a, * 40 mg SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74** MaaloxTC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (coadministered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600mg BID b , 7 days 40mg SD c 1.35 1.00 # Fenofibrate 160mg QD a , 7 days 40mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or C max (ratio of C max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL - 1.2 liters per day). ** Ratio based on a single sample taken 8-16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of C max 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months -norethindrone 1 mg -ethinyl estradiol 35 μg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 # See Section 7 for clinical significance. a Once daily b Twice daily c Single dose Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment." ], "pharmacokinetics_table": [ "
Co-administered drug and dosing regimen Atorvastatin
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QDa for 28 days 8.69 10.66
#Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 10 mg SDc 9.36 8.58
#Glecaprevir 400 mg QDa/pibrentasvir 120 mg QDa, 7 days 10 mg QDa for 7 days 8.28 22.00
#Telaprevir 750 mg q8hf, 10 days 20 mg SDc 7.88 10.60
#,‡Saquinavir 400 mg BIDb/ ritonavir 400mg BIDb, 15 days 40 mg QDa for 4 days 3.93 4.31
#Elbasvir 50 mg QDa/grazoprevir 200 mg QDa, 13 days 10 mg SDc 1.94 4.34
#Simeprevir 150 mg QDa, 10 days 40 mg SDc 2.12 1.70
#Clarithromycin 500 mg BIDb, 9 days 80 mg QDa for 8 days 4.54 5.38
#Darunavir 300 mg BIDb/ritonavir 100 mg BIDb, 9 days 10 mg QDa for 4 days 3.45 2.25
#Itraconazole 200 mg QDa, 4 days 40 mg SDc 3.32 1.20
#Letermovir 480 mg QDa, 10 days 20 mg SDc 3.29 2.17
#Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 10 mg QDa for 4 days 2.53 2.84
#Fosamprenavir 1400 mg BIDb, 14 days 10 mg QDa for 4 days 2.30 4.04
#Nelfinavir 1250 mg BIDb, 14 days 10 mg QDa for 28 days 1.74 2.22
#Grapefruit Juice, 240 mL QDa,* 40 mg SDc 1.37 1.16
Diltiazem 240 mg QDa, 28 days 40 mg SDc 1.51 1.00
Erythromycin 500 mg QIDe, 7 days 10 mg SDc 1.33 1.38
Amlodipine 10 mg, single dose 80 mg SDc 1.18 0.91
Cimetidine 300 mg QIDe, 2 weeks 10 mg QDa for 2 weeks 1.00 0.89
Colestipol 10 g BIDb, 24 weeks 40 mg QDa for 8 weeks NA 0.74**
MaaloxTC® 30 mL QIDe, 17 days 10 mg QDa for 15 days 0.66 0.67
Efavirenz 600 mg QDa, 14 days 10 mg for 3 days 0.59 1.01
#Rifampin 600 mg QDa, 7 days (coadministered)† 40 mg SDc 1.12 2.90
#Rifampin 600 mg QDa, 5 days (doses separated) † 40 mg SDc 0.20 0.60
#Gemfibrozil 600mg BID b, 7 days 40mg SDc 1.35 1.00
#Fenofibrate 160mg QDa, 7 days 40mg SDc 1.03 1.02
Boceprevir 800 mg TIDd, 7 days 40 mg SDc 2.32 2.66
", "
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Ratio of AUC Ratio of Cmax
80 mg QDa for 15 days Antipyrine, 600 mg SDc 1.03 0.89
80 mg QDa for 10 days # Digoxin 0.25 mg QDa, 20 days 1.15 1.20
40 mg QDa for 22 days Oral contraceptive QDa, 2 months -norethindrone 1 mg -ethinyl estradiol 35 μg 1.28 1.19 1.23 1.30
10 mg, SDc Tipranavir 500 mg BIDb/ritonavir 200 mg BIDb, 7 days 1.08 0.96
10 mg QDa for 4 days Fosamprenavir 1400 mg BIDb, 14 days 0.73 0.82
10 mg QDa for 4 days Fosamprenavir 700 mg BIDb/ritonavir 100 mg BIDb, 14 days 0.99 0.94
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for 2 years." ], "clinical_studies": [ "14 CLINICAL STUDIES Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% women; 95% White, 3% Black, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT- LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% White, 2% Black, 2% South Asian, 1% other; 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL < 160 mg/dL and triglycerides (TG) <600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059). Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% White, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level<130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 7). The overall risk reduction was consistent regardless of age (<65, ≥65) or sex. Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) Table 7: Overview of Efficacy Results in TNT Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HR a (95% CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS* First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedure b 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpoint b 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00) Suicide, homicide, and othertraumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non­fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 7). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. Primary Hyperlipidemia in Adults Atorvastatin calcium reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8.) Table 8: Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C Placebo 21 4 4 3 10 -3 7 10 22 -29 -39 -32 -19 6 -34 20 20 -33 -43 -35 -26 9 -41 40 21 -37 -50 -42 -29 6 -45 80 23 -45 -60 -50 -37 5 -53 a Results are pooled from 2 dose-response trials. In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mgper day or a fixed dose of the comparative agent (Table 9). Table 9 : Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Trial 1 Atorvastatin 10 mg 707 -27 a -36 a -28 a -17 a +7 Lovastatin 20 mg 191 -19 -27 -20 -6 +7 95% CI for Diff 1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7,2.0 Trial 2 Atorvastatin 10 mg 222 -25 b -35 b -27 b -17 b +6 Pravastatin 20 mg 77 -17 -23 -17 -9 +8 95% CI for Diff 1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 Trial 3 Atorvastatin 10 mg 132 -29 c -37 c -34 c -23 c +7 Simvastatin 10 mg 45 -24 -30 -30 -15 +7 95% CI for Diff 1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p < 0.05 b Significantly different from pravastatin, ANCOVA, p < 0.05 c Significantly different from simvastatin, ANCOVA, p < 0.05 Table 9 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily interchangeable. Hypertriglyceridemia in Adults The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267-1502). Table 10: Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo (N=12) Atorvastatin 10 mg (N=37) Atorvastatin 20 mg (N=13) Atorvastatin 80 mg (N=14) Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2) non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) Dysbetalipoproteinemia in Adults The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 11). Table 11: Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia ( Fredrickson Type III) Median % Change (min,max) Median (min, max) at Baseline (mg/dL) Atorvastatin 10 mg Atorvastatin 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) HoFH in Adults and Pediatric Patients In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% <18 years) with HoFH received maximum daily doses of 20 to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this trial was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%. HeFH in Pediatric Patients In a double-blind, placebo-controlled trail followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Blacks, 1.6% Asians, 4.8% other) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium(n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the trial required 1) a baseline LDL-C level > 190 mg/dL or 2) a baseline LDL-C level > 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 219 mg/dL (range: 139–385 mg/dL) in the atorvastatin calciumgroup compared to 230 mg/dL (range: 160–325 mg/dL) in the placebo group. Thedosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 12 ). Table 12: Lipid-altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1.0 0.7 Atorvastatin 140 -31.4 -39.6 2.8 -12.0 -34.0 The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0 to 242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0 to 385.0 mg/dL) in the placebo group during the 26-week double-blind phase. Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 boys and 81 girls). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of < 130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical trails in both adult and pediatric placebo-controlled trials." ], "clinical_studies_table": [ "
Endpoint Atorvastatin10 mg(N=5006) Atorvastatin80 mg(N=4995) HRa(95% CI)
PRIMARYENDPOINT n (%) n (%)
First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89)
Components of the Primary Endpoint
CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93)
Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67)
Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96)
SECONDARYENDPOINTS*
First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94)
First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedureb 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80)
First documented angina endpointb 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99)
All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19)
Components of All-Cause Mortality
Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03)
Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57)
Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55)
Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00)
Suicide, homicide, and othertraumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82)
", "
Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C
Placebo 21 4 4 3 10 -3 7
10 22 -29 -39 -32 -19 6 -34
20 20 -33 -43 -35 -26 9 -41
40 21 -37 -50 -42 -29 6 -45
80 23 -45 -60 -50 -37 5 -53
", "
Treatment (Daily Dose) N Total-C LDL-C Apo B TG HDL-C
Trial 1
Atorvastatin 10 mg 707 -27a -36a -28a -17a +7
Lovastatin 20 mg 191 -19 -27 -20 -6 +7
95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7,2.0
Trial2
Atorvastatin 10 mg 222 -25b -35b -27b -17b +6
Pravastatin 20 mg 77 -17 -23 -17 -9 +8
95% CI for Diff1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6
Trial 3
Atorvastatin 10 mg 132 -29c -37c -34c -23c +7
Simvastatin 10 mg 45 -24 -30 -30 -15 +7
95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9
", "
Placebo (N=12) Atorvastatin 10 mg (N=37) Atorvastatin 20 mg (N=13) Atorvastatin 80 mg (N=14)
Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3)
Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8)
LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8)
HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2)
non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3)
", "
Median % Change (min,max)
Median (min, max) at Baseline (mg/dL) Atorvastatin 10 mg Atorvastatin 80 mg
Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
", "
DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B
Placebo 47 -1.5 -0.4 -1.9 1.0 0.7
Atorvastatin 140 -31.4 -39.6 2.8 -12.0 -34.0
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Atorvastatin calcium tablets, USP 80 mg of atorvastatin: white coloured, oval shaped, biconvex, film-coated tablets with \"MA\" on one side and \"4\" on other side. NDC: 71335-1336-1: 30 Tablets in a BOTTLE NDC: 71335-1336-2: 60 Tablets in a BOTTLE NDC: 71335-1336-3: 90 Tablets in a BOTTLE NDC: 71335-1336-4: 180 Tablets in a BOTTLE Store at controlled room temperature 20º to 25ºC (68º to 77ºF). Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myopathy and Rhabdomyolysis Advise patients that atorvastatin calcium may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1) , Drug Interactions (7.1)] . Hepatic Dysfunction Inform patients that atorvastatin calcium may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3) ]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with atorvastatin calcium. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)] . Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if atorvastatin calcium should be discontinued [see Use in Specific Populations (8.1)] . Lactation Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [see Use in Specific Populations (8.2)]. This product’s labeling may have been updated. For the most recent prescribing information, please visit www.novadozpharma.com. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854 -3714 Issued on: 05/2023" ], "spl_unclassified_section": [ "PATIENT INFORMATION Atorvastatin Calcium Tablets, USP ( a TOR va sta tin KAL see um), for oral use What are atorvastatin calcium tablets? Atorvastatin calcium tablets are a prescription medicine that contains a cholesterol lowering medicine (statin) called atorvastatin. Atorvastatin calcium tablets are used: to reduce the risk of: heart attack, stroke, certain types of heart surgery and chest pain in adults who do not have heart disease but have other multiple risk factors for heart disease. heart attack and stroke in adults with type 2 diabetes mellitus who do not have heart disease but have other multiple risk factors. heart attack that does not cause death, stroke, certain types of heart surgery, hospitalization for congestive heart failure, and chest pain in adults with heart disease. along with diet to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia. in adults and children aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). This is an inherited condition that causes high levels of bad cholesterol along with other cholesterol lowering treatments or alone if such treatments are unavailable in adults and children aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). This is an inherited condition that causes high levels of bad cholesterol. along with diet for the treatment of adults with: primary dysbetalipoproteinemia (an inherited condition that causes high levels of cholesterol and fat). hypertriglyceridemia. It is not known if atorvastatin calcium tablets are safe and effective in children younger than 10 years of age with HeFH or HoFH or in children with other types of hyperlipidemias (other than HeFH or HoFH). Do not take atorvastatin calcium tablets if you: have liver problems (acute liver failure or decompensated cirrhosis) are allergic to atorvastatin or any of the ingredients in atorvastatin calcium tablets. Stop using atorvastatin calcium tablets and get medical help right away if you have symptoms of a serious allergic reaction including: swelling of your face, lips, tongue or throat problems breathing or swallowing o fainting or feeling dizzy very rapid heartbeat severe skin rash or itching flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets. Before you take atorvastatin calcium tablets , tell your doctor about all of your medical conditions, including if you : have unexplained muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have thyroid problems have kidney problems had a stroke are pregnant or plan to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you become pregnant, stop taking atorvastatin calcium tablets and call your doctor right away. are breastfeeding or plan to breastfeed. You and your doctor should decide if you will take atorvastatin calcium tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take atorvastatin calcium tablets. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your doctor if you take medicines for: your immune system (cyclosporine) cholesterol (gemfibrozil) infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole) birth control pills heart failure (digoxin) gout (colchicine) niacin fibrates viruses that treat HIV, AIDS, or hepatitis C (anti-virals) tipranavir plus ritonavir glecaprevir plus pibrentasvir ledipasvir plus sofosbuvir simeprevir saquinavir plus ritonavir darunavir plus ritonavir fosamprenavir fosamprenavir plus ritonavir elbasvir plus grazoprevir letermovir nelfinavir Ask your doctor or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take atorvastatin calcium tablets? Take atorvastatin calcium tablets exactly as your doctor tells you to take it. Do not change your dose or stop atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium tablets may be changed based on these blood test results. Take atorvastatin calcium tablets each day at any time of day. Atorvastatin calcium tablets can be taken with or without food. Your doctor may start you on a cholesterol lowering diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets. If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take atorvastatin calcium tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of atorvastatin calcium tablets at the same time. If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking atorvastatin calcium tablets? Avoid drinking more than 1.2 liters of grapefruit juice each day. What are the possible side effects of atorvastatin calcium tablets? Atorvastatin calcium tablets may cause serious side effects including: Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death. Tell your doctor right away if you have: unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take atorvastatin calcium tablets. muscle problems that do not go away after your doctor has told you to stop taking atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: are taking certain other medicines while you take atorvastatin calcium tablets drink large amounts of grapefruit juice are 65 years of age or older have thyroid problems (hypothyroidism) that are not controlled have kidney problems are taking higher doses of atorvastatin calcium tablets Liver problems. Your doctor should do blood tests to check your liver before you start taking atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your doctor right away if you have the following symptoms of liver problems: feel tired or weak nausea or vomiting loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Increase in blood sugar level. Your blood sugar level may increase while you are taking atorvastatin calcium tablets. Exercise regularly and make healthy food choices to maintain healthy body weight. The most common side effects of atorvastatin calcium tablets include: nasal congestion, sore throat, runny nose muscle and joint pain diarrhea pain in extremity urinary tract infection upset stomach nausea musculoskeletal pain muscle spasms trouble sleeping throat pain Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away. These are not all the side effects of atorvastatin calcium tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store atorvastatin calcium tablets? Store atorvastatin calcium tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Do not keep medicine that is out of date or that you no longer need. Keep atorvastatin calcium tablets and all medicines out of the reach of children. General information about the safe and effective use of atorvastatin calcium tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about atorvastatin calcium tablets, talk with your doctor. You can ask your pharmacist or doctor for information about atorvastatin calcium tablets that is written for health professionals. What are the ingredients in atorvastatin calcium tablets? Active Ingredient: atorvastatin calcium Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, magnesium aluminometasilicate, microcrystalline cellulose, polysorbate 80, precipitated calcium carbonate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol and lecithin. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854 -3714 Issued on: 05/2023 This Patient Package Information has been approved by the U.S. Food and Drug Administration" ], "spl_unclassified_section_table": [ "
Atorvastatin Calcium Tablets, USP (a TOR va sta tin KAL see um), for oral use
What are atorvastatin calcium tablets? Atorvastatin calcium tablets are a prescription medicine that contains a cholesterol lowering medicine (statin) called atorvastatin. Atorvastatin calcium tablets are used: to reduce the risk of: heart attack, stroke, certain types of heart surgery and chest pain in adults who do not have heart disease but have other multiple risk factors for heart disease. heart attack and stroke in adults with type 2 diabetes mellitus who do not have heart disease but have other multiple risk factors. heart attack that does not cause death, stroke, certain types of heart surgery, hospitalization for congestive heart failure, and chest pain in adults with heart disease. along with diet to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol in adults with primary hyperlipidemia. in adults and children aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). This is an inherited condition that causes high levels of bad cholesterol along with other cholesterol lowering treatments or alone if such treatments are unavailable in adults and children aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). This is an inherited condition that causes high levels of bad cholesterol. along with diet for the treatment of adults with: primary dysbetalipoproteinemia (an inherited condition that causes high levels of cholesterol and fat). hypertriglyceridemia. It is not known if atorvastatin calcium tablets are safe and effective in children younger than 10 years of age with HeFH or HoFH or in children with other types of hyperlipidemias (other than HeFH or HoFH).
Do not take atorvastatin calcium tablets if you: have liver problems (acute liver failure or decompensated cirrhosis)are allergic to atorvastatin or any of the ingredients in atorvastatin calcium tablets. Stop using atorvastatin calcium tablets and get medical help right away if you have symptoms of a serious allergic reaction including: swelling of your face, lips, tongue or throat problems breathing or swallowing o fainting or feeling dizzy very rapid heartbeat severe skin rash or itching flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets. Before you take atorvastatin calcium tablets, tell your doctor about all of your medical conditions, including if you: have unexplained muscle aches or weaknessdrink more than 2 glasses of alcohol dailyhave diabetes have thyroid problems have kidney problems had a stroke are pregnant or plan to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you become pregnant, stop taking atorvastatin calcium tablets and call your doctor right away. are breastfeeding or plan to breastfeed. You and your doctor should decide if you will take atorvastatin calcium tablets or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take atorvastatin calcium tablets. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your doctor if you take medicines for: your immune system (cyclosporine) cholesterol (gemfibrozil) infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole)birth control pills heart failure (digoxin) gout (colchicine) niacin fibrates viruses that treat HIV, AIDS, or hepatitis C (anti-virals) tipranavir plus ritonavirglecaprevir plus pibrentasvirledipasvir plus sofosbuvir simeprevir saquinavir plus ritonavirdarunavir plus ritonavir fosamprenavirfosamprenavir plus ritonavirelbasvir plus grazoprevir letermovir nelfinavir Ask your doctor or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take atorvastatin calcium tablets? Take atorvastatin calcium tablets exactly as your doctor tells you to take it. Do not change your dose or stop atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium tablets may be changed based on these blood test results. Take atorvastatin calcium tablets each day at any time of day. Atorvastatin calcium tablets can be taken with or without food. Your doctor may start you on a cholesterol lowering diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets.If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take atorvastatin calcium tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of atorvastatin calcium tablets at the same time. If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.
What should I avoid while taking atorvastatin calcium tablets? Avoid drinking more than 1.2 liters of grapefruit juice each day.
What are the possible side effects of atorvastatin calcium tablets? Atorvastatin calcium tablets may cause serious side effects including: Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death.Tell your doctor right away if you have: unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take atorvastatin calcium tablets.muscle problems that do not go away after your doctor has told you to stop taking atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: are taking certain other medicines while you take atorvastatin calcium tabletsdrink large amounts of grapefruit juice are 65 years of age or older have thyroid problems (hypothyroidism) that are not controlled have kidney problems are taking higher doses of atorvastatin calcium tablets Liver problems. Your doctor should do blood tests to check your liver before you start taking atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your doctor right away if you have the following symptoms of liver problems:feel tired or weak nausea or vomiting loss of appetite upper belly pain dark amber colored urineyellowing of your skin or the whites of your eyesIncrease in blood sugar level. Your blood sugar level may increase while you are taking atorvastatin calcium tablets. Exercise regularly and make healthy food choices to maintain healthy body weight. The most common side effects of atorvastatin calcium tablets include: nasal congestion, sore throat, runny nose muscle and joint paindiarrhea pain in extremity urinary tract infectionupset stomachnausea musculoskeletal painmuscle spasmstrouble sleepingthroat pain Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away. These are not all the side effects of atorvastatin calcium tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How do I store atorvastatin calcium tablets? Store atorvastatin calcium tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Do not keep medicine that is out of date or that you no longer need. Keep atorvastatin calcium tablets and all medicines out of the reach of children.
General information about the safe and effective use of atorvastatin calcium tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about atorvastatin calcium tablets, talk with your doctor. You can ask your pharmacist or doctor for information about atorvastatin calcium tablets that is written for health professionals.
What are the ingredients in atorvastatin calcium tablets? Active Ingredient: atorvastatin calcium Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, magnesium aluminometasilicate, microcrystalline cellulose, polysorbate 80, precipitated calcium carbonate, polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol and lecithin. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854 -3714 Issued on: 05/2023
" ], "package_label_principal_display_panel": [ "Atorvastatin Calcium 80 mg Tablets Label" ], "set_id": "00afce9b-48c9-487a-a738-e359c005c707", "id": "05b0f170-ac97-4a83-b03a-659a4b493ee2", "effective_time": "20250828", "version": "6", "openfda": { "application_number": [ "ANDA211933" ], "brand_name": [ "Atorvastatin calcium" ], "generic_name": [ "ATORVASTATIN CALCIUM" ], "manufacturer_name": [ "Bryant Ranch Prepack" ], "product_ndc": [ "71335-1336" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "ATORVASTATIN CALCIUM TRIHYDRATE" ], "rxcui": [ "259255" ], "spl_id": [ "05b0f170-ac97-4a83-b03a-659a4b493ee2" ], "spl_set_id": [ "00afce9b-48c9-487a-a738-e359c005c707" ], "package_ndc": [ "71335-1336-1", "71335-1336-2", "71335-1336-3", "71335-1336-4" ], "original_packager_product_ndc": [ "72205-025" ], "unii": [ "48A5M73Z4Q" ] } }, { "effective_time": "20131209", "recent_major_changes": [ "RECENT MAJOR CHANGES Dosage and Administration (2.6) 10/2012 Warnings and Precautions (5.1) 10/2012 Drug Interactions (7) 02/2012" ], "drug_interactions": [ "7 DRUG INTERACTIONS The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3) ]. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with atorvastatin calcium (7). Digoxin: Patients should be monitored appropriately (7.8). Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased (7.9). Rifampin should be simultaneously co-administered with atorvastatin calcium (7.7). 7.1 Strong Inhibitors of CYP 3A4 Atorvastatin calcium is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin calcium with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4. Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor telaprevir, compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin calcium should be avoided. In patients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium and the lowest dose necessary should be used. In patients taking the HIV protease inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of atorvastatin calcium should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended. Itraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3) ]. Therefore, in patients taking itraconazole, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (5.1) and Dosage and Administration (2.6) ]. 7.2 Grapefruit Juice Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 liters per day). 7.3 Cyclosporine Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3) ]. The co-administration of atorvastatin calcium with cyclosporine should be avoided [see Warnings and Precautions, Skeletal Muscle (5.1) ]. 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin calcium with gemfibrozil should be avoided [see Warnings and Precautions (5.1) ]. 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin calcium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1) ]. 7.6 Niacin The risk of skeletal muscle effects may be enhanced when atorvastatin calcium is used in combination with niacin; a reduction in atorvastatin calcium dosage should be considered in this setting [see Warnings and Precautions (5.1) ]. 7.7 Rifampin or other Inducers of Cytochrome P450 3A4 Concomitant administration of atorvastatin calcium with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin calcium with rifampin is recommended, as delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. 7.8 Digoxin When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately. 7.9 Oral Contraceptives Co-administration of atorvastatin calcium and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ]. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin calcium. 7.10 Warfarin Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment. 7.11 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine." ], "geriatric_use": [ "8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥ 65 years old and 2,800 (7%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly." ], "references": [ "15 REFERENCES 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents, Pediatrics. 89(3):495-501. 1992." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ]." ], "description": [ "11 DESCRIPTION Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Atorvastatin calcium is [R-(R * ,R * )]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin calcium is (C 33 H 34 FN 2 O 5 ) 2 Ca•3H 2 O and its molecular weight is 1209.42. Its structural formula is: Atorvastatin calcium, USP is a white to off-white crystalline powder. Atorvastatin calcium is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble to insoluble in water and pH 7.4 phosphate buffer; insoluble in acetonitrile; slightly soluble to very slightly soluble in ethanol; and freely soluble to slightly soluble in methanol. Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate; candelilla wax, FCC; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide. structure" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years." ], "warnings_and_cautions_table": [ "
Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
*Use with caution and with the lowest dose necessary (12.3)
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium, USP. 10, 20, 40, and 80 mg tablets (3)." ], "mechanism_of_action": [ "12.1 Mechanism of Action Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s). A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption: Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ]. Distribution: Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥ 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ]. Metabolism: Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion: Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration. Specific Populations Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ]. Pediatric: Pharmacokinetic data in the pediatric population are not available. Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women. Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5 ), Warnings and Precautions, Skeletal Muscle (5.1) ]. Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ]. Table 3 Table 4" ], "clinical_studies_table": [ "
TABLE 5. Overview of Efficacy Results in TNT
a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR = hazard ratio; CHD = coronary heart disease; CI = confidence interval; MI = myocardial infarction; CHF = congestive heart failure; CV = cardiovascular; PVD = peripheral vascular disease; CABG = coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
Endpoint Atorvastatin 10 mg (N = 5006) Atorvastatin 80 mg (N = 4995) HRa (95%CI)
PRIMARY ENDPOINT n (%) n (%)
First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89)
Components of the Primary Endpoint
CHD death 127 (2.5) 101 (2) 0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93)
Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67)
Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96)
SECONDARY ENDPOINTS*
First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94)
First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedureb 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80)
First documented angina endpointb 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99)
All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19)
Components of All-Cause Mortality
Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03)
Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57)
Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55)
Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2)
Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82)
", "
TABLE 6. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline)a
a Results are pooled from 2 dose-response studies.
Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C
Placebo 21 4 4 3 10 -3 7
10 22 -29 -39 -32 -19 6 -34
20 20 -33 -43 -35 -26 9 -41
40 21 -37 -50 -42 -29 6 -45
80 23 -45 -60 -50 -37 5 -53
", "
TABLE 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)
1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p ≤ 0.05 b Significantly different from pravastatin, ANCOVA, p ≤ 0.05 c Significantly different from simvastatin, ANCOVA, p ≤ 0.05
Treatment Non-HDL-C/ HDL-C
(Daily Dose) N Total-C LDL-C Apo B TG HDL-C
Study 1
Atorvastatin Calcium 10 mg 707 -27a -36a -28a -17a +7 -37a
Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28
95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10, -6.5 -15.2, -7.1 -1.7, 2 -11.1, -7.1
Study 2
Atorvastatin Calcium 10 mg 222 -25b -35b -27b -17b +6 -36b
Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28
95% CI for Diff1 -10.8,-6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1
Study 3
Atorvastatin Calcium 10 mg 132 -29c -37c -34c -23c +7 -39c
Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33
95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9
", "
TABLE 8. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline
Placebo Atorvastatin Calcium 10 mg Atorvastatin Calcium 20 mg Atorvastatin Calcium 80 mg
(N = 12) (N = 37) (N = 13) (N = 14)
Triglycerides -12.4 (-36.6, 82.7) -41 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3)
Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8)
LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6,-13.8)
HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11(-3.2, 25.2) 7.5 (-10.8, 37.2)
VLDL-C -1 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62 (-88.2, 37.6)
non-HDL-C -2.8 (-17.6, 30) -33 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3)
", "
TABLE 9. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrickson Type III)
Median (min, max) at Baseline (mg/dL) Median % Change (min, max)
Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg
Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
", "
TABLE 10. Lipid-altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population)
DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B
Placebo 47 -1.5 -0.4 -1.9 1 0.7
Atorvastatin Calcium 140 -31.4 -39.6 2.8 -12 -34
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet. Atorvastatin calcium tablets are an inhibitor of HMG-CoA reductase (statin) indicated as an adjunct therapy to diet to: Reduce the risk of MI, stroke, revascularization procedures, and angina in patients without CHD, but with multiple risk factors (1.1). Reduce the risk of MI and stroke in patients with type 2 diabetes without CHD, but with multiple risk factors (1.1). Reduce the risk of non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for CHF, and angina in patients with CHD (1.1). Reduce elevated total-C, LDL-C, apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (1.2). Reduce elevated TG in patients with hypertriglyceridemia and primary dysbetalipoproteinemia (1.2). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) (1.2). Reduce elevated total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy (1.2). Limitations of Use Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias. 1.1 Prevention of Cardiovascular Disease In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke Reduce the risk for revascularization procedures and angina In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to: Reduce the risk of myocardial infarction Reduce the risk of stroke In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to: Reduce the risk of non-fatal myocardial infarction Reduce the risk of fatal and non-fatal stroke Reduce the risk for revascularization procedures Reduce the risk of hospitalization for CHF Reduce the risk of angina 1.2 Hyperlipidemia Atorvastatin calcium tablets are indicated: As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia ( Fredrickson Types IIa and IIb); As an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV); For the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet; To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable; As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: a. LDL-C remains ≥ 190 mg/dL or b. LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other CVD risk factors are present in the pediatric patient 1.3 Limitations of Use Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V)." ], "set_id": "00b6912b-d195-4d7d-8333-e9b0fa20fcc1", "id": "4cea1f5c-07d8-4ae8-8d22-5578b510c62d", "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2 )]. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin calcium therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ]. Atorvastatin calcium has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies , Homozygous Familial Hypercholesterolemia (14.5) ]." ], "contraindications": [ "4 CONTRAINDICATIONS Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels (4.1). Women who are pregnant or may become pregnant (4.3). Nursing mothers (4.4). Hypersensitivity to any component of this medication (4.2). 4.1 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels 4.2 Hypersensitivity to any component of this medication 4.3 Pregnancy Women who are pregnant or may become pregnant . Atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of atorvastatin calcium use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of teratogenicity. ATORVASTATIN CALCIUM SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin calcium should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Population s (8.1) ]. 4.4 Nursing Mothers It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require atorvastatin calcium treatment should not breastfeed their infants [see Use in Specific Populations (8.3) ]." ], "drug_interactions_table": [ "
Interacting Agents Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily
" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category X Atorvastatin calcium is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m 2 ) [see Contraindications, Pregnancy (4.3) ]. In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin calcium treatment should be advised not to nurse their infants [see Contraindications (4) ]." ], "spl_product_data_elements": [ "Atorvastatin Calcium Atorvastatin Calcium ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN CALCIUM CARBONATE CANDELILLA WAX CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE (TYPE H) LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE HYPROMELLOSES POLYETHYLENE GLYCOLS TALC TITANIUM DIOXIDE POLYSORBATE 80 WATER DIMETHICONE SILICON DIOXIDE POLYSORBATE 65 METHYLCELLULOSE (400 MPA.S) RX828 elliptical" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected (5.1, 8.5). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter (5.2). A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo (5.5). 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin calcium and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values > 10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin calcium. Atorvastatin calcium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin calcium and fibric acid derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Drug Interaction s (7) ). Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.6 ) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. Table 1. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis *Use with caution and with the lowest dose necessary (12.3) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11) ]. Atorvastatin calcium therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures). 5.2 Liver Dysfunction Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin calcium. It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium. Atorvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin calcium [see Contraindications (4.1) ]. 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin calcium. Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine. 5.4 CNS Toxicity Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose. 5.5 Use in Patients with Recent Stroke or TIA In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1) ]." ], "adverse_reactions_table": [ "
Table 2. Clinical adverse reactions occurring in ≥ 2% in patents treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients).
*Adverse Reaction ≥ 2% in any dose greater than placebo
Any dose 10 mg 20 mg 40 mg 80 mg Placebo
Adverse Reaction* N = 8755 N = 3908 N = 188 N = 604 N = 4055 N = 7311
Nasopharyngitis 8.3 12.9 5.3 7 4.2 8.2
Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5
Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3
Pain in extremity 6 8.5 3.7 9.3 3.1 5.9
Urinary tract infection 5.7 6.9 6.4 8 4.1 5.6
Dyspepsia 4.7 5.9 3.2 6 3.3 4.3
Nausea 4 3.7 3.7 7.1 3.8 3.5
Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6
Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3
Myalgia 3.5 3.6 5.9 8.4 2.7 3.1
Insomnia 3 2.8 1.1 5.3 2.8 2.9
Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1
" ], "openfda": {}, "version": "1", "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Dose range: 10 to 80 mg once daily (2.1). Recommended start dose: 10 or 20 mg once daily (2.1). Patients requiring large LDL-C reduction (> 45%) may start at 40 mg once daily (2.1). Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily (2.2). 2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson Types IIa and IIb) The recommended starting dose of atorvastatin calcium tablets is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines ). After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly. 2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines , Clinical Pharmacolog y (12) , and Indications and Usage (1.2) ]. Adjustments should be made at intervals of 4 weeks or more. 2.3 Homozygous Familial Hypercholesterolemia The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin calcium tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 2.4 Concomitant Lipid-Lowering Therapy Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ]. 2.5 Dosage in Patients With Renal Impairment Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (5.1), Clinical Pharmacology, Pharmacokinetics (12.3) ]. 2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or Certain Protease Inhibitors In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor (telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution should be used when prescribing atorvastatin calcium tablets and the lowest dose necessary employed. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1) ] Liver enzyme abnormalities [see Warnings and Precautions (5.2) ] The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Ranbaxy Pharmaceuticals Inc. at (1-888-Ranbaxy (726-2299)) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Adverse Experiences Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n = 8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6%), and urinary tract infection (5.7%). Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n = 8755), from seventeen placebo-controlled trials. Table 2. Clinical adverse reactions occurring in ≥ 2% in patents treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients). *Adverse Reaction ≥ 2% in any dose greater than placebo Any dose 10 mg 20 mg 40 mg 80 mg Placebo Adverse Reaction * N = 8755 N = 3908 N = 188 N = 604 N = 4055 N = 7311 Nasopharyngitis 8.3 12.9 5.3 7 4.2 8.2 Arthralgia 6.9 8.9 11.7 10.6 4.3 6.5 Diarrhea 6.8 7.3 6.4 14.1 5.2 6.3 Pain in extremity 6 8.5 3.7 9.3 3.1 5.9 Urinary tract infection 5.7 6.9 6.4 8 4.1 5.6 Dyspepsia 4.7 5.9 3.2 6 3.3 4.3 Nausea 4 3.7 3.7 7.1 3.8 3.5 Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3 3.6 Muscle Spasms 3.6 4.6 4.8 5.1 2.4 3 Myalgia 3.5 3.6 5.9 8.4 2.7 3.1 Insomnia 3 2.8 1.1 5.3 2.8 2.9 Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 Other adverse reactions reported in placebo-controlled studies include: Body as a whole : malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system : musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system : transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system : nightmare; Respiratory system: epistaxis; Skin and appendages : urticaria; Special senses : vision blurred, tinnitus; Urogenital system: white blood cells urine positive. Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [see Clinical Studies (14.1) ] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of the group treated with atorvastatin calcium was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up. Collaborative Atorvastatin Diabetes Study (CARDS) In CARDS [see Clinical Studies (14.1) ] involving 2,838 subjects (age range 39 to 77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1% other) with type 2 diabetes treated with atorvastatin calcium 10 mg daily (n = 1,428) or placebo (n = 1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported. Treating to New Targets Study (TNT) In TNT [see Clinical Studies (14.1) ] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1% Asians, 2% other) with clinically evident CHD treated with atorvastatin calcium 10 mg daily (n = 5006) or atorvastatin calcium 80 mg daily (n = 4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 x ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%). Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL) In IDEAL [see Clinical Studies (14.1) ] involving 8,888 subjects (age range 26 to 80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin calcium 80 mg/day (n = 4439) or simvastatin 20 to 40 mg daily (n = 4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years. Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL involving 4731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin calcium 80 mg (n = 2365) or placebo (n = 2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (> 10 x ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5) ]. In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin calcium vs. 2 (4%) placebo]. There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin calcium 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin calcium 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium 80 mg group (5%) than in the placebo group (4%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions associated with atorvastatin calcium therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, fatigue, tendon rupture, fatal and non-fatal hepatic failure, dizziness, depression, peripheral neuropathy, and pancreatitis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1) ]. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). 6.3 Pediatric Patients (ages 10 to 17 years) In a 26-week controlled study in boys and postmenarchal girls (n = 140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20 mg daily was generally similar to that of placebo [see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4) ]." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease (12.3). 8.1 Pregnancy Pregnancy Category X Atorvastatin calcium is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m 2 ) [see Contraindications, Pregnancy (4.3) ]. In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day. Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking atorvastatin calcium, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy. 8.3 Nursing Mothers It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother’s milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin calcium treatment should be advised not to nurse their infants [see Contraindications (4) ]. 8.4 Pediatric Use Safety and effectiveness in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months’ duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10 to 17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 to 17 years of age) (2.2 )]. Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin calcium therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ]. Atorvastatin calcium has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age. Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies , Homozygous Familial Hypercholesterolemia (14.5) ]. 8.5 Geriatric Use Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥ 65 years old and 2,800 (7%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly. 8.6 Hepatic Impairment Atorvastatin calcium is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3) ]." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Atorvastatin calcium tablets 20 mg are white, elliptical, film-coated tablets, debossed with ‘ RX 828’ on one side and plain on the other side. They are supplied as follows: NDC 33261-0972-30 Bottles of 30 NDC 33261-0972-90 Bottles of 90 Storage Store at 20 - 25° C (68 - 77° F) [See USP Controlled Room Temperature]. Dispense in tight containers (USP)." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Patients taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment. Patients should be advised about substances they should not take concomitantly with atorvastatin [ see Warnings and Precautions (5.1)] . Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium tablets. 17.1 Muscle Pain All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing atorvastatin calcium tablets. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (> 1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium tablets if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking atorvastatin calcium tablets and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should be advised to not use atorvastatin calcium tablets. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional. Manufactured for: Ranbaxy Pharmaceuticals Inc. Jacksonville, FL 32257 USA by: Ohm Laboratories Inc. North Brunswick, NJ 08902 USA AND BY: Ranbaxy Laboratories Ltd. New Delhi – 110019, India Repackaged By : Aidarex Pharmaceuticals LLC, Corona, CA 92880 November 2012 PATIENT INFORMATION ATORVASTATIN CALCIUM TABLETS Rx only Read the Patient Information that comes with atorvastatin calcium tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition or treatment. If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist. What are Atorvastatin Calcium Tablets? Atorvastatin calcium tablets are a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C (\"bad\" cholesterol) and triglycerides in your blood. It can raise your HDL-C (\"good\" cholesterol) as well. Atorvastatin calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone. Atorvastatin calcium tablets can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as: age, smoking, high blood pressure, low HDL-C, heart disease in the family. Atorvastatin calcium tablets can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as: eye problems, kidney problems, smoking, or high blood pressure. Atorvastatin calcium tablets start to work in about 2 weeks. What is Cholesterol? Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family. Who Should Not Take Atorvastatin Calcium Tablets? Do not take atorvastatin calcium tablets if you: are pregnant or think you may be pregnant, or are planning to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you get pregnant, stop taking atorvastatin calcium tablets and call your doctor right away. are breast feeding. Atorvastatin calcium can pass into your breast milk and may harm your baby. have liver problems. are allergic to atorvastatin calcium tablets or any of its ingredients. The active ingredient is atorvastatin calcium, USP. See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets. Atorvastatin calcium tablets have not been studied in children under 10 years of age. Before You Start Atorvastatin Calcium Tablets Tell your doctor if you: have muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have a thyroid problem have kidney problems Some medicines should not be taken with atorvastatin calcium tablets. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for: your immune system cholesterol infections birth control heart failure HIV or AIDS Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist. How Should I Take Atorvastatin Calcium Tablets? Take atorvastatin calcium tablets exactly as prescribed by your doctor. Do not change your dose or stop atorvastatin calcium tablets without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium tablets may be changed based on these blood test results. Take atorvastatin calcium tablets each day at any time of day at about the same time each day. Atorvastatin calcium tablets can be taken with or without food. Don't break atorvastatin calcium tablets before taking. Your doctor should start you on a low-fat diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets. If you miss a dose of atorvastatin calcium tablets, take it as soon as you remember. Do not take atorvastatin calcium tablets if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of atorvastatin calcium tablets at the same time. If you take too much atorvastatin calcium tablets or overdose, call your doctor or Poison Control Center right away. Or go to the nearest emergency room. What Should I Avoid While Taking Atorvastatin Calcium Tablets? Talk to your doctor before you start any new medicines. This includes prescription and non-prescription medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can interact causing serious side effects. Do not get pregnant. If you get pregnant, stop taking atorvastatin calcium tablets right away and call your doctor. What are the Possible Side Effects of Atorvastatin Calcium Tablets? Atorvastatin calcium tablets can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or atorvastatin calcium tablets are stopped. These serious side effects include: Muscle problems. Atorvastatin calcium tablets can cause serious muscle problems that can lead to kidney problems, including kidney failure. You have a higher chance for muscle problems if you are taking certain other medicines with atorvastatin calcium tablets. Liver problems. Your doctor should do blood tests to check your liver before you start taking atorvastatin calcium tablets, and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your doctor right away if you have the following symptoms of liver problems: feel tired or weak loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Call your doctor right away if you have: muscle problems like weakness, tenderness, or pain that happen without a good reason, especially if you also have a fever or feel more tired than usual. This may be an early sign of a rare muscle problem. muscle problems that do not go away even after your doctor has advised you to stop taking atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle problems. allergic reactions including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing which may require treatment right away. nausea and vomiting. passing brown or dark-colored urine. you feel more tired than usual your skin and whites of your eyes get yellow. stomach pain. allergic skin reactions. In clinical studies, patients reported the following common side effects while taking atorvastatin calcium: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests. The following additional side effects have been reported with atorvastatin calcium tablets: tiredness, tendon problems, memory loss, and confusion. Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away. These are not all the side effects of atorvastatin calcium tablets. Ask your doctor or pharmacist for a complete list. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store Atorvastatin Calcium Tablets Store atorvastatin calcium tablets at room temperature, 68 - 77° F (20 - 25° C). Do not keep medicine that is out of date or that you no longer need. Keep atorvastatin calcium tablets and all medicines out of the reach of children. Be sure that if you throw medicine away, it is out of the reach of children. General Information About Atorvastatin Calcium Tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same problem you have. It may harm them. This leaflet summarizes the most important information about atorvastatin calcium tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about atorvastatin calcium tablets that is written for health professionals. What are the Ingredients in Atorvastatin Calcium Tablets? Active Ingredient: atorvastatin calcium, USP Inactive Ingredients: calcium carbonate; candelilla wax, FCC; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide. Manufactured for: Ranbaxy Pharmaceuticals Inc. Jacksonville, FL 32257 USA by: Ohm Laboratories Inc. North Brunswick, NJ 08902 USA AND BY: Ranbaxy Laboratories Ltd. New Delhi – 110019, India Repackaged By : Aidarex Pharmaceuticals LLC, Corona, CA 92880 November 2012" ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤ 251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age > 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP < 140/90 mm Hg for non-diabetic patients; < 130/80 mm Hg for diabetic patients) and allocated to either atorvastatin calcium 10 mg daily (n = 5168) or placebo (n = 5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3% for placebo), p = 0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive. Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p = 0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p = 0.51) or noncardiovascular causes (p = 0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA 1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p = 0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p = 0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p = 0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p = 0.059). Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p = 0.0002 (see Figure 3 and Table 5). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or gender. Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) TABLE 5. Overview of Efficacy Results in TNT a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR = hazard ratio; CHD = coronary heart disease; CI = confidence interval; MI = myocardial infarction; CHF = congestive heart failure; CV = cardiovascular; PVD = peripheral vascular disease; CABG = coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons Endpoint Atorvastatin 10 mg (N = 5006) Atorvastatin 80 mg (N = 4995) HR a (95%CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS * First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedure b 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpoint b 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2) Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 5). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 5). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium 80 mg/day was compared to treatment with simvastatin 20 to 40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin calcium and 105, 179, 142, 47, and 132 mg/dL during treatment with 20 to 40 mg of simvastatin. There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin calcium 80 mg/day group vs. 463 (10.4%) in the simvastatin 20 to 40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p = 0.07. There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin calcium 80 mg/day group vs. 374 (8.4%) in the simvastatin 20 to 40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the atorvastatin calcium 80 mg group and the simvastatin 20 to 40 mg group. figure1 figure2 figure3 14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia ( Fredrickson Types IIa and IIb) Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. Atorvastatin calcium is effective in a wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly. In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 6.) TABLE 6. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a a Results are pooled from 2 dose-response studies. Dose N TC LDL-C Apo B TG HDL-C Non-HDL-C/ HDL-C Placebo 21 4 4 3 10 -3 7 10 22 -29 -39 -32 -19 6 -34 20 20 -33 -43 -35 -26 9 -41 40 21 -37 -50 -42 -29 6 -45 80 23 -45 -60 -50 -37 5 -53 In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25 th and 75 th percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C. In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 7). TABLE 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p ≤ 0.05 b Significantly different from pravastatin, ANCOVA, p ≤ 0.05 c Significantly different from simvastatin, ANCOVA, p ≤ 0.05 Treatment Non-HDL-C/ HDL-C (Daily Dose) N Total-C LDL-C Apo B TG HDL-C Study 1 Atorvastatin Calcium 10 mg 707 -27 a -36 a -28 a -17 a +7 -37 a Lovastatin 20 mg 191 -19 -27 -20 -6 +7 -28 95% CI for Diff 1 -9.2, -6.5 -10.7, -7.1 -10, -6.5 -15.2, -7.1 -1.7, 2 -11.1, -7.1 Study 2 Atorvastatin Calcium 10 mg 222 -25 b -35 b -27 b -17 b +6 -36 b Pravastatin 20 mg 77 -17 -23 -17 -9 +8 -28 95% CI for Diff 1 -10.8,-6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1 Study 3 Atorvastatin Calcium 10 mg 132 -29 c -37 c -34 c -23 c +7 -39 c Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33 95% CI for Diff 1 -8.7, -2.7 -10.1, -2.6 -8, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9 The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is not known. Table 7 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable. 14.3 Hypertriglyceridemia (Fredrickson Type IV) The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 8). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267 to 1502). TABLE 8. Combined Patients With Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo Atorvastatin Calcium 10 mg Atorvastatin Calcium 20 mg Atorvastatin Calcium 80 mg (N = 12) (N = 37) (N = 13) (N = 14) Triglycerides -12.4 (-36.6, 82.7) -41 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6,-13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11(-3.2, 25.2) 7.5 (-10.8, 37.2) VLDL-C -1 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62 (-88.2, 37.6) non-HDL-C -2.8 (-17.6, 30) -33 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) 14.4 Dysbetalipoproteinemia (Fredrickson Type III) The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below (Table 9). TABLE 9. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrickson Type III) Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) 14.5 Homozygous Familial Hypercholesterolemia In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%. 14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n = 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase (see Table 10). TABLE 10. Lipid-altering Effects of Atorvastatin Calcium in Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1 0.7 Atorvastatin Calcium 140 -31.4 -39.6 2.8 -12 -34 The mean achieved LDL-C value was 130.7 mg/dL (range: 70 to 242 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152 to 385 mg/dL) in the placebo group during the 26-week double-blind phase. The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin calcium therapy in childhood to reduce morbidity and mortality in adulthood has not been established." ], "package_label_principal_display_panel": [ "PACKAGE LABEL. PRINCIPAL DISPLAY PANEL 33261-0972-30 ATORVASTATIN CALCIUM TABLETS 20 mg Rx only 30 Tablet 33261-0972-90 ATORVASTATIN CALCIUM TABLETS 20 mg Rx only 90 Tablet IMAGE LABEL IMAGE LABEL" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s). A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. 12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ]. 12.3 Pharmacokinetics Absorption: Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ]. Distribution: Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥ 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ]. Metabolism: Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion: Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration. Specific Populations Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ]. Pediatric: Pharmacokinetic data in the pediatric population are not available. Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women. Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5 ), Warnings and Precautions, Skeletal Muscle (5.1) ]. Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ]. Table 3 Table 4" ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years." ], "overdosage": [ "10 OVERDOSAGE There is no specific treatment for atorvastatin calcium overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance." ] }, { "effective_time": "20181218", "recent_major_changes": [ "Contraindication ( 4 ) 02/2014 Warnings and Precautions Myopathy/Rhabdomyolysis ( 5.1 ) 02/2014" ], "drug_interactions": [ "7. DRUG INTERACTIONS Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. Grapefruit juice Avoid grapefruit juice Other Lipid-lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with simvastatin. ( 5.1 , 7.2 , 7.4 ) Coumarin anticoagulants: Concomitant use with simvastatin tablets prolongs INR. Achieve stable INR prior to starting simvastatin tablets. Monitor INR frequently until stable upon initiation or alteration of simvastatin tablets therapy. ( 7.6 ) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) .] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4) ] . If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] . Other fibrates: Caution should be used when prescribing with simvastatin [ see Warnings and Precautions (5.1) ] . 7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) and Table 3 in Clinical Pharmacology (12.3) ]. 7.4 Niacin Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.5 Digoxin In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3) ] . 7.6 Coumarin Anticoagulants In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. 7.7 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine." ], "geriatric_use": [ "8.5 Geriatric Use Of the 2,423 patients who received simvastatin tablets in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin tablets, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin tablets should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3) .] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin tablets significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1) ]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS. Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin tablets should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined." ], "description": [ "11. DESCRIPTION Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus . After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S* ,4 S* ),-8aβ]]. The empirical formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Its structural formula is: Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Simvastatin tablets USP for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin and the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, hypromellose E5, croscarmellose sodium, ferric oxide red, lactose monohydrate, magnesium stearate, maize starch, talc, titanium dioxide, butylated hydroxyanisole , ascorbic acid, citric acid monohydrate, and triethyl citrate. Simvastatin" ], "nonclinical_toxicology": [ "13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear. 13.2 Animal Toxicology and/or Pharmacology CNS Toxicity Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class. There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times)." ], "warnings_and_cautions_table": [ "
Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations
Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin
Verapamil Diltiazem Dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice
" ], "dosage_forms_and_strengths": [ "3. DOSAGE FORMS AND STRENGTHS Simvastatin tablets 5 mg are brick red colored, round shaped, biconvex, film coated tablet debossed “SI” on one side and plain on other side. Simvastatin tablets 10 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed “S 4” on one side and plain on the other side Simvastatin tablets 20 mg are brick red colored,oval shaped, biconvex,film-coated tablets, debossed “S 5” on one side and plain on the other side. Simvastatin tablets 40 mg are brick red colored,oval shaped, biconvex,film-coated tablets,debossed “S 6” on one side and plain on the other side Simvastatin tablets 80 mg are brick red colored, capsule-shaped, biconvex, film-coated tablets, debossed with “SMV” on one side and “80” on the other side Tablets: 5 mg; 10 mg; 20 mg; 40.0#160;mg; 80 mg ( 3 )" ], "clinical_pharmacology_table": [ "
Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio Results based on a chemical assay except results with propranolol as indicated. with / without co-administered drug) No Effect = 1.00
AUC C max C max
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 days 80 mg simvastatin acid Simvastatin acid refers to the β-hydroxyacid of simvastatin. simvastatin 12 8.9 15 5.3
Nelfinavir 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid simvastatin 6 6.2
Itraconazole 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 13.113.1
Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.851.35 2.180.91
Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
Grapefruit Juice The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. (high dose) 200 mL of double-strength TID Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice (low dose) 8 oz (about 237mL) of single-strength Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75
Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7
No dosing adjustments required for the following:
Fenofibrate 160 mg QD X 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-release Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)] . 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C." ], "pharmacokinetics_table": [ "
Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio Results based on a chemical assay except results with propranolol as indicated. with / without co-administered drug) No Effect = 1.00
AUC C max C max
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 days 80 mg simvastatin acid Simvastatin acid refers to the β-hydroxyacid of simvastatin. simvastatin 12 8.9 15 5.3
Nelfinavir 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid simvastatin 6 6.2
Itraconazole 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 13.113.1
Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.851.35 2.180.91
Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
Grapefruit Juice The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. (high dose) 200 mL of double-strength TID Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice (low dose) 8 oz (about 237mL) of single-strength Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75
Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7
No dosing adjustments required for the following:
Fenofibrate 160 mg QD X 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-release Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)] . 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin tablets 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5) ]. Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance). Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio Results based on a chemical assay except results with propranolol as indicated. with / without co-administered drug) No Effect = 1.00 AUC C max C max Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] Telithromycin Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 days 80 mg simvastatin acid Simvastatin acid refers to the β-hydroxyacid of simvastatin. simvastatin 12 8.9 15 5.3 Nelfinavir 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid simvastatin 6 6.2 Itraconazole 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1) ] Grapefruit Juice The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. (high dose) 200 mL of double-strength TID Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice (low dose) 8 oz (about 237mL) of single-strength Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Avoid taking with >10 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Avoid taking with >20 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 No dosing adjustments required for the following: Fenofibrate 160 mg QD X 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)] . 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin(40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL." ], "clinical_studies_table": [ "
Table 4: Summary of Heart Protection Study Results
Endpoint Simvastatin Tablets (N=10,269) n(%) n = number of patients with indicated event Placebo (N=10,267) n (%) Risk Reduction (%) (95% CI) p-Value
Primary
Mortality 1,328 (12.9) 1,507 (14.7) 13 (6 to 19) p=0.0003
CHD mortality 587 (5.7) 707 (6.9) 18 (8 to 26) p=0.0005
Secondary
Non-fatal MI 357 (3.5) 574 (5.6) 38 (30 to 46) p<0.0001
Stroke 444 (4.3) 585 (5.7) 25 (15 to 34) p<0.0001
Tertiary
Coronary revascularization 513 (5) 725 (7.1) 30 (22 to 38) p<0.0001
Peripheral and other non-coronary revascularization 450 (4.4) 532 (5.2) 16 (5 to 26) p=0.006
", "
Table 5: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)
TREATMENT N TOTAL-C LDL-C HDL-C TG median percent change
Lower Dose Comparative Study mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL (Mean % Change at Week 6)
Simvastatin Tablets 5 mg q.p.m. 109 -19 -26 10 -12
Simvastatin Tablets 10 mg q.p.m. 110 -23 -30 12 -15
Scandinavian Simvastatin Survival Study mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL (Mean % Change at Week 6)
Placebo 2223 -1 -1 0 -2
Simvastatin Tablets 20 mg q.p.m. 2221 -28 -38 8 -19
Upper Dose Comparative Study mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL (Mean % Change Averaged at Weeks 18 and 24)
Simvastatin Tablets 40 mg q.p.m. 433 -31 -41 9 -18
Simvastatin Tablets 80 mg q.p.m. 21% and 36% median reduction in TG in patients with TG ≤ 200 mg/dL and TG > 200 mg/dL, respectively. Patients with TG > 350 mg/dL were excluded 664 -36 -47 8 -24
Multi-Center Combined Hyperlipidemia Study mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL. (Mean % Change at Week 6)
Placebo 125 1 2 3 -4
Simvastatin Tablets 40 mg q.p.m. 123 -25 -29 13 -28
Simvastatin Tablets 80 mg q.p.m. 124 -31 -36 16 -33
", "
Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25 th and 75 th percentile) from Baseline The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215
TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C
Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8)
Simvastatin Tablets 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23)
Simvastatin Tablets 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32)
", "
Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C+IDL Non-HDL-C
Placebo 7 -8 (-24, +34) -8(-27, +23) -2(-21, +16) +4(-22, +90) -4(-28, +78) -8 (-26, -39)
Simvastatin Tablets 40 mg/day 7 -50 (-66, -39) -50(-60, -31) +7(-8, +23) -41(-74, -16) -58(-90, -37) -57(-72, -44)
Simvastatin Tablets 80 mg/day 7 -52 (-55, -41) -51(-57, -28) +7(-5, +29) -38(-58, +2) -60 (-72, -39) -59 (-61, -46)
", "
Table 8: Lipid-Lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
Dosage Duration N Total-C LDL-C HDL-C TG median percent change Apo B
Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8.0) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6)
Mean baseline, mg/dL (SD) 278.6(51.8) 211.9(49.0) 46.9(11.9) 90.0(50.7) 186.3(38.1)
Simvastatin Tablets 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33.0) 8.3 (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4 (-35.9, -29.0)
Mean baseline, mg/dL (SD) 270.2(44.0) 203.8(41.5) 47.7(9.0) 78.3(46.0) 179.9(33.8)
" ], "indications_and_usage": [ "1. INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. Simvastatin tablets are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. ( 1.1 ) Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. ( 1.2 ) Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta-lipoproteinemia. ( 1.2 ) Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. ( 1.2 ) Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. ( 1.2 , 1.3 ) Limitations of Use Simvastatin tablets have not been studied in Fredrickson Types I and V dyslipidemias. ( 1.4 ) 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets are indicated to: Reduce the risk of total mortality by reducing CHD deaths. Reduce the risk of non-fatal myocardial infarction and stroke. Reduce the need for coronary and non-coronary revascularization procedures. 1.2 Hyperlipidemia Simvastatin tablets are indicated to: Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb). Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia). Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin tablets are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: LDL cholesterol remains ≥190 mg/dL; or LDL cholesterol remains ≥160 mg/dL and There is a positive family history of premature cardiovascular disease (CVD) or Two or more other CVD risk factors are present in the adolescent patient. The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined. 1.4 Limitations of Use Simvastatin tablets have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V)." ], "set_id": "00ba937b-a895-45db-9694-c95b3f7bbf80", "id": "caa74c64-7ace-4242-b7e3-7509d563474f", "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population . In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5) , Adverse Reactions (6.1) , Clinical Studies (14.2) .] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1) ]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls." ], "contraindications": [ "4. CONTRAINDICATIONS Simvastatin tablets are contraindicated in the following conditions: Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions (5.1) ] . Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1) ] . Hypersensitivity to any component of this medication [see Adverse Reactions (6.2) ] . Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2) ] . Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] . Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with simvastatin tablets should not breastfeed their infants [see Use in Specific Populations (8.3) ] . Concomitant administration of strong CYP3A4 inhibitors. ( 4 , 5.1 ) Concomitant administration of gemfibrozil, cyclosporine, or danazol. ( 4 , 5.1 ) Hypersensitivity to any component of this medication. ( 4 , 6.2 ) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. ( 4 , 5.2 ) Women who are pregnant or may become pregnant. ( 4 , 8.1 ) Nursing mothers. ( 4 , 8.3 )" ], "drug_interactions_table": [ "
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice Avoid grapefruit juice
" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category X [See Contraindications (4) .] Simvastatin tablets are contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. If simvastatin tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology,, 10(6):439-446, 1996. of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. Women of childbearing potential, who require treatment with simvastatin tablets for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin tablets should be considered. If pregnancy occurs, simvastatin tablets should be immediately discontinued." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4) ] ." ], "spl_product_data_elements": [ "simvastatin simvastatin MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2910 (5 MPA.S) CROSCARMELLOSE SODIUM FERRIC OXIDE RED LACTOSE MONOHYDRATE MAGNESIUM STEARATE TALC STARCH, CORN BUTYLATED HYDROXYANISOLE TITANIUM DIOXIDE ASCORBIC ACID CITRIC ACID MONOHYDRATE TRIETHYL CITRATE SIMVASTATIN SIMVASTATIN Brick Red OVAL S4 simvastatin simvastatin MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2910 (5 MPA.S) CROSCARMELLOSE SODIUM FERRIC OXIDE RED LACTOSE MONOHYDRATE MAGNESIUM STEARATE TALC STARCH, CORN BUTYLATED HYDROXYANISOLE TITANIUM DIOXIDE ASCORBIC ACID CITRIC ACID MONOHYDRATE TRIETHYL CITRATE SIMVASTATIN SIMVASTATIN Brick Red OVAL S5 simvastatin simvastatin MICROCRYSTALLINE CELLULOSE HYDROXYPROPYL CELLULOSE (1600000 WAMW) HYPROMELLOSE 2910 (5 MPA.S) CROSCARMELLOSE SODIUM FERRIC OXIDE RED LACTOSE MONOHYDRATE MAGNESIUM STEARATE TALC STARCH, CORN BUTYLATED HYDROXYANISOLE TITANIUM DIOXIDE ASCORBIC ACID CITRIC ACID MONOHYDRATE TRIETHYL CITRATE SIMVASTATIN SIMVASTATIN Brick Red OVAL S6" ], "warnings_and_cautions": [ "5. WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80-mg dose. ( 5.1 ) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4 , 5.1 , 8.5 , 8.6 ) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. ( 5.1 ) Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2 ) 5.1 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years),female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin. 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [See Dosage and Administration, Restricted Dosing for 80 mg (2.2) .] If, however, a patient who is currently tolerating the 80-mg dose of simvastatin needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2) .] There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing simvastatin. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Simvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Simvastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [See Clinical Pharmacology (12.3) .] . Combination of these drugs with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1) .] The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [See Contraindications (4) and Drug Interactions (7.1 and 7.2) .] Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2) .] Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7) .] The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3) ] [also see Dosage and Administration , Patients with Homozygous Familial Hypercholesterolemia (2.4) ] Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid- modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin- containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4) ] . Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3 , 2.4) Drug Interactions (7) , Clinical Pharmacology (12.3) ]. Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, e.g.: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin Verapamil Diltiazem Dronedarone Do not exceed 10 mg simvastatin daily Amiodarone Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. Grapefruit juice Avoid grapefruit juice 5.2 Liver Dysfunction Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies . When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1) ] , the number of patients with more than one transaminase elevation to > 3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to > 3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg. In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose. It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, promptly interrupt therapy. If an alternate etiology is not found do not restart simvastatin. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1) ] . The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin. Moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment. 5.3 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin." ], "adverse_reactions_table": [ "
Table 2: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin Tablets and Greater than Placebo in 4S
Simvastatin Tablets (N = 2,221) % Placebo (N = 2,223) %
Body as a Whole Edema/swelling Abdominal pain 2.7 5.9 2.3 5.8
Cardiovascular System Disorders Atrial fibrillation 5.7 5.1
Digestive System Disorders Constipation Gastritis 2.2 4.9 1.6 3.9
Endocrine Disorders Diabetes mellitus 4.2 3.6
Musculoskeletal Disorders Myalgia 3.7 3.2
Nervous System / Psychiatric Disorders Headache Insomnia Vertigo 2.5 4.0 4.5 2.1 3.8 4.2
Respiratory System Disorders Bronchitis Sinusitis 6.6 2.3 6.3 1.8
Skin / Skin Appendage Disorders Eczema 4.5 3.0
Urogenital System Disorders Infection, urinary tract 3.2 3.1
" ], "openfda": {}, "version": "12", "dosage_and_administration": [ "2. DOSAGE AND ADMINISTRATION Dose range is 5 to 40 mg/day. ( 2.1 ) Recommended usual starting dose is 10 or 20 mg once a day in the evening. ( 2.1 ) Recommended starting dose for patients at high risk of CHD is 40 mg/day. ( 2.1 ) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80-mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. ( 2.2 ) Patients who are currently tolerating the 80-mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. ( 2.2 ) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. ( 2.2 ) Adolescents (10 to 17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. ( 2.5 ) 2.1 Recommended Dosing The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. 2.2 Restricted Dosing for 80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. [see Warnings and Precautions (5.1) ] Patients who are currently tolerating the 80-mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of simvastatin tablets should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 2.3 Coadministration with Other Drugs Patients taking Verapamil, Diltiazem, or Dronedarone The dose of simvastatin tablets should not exceed 10 mg/day [see Warnings and Precautions (5.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ]. . Patients taking Amiodarone, Amlodipine or Ranolazine The dose of simvastatin tablets should not exceed 20 mg/day [see Warnings and Precautions (5.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ]. 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2) ] . Simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the dose of simvastatin tablets should be reduced by 50% if initiating lomitapide. Simvastatin tablets dosage should not exceed 20 mg/day (or 40 mg/day for patients who have previously taken simvastatin tablets 80 mg/day chronically, e.g., for 12 months or more, without evidence of muscle toxicity) while taking lomitapide. 2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 89(3):495-501. 1992. and Clinical Studies (14.2) ]. Adjustments should be made at intervals of 4 weeks or more. 2.6 Patients with Renal Impairment Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 2.7 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products Because of an increased risk for myopathy, in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (greater than or equal to 1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [see Warnings and Precautions (5.1) ]" ], "adverse_reactions": [ "6. ADVERSE REACTIONS Most common adverse reactions (incidence ≥5.0%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%). Scandinavian Simvastatin Survival Study In 4S involving 4,444 (age range 35 to 71 years, 19% women, 100% Caucasians) treated with 20 to 40 mg/day of simvastatin (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2. Table 2: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin Tablets and Greater than Placebo in 4S Simvastatin Tablets (N = 2,221) % Placebo (N = 2,223) % Body as a Whole Edema/swelling Abdominal pain 2.7 5.9 2.3 5.8 Cardiovascular System Disorders Atrial fibrillation 5.7 5.1 Digestive System Disorders Constipation Gastritis 2.2 4.9 1.6 3.9 Endocrine Disorders Diabetes mellitus 4.2 3.6 Musculoskeletal Disorders Myalgia 3.7 3.2 Nervous System / Psychiatric Disorders Headache Insomnia Vertigo 2.5 4.0 4.5 2.1 3.8 4.2 Respiratory System Disorders Bronchitis Sinusitis 6.6 2.3 6.3 1.8 Skin / Skin Appendage Disorders Eczema 4.5 3.0 Urogenital System Disorders Infection, urinary tract 3.2 3.1 Heart Protection Study In the Heart Protection Study (HPS), involving 20,536 patients (age range 40 to 80 years, 25% women, 97% Caucasians, 3% other races) treated with simvastatin tablets 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with simvastatin tablets compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin tablets. Other Clinical Studies In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia. Laboratory Tests Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.2) ]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.1) .] Adolescent Patients (ages 10 to 17 years) In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10 to 17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or simvastatin tablets (10 to 40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2) ] . 6.2 Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [See Warnings and Precautions (5.1) ] An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks)." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology CNS Toxicity Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class. There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times)." ], "use_in_specific_populations": [ "8. USE IN SPECIFIC POPULATIONS Severe renal impairment: patients should be started at 5 mg/day and be closely monitored. ( 2.6 , 8.6 ) 8.1 Pregnancy Pregnancy Category X [See Contraindications (4) .] Simvastatin tablets are contraindicated in women who are or may become pregnant. Lipid lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. If simvastatin tablets are used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology,, 10(6):439-446, 1996. of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. Women of childbearing potential, who require treatment with simvastatin tablets for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin tablets should be considered. If pregnancy occurs, simvastatin tablets should be immediately discontinued. 8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4) ] . 8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population . In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5) , Adverse Reactions (6.1) , Clinical Studies (14.2) .] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1) ]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls. 8.5 Geriatric Use Of the 2,423 patients who received simvastatin tablets in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin tablets, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin tablets should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3) .] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin tablets significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1) ]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS. Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin tablets should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment Caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment. [See Dosage and Administration (2.6) .] 8.7 Hepatic Impairment Simvastatin tablets are contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and Precautions (5.2) ] ." ], "how_supplied": [ "16. HOW SUPPLIED/STORAGE AND HANDLING Product: 70786-0004 Product: 70786-0005 Product: 70786-0006" ], "information_for_patients": [ "17. PATIENT COUNSELING INFORMATION Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ]. Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin tablets. 17.1 Muscle Pain All patients starting therapy with simvastatin tablets should be advised of the risk of myopathy , including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing simvastatin tablets. Patients using the 80-mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80-mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of simvastatin tablets are increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver function tests be performed before the initiation of simvastatin tablets, and thereafter when clinically indicated. All patients treated with simvastatin tablets should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using simvastatin tablets. Discuss future pregnancy plans with your patients, and discuss when to stop taking simvastatin tablets if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking simvastatin tablets and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should not use simvastatin tablets. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. Manufactured For: Accord Healthcare, Inc., 1009, Slater Road, Suite 210-B, Durham, NC 27703, USA Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad -380 009, India. 10 9351 1 659550 Issued February 2015" ], "clinical_studies": [ "14. CLINICAL STUDIES 14.1 Clinical Studies in Adults Reductions in Risk of CHD Mortality and Cardiovascular Events In 4S, the effect of therapy with simvastatin tablets on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin tablets 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin tablets led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin tablets significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin tablets group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin tablets significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin tablets significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin tablets significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin tablets reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin tablets on mortality in women could not be adequately assessed. However, simvastatin tablets significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin tablets on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin tablets resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years) , compared with younger patients. The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin tablets 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL. The HPS results showed that simvastatin tablets 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4). Table 4: Summary of Heart Protection Study Results Endpoint Simvastatin Tablets (N=10,269) n(%) n = number of patients with indicated event Placebo (N=10,267) n (%) Risk Reduction (%) (95% CI) p-Value Primary Mortality 1,328 (12.9) 1,507 (14.7) 13 (6 to 19) p=0.0003 CHD mortality 587 (5.7) 707 (6.9) 18 (8 to 26) p=0.0005 Secondary Non-fatal MI 357 (3.5) 574 (5.6) 38 (30 to 46) p<0.0001 Stroke 444 (4.3) 585 (5.7) 25 (15 to 34) p<0.0001 Tertiary Coronary revascularization 513 (5) 725 (7.1) 30 (22 to 38) p<0.0001 Peripheral and other non-coronary revascularization 450 (4.4) 532 (5.2) 16 (5 to 26) p=0.006 Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin tablets had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin tablets had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Treatment with simvastatin tablets produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin tablets in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to simvastatin tablets treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD. Angiographic Studies In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin tablets significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions. Modifications of Lipid Profiles Primary Hyperlipidemia (Fredrickson type lla and llb) Simvastatin tablets have been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin tablets significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin tablets also decreased TG and increased HDL-C ( see Table 5 ). Table 5: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks) TREATMENT N TOTAL-C LDL-C HDL-C TG median percent change Lower Dose Comparative Study mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL (Mean % Change at Week 6) Simvastatin Tablets 5 mg q.p.m. 109 -19 -26 10 -12 Simvastatin Tablets 10 mg q.p.m. 110 -23 -30 12 -15 Scandinavian Simvastatin Survival Study mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL (Mean % Change at Week 6) Placebo 2223 -1 -1 0 -2 Simvastatin Tablets 20 mg q.p.m. 2221 -28 -38 8 -19 Upper Dose Comparative Study mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL (Mean % Change Averaged at Weeks 18 and 24) Simvastatin Tablets 40 mg q.p.m. 433 -31 -41 9 -18 Simvastatin Tablets 80 mg q.p.m. 21% and 36% median reduction in TG in patients with TG ≤ 200 mg/dL and TG > 200 mg/dL, respectively. Patients with TG > 350 mg/dL were excluded 664 -36 -47 8 -24 Multi-Center Combined Hyperlipidemia Study mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL. (Mean % Change at Week 6) Placebo 125 1 2 3 -4 Simvastatin Tablets 40 mg q.p.m. 123 -25 -29 13 -28 Simvastatin Tablets 80 mg q.p.m. 124 -31 -36 16 -33 Hypertriglyceridemia (Frederickson type IV) The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6. Table 6: Six-week, Lipid-lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25 th and 75 th percentile) from Baseline The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215 TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8) Simvastatin Tablets 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23) Simvastatin Tablets 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32) Dysbetalipoproteinemia (Fredrickson type lll) The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7. Table 7: Six-week, Lipid-lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291. TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C+IDL Non-HDL-C Placebo 7 -8 (-24, +34) -8 (-27, +23) -2 (-21, +16) +4 (-22, +90) -4 (-28, +78) -8 (-26, -39) Simvastatin Tablets 40 mg/day 7 -50 (-66, -39) -50 (-60, -31) +7 (-8, +23) -41 (-74, -16) -58 (-90, -37) -57 (-72, -44) Simvastatin Tablets 80 mg/day 7 -52 (-55, -41) -51 (-57, -28) +7 (-5, +29) -38 (-58, +2) -60 (-72, -39) -59 (-61, -46) Homozygous Familial Hypercholesterolemia In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40- and 80-mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80-mg dose. Endocrine Function In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20 to 40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown. Simvastatin 14.2 Clinical Studies in Adolescents In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo. Simvastatin tablets significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study. Table 8: Lipid-Lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline) Dosage Duration N Total-C LDL-C HDL-C TG median percent change Apo B Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8.0) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6) Mean baseline, mg/dL (SD) 278.6 (51.8) 211.9 (49.0) 46.9 (11.9) 90.0 (50.7) 186.3 (38.1) Simvastatin Tablets 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33.0) 8.3 (4.6, 11.9) -7.9 (-15.8, 0.0) -32.4 (-35.9, -29.0) Mean baseline, mg/dL (SD) 270.2 (44.0) 203.8 (41.5) 47.7 (9.0) 78.3 (46.0) 179.9 (33.8) After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64.0 to 289.0 mg/dL) in the simvastatin tablets 40 mg group compared to 207.8 mg/dL (range: 128.0 to 334.0 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established." ], "package_label_principal_display_panel": [ "SIMVASTATIN 10MG TAB 30EA Label Image", "SIMVASTATIN 20MG TAB 90EA Label Image", "SIMVASTATIN 40MG TAB 30EA Label Image" ], "clinical_pharmacology": [ "12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C. 12.2 Pharmacodynamics Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. 12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin tablets 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5) ]. Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance). Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of medicinal products that are inhibitors of the transport protein OATP1B1 may lead to increased plasma concentrations of simvastatin acid and an increased risk of myopathy. For example, cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . Table 3: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio Results based on a chemical assay except results with propranolol as indicated. with / without co-administered drug) No Effect = 1.00 AUC C max C max Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] Telithromycin Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. 200 mg QD for 4 days 80 mg simvastatin acid Simvastatin acid refers to the β-hydroxyacid of simvastatin. simvastatin 12 8.9 15 5.3 Nelfinavir 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid simvastatin 6 6.2 Itraconazole 200 mg QD for 4 days 80 mg simvastatin acid simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1) ] Grapefruit Juice The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. (high dose) 200 mL of double-strength TID Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice (low dose) 8 oz (about 237mL) of single-strength Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Avoid taking with >10 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.10 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid simvastatin 1.96 3.90 2.14 3.75 Avoid taking with >20 mg simvastatin , based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid simvastatin 1.7 2 1.6 2 Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid simvastatin 1.4 1.6 1.4 1.7 No dosing adjustments required for the following: Fenofibrate 160 mg QD X 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)] . 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7.0 to 4.7 ng·eq/mL In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin(40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear." ], "overdosage": [ "10. OVERDOSAGE Significant lethality was observed in mice after a single oral dose of 9 g/m 2 . No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m 2 , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools. A few cases of overdosage with simvastatin tablets have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present." ] }, { "effective_time": "20170731", "drug_interactions": [ "7. DRUG INTERACTIONS For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or erythromycin, the risk of myopathy increases [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with pravastatin sodium. ( 7 ) Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg once daily. ( 2.5 , 7.1 ) Clarithromycin: combination increases exposure. Limit pravastatin to 40 mg once daily. ( 2.6 , 7.2 ) 7.1 Cyclosporine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see Dosage and Administration ( 2.5 ) , Warnings and Precautions ( 5.1 ) , and Clinical Pharmacology ( 12.3 ) ]. 7.2 Clarithromycin The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin [see Dosage and Administration ( 2.6 ) , Warnings and Precautions ( 5.1 ) , and Clinical Pharmacology ( 12.3 ) ]. 7.3 Colchicine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine [see Warnings and Precautions ( 5.1 ) ]. 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided [see Warnings and Precautions ( 5.1 ) ]. 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions ( 5.1 ) ]. 7.6 Niacin The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting [see Warnings and Precautions ( 5.1 ) ]." ], "geriatric_use": [ "8.5 Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3 ) ]. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]." ], "references": [ "15. REFERENCES Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins - An integrated approach to mechanisms and disorders. N Engl J Med . 1967;276: 34-44, 94-103, 148-156, 215-225, 273-281. Manson JM, Freyssinges C, Ducrocq MB, Stephenson WP. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol . 1996;10(6):439-446. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group (WOS). Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med . 1995;333:1301-1307. The Long-term Intervention with Pravastatin in Ischemic Disease Group (LIPID). Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med . 1998;339:1349-1357. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators (CARE). The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med . 1996;335:1001-1009. Pitt B, Mancini GBJ, Ellis SG, et al, for the PLAC I Investigators. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol . 1995;26:1133-1139. Jukema JW, Bruschke AVG, van Boven AJ, et al, for the Regression Growth Evaluation Statin Study Group (REGRESS). Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic man with normal to moderately elevated serum cholesterol levels. Circ . 1995;91:2528-2540. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries: Design features of a clinical trial with carotid atherosclerosis outcome (PLAC II). Control Clin Trials . 1992;13:495-506. Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circ . 1995;92:1758-1764." ], "description": [ "11. DESCRIPTION Pravastatin sodium is one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula: Pravastatin sodium, USP is white to yellowish white powder or crystalline powder, hygroscopic in nature. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7. It is freely soluble in water and in methanol. Soluble in ethanol. Each pravastatin sodium tablet, USP intended for oral administration contains 10 mg or 20 mg or 40 mg or 80 mg of pravastatin sodium. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyoxyl 35 castor oil and sodium carbonate anhydrous. Pravastatin Sodium Tablets, USP" ], "nonclinical_toxicology": [ "13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 2 year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p < 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 ) and at approximately 4 times the HD, based on AUC. In a 2 year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p < 0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2 year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae . In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. 13.2 Animal Toxicology And/Or Pharmacology CNS Toxicity CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52 day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8 to 12 year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls." ], "dosage_forms_and_strengths": [ "3. DOSAGE FORMS AND STRENGTHS Pravastatin sodium tablets, USP are supplied as: 10 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC46' on one side and plain on the other side. 20 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC45' on one side and plain on the other side. 40 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC44' on one side and plain on the other side. 80 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC43' on one side and plain on the other side. Tablets: 10 mg, 20 mg, 40 mg and 80 mg. ( 3 )" ], "clinical_pharmacology_table": [ "
Table 3 Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin
BID = twice daily; OD = once daily; QID = four times daily
Coadministered Drug and Dosing Regimen Pravastatin
Dose (mg) Change in AUC Change in C max
Cyclosporine 5 mg/kg single dose 40 mg single dose ↑ 282% ↑ 327%
Clarithromycin 500 mg BID for 9 days 40 mg OD for 8days ↑ 110% ↑ 128%
Boceprevir 800 mg TID for 6 days 40 mg single dose ↑ 63% ↑ 49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑ 81% ↑ 63%
Colestipol 10 g single dose 20 mg single dose ↓ 47% ↓ 53%
Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓ 40% ↑ 12% ↓ 12% ↓ 39% ↑ 30% ↓ 6.8%
Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓ 51% ↓ 38% ↓ 18% ↑ 4.9% ↑ 23% ↓ 33%
Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓ 34% ↓ 16% ↓ 33% ↓ 16%
Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑ 31% ↑ 42%
Cimetidine 300 mg QID for 3 days 20 mg single dose ↑ 30% ↑ 9.8%
Antacids 15 mL QID for 3 days 20 mg single dose ↓ 28% ↓ 24%
Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑ 23% ↑ 26%
Probucol 500 mg single dose 20 mg single dose ↑ 14% ↑ 24%
Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓ 13% ↑ 6.7%
Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑ 11% (compared to Day 1) ↑ 17% (compared to Day 1)
Gemfibrozil 600 mg single dose 20 mg single dose ↓ 7% ↓ 20%
Aspirin 324 mg single dose 20 mg single dose ↑ 4.7% ↑ 8.9%
Nicotinic Acid 1 g single dose 20 mg single dose ↓ 3.6% ↓ 8.2%
Diltiazem 20 mg single dose ↑ 2.7% ↑ 30%
Grapefruit juice 40 mg single dose ↓ 1.8% ↑ 3.7%
", "
Table 4 Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs
Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max
BID = twice daily; OD = once daily
20 mg BID for 6 days Warfarin 5 mg OD for 6 days Chain in mean prothrombin time ↑ 17% ↑ 0.4 sec ↑ 15%
20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑ 4.6% ↑ 5.3%
20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑ 3% ↑ 1.6% ↑ Less than 1% Not Reported
20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C." ], "pharmacokinetics_table": [ "
Table 3 Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin
BID = twice daily; OD = once daily; QID = four times daily
Coadministered Drug and Dosing Regimen Pravastatin
Dose (mg) Change in AUC Change in C max
Cyclosporine 5 mg/kg single dose 40 mg single dose ↑ 282% ↑ 327%
Clarithromycin 500 mg BID for 9 days 40 mg OD for 8days ↑ 110% ↑ 128%
Boceprevir 800 mg TID for 6 days 40 mg single dose ↑ 63% ↑ 49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑ 81% ↑ 63%
Colestipol 10 g single dose 20 mg single dose ↓ 47% ↓ 53%
Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓ 40% ↑ 12% ↓ 12% ↓ 39% ↑ 30% ↓ 6.8%
Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓ 51% ↓ 38% ↓ 18% ↑ 4.9% ↑ 23% ↓ 33%
Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓ 34% ↓ 16% ↓ 33% ↓ 16%
Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑ 31% ↑ 42%
Cimetidine 300 mg QID for 3 days 20 mg single dose ↑ 30% ↑ 9.8%
Antacids 15 mL QID for 3 days 20 mg single dose ↓ 28% ↓ 24%
Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑ 23% ↑ 26%
Probucol 500 mg single dose 20 mg single dose ↑ 14% ↑ 24%
Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓ 13% ↑ 6.7%
Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑ 11% (compared to Day 1) ↑ 17% (compared to Day 1)
Gemfibrozil 600 mg single dose 20 mg single dose ↓ 7% ↓ 20%
Aspirin 324 mg single dose 20 mg single dose ↑ 4.7% ↑ 8.9%
Nicotinic Acid 1 g single dose 20 mg single dose ↓ 3.6% ↓ 8.2%
Diltiazem 20 mg single dose ↑ 2.7% ↑ 30%
Grapefruit juice 40 mg single dose ↓ 1.8% ↑ 3.7%
", "
Table 4 Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs
Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max
BID = twice daily; OD = once daily
20 mg BID for 6 days Warfarin 5 mg OD for 6 days Chain in mean prothrombin time ↑ 17% ↑ 0.4 sec ↑ 15%
20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑ 4.6% ↑ 5.3%
20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑ 3% ↑ 1.6% ↑ Less than 1% Not Reported
20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics General Absorption Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects. [See Warnings and Precautions ( 5.2 ) .] Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C max , T max , and t ½ values were similar in older and younger subjects. [See Use in Specific Populations ( 8.5 ) .] Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8 to 11 years, N=14) and adolescents (12 to 16 years, N=10), respectively. The corresponding values for C max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability. [See Use in Specific Populations ( 8.4 ) .] Drug-Drug Interactions Table 3 Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin BID = twice daily; OD = once daily; QID = four times daily Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑ 282% ↑ 327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8days ↑ 110% ↑ 128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑ 63% ↑ 49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑ 81% ↑ 63% Colestipol 10 g single dose 20 mg single dose ↓ 47% ↓ 53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓ 40% ↑ 12% ↓ 12% ↓ 39% ↑ 30% ↓ 6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓ 51% ↓ 38% ↓ 18% ↑ 4.9% ↑ 23% ↓ 33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓ 34% ↓ 16% ↓ 33% ↓ 16% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑ 31% ↑ 42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑ 30% ↑ 9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓ 28% ↓ 24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑ 23% ↑ 26% Probucol 500 mg single dose 20 mg single dose ↑ 14% ↑ 24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓ 13% ↑ 6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑ 11% (compared to Day 1) ↑ 17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓ 7% ↓ 20% Aspirin 324 mg single dose 20 mg single dose ↑ 4.7% ↑ 8.9% Nicotinic Acid 1 g single dose 20 mg single dose ↓ 3.6% ↓ 8.2% Diltiazem 20 mg single dose ↑ 2.7% ↑ 30% Grapefruit juice 40 mg single dose ↓ 1.8% ↑ 3.7% Table 4 Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max BID = twice daily; OD = once daily 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Chain in mean prothrombin time ↑ 17% ↑ 0.4 sec ↑ 15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑ 4.6% ↑ 5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑ 3% ↑ 1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change" ], "clinical_studies_table": [ "
Table 5 LIPID - Primary and Secondary Endpoints
Number (%) of Subjects
Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p-value
Primary Endpoint
CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004
Secondary Endpoints
Total mortality 498 (11.0) 633 (14.1) 23% <0.0001
CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001
Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001
Stroke
All-cause 169 (3.7) 204 (4.5) 19% 0.0477
Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154
Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001
", "
Table 6 CARE - Primary and Secondary Endpoints
Number (%) of Subjects
Event Pravastatin 40 mg (N=2081) Placebo (N=2078) Risk Reduction p-value
Primary Endpoint
CHD mortality or nonfatal MI The risk reduction due to treatment with pravastatin was consistent in both sexes. 212 (10.2) 274 (13.2) 24% 0.003
Secondary Endpoints
Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001
Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029
", "
Table 7 Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Sodium Once Daily Administration
Dose Total-C LDL-C HDL-C TG
Mean Percent Changes From Baseline After 8 Weeks A multicenter, doubleblind, placebo-controlled study.
Placebo (N=36) −3% −4% +1% −4%
10 mg (N=18) −16% −22% +7% −15%
20 mg (N=19) −24% −32% +2% −11%
40 mg (N=18) −25% −34% +12% −24%
Mean Percent Changes From Baseline After 6 Weeks Pooled analysis of 2 multicenter, doubleblind, placebo-controlled studies.
Placebo (N=162) 0% −1% −1% +1%
80 mg (N=277) −27% −37% +3% −19%
", "
Table 8 Patients with Fredrickson Type IV Hyperlipidemia Median (25 th, 75 thpercentile) % Change from Baseline
Pravastatin 40 mg (N=429) Placebo (N=430)
TG −21.1 (−34.8, 1.3) −6.3 (−23.1, 18.3)
Total-C −22.1 (−27.1, −14.8) 0.2 (−6.9, 6.8)
LDL-C −31.7 (−39.6, −21.5) 0.7 (−9, 10)
HDL-C 7.4 (−1.2, 17.7) 2.8 (−5.7, 11.7)
Non-HDL-C −27.2 (−34, −18.5) −0.8 (−8.2, 7)
", "
Table 9 Patients with Fredrickson Type III Dysbetalipoproteinemia Median (min, max) % Change from Baseline
Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20)
Study 1
Total-C 386.5 (245, 672) −32.7 (−58.5, 4.6)
TG 443 (275, 1299) −23.7 (−68.5, 44.7)
VLDL-C a 206.5 (110, 379) −43.8 (−73.1, −14.3)
LDL-C 117.5 (80, 170) −40.8 (−63.7, 4.6)
HDL-C 30 (18, 88) 6.4 (−45, 105.6)
Non-HDL-C 344.5 (215, 646) −36.7 (−66.3, 5.8)
a N=14
Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26)
Study 2
Total-C 340.3 (230.1, 448.6) −31.4 (−54.5, −13)
TG 343.2 (212.6, 845.9) −11.9 (−56.5, 44.8)
VLDL-C 145 (71.5, 309.4) −35.7 (−74.7, 19.1)
LDL-C 128.6 (63.8, 177.9) −30.3 (−52.2, 13.5)
HDL-C 38.7 (27.1, 58) 5 (−17.7, 66.7)
Non-HDL-C 295.8 (195.3, 421.5) −35.5 (−81, −13.5)
", "
Table 10 Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a
Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo
a The above least-squares mean values were calculated based on log-transformed lipid values.
b Significant at p ≤ 0.0001 when compared with placebo.
LDL-C −26.04 b −21.07 b −24.07 b −1.52 (−26.74, −18.86)
TC −20.75 b −13.08 b −17.72 b −0.65 (−20.40, −13.83)
HDL-C 1.04 13.71 5.97 3.13 (−1.71, 7.43)
TG −9.58 −0.30 −5.88 −3.27 (−13.95, 10.01)
ApoB (N) −23.16 b (61) −18.08 b (39) −21.11 b (100) −0.97 (106) (−24.29, −16.18)
" ], "indications_and_usage": [ "1. INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Pravastatin sodium tablet, USP is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of MI, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident CHD. ( 1.1 ) Reduce the risk of total mortality by reducing coronary death, MI, revascularization, stroke/TIA, and the progression of coronary atherosclerosis in patients with clinically evident CHD. ( 1.1 ) Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. ( 1.2 ) Reduce elevated serum TG levels in patients with hypertriglyceridemia. ( 1.2 ) Treat patients with primary dysbetalipoproteinemia who are not responding to diet. ( 1.2 ) Treat children and adolescent patients ages 8 years and older with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. ( 1.2 ) Limitations of use: Pravastatin sodium tablets, USP have not been studied in Fredrickson Types I and V dyslipidemias. ( 1.3 ) 1.1 Prevention of Cardiovascular Disease In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets, USP are indicated to: reduce the risk of myocardial infarction (MI). reduce the risk of undergoing myocardial revascularization procedures. reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes. In patients with clinically evident CHD, pravastatin sodium tablet is indicated to: reduce the risk of total mortality by reducing coronary death. reduce the risk of MI. reduce the risk of undergoing myocardial revascularization procedures. reduce the risk of stroke and stroke/transient ischemic attack (TIA). slow the progression of coronary atherosclerosis. 1.2 Hyperlipidemia Pravastatin sodium tablet is indicated: as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia ( Fredrickson Types IIa and IIb). 1 as an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV). for the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet. as an adjunct to diet and lifestyle modification for treatment of heterozygous familial hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present: LDL-C remains ≥ 190 mg/dL or LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors are present in the patient. 1.3 Limitations of Use Pravastatin sodium has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V)." ], "set_id": "00bf4e02-633e-453b-8c3c-fb8b1d829887", "id": "559efa5b-917e-2b52-e054-00144ff88e88", "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of pravastatin sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. [See Adverse Reactions ( 6.4 ) .] Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy [see Contraindications ( 4.3 ) and Use in Specific Populations ( 8.1 ) ]. For dosing information [see Dosage and Administration ( 2.3 ) .] Doubleblind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted." ], "contraindications": [ "4. CONTRAINDICATIONS Hypersensitivity to any component of this medication. ( 4.1 , 6.2 , 11 ) Active liver disease or unexplained, persistent elevations of serum transaminases. ( 4.2 , 5.2 ) Women who are pregnant or may become pregnant. ( 4.3 , 8.1 ) Nursing mothers. ( 4.4 , 8.3 ) 4.1 Hypersensitivity Hypersensitivity to any component of this medication. 4.2 Liver Active liver disease or unexplained, persistent elevations of serum transaminases [see Warnings and Precautions ( 5.2 ) ]. 4.3 Pregnancy Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 ) ]. 4.4 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk. Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breastfeed their infants [see Use in Specific Populations ( 8.3 ) ]." ], "pregnancy": [ "4.3 Pregnancy Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 ) ].", "8.1 Pregnancy Pregnancy Category X [See Contraindications ( 4.3 ) .] Safety in pregnant women has not been established. Available data in women inadvertently taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether pravastatin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus and patients have been informed of the potential hazards. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with pravastatin sodium during pregnancy [see Contraindications ( 4.3 ) ], treatment should be immediately discontinued as soon as pregnancy is recognized. Pravastatin sodium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning) increased mortality of offspring and developmental delays were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 )." ], "nursing_mothers": [ "4.4 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk. Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breastfeed their infants [see Use in Specific Populations ( 8.3 ) ].", "8.3 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk. Because of the potential for serious adverse reactions in nursing infants, women taking pravastatin sodium should not nurse [see Contraindications ( 4.4 ) ]. Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breastmilk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD." ], "spl_product_data_elements": [ "pravastatin sodium pravastatin sodium CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POLYOXYL 35 CASTOR OIL SODIUM CARBONATE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE PRAVASTATIN SODIUM PRAVASTATIN WHITE TO OFF-WHITE OVAL ZC46 pravastatin sodium pravastatin sodium CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POLYOXYL 35 CASTOR OIL SODIUM CARBONATE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE PRAVASTATIN SODIUM PRAVASTATIN WHITE TO OFF-WHITE OVAL ZC45 pravastatin sodium pravastatin sodium CROSCARMELLOSE SODIUM MAGNESIUM STEARATE POLYOXYL 35 CASTOR OIL SODIUM CARBONATE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE PRAVASTATIN SODIUM PRAVASTATIN WHITE TO OFF-WHITE OVAL ZC44 pravastatin sodium pravastatin sodium MAGNESIUM STEARATE POLYOXYL 35 CASTOR OIL SODIUM CARBONATE CELLULOSE, MICROCRYSTALLINE ANHYDROUS LACTOSE CROSCARMELLOSE SODIUM PRAVASTATIN SODIUM PRAVASTATIN WHITE TO OFF-WHITE OVAL ZC43" ], "warnings_and_cautions": [ "5. WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. Patients should be advised to promptly report to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness. Pravastatin therapy should be discontinued if myopathy is diagnosed or suspected. ( 5.1 , 8.5 ) Liver enzyme abnormalities: persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2 ) 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse Reactions (6) ]. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), was rare (< 0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Predisposing factors include advanced age (≥ 65), uncontrolled hypothyroidism, and renal impairment. There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum CPK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents. All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing pravastatin. Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to 40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The benefit of further alterations in lipid levels by the combined use of pravastatin sodium with fibrates should be carefully weighed against the potential risks of this combination. Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine [see Drug Interactions (7.3) ]. 5.2 Liver Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In 3 long-term (4.8 to 5.9 years), placebo-controlled clinical trials (WOS, LIPID, CARE), 19,592 subjects (19,768 randomized) were exposed to pravastatin or placebo [see Clinical Studies ( 14 ) ]. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3 times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or 4 times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency (≤ 1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic (> 6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥ 2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation. It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin [see Contraindications ( 4.2 ) ]. Caution should be exercised when pravastatin is administered to patients who have a recent (< 6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart pravastatin sodium. 5.3 Endocrine Function Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p < 0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥ 50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones. In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8 to 13 years and 40 mg in the adolescents aged 14 to 18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo." ], "adverse_reactions_table": [ "
Table 1 Adverse Events in ≥ 2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients)
Body System/Event 5 mg N=100 10 mg N=153 20 mg N=478 40 mg N=171 Any Dose N=902 Placebo N=411
Cardiovascular Angina Pectoris 5 4.6 4.8 3.5 4.5 3.4
Dermatologic Rash 3 2.6 6.7 1.2 4.5 1.4
Gastrointestinal Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension 4 8 2 0 2 5.9 8.5 3.3 3.3 3.3 10.5 6.5 4.6 3.6 2.1 2.3 4.7 0 0.6 0.6 7.4 6.7 3.2 2.5 2 7.1 5.6 4.4 2.7 2.4
General Fatigue Chest Pain Influenza 4 4 4 1.3 1.3 2.6 5.2 3.3 1.9 0 1.2 0.6 3.4 2.7 2 3.9 1.9 0.7
Musculoskeletal Musculoskeletal Pain Myalgia 13 1 3.9 2.6 13.2 2.9 5.3 1.2 10.1 2.3 10.2 1.2
Nervous System Headache Dizziness 5 4 6.5 1.3 7.5 5.2 3.5 0.6 6.3 3.5 4.6 3.4
Respiratory Pharyngitis Upper Respiratory Infection Rhinitis Cough 2 6 7 4 4.6 9.8 5.2 1.3 1.5 5.2 3.8 3.1 1.2 4.1 1.2 1.2 2 5.9 3.9 2.5 2.7 5.8 4.9 1.7
Investigation ALT Increased g-GT Increased CPK Increased 2 3 5 2 2.6 1.3 4 2.1 5.2 1.2 0.6 2.9 2.9 2 4.1 1.2 1.2 3.6
", "
Table 2 Adverse Events in ≥ 2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials
Body System/Event Pravastatin (N=10,764) % of patients Placebo (N=10,719) % of patients
Dermatologic Rash (including dermatitis) 7.2 7.1
General Edema 3 2.7
Fatigue 8.4 7.8
Chest Pain 10 9.8
Fever 2.1 1.9
Weight Gain 3.8 3.3
Weight Loss 3.3 2.8
Musculoskeletal
Musculoskeletal Pain 24.9 24.4
Muscle Cramp 5.1 4.6
Musculoskeletal Traumatism 10.2 9.6
Nervous System
Dizziness 7.3 6.6
Sleep Disturbance 3 2.4
Anxiety/Nervousness 4.8 4.7
Paresthesia 3.2 3
Renal/Genitourinary Urinary Tract Infection 2.7 2.6
Respiratory
Upper Respiratory Tract Infection 21.2 20.2
Cough 8.2 7.4
Influenza 9.2 9
Pulmonary Infection 3.8 3.5
Sinus Abnormality Tracheobronchitis 7 3.4 6.7 3.1
Special Senses Vision Disturbance (includes blurred vision, diplopia) 3.4 3.3
Infections Viral Infection 3.2 2.9
" ], "openfda": {}, "version": "8", "dosage_and_administration": [ "2. DOSAGE AND ADMINISTRATION Adults: the recommended starting dose is 40 mg once daily. Use 80 mg dose only for patients not reaching LDL-C goal with 40 mg. ( 2.2 ) Significant renal impairment: the recommended starting dose is 10 mg once daily. ( 2.2 ) Children (ages 8 to 13 years, inclusive): the recommended starting dose is 20 mg once daily. ( 2.3 ) Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg once daily. ( 2.3 ) 2.1 General Dosing Information The patient should be placed on a standard cholesterol-lowering diet before receiving pravastatin sodium tablets and should continue on this diet during treatment with pravastatin sodium tablets [see NCEP Treatment Guidelines for details on dietary therapy]. 2.2 Adult Patients The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal impairment, a starting dose of 10 mg daily is recommended. Pravastatin sodium tablets can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient's response to therapy and established treatment guidelines. 2.3 Pediatric Patients Children (Ages 8 to 13 Years, Inclusive) The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population. Adolescents (Ages 14 to 18 Years) The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population. Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C [see Indications and Usage ( 1.2 ) ]. 2.4 Concomitant Lipid-Altering Therapy Pravastatin sodium tablets may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, pravastatin sodium tablets should be given either 1 hour or more before or at least 4 hours following the resin. [See Clinical Pharmacology ( 12.3 ) .] 2.5 Dosage in Patients Taking Cyclosporine In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 ) ]. 2.6 Dosage in Patients Taking Clarithromycin In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions ( 7.2 ) ]." ], "adverse_reactions": [ "6. ADVERSE REACTIONS Pravastatin is generally well tolerated; adverse reactions have usually been mild and transient. In 4 month-long placebo-controlled trials, 1.7% of pravastatin-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant. In short-term clinical trials, the most commonly reported adverse reactions (≥ 2% and > placebo) regardless of causality were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Clinical Events Short-Term Controlled Trials In the pravastatin sodium placebo-controlled clinical trials database of 1313 patients (age range 20 to 76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness. All adverse clinical events (regardless of causality) reported in ≥ 2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1 Adverse Events in ≥ 2% of Patients Treated with Pravastatin 5 to 40 mg and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials (% of patients) Body System/Event 5 mg N=100 10 mg N=153 20 mg N=478 40 mg N=171 Any Dose N=902 Placebo N=411 Cardiovascular Angina Pectoris 5 4.6 4.8 3.5 4.5 3.4 Dermatologic Rash 3 2.6 6.7 1.2 4.5 1.4 Gastrointestinal Nausea/Vomiting Diarrhea Flatulence Dyspepsia/Heartburn Abdominal Distension 4 8 2 0 2 5.9 8.5 3.3 3.3 3.3 10.5 6.5 4.6 3.6 2.1 2.3 4.7 0 0.6 0.6 7.4 6.7 3.2 2.5 2 7.1 5.6 4.4 2.7 2.4 General Fatigue Chest Pain Influenza 4 4 4 1.3 1.3 2.6 5.2 3.3 1.9 0 1.2 0.6 3.4 2.7 2 3.9 1.9 0.7 Musculoskeletal Musculoskeletal Pain Myalgia 13 1 3.9 2.6 13.2 2.9 5.3 1.2 10.1 2.3 10.2 1.2 Nervous System Headache Dizziness 5 4 6.5 1.3 7.5 5.2 3.5 0.6 6.3 3.5 4.6 3.4 Respiratory Pharyngitis Upper Respiratory Infection Rhinitis Cough 2 6 7 4 4.6 9.8 5.2 1.3 1.5 5.2 3.8 3.1 1.2 4.1 1.2 1.2 2 5.9 3.9 2.5 2.7 5.8 4.9 1.7 Investigation ALT Increased g-GT Increased CPK Increased 2 3 5 2 2.6 1.3 4 2.1 5.2 1.2 0.6 2.9 2.9 2 4.1 1.2 1.2 3.6 The safety and tolerability of pravastatin sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK > 10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. Long-Term Controlled Morbidity and Mortality Trials In the pravastatin sodium placebo-controlled clinical trials database of 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on pravastatin sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality. Adverse event data were pooled from 7 doubleblind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥ 2% of patients treated with pravastatin in these studies are identified in Table 2. Table 2 Adverse Events in ≥ 2% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials Body System/Event Pravastatin (N=10,764) % of patients Placebo (N=10,719) % of patients Dermatologic Rash (including dermatitis) 7.2 7.1 General Edema 3 2.7 Fatigue 8.4 7.8 Chest Pain 10 9.8 Fever 2.1 1.9 Weight Gain 3.8 3.3 Weight Loss 3.3 2.8 Musculoskeletal Musculoskeletal Pain 24.9 24.4 Muscle Cramp 5.1 4.6 Musculoskeletal Traumatism 10.2 9.6 Nervous System Dizziness 7.3 6.6 Sleep Disturbance 3 2.4 Anxiety/Nervousness 4.8 4.7 Paresthesia 3.2 3 Renal/Genitourinary Urinary Tract Infection 2.7 2.6 Respiratory Upper Respiratory Tract Infection 21.2 20.2 Cough 8.2 7.4 Influenza 9.2 9 Pulmonary Infection 3.8 3.5 Sinus Abnormality Tracheobronchitis 7 3.4 6.7 3.1 Special Senses Vision Disturbance (includes blurred vision, diplopia) 3.4 3.3 Infections Viral Infection 3.2 2.9 In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in < 2 % of pravastatin-treated patients in the long-term trials included the following: Dermatologic scalp hair abnormality (including alopecia), urticaria. Endocrine/Metabolic sexual dysfunction, libido change. General flushing. Immunologic allergy, edema head/neck. Musculoskeletal muscle weakness. Nervous System vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy). Special Senses taste disturbance. 6.2 Postmarketing Experience In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with pravastatin sodium, regardless of causality assessment: There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1) ]. Musculoskeletal myopathy, rhabdomyolysis. Nervous System dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome). Gastrointestinal abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure. Dermatologic a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails). Renal urinary abnormality (including dysuria, frequency, nocturia). Respiratory dyspnea. Reproductive gynecomastia. Laboratory Abnormalities liver function test abnormalities, thyroid function abnormalities. 6.3 Laboratory Test Abnormalities Increases in ALT, AST values and CPK have been observed [see Warnings and Precautions ( 5.1 , 5.2 ) ]. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins. 6.4 Pediatric Patients In a 2 year, doubleblind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8 to 18.5 years, 53% female, 95% Caucasians, < 1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo. [See Warnings and Precautions ( 5.3 ) , Use in Specific Populations ( 8.4 ) , and Clinical Pharmacology ( 12.3 ) .]" ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology And/Or Pharmacology CNS Toxicity CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52 day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately 1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8 to 12 year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls." ], "spl_unclassified_section": [ "PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Zydus Pharmaceuticals (USA) Inc. as follows: (10 mg / 100 UD) NDC 68084-500-01 packaged from NDC 68382-070 (20 mg / 100 UD) NDC 68084-501-01 packaged from NDC 68382-071 (40 mg / 100 UD) NDC 68084-502-01 packaged from NDC 68382-072 (80 mg / 30 UD) NDC 68084-746-25 packaged from NDC 68382-073 Packaged and Distributed by: American Health Packaging Columbus, OH 43217 8250001/0415" ], "use_in_specific_populations": [ "8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [See Contraindications ( 4.3 ) .] Safety in pregnant women has not been established. Available data in women inadvertently taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether pravastatin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus and patients have been informed of the potential hazards. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥ 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with pravastatin sodium during pregnancy [see Contraindications ( 4.3 ) ], treatment should be immediately discontinued as soon as pregnancy is recognized. Pravastatin sodium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning) increased mortality of offspring and developmental delays were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). 8.3 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk. Because of the potential for serious adverse reactions in nursing infants, women taking pravastatin sodium should not nurse [see Contraindications ( 4.4 ) ]. Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breastmilk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD. 8.4 Pediatric Use The safety and effectiveness of pravastatin sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. [See Adverse Reactions ( 6.4 ) .] Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy [see Contraindications ( 4.3 ) and Use in Specific Populations ( 8.1 ) ]. For dosing information [see Dosage and Administration ( 2.3 ) .] Doubleblind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted. 8.5 Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3 ) ]. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. 8.6 Homozygous Familial Hypercholesterolemia Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that statins are less effective because the patients lack functional LDL receptors." ], "how_supplied": [ "16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Pravastatin Sodium Tablets USP, 10 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC46' on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-500-01 Pravastatin Sodium Tablets USP, 20 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC45' on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-501-01 Pravastatin Sodium Tablets USP, 40 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC44' on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-502-01 Pravastatin Sodium Tablets USP, 80 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of 'ZC43' on one side and plain on the other side and are supplied as follows: Unit dose packages of 30 (5 x 6) NDC 68084-746-25 16.2 Storage Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature]. Protect from light and moisture" ], "information_for_patients": [ "17. PATIENT COUNSELING INFORMATION Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing pravastatin [see Warnings and Precautions ( 5.1 ) ]. It is recommended that liver enzyme tests be performed before the initiation of pravastatin sodium, and thereafter when clinically indicated. All patients treated with pravastatin sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions ( 5.2 ) ]. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." ], "clinical_studies": [ "14. CLINICAL STUDIES 14.1 Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), 3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L). In this randomized, doubleblind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively. Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin sodium group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients. Pravastatin sodium also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-cardiovascular causes. Pravastatin Sodium Tablets, USP 14.2 Secondary Prevention of Cardiovascular Events In the LIPID4 study, the effect of pravastatin, 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had experienced either an MI `(5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age. Pravastatin significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 5 LIPID - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p -value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE5 study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25th , 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with pravastatin significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 6). Table 6 CARE - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=2081) Placebo (N=2078) Risk Reduction p -value Primary Endpoint CHD mortality or nonfatal MI The risk reduction due to treatment with pravastatin was consistent in both sexes. 212 (10.2) 274 (13.2) 24% 0.003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001 Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029 In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range: 130-190 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment group (p=0.02). In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by coronary angiography in 885 patients with angina pectoris, angiographically documented coronary artery disease, and hypercholesterolemia (baseline total cholesterol range: 160-310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001). Analysis of pooled events from PLAC I, PLAC II,8 REGRESS, and KAPS9 studies (combined N=1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of nonfatal MI. 14.3 Primary Hypercholesterolemia (Fredrickson Types IIa and IIb) Pravastatin sodium is highly effective in reducing Total-C, LDL-C, and TG in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy. In addition, pravastatin sodium is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous MI. A single daily dose is as effective as the same total daily dose given twice a day. In multicenter, doubleblind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 7). In a pooled analysis of 2 multicenter, doubleblind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25 th and 75 th percentile changes from baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 7). Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin sodium across all doses produced variable increases in HDL-C (see Table 7). Table 7 Primary Hypercholesterolemia Studies: Dose Response of Pravastatin Sodium Once Daily Administration Dose Total-C LDL-C HDL-C TG Mean Percent Changes From Baseline After 8 Weeks A multicenter, doubleblind, placebo-controlled study. Placebo (N=36) −3% −4% +1% −4% 10 mg (N=18) −16% −22% +7% −15% 20 mg (N=19) −24% −32% +2% −11% 40 mg (N=18) −25% −34% +12% −24% Mean Percent Changes From Baseline After 6 Weeks Pooled analysis of 2 multicenter, doubleblind, placebo-controlled studies. Placebo (N=162) 0% −1% −1% +1% 80 mg (N=277) −27% −37% +3% −19% In another clinical trial, patients treated with pravastatin in combination with cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance). 14.4 Hypertriglyceridemia (Fredrickson Type IV) The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG > 200 mg/dL and LDL-C < 160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200.5, 349.5) mg/dL (see Table 8.) Table 8 Patients with Fredrickson Type IV Hyperlipidemia Median (25 th , 75 th percentile) % Change from Baseline Pravastatin 40 mg (N=429) Placebo (N=430) TG −21.1 (−34.8, 1.3) −6.3 (−23.1, 18.3) Total-C −22.1 (−27.1, −14.8) 0.2 (−6.9, 6.8) LDL-C −31.7 (−39.6, −21.5) 0.7 (−9, 10) HDL-C 7.4 (−1.2, 17.7) 2.8 (−5.7, 11.7) Non-HDL-C −27.2 (−34, −18.5) −0.8 (−8.2, 7) 14.5 Dysbetalipoproteinemia (Fredrickson Type III) The response to pravastatin in two doubleblind crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 9. Table 9 Patients with Fredrickson Type III Dysbetalipoproteinemia Median (min, max) % Change from Baseline Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20) Study 1 Total-C 386.5 (245, 672) −32.7 (−58.5, 4.6) TG 443 (275, 1299) −23.7 (−68.5, 44.7) VLDL-C a 206.5 (110, 379) −43.8 (−73.1, −14.3) LDL-C 117.5 (80, 170) −40.8 (−63.7, 4.6) HDL-C 30 (18, 88) 6.4 (−45, 105.6) Non-HDL-C 344.5 (215, 646) −36.7 (−66.3, 5.8) a N=14 Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26) Study 2 Total-C 340.3 (230.1, 448.6) −31.4 (−54.5, −13) TG 343.2 (212.6, 845.9) −11.9 (−56.5, 44.8) VLDL-C 145 (71.5, 309.4) −35.7 (−74.7, 19.1) LDL-C 128.6 (63.8, 177.9) −30.3 (−52.2, 13.5) HDL-C 38.7 (27.1, 58) 5 (−17.7, 66.7) Non-HDL-C 295.8 (195.3, 421.5) −35.5 (−81, −13.5) 14.6 Pediatric Clinical Study A doubleblind, placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The children (aged 8 to 13 years) were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the adolescents (aged 14 to 18 years) were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level > 95 th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively. Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was similar. Table 10 Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo a The above least-squares mean values were calculated based on log-transformed lipid values. b Significant at p ≤ 0.0001 when compared with placebo. LDL-C −26.04 b −21.07 b −24.07 b −1.52 (−26.74, −18.86) TC −20.75 b −13.08 b −17.72 b −0.65 (−20.40, −13.83) HDL-C 1.04 13.71 5.97 3.13 (−1.71, 7.43) TG −9.58 −0.30 −5.88 −3.27 (−13.95, 10.01) ApoB (N) −23.16 b (61) −18.08 b (39) −21.11 b (100) −0.97 (106) (−24.29, −16.18) The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin group compared to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group. The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established." ], "package_label_principal_display_panel": [ "Package/Label Display Panel – Carton – 10 mg NDC 68084-500-01 PRAVASTATIN SODIUM Tablets, USP 10 mg 100 Tablets (10 x 10) Each Tablet Contains: Pravastatin sodium, USP.............................. 10 mg Usual Dosage: See package insert for full prescribing information. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Keep this and all drugs out of reach of children. Rx Only The drug product contained in this package is from NDC # 68382-070, Zydus Pharmaceuticals USA Inc. Packaged and Distributed by: American Health Packaging Columbus, Ohio 43217 050001 Rev. 01/2015 10 mg Pravastatin Carton", "Package/Label Display Panel – Blister – 10 mg PRAVASTATIN SODIUM Tablet, USP 10 mg 10 mg Pravastatin Blister", "Package/Label Display Panel – Carton -20 mg NDC 68084-501-01 PRAVASTATIN SODIUM Tablets, USP 20 mg 100 Tablets (10 x 10) Each Tablet Contains: Pravastatin sodium, USP.............................. 20 mg Usual Dosage: See package insert for full prescribing information. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Keep this and all drugs out of reach of children. Rx Only The drug product contained in this package is from NDC # 68382-071, Zydus Pharmaceuticals USA Inc. Packaged and Distributed by: American Health Packaging Columbus, Ohio 43217 050101 Rev. 01/2015 20 mg Pravastatin Carton", "Package/Label Display Panel – Blister – 20 mg PRAVASTATIN SODIUM Tablet, USP 20 mg 20 mg Pravastatin Blister", "Package/Label Display Panel – Carton – 40 mg NDC 68084-502-01 PRAVASTATIN SODIUM Tablets, USP 40 mg 100 Tablets (10 x 10) Each tablet contains: Pravastatin sodium, USP................................40 mg Usual Dosage: See package insert for complete prescribing information. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture and light. Keep this and all drugs out of reach of children. Rx only The drug product contained in this package is from NDC # 68382-072, Zydus Pharmaceuticals (USA) Inc. Packaged and Distributed by: American Health Packaging Columbus, Ohio 43217 050201 Rev. 06/2013 40 mg Pravastatin Carton", "Package/Label Display Panel – Blister – 40 mg PRAVASTATIN SODIUM Tablet, USP 40 mg 40 mg Pravastatin Blister", "Package/Label Display Panel – Carton – 80 mg NDC 68084-746-25 PRAVASTATIN SODIUM Tablets, USP 80 mg 30 Tablets (5 x 6) Each tablet contains: Pravastatin sodium, USP........................80 mg Usual Dosage: See package insert for complete prescribing information. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Keep this and all drugs out of reach of children. Rx Only The drug product contained in this package is from NDC # 68382-073, Zydus Pharmaceuticals (USA) Inc. Packaged and Distributed by: American Health Packaging Columbus, Ohio 43217 074625 Rev. 03/2014 80 mg Pravastatin Carton", "Package/Label Display Panel – Blister – 80 mg PRAVASTATIN SODIUM Tablet, USP 80 mg 80 mg Pravastatin Blister" ], "clinical_pharmacology": [ "12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C. 12.3 Pharmacokinetics General Absorption Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945). Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects. [See Warnings and Precautions ( 5.2 ) .] Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C max , T max , and t ½ values were similar in older and younger subjects. [See Use in Specific Populations ( 8.5 ) .] Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8 to 11 years, N=14) and adolescents (12 to 16 years, N=10), respectively. The corresponding values for C max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability. [See Use in Specific Populations ( 8.4 ) .] Drug-Drug Interactions Table 3 Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin BID = twice daily; OD = once daily; QID = four times daily Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑ 282% ↑ 327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8days ↑ 110% ↑ 128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑ 63% ↑ 49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑ 81% ↑ 63% Colestipol 10 g single dose 20 mg single dose ↓ 47% ↓ 53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓ 40% ↑ 12% ↓ 12% ↓ 39% ↑ 30% ↓ 6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓ 51% ↓ 38% ↓ 18% ↑ 4.9% ↑ 23% ↓ 33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓ 34% ↓ 16% ↓ 33% ↓ 16% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑ 31% ↑ 42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑ 30% ↑ 9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓ 28% ↓ 24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑ 23% ↑ 26% Probucol 500 mg single dose 20 mg single dose ↑ 14% ↑ 24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓ 13% ↑ 6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑ 11% (compared to Day 1) ↑ 17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓ 7% ↓ 20% Aspirin 324 mg single dose 20 mg single dose ↑ 4.7% ↑ 8.9% Nicotinic Acid 1 g single dose 20 mg single dose ↓ 3.6% ↓ 8.2% Diltiazem 20 mg single dose ↑ 2.7% ↑ 30% Grapefruit juice 40 mg single dose ↓ 1.8% ↑ 3.7% Table 4 Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max BID = twice daily; OD = once daily 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Chain in mean prothrombin time ↑ 17% ↑ 0.4 sec ↑ 15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑ 4.6% ↑ 5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑ 3% ↑ 1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change" ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 2 year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p < 0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 ) and at approximately 4 times the HD, based on AUC. In a 2 year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p < 0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2 year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae . In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance." ], "overdosage": [ "10. OVERDOSAGE To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required." ] }, { "spl_product_data_elements": [ "PRAVASTATIN SODIUM PRAVASTATIN SODIUM PRAVASTATIN SODIUM PRAVASTATIN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE FERRIC OXIDE YELLOW off-white to light yellow APO;PRA;80 figure1.jpg pravastatin-structure" ], "recent_major_changes": [ "Contraindications, Pregnancy and Lactation Removed ( 4 ) 05/2022 Warnings and Precautions, Immune-Mediated Necrotizing Myopathy Updated ( 5.2 ) 05/2022" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Pravastatin sodium tablets are indicated: To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia. Pravastatin sodium tablets are an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take orally once daily at any time of the day, with or without food ( 2.1 ). For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablet 80 mg daily, prescribe alternative LDL-C lowering treatment ( 2.1 ). Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pravastatin sodium tablets, and adjust the dosage if necessary ( 2.1 ). Adults: recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. ( 2.2 ) Pediatric Patients ( 2.3 ): aged 8 to 13 years, the recommended dosage is 20 mg once daily. aged 14 to 18 years, the recommended starting dosage is 40 mg once daily. Severe renal impairment: recommended starting dosage is pravastatin sodium 10 mg once daily. Use another pravastatin sodium product to initiate dosing. Recommended maximum pravastatin sodium tablets dosage is 40 mg once daily. ( 2.4 ) See full prescribing information for dosage modifications due to drug interactions ( 2.5 , 7 ). 2.1 Important Dosage and Administration Information Take orally pravastatin sodium tablets once daily as a single dose at any time of the day, with or without food. For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving pravastatin sodium tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating pravastatin sodium tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage is pravastatin sodium tablets 40 mg to 80 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 8 Years of Age and Older with HeFH In pediatric patients aged 8 to 13 years, the recommended dosage is pravastatin sodium tablets 20 mg once daily. In pediatric patients aged 14 to 18 years, the recommended starting dosage is pravastatin sodium tablets 40 mg once daily. 2.4 Recommended Dosage in Patients with Renal Impairment In patients with severe renal impairment, the recommended starting dosage is pravastatin sodium 10 mg once daily. The maximum recommended dosage of pravastatin sodium tablets in patients with severe renal impairment is 40 mg once daily [see Clinical Pharmacology ( 12.3 )]. The recommended dosage of pravastatin sodium tablets for patients with mild or moderate renal impairment is the same as patients with normal renal function. 2.5 Dosage and Administration Modifications Due to Drug Interactions In patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or 4 hours after the bile acid sequestrant [See Drug Interactions ( 7.2 )]. Concomitant use of pravastatin sodium tablets with the following drugs requires dosage modifications of pravastatin sodium tablet s [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 )]: Cyclosporine In patients taking cyclosporine, the recommended starting dosage is pravastatin sodium 10 mg once daily. The maximum recommended dosage of pravastatin sodium tablet in patients taking cyclosporine is 20 mg once daily. Clarithromycin and Erythromycin The maximum recommended dosage is pravastatin sodium tablets 40 mg once daily ." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Pravastatin Sodium Tablets, USP are supplied as: 10 mg tablets: Light pink, round, unscored tablets, imprinted “APO” on one side and “PRA” over “10” on the other side. 20 mg tablets: Off-white to light yellow, round, unscored tablets, imprinted “APO” on one side and “PRA” over “20” on the other side. 40 mg tablets: Light green, round, unscored tablets, imprinted “APO” on one side and “PRA” over “40” on the other side. 80 mg tablets: Off-white to light yellow, round, unscored tablets, imprinted “APO” on one side and “PRA” over “80” on the other side. Tablets: 10 mg, 20 mg, 40 mg, 80 mg. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Acute liver failure or decompensated cirrhosis [see Warnings and Precautions ( 5.3 )]. Hypersensitivity to any pravastatin or any excipients in pravastatin sodium tablets. Hypersensitivity to pravastatin or any excipient in pravastatin sodium tablets ( 4 ) Acute liver failure or decompensated cirrhosis ( 4 , 5.3 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis : Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher pravastatin sodium tablets dosage. Discontinue pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing pravastatin sodium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 , 7.1 , 8.5 , 8.6 ) Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue pravastatin sodium tablets if IMNM is suspected ( 5.2 ). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including pravastatin sodium tablets. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) to greater than 10 times the upper limit of normal (ULN), occurred <0.1% in pravastatin sodium tablets-treated patients in clinical trials. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher pravastatin sodium tablets dosage [see Drug Interactions ( 7.1 )] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Pravastatin sodium tablets are not recommended in patients taking gemfibrozil [see Drug Interactions ( 7 )]. There are pravastatin sodium tablets dosage restrictions for patients taking cyclosporin and select macrolide antibiotics [see Dosage and Administration ( 2.5 )] . The following drugs when used concomitantly with pravastatin sodium tablets may also increase the risk of myopathy and rhabdomyolysis: niacin, fibrates, and colchicine [see Drug Interactions ( 7 )]. Discontinue pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if pravastatin sodium tablets is discontinued. Temporarily discontinue pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the pravastatin sodium tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue pravastatin sodium tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of pravastatin sodium tablets [see Adverse Reactions ( 6.1 ) ] . In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1% of patients receiving either pravastatin sodium tablets or placebo in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with pravastatin sodium tablets. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin sodium tablets. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before pravastatin sodium tablets initiation and when clinically indicated thereafter. Pravastatin sodium tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )] . If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue pravastatin sodium tablets. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pravastatin sodium tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.1 )] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions ( 5.2 )] Hepatic Dysfunction [see Warnings and Precautions ( 5.3 )] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)] In short-term clinical trials, the most commonly reported adverse reactions (≥2% and greater than placebo) were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In pravastatin sodium tablets placebo-controlled clinical trials, 1313 patients (age range 20 to 76 years, 32% women, 93.5% White, 5% Black, 0.9% Hispanic, 0.4% Asian, 0.2% Other) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium tablets and 1.2% patients on placebo discontinued due to adverse reactions (regardless of causality). The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: hepatic transaminase elevations, nausea, anxiety/depression, and dizziness. Adverse reactions (regardless of causality) reported in ≥2% of pravastatin sodium tablets-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1: Adverse Reactions in ≥ 2% of Patients Treated with Pravastatin (Any Dose) and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials % Placebo N=411 % Any Dose N=902 Nausea/Vomiting 7.1 7.4 Diarrhea 5.6 6.7 Headache 4.6 6.3 Upper Respiratory Infection 5.8 5.9 Angina Pectoris 3.4 4.5 Rash 1.4 4.5 CPK Increased 3.6 4.1 Dizziness 3.4 3.5 ALT Increased 1.2 2.9 Chest Pain 1.9 2.7 Cough 1.7 2.5 Myalgia 1.2 2.3 Influenza 0.7 2.0 g-GT Increased 1.2 2.0 Adverse Reactions (regardless of causality) The safety and tolerability of pravastatin sodium tablets at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin sodium tablets at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. In pravastatin sodium tablets placebo-controlled clinical trials, 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% White, 0.8% Black, 0.5% Hispanic, 0.1% Asian, 0.1% Other, 46.1% not recorded) had a median treatment duration of 261 weeks. Adverse reactions (regardless of causality) were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID] ; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. Adverse reactions (regardless of causality) occurring in ≥5% of patients treated with pravastatin sodium tablets in these studies are identified in Table 2: Table 2: Adverse Events in ≥ 5% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater Than Placebo in Long-Term Placebo-Controlled Trials Placebo (N=10,719) % of patients Pravastatin Sodium Tablets (N=10,764) % of patients Musculoskeletal Pain 24.4 24.9 Upper Respiratory Tract Infection 20.2 21.2 Musculoskeletal Traumatism 9.6 10.2 Chest Pain 9.8 10.0 Influenza 9.0 9.2 Fatigue 7.8 8.4 Cough 7.4 8.2 Dizziness 6.6 7.3 Rash (including dermatitis) 7.1 7.2 Sinus Abnormality 6.7 7.0 Muscle Cramp 4.6 5.1 Adverse Reactions (regardless of causality) No new adverse reactions were identified in a study of pediatric patients with HeFH. Laboratory Abnormalities Increases in ALT, AST values and CK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pravastatin sodium tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis, immune-mediated necrotizing myopathy associated with statin use. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. Rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome). Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure. Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails), lichen planus. Renal: urinary abnormality (including dysuria, frequency, nocturia). Respiratory: dyspnea, interstitial lung disease. Psychiatric: nightmare. Reproductive: gynecomastia. Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities." ], "adverse_reactions_table": [ "
% Placebo N=411% Any DoseN=902
Nausea/Vomiting 7.1 7.4
Diarrhea 5.6 6.7
Headache 4.6 6.3
Upper Respiratory Infection 5.8 5.9
Angina Pectoris 3.4 4.5
Rash 1.4 4.5
CPK Increased 3.6 4.1
Dizziness 3.4 3.5
ALT Increased 1.2 2.9
Chest Pain 1.9 2.7
Cough 1.7 2.5
Myalgia 1.2 2.3
Influenza 0.7 2.0
g-GT Increased 1.2 2.0
", "
Placebo (N=10,719)% of patientsPravastatin Sodium Tablets (N=10,764)% of patients
Musculoskeletal Pain 24.4 24.9
Upper Respiratory Tract Infection 20.2 21.2
Musculoskeletal Traumatism 9.6 10.2
Chest Pain 9.8 10.0
Influenza 9.0 9.2
Fatigue 7.8 8.4
Cough 7.4 8.2
Dizziness 6.6 7.3
Rash (including dermatitis) 7.1 7.2
Sinus Abnormality 6.7 7.0
Muscle Cramp 4.6 5.1
" ], "drug_interactions": [ "7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of pravastatin sodium tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 2.5 , 7.1 ) Bile Acid Sequestrants: in patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant ( 7.2 ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Sodium Tablets Pravastatin sodium is a substrate of the transport protein OATP1B1. Pravastatin sodium plasma levels can be significantly increased with concomitant administration of inhibitors of OATP1B1. Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with pravastatin sodium tablets and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 ) ] . Table 3: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin Sodium Tablets Gemfibrozil Clinical Impact: There is an increased risk of myopathy/rhabdomyolysis when pravastatin sodium tablets are administered with gemfibrozil Intervention: Avoid concomitant use of gemfibrozil with pravastatin sodium tablets Cyclosporine Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with pravastatin sodium tablets. Intervention: Initiate with a dosage of pravastatin sodium 10 mg once daily. Do not exceed pravastatin sodium tablets 20 mg once daily [see Dosage and Administration ( 2.5 )]. Select Macrolide Antibiotics Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with pravastatin sodium tablets. Other macrolides (e.g., azithromycin) have the potential to increase pravastatin sodium tablets exposures and increase the risk of myopathy and rhabdomyolysis when used concomintantly. Intervention: For patients taking erythromycin or clarithromycin, do not exceed 40 mg pravastatin sodium tablets once daily [see Dosage and Administration ( 2.5 )]. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with pravastatin sodium tablets. Intervention: Consider if the benefit of using niacin concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with pravastatin sodium tablets. Intervention: Consider if the benefit of using fibrates concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with pravastatin sodium tablets. Intervention: Consider if the benefit of using colchicine concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. 7.2 Drug Interactions that Decrease the Efficacy of pravastatin sodium tablets Table 4 presents drug interactions that may decrease the efficacy of pravastatin sodium tablets and instructions for preventing or managing them. Table 4: Drug Interactions that Decrease the Efficacy of Pravastatin Sodium Tablets Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [see Clinical Pharmacology ( 12.3 )] . Intervention: In patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant [see Dosage and Administration ( 2.5 )]." ], "drug_interactions_table": [ "
Gemfibrozil
Clinical Impact: There is an increased risk of myopathy/rhabdomyolysis when pravastatin sodium tablets are administered with gemfibrozil
Intervention: Avoid concomitant use of gemfibrozil with pravastatin sodium tablets
Cyclosporine
Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with pravastatin sodium tablets.
Intervention: Initiate with a dosage of pravastatin sodium 10 mg once daily. Do not exceed pravastatin sodium tablets 20 mg once daily [see Dosage and Administration (2.5)].
SelectMacrolideAntibiotics
Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with pravastatin sodium tablets. Other macrolides (e.g., azithromycin) have the potential to increase pravastatin sodium tablets exposures and increase the risk of myopathy and rhabdomyolysis when used concomintantly.
Intervention: For patients taking erythromycin or clarithromycin, do not exceed 40 mg pravastatin sodium tablets once daily [see Dosage and Administration (2.5)].
Niacin
Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with pravastatin sodium tablets.
Intervention: Consider if the benefit of using niacin concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with pravastatin sodium tablets.
Intervention: Consider if the benefit of using fibrates concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with pravastatin sodium tablets.
Intervention: Consider if the benefit of using colchicine concomitantly with pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.
", "
Bile Acid Sequestrants
Clinical Impact: Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [see Clinical Pharmacology (12.3)].
Intervention: In patients taking a bile acid sequestrant, administer pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant [see Dosage and Administration (2.5)].
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm ( 8.1 ) Lactation: Breastfeeding not recommended during treatment with pravastatin sodium tablets ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue pravastatin sodium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pravastatin sodium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pravastatin sodium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with pravastatin sodium tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m 2 ). An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1,000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1,000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1,000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including pravastatin sodium tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pravastatin sodium tablets [see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.1 )] . 8.4 Pediatric Use The safety and effectiveness of pravastatin sodium tablets as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of pravastatin sodium tablets for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population. The safety and effectiveness of pravastatin sodium tablets have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use In clinical studies, 4,797 (36.4%) pravastatin sodium tablets-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Mean pravastatin AUCs are 25% to 50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3 )]. Advanced age (≥65 years) is a risk factor for pravastatin sodium tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving pravastatin sodium tablets for the increased risk of myopathy [see Warnings and Precautions ( 5.1 )]. 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment, the recommended starting dose is pravastatin sodium 10 mg once daily. The maximum recommended dosage in patients with severe renal impairment is pravastatin sodium tablets 40 mg once daily. The recommended dosage for patients with mild or moderate renal impairment is the same as patients with normal renal function. [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.3 )]. 8.7 Hepatic Impairment Pravastatin sodium tablets shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [Clinical Pharmacology ( 12.3 )]. Pravastatin sodium tablets are contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 ) , Warnings and Precautions ( 5.3 )]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Discontinue pravastatin sodium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pravastatin sodium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, pravastatin sodium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology ( 12.1 )]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with pravastatin sodium tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data) . In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m 2 ). An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1,000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1,000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1,000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 )." ], "nursing_mothers": [ "8.2 Lactation Risk Summary Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including pravastatin sodium tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with pravastatin sodium tablets [see Use in Specific Populations ( 8.1 ), Clinical Pharmacology ( 12.1 )] ." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of pravastatin sodium tablets as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of pravastatin sodium tablets for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population. The safety and effectiveness of pravastatin sodium tablets have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH)." ], "geriatric_use": [ "8.5 Geriatric Use In clinical studies, 4,797 (36.4%) pravastatin sodium tablets-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Mean pravastatin AUCs are 25% to 50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max ), time to maximum plasma concentration (T max ), and half-life (t ½ ) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3 )]. Advanced age (≥65 years) is a risk factor for pravastatin sodium tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving pravastatin sodium tablets for the increased risk of myopathy [see Warnings and Precautions ( 5.1 )]." ], "overdosage": [ "10 OVERDOSAGE No specific antidotes for pravastatin sodium tablets are known. Contact Poison Control (1-800-222-1222) for latest recommendations." ], "description": [ "11 DESCRIPTION Pravastatin sodium is a statin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Pravastatin sodium is designated chemically as Sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[[(2S)-methylbutanoyl]oxy]-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]heptanoate. Structural Formula: Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/ water) of 0.59 at a pH of 7.0. It is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether. Pravastatin sodium tablets for oral use contains 10 mg, 20 mg, 40 mg and 80mg pravastatin sodium. Inactive ingredients include: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The 10 mg tablet also contains Red Ferric Oxide, the 20 mg tablet also contains Yellow Ferric Oxide, the 40 mg tablet also contains a blend of Yellow Ferric Oxide and FD&C Blue #1 Aluminum Lake, and the 80 mg tablet also contains Yellow Ferric Oxide." ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. 12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of pravastatin is usually achieved by 4 weeks and is maintained after that. 12.3 Pharmacokinetics Absorption Pravastatin sodium is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-­epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans and the elimination half-life (t ½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations ( 8.6 )]. Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C max , T max , and t ½ values were similar in older and younger subjects [see Use in Specific Populations (8.5) ]. Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for C max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [see Use in Specific Populations (8.4) ]. Drug-Drug Interactions Table 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ↓47% ↓53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓51% ↓38% ↓18% ↑4.9% ↑23% ↓33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑­33% ↑­26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓28% ↓24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓7.0% ↓20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ↓3.6% ↓8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 40 mg single dose ↓1.8% ↑3.7% BID = twice daily; OD = once daily; QID = four times daily Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17%↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0%↑1.6%↑Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change BID = twice daily; OD = once daily" ], "clinical_pharmacology_table": [ "
Coadministered Drug and Dosing RegimenPravastatin
Dose (mg)Change in AUCChange in Cmax
Cyclosporine 5 mg/kg single dose40 mg single dose↑282%↑327%
Clarithromycin 500 mg BID for 9 days40 mg OD for 8 days↑110%↑128%
Boceprevir 800 mg TID for 6 days40 mg single dose↑63%↑49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days40 mg single dose↑81%↑63%
Colestipol 10 g single dose20 mg single dose↓47%↓53%
Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8%
Cholestyramine 24 g OD for 4 weeks20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks↓51% ↓38% ↓18%↑4.9% ↑23% ↓33%
Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16%
Kaletra 400 mg/100 mg BID for 14 days20 mg OD for 4 days↑­33%↑­26%
Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days40 mg single dose↑31% ↑42%
Cimetidine 300 mg QID for 3 days20 mg single dose↑30%↑9.8%
Antacids 15 mL QID for 3 days20 mg single dose↓28%↓24%
Digoxin 0.2 mg OD for 9 days20 mg OD for 9 days↑23%↑26%
Probucol 500 mg single dose20 mg single dose↑14%↑24%
Warfarin 5 mg OD for 6 days20 mg BID for 6 days↓13%↑6.7%
Itraconazole 200 mg OD for 30 days40 mg OD for 30 days↑11% (compared to Day 1)↑17% (compared to Day 1)
Gemfibrozil 600 mg single dose20 mg single dose↓7.0%↓20%
Aspirin 324 mg single dose20 mg single dose↑4.7%↑8.9%
Niacin 1 g single dose20 mg single dose↓3.6%↓8.2%
Diltiazem20 mg single dose↑2.7%↑30%
Grapefruit juice40 mg single dose↓1.8%↑3.7%
", "
Pravastatin Dosing RegimenName and DoseChange in AUCChange in Cmax
20 mg BID for 6 daysWarfarin 5 mg OD for 6 days Change in mean prothrombin time↑17%↑0.4 sec↑15%
20 mg OD for 9 daysDigoxin 0.2 mg OD for 9 days↑4.6%↑5.3%
20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeksAntipyrine 1.2 g single dose↑3.0%↑1.6%↑Less than 1%Not Reported
20 mg OD for 4 daysKaletra 400 mg/100 mg BID for 14 daysNo changeNo change
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Pravastatin sodium is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin C max and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, C max , and C min plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-­epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14 C-pravastatin, the radioactive elimination t ½ for pravastatin is 1.8 hours in humans and the elimination half-life (t ½ ) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and C max values, respectively, and a 0.61 hour shorter t ½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations ( 8.6 )] . Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations ( 8.6 )]. Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, C max , T max , and t ½ values were similar in older and younger subjects [see Use in Specific Populations (8.5) ]. Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for C max were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [see Use in Specific Populations (8.4) ]. Drug-Drug Interactions Table 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ↓47% ↓53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓51% ↓38% ↓18% ↑4.9% ↑23% ↓33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑­33% ↑­26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓28% ↓24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓7.0% ↓20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ↓3.6% ↓8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 40 mg single dose ↓1.8% ↑3.7% BID = twice daily; OD = once daily; QID = four times daily Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17%↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0%↑1.6%↑Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change BID = twice daily; OD = once daily" ], "pharmacokinetics_table": [ "
Coadministered Drug and Dosing RegimenPravastatin
Dose (mg)Change in AUCChange in Cmax
Cyclosporine 5 mg/kg single dose40 mg single dose↑282%↑327%
Clarithromycin 500 mg BID for 9 days40 mg OD for 8 days↑110%↑128%
Boceprevir 800 mg TID for 6 days40 mg single dose↑63%↑49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days40 mg single dose↑81%↑63%
Colestipol 10 g single dose20 mg single dose↓47%↓53%
Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8%
Cholestyramine 24 g OD for 4 weeks20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks↓51% ↓38% ↓18%↑4.9% ↑23% ↓33%
Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16%
Kaletra 400 mg/100 mg BID for 14 days20 mg OD for 4 days↑­33%↑­26%
Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days40 mg single dose↑31% ↑42%
Cimetidine 300 mg QID for 3 days20 mg single dose↑30%↑9.8%
Antacids 15 mL QID for 3 days20 mg single dose↓28%↓24%
Digoxin 0.2 mg OD for 9 days20 mg OD for 9 days↑23%↑26%
Probucol 500 mg single dose20 mg single dose↑14%↑24%
Warfarin 5 mg OD for 6 days20 mg BID for 6 days↓13%↑6.7%
Itraconazole 200 mg OD for 30 days40 mg OD for 30 days↑11% (compared to Day 1)↑17% (compared to Day 1)
Gemfibrozil 600 mg single dose20 mg single dose↓7.0%↓20%
Aspirin 324 mg single dose20 mg single dose↑4.7%↑8.9%
Niacin 1 g single dose20 mg single dose↓3.6%↓8.2%
Diltiazem20 mg single dose↑2.7%↑30%
Grapefruit juice40 mg single dose↓1.8%↑3.7%
", "
Pravastatin Dosing RegimenName and DoseChange in AUCChange in Cmax
20 mg BID for 6 daysWarfarin 5 mg OD for 6 days Change in mean prothrombin time↑17%↑0.4 sec↑15%
20 mg OD for 9 daysDigoxin 0.2 mg OD for 9 days↑4.6%↑5.3%
20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeksAntipyrine 1.2 g single dose↑3.0%↑1.6%↑Less than 1%Not Reported
20 mg OD for 4 daysKaletra 400 mg/100 mg BID for 14 daysNo changeNo change
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 ) and at approximately 4 times the HD, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae . In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m 2 ) and at approximately 4 times the HD, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro , with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae . In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child." ], "clinical_studies": [ "14 CLINICAL STUDIES Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6,595 male patients 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL . In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N=3,302) or placebo (N=3,293) and followed for a median duration of 4.8 years. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively. Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin sodium group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar across the age range studied and throughout the range of baseline LDL cholesterol levels. Pravastatin sodium also decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients.) Cardiovascular deaths were decreased by 32% (73 vs 50) and there was no increase in death from non-cardiovascular causes. Secondary Prevention of Cardiovascular Events In the LIPID study, the effect of pravastatin sodium tablets, 40 mg daily, was assessed in 9,014 patients (7,498 men; 1,516 women; 3,514 patients ≥65 years; 782 patients with diabetes) who had experienced either an MI (5,754 patients) or had been hospitalized for unstable angina pectoris (3,260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin sodium tablets significantly reduced the risk for total mortality by reducing coronary death (see Table 7 ). The risk reduction due to treatment with pravastatin sodium tablets on CHD mortality was consistent regardless of age. Pravastatin sodium tablets significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 7: LIPID - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p -value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE study, the effect of pravastatin sodium tablets, 40 mg daily, on CHD death and nonfatal MI was assessed in 4,159 patients (3,583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75 th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with pravastatin sodium tablets significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 8 ). Table 8: CARE - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=2,081) Placebo (N=2,078) Risk Reduction p -value Primary Endpoint CHD mortality or nonfatal MI a 212 (10.2) 274 (13.2) 24% 0.003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001 Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029 a The risk reduction due to treatment with pravastatin sodium was consistent in both sexes. Primary Hyperlipidemia In multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin sodium tablets in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, and TG (see Table 9). In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25 th and 75 th percentile changes from baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 9 ). Table 9: Primary Hyperlipidemia Trials Dose Response of Pravastatin Sodium Once Daily Administration Dose Total-C LDL-C HDL-C TG Mean Percent Changes From Baseline After 8 Weeks a Placebo (N=36) -3% -4% +1% -4% 10 mg (N=18) -16% -22% +7% -15% 20 mg (N=19) -24% -32% +2% -11% 40 mg (N=18) -25% -34% +12% -24% Mean Percent Changes From Baseline After 6 Weeks b Placebo (N=162) 0% -1% -1% +1% 80 mg (N=277) -27% -37% +3% -19% a A multicenter, double-blind, placebo-controlled study. b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies. Dysbetalipoproteinemia The response to pravastatin in two double-blind crossover studies of 46 patients with genotype E2/E2 and dysbetalipoproteinemia is shown in Table 11. Table 11: Patients with Dysbetalipoproteinemia Median (min, max) % Change from Baseline Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20) Study 1 Total-C 386.5 (245.0, 672.0) -32.7 (-58.5, 4.6) TG 443.0 (275.0, 1299.0) -23.7 (-68.5, 44.7) VLDL-C a 206.5 (110.0, 379.0) -43.8 (-73.1, -14.3) LDL-C a 117.5 (80.0, 170.0) -40.8 (-63.7, 4.6) HDL-C 30.0 (18.0, 88.0) 6.4 (-45.0, 105.6) Non-HDL-C 344.5 (215.0, 646.0) -36.7 (-66.3, 5.8) a N=14 Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26) Study 2 Total-C 340.3 (230.1, 448.6) -31.4 (-54.5, -13.0) TG 343.2 (212.6, 845.9) -11.9 (-56.5, 44.8) VLDL-C 145.0 (71.5, 309.4) -35.7 (-74.7, 19.1) LDL-C 128.6 (63.8, 177.9) -30.3 (-52.2, 13.5) HDL-C 38.7 (27.1, 58.0) 5.0 (-17.7, 66.7) Non-HDL-C 295.8 (195.3, 421.5) -35.5 (-81.0, -13.5) HeFH in Pediatric Patients Aged 8 Years and Above A double-blind, placebo-controlled study in 214 pediatric patients (100 males and 114 females) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The pediatric patients aged 8 to 13 years were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the pediatric patients aged 14 to 18 years were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95 th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively. Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both pediatric age groups (see Table 12 ). The effect of pravastatin treatment in the 2 age groups was similar. Table 12: Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo LDL-C -26.04 b -21.07 b -24.07 b -1.52 (-26.74, -18.86) TC -20.75 b -13.08 b -17.72 b -0.65 (-20.40, -13.83) HDL-C 1.04 13.71 5.97 3.13 (-1.71, 7.43) TG -9.58 -0.30 -5.88 -3.27 (-13.95, 10.01) ApoB (N) -23.16 b (61) -18.08 b (39) -21.11 b (100) -0.97 (106) (-24.29, -16.18) a The above least-squares mean values were calculated based on log-transformed lipid values. b Significant at p≤0.0001 when compared with placebo. The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin group k to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group." ], "clinical_studies_table": [ "
Number (%) of Subjects
Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p-value
Primary Endpoint
CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004
Secondary Endpoints
Total mortality 498 (11.0) 633 (14.1) 23% <0.0001
CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001
Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001
Stroke
All-cause 169 (3.7) 204 (4.5) 19% 0.0477
Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154
Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001
", "
Number (%) of Subjects
Event Pravastatin 40 mg (N=2,081)Placebo (N=2,078)Risk Reductionp-value
Primary Endpoint
CHD mortality or nonfatal MIa 212 (10.2) 274 (13.2) 24% 0.003
Secondary Endpoints
Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001
Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029
", "
DoseTotal-CLDL-CHDL-CTG
Mean Percent Changes From Baseline After 8 Weeksa
Placebo (N=36) -3% -4% +1% -4%
10 mg (N=18) -16% -22% +7% -15%
20 mg (N=19) -24% -32% +2% -11%
40 mg (N=18) -25% -34% +12% -24%
Mean Percent Changes From Baseline After 6 Weeksb
Placebo (N=162) 0% -1% -1% +1%
80 mg (N=277) -27% -37% +3% -19%
", "
Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20)
Study 1
Total-C 386.5 (245.0, 672.0) -32.7 (-58.5, 4.6)
TG 443.0 (275.0, 1299.0) -23.7 (-68.5, 44.7)
VLDL-Ca 206.5 (110.0, 379.0) -43.8 (-73.1, -14.3)
LDL-Ca 117.5 (80.0, 170.0) -40.8 (-63.7, 4.6)
HDL-C 30.0 (18.0, 88.0) 6.4 (-45.0, 105.6)
Non-HDL-C 344.5 (215.0, 646.0) -36.7 (-66.3, 5.8)
a N=14
Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26)
Study 2
Total-C 340.3 (230.1, 448.6) -31.4 (-54.5, -13.0)
TG 343.2 (212.6, 845.9) -11.9 (-56.5, 44.8)
VLDL-C 145.0 (71.5, 309.4) -35.7 (-74.7, 19.1)
LDL-C 128.6 (63.8, 177.9) -30.3 (-52.2, 13.5)
HDL-C 38.7 (27.1, 58.0) 5.0 (-17.7, 66.7)
Non-HDL-C 295.8 (195.3, 421.5) -35.5 (-81.0, -13.5)
", "
Pravastatin20 mg(Aged 8 to 13 years)N=65Pravastatin40 mg(Aged 14 to 18 years)N=41CombinedPravastatin (Aged 8 to 18 years)N=106CombinedPlacebo(Aged 8 to 18years)N=10895% CI of the Difference Between Combined Pravastatin and Placebo
LDL-C -26.04b -21.07b -24.07b -1.52 (-26.74, -18.86)
TC -20.75b -13.08b -17.72b -0.65 (-20.40, -13.83)
HDL-C 1.04 13.71 5.97 3.13 (-1.71, 7.43)
TG -9.58 -0.30 -5.88 -3.27 (-13.95, 10.01)
ApoB (N) -23.16b (61) -18.08b (39) -21.11b (100) -0.97 (106) (-24.29, -16.18)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Pravastatin Sodium Tablets, USP 80 mg are available for oral administration as off-white to light yellow, round, unscored tablets, imprinted \"APO\" on one side and \"PRA\" over \"80\" on the other side. They are supplied as follows: NDC: 72162-1711-2: 58 Tablets in a BOTTLE NDC: 72162-1711-3: 30 Tablets in a BOTTLE NDC: 72162-1711-4: 88 Tablets in a BOTTLE NDC: 72162-1711-9: 90 Tablets in a BOTTLE NDC: 72162-1711-5: 500 Tablets in a BOTTLE Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. Protect from light and moisture. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Myopathy and Rhabdomyolysis Advise patients that pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] . Hepatic Dysfunction Inform patients that pravastatin sodium tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions ( 5.3 )]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with pravastatin sodium tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions ( 5.4 )]. Pregnancy Advise pregnant patients and patients who may become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if pravastatin sodium tablets should be discontinued [see Use in Specific Populations ( 8.1 )] . Lactation Advise patients that breastfeeding is not recommended during treatment with pravastatin sodium tablets [see Use in Specific Populations ( 8.2 )] . APOTEX INC. PRAVASTATIN SODIUM TABLETS, USP 10 mg, 20 mg, 40 mg and 80 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326 Rev. 13" ], "package_label_principal_display_panel": [ "Pravastatin Sodium 80 mg Tablets Label" ], "set_id": "00c49d0a-f84c-431e-8fa2-bce0e2d9dbc9", "id": "1b6b0dcb-d9c7-48dc-b2f3-a9cfc36f13c4", "effective_time": "20251205", "version": "105", "openfda": {} }, { "effective_time": "20181214", "recent_major_changes": [ "Dosage and Administration Recommended Dosing (2.1) 06/2011 Restricted Dosing for 80 mg (2.2) 06/2011 Coadministration with Other Drugs (2.3) 06/2011 Patients with Homozygous Familial Hypercholesterolemia (2.4) 06/2011 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products (2.7) 06/2011 Contraindications (4) 06/2011 Warnings and Precautions Myopathy/Rhabdomyolysis (5.1) 06/2011 Liver Dysfunction (5.2) 06/2011" ], "drug_interactions": [ "7 DRUG INTERACTIONS Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily) Coumarin anticoagulants: Concomitant use with simvastatin prolongs INR. Achieve stable INR prior to starting simvastatin. Monitor INR frequently until stable upon initiation or alteration of simvastatin therapy. (7.6) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol Strong CYP3A4 Inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4. Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) .] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4) ]. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of simvastatin be considered during concomitant use of voriconazole and simvastatin to reduce the risk of myopathy, including rhabdomyolysis [see Warnings and Precautions (5.1) ]. Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [see Contraindications (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] . Other fibrates: Caution should be used when prescribing with simvastatin [see Warnings and Precautions (5.1) ] . 7.3 Amiodarone, Ranolazine, or Calcium Channel Blockers The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) , Warnings and Precautions (5.1) , and Table 3 in Clinical Pharmacology (12.3) ] . 7.4 Niacin Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. [See Warnings and Precautions (5.1 ) and Clinical Pharmacology (12.3) .] 7.5 Digoxin In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3) ] . 7.6 Coumarin Anticoagulants In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20 to 40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. 7.7 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine." ], "geriatric_use": [ "8.5 Geriatric Use Of the 2,423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3) .] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1) ] . In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS. Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) .]" ], "pharmacodynamics": [ "12.2 Pharmacodynamics Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined." ], "description": [ "11 DESCRIPTION Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus . After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2 H -pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1 S -[1α,3α,7β,8β(2 S *,4 S *),-8aβ]]. The molecular formula of simvastatin is C 25 H 38 O 5 and its molecular weight is 418.57. Its structural formula is: Simvastatin USP is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in chloroform, methanol and ethanol. Tablets simvastatin for oral administration contain either 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of simvastatin USP and the following inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, hydroxypropyl cellulose, hypromellose, titanium dioxide, talc, citric acid monohydrate, isopropyl alcohol, magnesium stearate and butylated hydroxyanisole. Simvastatin 5 mg also contains ferric oxide yellow, simvastatin 10 mg and simvastatin 20 mg also contains ferric oxide red and ferric oxide yellow, simvastatin 40 mg and simvastatin 80 mg also contains ferric oxide red. Chemical Structure" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80 mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear. 13.2 Animal Toxicology and/or Pharmacology CNS Toxicity Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class. There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times)." ], "warnings_and_cautions_table": [ "
TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Interacting Agents Prescribing Recommendations
Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin
Amiodarone Verapamil Diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Tablets simvastatin 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side. Tablets simvastatin 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side. Tablets simvastatin 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side. Tablets simvastatin 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side. Tablets simvastatin 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side. Tablets: 5 mg; 10 mg; 20 mg; 40 mg; 80 mg (3)" ], "clinical_pharmacology_table": [ "
TABLE 3 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
* Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with/without coadministered drug) No Effect = 1
AUC Cmax
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin† 200 mg QD for 4 days 80 mg simvastatin acid‡ simvastatin 12 8.9 15 5.3
Nelfinavir† 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid‡ simvastatin 6 6.2
Itraconazole† 200 mg QD for 4 days 80 mg simvastatin acid‡ simvastatin 13.1 13.1
Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91
Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
Grapefruit Juice§ (high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice§ (low dose) 8 oz (about 237 mL) of single-strength# 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.1 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Day 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
No dosing adjustments required for the following:
Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-releaseÞ 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7 to 4.7 ng·eq/mL
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C." ], "pharmacokinetics_table": [ "
TABLE 3 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure
* Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4)].
Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with/without coadministered drug) No Effect = 1
AUC Cmax
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]
Telithromycin† 200 mg QD for 4 days 80 mg simvastatin acid‡ simvastatin 12 8.9 15 5.3
Nelfinavir† 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid‡ simvastatin 6 6.2
Itraconazole† 200 mg QD for 4 days 80 mg simvastatin acid‡ simvastatin 13.1 13.1
Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91
Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1)]
Grapefruit Juice§ (high dose) 200 mL of double-strength TID 60 mg single dose simvastatin acid simvastatin 7 16
Grapefruit Juice§ (low dose) 8 oz (about 237 mL) of single-strength# 20 mg single dose simvastatin acid simvastatin 1.3 1.9
Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.1 2.69 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79
Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1)]
Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Day 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75
No dosing adjustments required for the following:
Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83
Niacin extended-releaseÞ 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7 to 4.7 ng·eq/mL
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-­derived radioactivity crossed the blood-brain barrier. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5) ] . Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance). Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . TABLE 3 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4) ] . Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with/without coadministered drug) No Effect = 1 AUC C max Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 12 8.9 15 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1) ] Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.1 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Day 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 No dosing adjustments required for the following: Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release Þ 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7 to 4.7 ng·eq/mL In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL." ], "clinical_studies_table": [ "
TABLE 4 Summary of Heart Protection Study Results
† n = number of patients with indicated event
Endpoint Simvastatin (N=10,269) n (%)† Placebo (N=10,267) n (%)† Risk Reduction (%) (95% CI) p-Value
Primary Mortality CHD mortality 1,328 (12.9) 587 (5.7) 1,507 (14.7) 707 (6.9) 13 (6-19) 18 (8-26) p=0.0003 p=0.0005
Secondary Non-fatal MI Stroke 357 (3.5) 444 (4.3) 574 (5.6) 585 (5.7) 38 (30-46) 25 (15-34) p<0.0001 p<0.0001
Tertiary Coronary revascularization Peripheral and other non-coronary revascularization 513 (5) 450 (4.4) 725 (7.1) 532 (5.2) 30 (22-38) 16 (5-26) p<0.0001 p=0.006
", "
TABLE 5 Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)
† median percent change ‡ mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL § mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL || mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL 21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded †† mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.
TREATMENT N TOTAL-C LDL-C HDL-C TG†
Lower Dose Comparative Study‡ (Mean % Change at Week 6) Simvastatin 5 mg q.p.m. Simvastatin 10 mg q.p.m. 109 110 -19 -23 -26 -30 10 12 -12 -15
Scandinavian Simvastatin Survival Study§ (Mean % Change at Week 6) Placebo Simvastatin 20 mg q.p.m. 2223 2221 -1 -28 -1 -38 0 8 -2 -19
Upper Dose Comparative Study|| (Mean % Change Averaged at Weeks 18 and 24) Simvastatin 40 mg q.p.m. Simvastatin 80 mg q.p.m. 433 664 -31 -36 -41 -47 9 8 -18 -24
Multi-Center Combined Hyperlipidemia Study†† (Mean % Change at Week 6) Placebo Simvastatin 40 mg q.p.m Simvastatin 80 mg q.p.m 125 123 124 1 -25 -31 2 -29 -36 3 13 16 -4 -28 -33
", "
TABLE 6 Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline†
† The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.
TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C
Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8)
Simvastatin 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23)
Simvastatin 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32)
", "
TABLE 7 Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent Change (min, max) from Baseline†
† The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.
TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C
Placebo 7 -8 (-24, +34) -8 (-27, +23) -2 (-21, +16) +4 (-22, +90) -4 (-28, +78) -8 (-26, -39)
Simvastatin 40 mg/day 7 -50 (-66, -39) -50 (-60, -31) +7 (-8, +23) -41 (-74, -16) -58 (-90, -37) -57 (-72, -44)
Simvastatin 80 mg/day 7 -52 (-55, -41) -51 (-57, -28) +7 (-5, +29) -38 (-58, +2) -60 (-72, -39) -59 (-61, -46)
", "
TABLE 8 Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline)
† median percent change
Dosage Duration N Total-C LDL-C HDL-C TG† Apo B
Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6)
Mean baseline, mg/dL (SD) 278.6 (51.8) 211.9 (49) 46.9 (11.9) 90 (50.7) 186.3 (38.1)
Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33) 8.3 (4.6, 11.9) -7.9 (-15.8, 0) -32.4 (-35.9, -29)
Mean baseline, mg/dL (SD) 270.2 (44) 203.8 (41.5) 47.7 (9) 78.3 (46) 179.9 (33.8)
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin tablets, USP can be started simultaneously with diet. Simvastatin tablets, USP are an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of total mortality by reducing CHD deaths and reduce the risk of non-fatal myocardial infarction, stroke, and the need for revascularization procedures in patients at high risk of coronary events. (1.1) Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (1.2) Reduce elevated TG in patients with hypertriglyceridemia and reduce TG and VLDL-C in patients with primary dysbeta­lipoproteinemia. (1.2) Reduce total-C and LDL-C in adult patients with homozygous familial hypercholesterolemia. (1.2) Reduce elevated total-C, LDL-C, and Apo B in boys and postmenarchal girls, 10 to 17 years of age with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. (1.2 , 1.3) Limitations of Use Simvastatin tablets, USP have not been studied in Fredrickson Types I and V dyslipidemias. (1.4) 1.1 Reductions in Risk of CHD Mortality and Cardiovascular Events In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin tablets, USP are indicated to: Reduce the risk of total mortality by reducing CHD deaths. Reduce the risk of non-fatal myocardial infarction and stroke. Reduce the need for coronary and non-coronary revascularization procedures. 1.2 Hyperlipidemia Simvastatin tablets, USP are indicated to: Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb). Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type IV hyperlipidemia). Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia). Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable. 1.3 Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH) Simvastatin tablets, USP are indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present: 1. LDL cholesterol remains ≥190 mg/dL; or 2. LDL cholesterol remains ≥160 mg/dL and There is a positive family history of premature cardiovascular disease (CVD) or Two or more other CVD risk factors are present in the adolescent patient. The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined. 1.4 Limitations of Use Simvastatin tablets, USP have not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V)." ], "set_id": "012be6a1-42eb-478c-94c2-3326c40fbe72", "id": "e80b1658-ea6d-470f-a96e-774ebd5ec954", "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5) , Adverse Reactions (6.1) , Clinical Studies (14.2) .] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1) ]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls." ], "contraindications": [ "4 CONTRAINDICATIONS Simvastatin tablets are contraindicated in the following conditions: Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1) ]. Concomitant administration of gemfibrozil, cyclosporine , or danazol [see Warnings and Precautions (5.1) ]. Hypersensitivity to any component of this medication [see Adverse Reactions (6.2) ] . Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2) ] . Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin tablets may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of use with simvastatin tablets during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Simvastatin tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, simvastatin tablets should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] . Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require treatment with simvastatin tablets should not breastfeed their infants [see Use in Specific Populations (8.3) ] . Concomitant administration of strong CYP3A4 inhibitors. (4 , 5.1) Concomitant administration of gemfibrozil, cyclosporine, or danazol. (4 , 5.1) Hypersensitivity to any component of this medication. (4 , 6.2) Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. (4 , 5.2 ) Women who are pregnant or may become pregnant. (4 , 8.1) Nursing mothers. (4 , 8.3)" ], "drug_interactions_table": [ "
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine Do not exceed 20 mg simvastatin daily
Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily)
" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category X [See Contraindications (4) .] Simvastatin is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin may cause fetal harm when administered to a pregnant woman. If simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin should be considered. If pregnancy occurs, simvastatin should be immediately discontinued. ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ 2 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology , 10(6):439-446, 1996." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4) ] ." ], "spl_product_data_elements": [ "Simvastatin Simvastatin SIMVASTATIN SIMVASTATIN ASCORBIC ACID LACTOSE MONOHYDRATE CELLULOSE, MICROCRYSTALLINE STARCH, CORN HYDROXYPROPYL CELLULOSE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE TALC CITRIC ACID MONOHYDRATE ISOPROPYL ALCOHOL MAGNESIUM STEARATE BUTYLATED HYDROXYANISOLE FERRIC OXIDE RED FERRIC OXIDE YELLOW Light Pink Biconvex A;02" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Patients should be advised of the increased risk of myopathy including rhabdomyolysis with the 80 mg dose. (5.1) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. (4 , 5.1 , 8.5 , 8.6) Patients should be advised to report promptly any symptoms of myopathy. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. See Drug Interaction table. (5.1) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur. Monitor liver enzymes before and during treatment. (5.2) 5.1 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80 mg dose of simvastatin should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2) ] . If, however, a patient who is currently tolerating the 80 mg dose of simvastatin needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2) .] All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases , muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Therapy with simvastatin should be temporarily stopped a few days prior to elective major surgery and when any major medical or surgical condition supervenes. Drug Interactions The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole , the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). Combination of these drugs with simvastatin is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1) .] In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the simvastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with simvastatin. [See Drug Interactions (7.1) .] The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2) ]. Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [see Drug Interactions (7.2) ] . Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7) ] . The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), amiodarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3) ] . Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4) ] . Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3) , Drug Interactions (7) , Clinical Pharmacology (12.3) ] . TABLE 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol Contraindicated with simvastatin Amiodarone Verapamil Diltiazem Do not exceed 10 mg simvastatin daily Amlodipine Ranolazine Do not exceed 20 mg simvastatin daily Grapefruit juice Avoid large quantities of grapefruit juice (>1 quart daily) 5.2 Liver Dysfunction Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity. In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1) ] , the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg. In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40 and 80 mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose. It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3X ULN or greater persist, withdrawal of therapy with simvastatin is recommended. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1) ] . The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin. As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment." ], "adverse_reactions_table": [ "
TABLE 2 Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin and Greater than Placebo in 4S
Simvastatin (N = 2,221) % Placebo (N = 2,223) %
Body as a Whole Edema/swelling Abdominal pain 2.7 5.9 2.3 5.8
Cardiovascular System Disorders Atrial fibrillation 5.7 5.1
Digestive System Disorders Constipation Gastritis 2.2 4.9 1.6 3.9
Endocrine Disorders Diabetes mellitus 4.2 3.6
Musculoskeletal Disorders Myalgia 3.7 3.2
Nervous System/Psychiatric Disorders Headache Insomnia Vertigo 2.5 4 4.5 2.1 3.8 4.2
Respiratory System Disorders Bronchitis Sinusitis 6.6 2.3 6.3 1.8
Skin/Skin Appendage Disorders Eczema 4.5 3
Urogenital System Disorders Infection, urinary tract 3.2 3.1
" ], "openfda": {}, "version": "3254", "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Dose range is 5 to 40 mg/day. (2.1) Recommended usual starting dose is 10 or 20 mg once a day in the evening. (2.1) Recommended starting dose for patients at high risk of CHD is 40 mg/day. (2.1) Due to the increased risk of myopathy, including rhabdomyolysis, use of the 80 mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity. (2.2) Patients who are currently tolerating the 80 mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. (2.2) Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40 mg dose of simvastatin tablets should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. (2.2) Adolescents (10 to 17 years of age) with HeFH: starting dose is 10 mg/day; maximum recommended dose is 40 mg/day. (2.5) 2.1 Recommended Dosing The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, simvastatin tablets can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter. 2.2 Restricted Dosing for 80 mg Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80 mg dose of simvastatin tablets should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1) ] . Patients who are currently tolerating the 80 mg dose of simvastatin tablets who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction. Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80 mg dose of simvastatin tablets, patients unable to achieve their LDL-C goal utilizing the 40 mg dose of simvastatin tablets should not be titrated to the 80 mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering. 2.3 Coadministration with Other Drugs Patients taking Amiodarone, Verapamil, or Diltiazem The dose of simvastatin tablets should not exceed 10 mg/day [see Warnings and Precautions (5.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ] . Patients taking Amlodipine or Ranolazine The dose of simvastatin tablets should not exceed 20 mg/day [see Warnings and Precautions (5.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.3) ] . 2.4 Patients with Homozygous Familial Hypercholesterolemia The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2) ] . Simvastatin tablets should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. 2.5 Adolescents (10 to 17 years of age) with Heterozygous Familial Hypercholesterolemia The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines 1 and Clinical Studies (14.2) ]. Adjustments should be made at intervals of 4 weeks or more. ———————————— 1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992. 2.6 Patients with Renal Impairment Because simvastatin tablets do not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when simvastatin tablets are administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 2.7 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1) .]" ], "adverse_reactions": [ "6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5%) are: upper respiratory infection, headache, abdominal pain, constipation, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%). Scandinavian Simvastatin Survival Study In 4S involving 4,444 (age range 35 to 71 years, 19% women, 100% Caucasians) treated with 20 to 40 mg/day of simvastatin (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2. TABLE 2 Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Simvastatin and Greater than Placebo in 4S Simvastatin (N = 2,221) % Placebo (N = 2,223) % Body as a Whole Edema/swelling Abdominal pain 2.7 5.9 2.3 5.8 Cardiovascular System Disorders Atrial fibrillation 5.7 5.1 Digestive System Disorders Constipation Gastritis 2.2 4.9 1.6 3.9 Endocrine Disorders Diabetes mellitus 4.2 3.6 Musculoskeletal Disorders Myalgia 3.7 3.2 Nervous System/Psychiatric Disorders Headache Insomnia Vertigo 2.5 4 4.5 2.1 3.8 4.2 Respiratory System Disorders Bronchitis Sinusitis 6.6 2.3 6.3 1.8 Skin/Skin Appendage Disorders Eczema 4.5 3 Urogenital System Disorders Infection, urinary tract 3.2 3.1 Heart Protection Study In the Heart Protection Study (HPS), involving 20,536 patients (age range 40 to 80 years, 25% women, 97% Caucasians, 3% other races) treated with simvastatin 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with simvastatin compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with simvastatin. Other Clinical Studies In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia. Laboratory Tests Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.2) ] . Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.1) .] Adolescent Patients (ages 10 to 17 years) In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10 to 17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or simvastatin (10 to 40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2) ] . 6.2 Postmarketing Experience Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, memory impairment, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, hepatic failure, and depression. An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology CNS Toxicity Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose. CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class. There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times)." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Severe renal impairment: Patients should be started at 5 mg/day and be closely monitored. ( 2.6 , 8.6) 8.1 Pregnancy Pregnancy Category X [See Contraindications (4) .] Simvastatin is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use with simvastatin during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero . Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin may cause fetal harm when administered to a pregnant woman. If simvastatin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review 2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m 2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice. Women of childbearing potential, who require treatment with simvastatin for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of simvastatin should be considered. If pregnancy occurs, simvastatin should be immediately discontinued. ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ 2 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology , 10(6):439-446, 1996. 8.3 Nursing Mothers It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4) ] . 8.4 Pediatric Use Safety and effectiveness of simvastatin in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5) , Adverse Reactions (6.1) , Clinical Studies (14.2) .] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1) ]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls. 8.5 Geriatric Use Of the 2,423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, simvastatin should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3) .] A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70 to 78 years of age compared with patients between 18 to 30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65 to 69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1) ] . In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS. Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) .] 8.6 Renal Impairment Caution should be exercised when simvastatin is administered to patients with severe renal impairment. [See Dosage and Administration (2.6) .] 8.7 Hepatic Impairment Simvastatin is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and Precautions (5.2) ] ." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Simvastatin Tablets USP, 5 mg are yellow colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘15’ on the other side. They are supplied as follows: Simvastatin Tablets USP, 10 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘01’ on the other side. They are supplied as follows: Simvastatin Tablets USP, 20 mg are light pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘02’ on the other side. They are supplied as follows: Simvastatin Tablets USP, 40 mg are pink colored, round shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘03’ on the other side. They are supplied as follows: Simvastatin Tablets USP, 80 mg are pink colored, capsule shaped, biconvex, film coated tablets, debossed with ‘A’ on one side and ‘04’ on the other side. They are supplied as follows: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel. Patients should be advised about substances they should not take concomitantly with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] . Patients should also be advised to inform other healthcare professionals prescribing a new medication or increasing the dose of an existing medication that they are taking simvastatin. 17.1 Muscle Pain All patients starting therapy with simvastatin should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Patients using the 80 mg dose should be informed that the risk of myopathy, including rhabdomyolysis, is increased with use of the 80 mg dose. The risk of myopathy, including rhabdomyolysis, occurring with use of simvastatin is increased when taking certain types of medication or consuming larger quantities of grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional. 17.2 Liver Enzymes It is recommended that liver function tests be performed before the initiation of simvastatin, and thereafter when clinically indicated. 17.3 Pregnancy Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using simvastatin. Discuss future pregnancy plans with your patients, and discuss when to stop taking simvastatin if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking simvastatin and call their healthcare professional. 17.4 Breastfeeding Women who are breastfeeding should not use simvastatin. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional. Manufactured for: Aurobindo Pharma USA, Inc. 2400 Route 130 North Dayton, NJ 08810 Manufactured by: Aurobindo Pharma Limited Hyderabad–500 072, India Revised: 06/2011" ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Clinical Studies in Adults Reductions in Risk of CHD Mortality and Cardiovascular Events In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212 to 309 mg/dL (5.5 to 8 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20 to 40 mg/day (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non­-fatal myocardial infarction [MI]) by 34% (p<0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p<0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients (≥65 years), compared with younger patients. The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo). Patients were allocated to treatment using a covariate adaptive method 3 which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40 to 80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥65 years (6%). At baseline, 3,421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-­C levels below 80 mg/dL; 7,068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL. The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-­fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 4). ————————————————— 3 D.R. Taves, Minimization: a new method of assigning patients to treatment and control groups. Clin. Pharmacol. Ther. 15 (1974), pp. 443-453 TABLE 4 Summary of Heart Protection Study Results † n = number of patients with indicated event Endpoint Simvastatin (N=10,269) n (%) † Placebo (N=10,267) n (%) † Risk Reduction (%) (95% CI) p-Value Primary Mortality CHD mortality 1,328 (12.9) 587 (5.7) 1,507 (14.7) 707 (6.9) 13 (6-19) 18 (8-26) p=0.0003 p=0.0005 Secondary Non-fatal MI Stroke 357 (3.5) 444 (4.3) 574 (5.6) 585 (5.7) 38 (30-46) 25 (15-34) p<0.0001 p<0.0001 Tertiary Coronary revascularization Peripheral and other non-coronary revascularization 513 (5) 450 (4.4) 725 (7.1) 532 (5.2) 30 (22-38) 16 (5-26) p<0.0001 p=0.006 Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 1). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin had events and 1,212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2,033 patients treated with simvastatin had events and 2,585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p<0.0001). Treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetics showed risk reductions for MCE and MVE due to simvastatin treatment regardless of baseline HbA1c levels or obesity with the greatest effects seen for diabetics without CHD. Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population. Angiographic Studies In the Multicenter Anti-Atheroma Study, the effect of simvastatin on atherosclerosis was assessed by quantitative coronary angiography in hypercholesterolemic patients with CHD. In this randomized, double-blind, controlled study, patients were treated with simvastatin 20 mg/day or placebo. Angiograms were evaluated at baseline, two and four years. The co-primary study endpoints were mean change per-patient in minimum and mean lumen diameters, indicating focal and diffuse disease, respectively. Simvastatin significantly slowed the progression of lesions as measured in the Year 4 angiogram by both parameters, as well as by change in percent diameter stenosis. In addition, simvastatin significantly decreased the proportion of patients with new lesions and with new total occlusions. Modifications of Lipid Profiles Primary Hyperlipidemia (Fredrickson type lla and llb) Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4 to 6 weeks and maintained during chronic therapy. Simvastatin consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased TG and increased HDL-C (see Table 5). TABLE 5 Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks) † median percent change ‡ mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL § mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL || mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL ¶ 21% and 36% median reduction in TG in patients with TG ≤200 mg/dL and TG >200 mg/dL, respectively. Patients with TG >350 mg/dL were excluded †† mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL. TREATMENT N TOTAL-C LDL-C HDL-C TG † Lower Dose Comparative Study ‡ (Mean % Change at Week 6) Simvastatin 5 mg q.p.m. Simvastatin 10 mg q.p.m. 109 110 -19 -23 -26 -30 10 12 -12 -15 Scandinavian Simvastatin Survival Study § (Mean % Change at Week 6) Placebo Simvastatin 20 mg q.p.m. 2223 2221 -1 -28 -1 -38 0 8 -2 -19 Upper Dose Comparative Study || (Mean % Change Averaged at Weeks 18 and 24) Simvastatin 40 mg q.p.m. Simvastatin 80 mg q.p.m. ¶ 433 664 -31 -36 -41 -47 9 8 -18 -24 Multi-Center Combined Hyperlipidemia Study †† (Mean % Change at Week 6) Placebo Simvastatin 40 mg q.p.m Simvastatin 80 mg q.p.m 125 123 124 1 -25 -31 2 -29 -36 3 13 16 -4 -28 -33 Hypertriglyceridemia (Fredrickson type IV) The results of a subgroup analysis in 74 patients with type IV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 6. TABLE 6 Six-week, Lipid-lowering Effects of Simvastatin in Type IV Hyperlipidemia Median Percent Change (25 th and 75 th percentile) from Baseline † † The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215. TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8) Simvastatin 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23) Simvastatin 80 mg/day 74 -32 (-38, -24) -37 (-46, -26) +15 (+5, +23) -34 (-45, -18) -41 (-57, -28) -38 (-49, -32) Dysbetalipoproteinemia (Fredrickson type III) The results of a subgroup analysis in 7 patients with type III hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG>0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 7. TABLE 7 Six-week, Lipid-lowering Effects of Simvastatin in Type III Hyperlipidemia Median Percent Change (min, max) from Baseline † † The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291. TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C + IDL Non-HDL-C Placebo 7 -8 (-24, +34) -8 (-27, +23) -2 (-21, +16) +4 (-22, +90) -4 (-28, +78) -8 (-26, -39) Simvastatin 40 mg/day 7 -50 (-66, -39) -50 (-60, -31) +7 (-8, +23) -41 (-74, -16) -58 (-90, -37) -57 (-72, -44) Simvastatin 80 mg/day 7 -52 (-55, -41) -51 (-57, -28) +7 (-5, +29) -38 (-58, +2) -60 (-72, -39) -59 (-61, -46) Homozygous Familial Hypercholesterolemia In a controlled clinical study, 12 patients 15 to 39 years of age with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses, or 80 mg/day in 3 divided doses. In 11 patients with reductions in LDL-C, the mean LDL-C changes for the 40 and 80 mg doses were 14% (range 8% to 23%, median 12%) and 30% (range 14% to 46%, median 29%), respectively. One patient had an increase of 15% in LDL-C. Another patient with absent LDL-C receptor function had an LDL-C reduction of 41% with the 80 mg dose. Endocrine Function In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20 to 40 mg had no detectable effect on spermatogenesis. In 4S, in which 4,444 patients were randomized to simvastatin 20 to 40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-­menopausal women are unknown. Figure 1 The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS 14.2 Clinical Studies in Adolescents In a double-blind, placebo-controlled study, 175 patients (99 adolescent boys and 76 post-menarchal girls) 10 to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) were randomized to simvastatin (n=106) or placebo (n=67) for 24 weeks (base study). Inclusion in the study required a baseline LDL-C level between 160 and 400 mg/dL and at least one parent with an LDL-­C level >189 mg/dL. The dosage of simvastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. In a 24-week extension, 144 patients elected to continue therapy with simvastatin 40 mg or placebo. Simvastatin significantly decreased plasma levels of total-C, LDL-C, and Apo B (see Table 8). Results from the extension at 48 weeks were comparable to those observed in the base study. TABLE 8 Lipid-lowering Effects of Simvastatin in Adolescent Patients with Heterozygous Familial Hypercholesterolemia (Mean Percent Change from Baseline) † median percent change Dosage Duration N Total-C LDL-C HDL-C TG † Apo B Placebo 24 Weeks 67 % Change from Baseline (95% CI) 1.6 (-2.2, 5.3) 1.1 (-3.4, 5.5) 3.6 (-0.7, 8) -3.2 (-11.8, 5.4) -0.5 (-4.7, 3.6) Mean baseline, mg/dL (SD) 278.6 (51.8) 211.9 (49) 46.9 (11.9) 90 (50.7) 186.3 (38.1) Simvastatin 24 Weeks 106 % Change from Baseline (95% CI) -26.5 (-29.6, -23.3) -36.8 (-40.5, -33) 8.3 (4.6, 11.9) -7.9 (-15.8, 0) -32.4 (-35.9, -29) Mean baseline, mg/dL (SD) 270.2 (44) 203.8 (41.5) 47.7 (9) 78.3 (46) 179.9 (33.8) After 24 weeks of treatment, the mean achieved LDL-C value was 124.9 mg/dL (range: 64 to 289 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range: 128 to 334 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children with HeFH. The long-term efficacy of simvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established." ], "package_label_principal_display_panel": [ "image of label IMAGE OF LABEL" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C. 12.2 Pharmacodynamics Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. 12.3 Pharmacokinetics Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin. Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-­derived radioactivity crossed the blood-brain barrier. The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal. In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age. Clinical study experience in the elderly (n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5) ] . Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance). Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . TABLE 3 Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure * Results based on a chemical assay except results with propranolol as indicated. † Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone. ‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin. § The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied. ¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3. # Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3. Þ Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.4) ] . Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with/without coadministered drug) No Effect = 1 AUC C max Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1) ] Telithromycin † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 12 8.9 15 5.3 Nelfinavir † 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid ‡ simvastatin 6 6.2 Itraconazole † 200 mg QD for 4 days 80 mg simvastatin acid ‡ simvastatin 13.1 13.1 Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg 40 mg simvastatin acid simvastatin simvastatin acid simvastatin 7.3 10.3 8.5 10.6 9.2 9.4 9.5 11.4 Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid simvastatin 2.85 1.35 2.18 0.91 Avoid >1 quart of grapefruit juice with simvastatin [see Warnings and Precautions (5.1) ] Grapefruit Juice § (high dose) 200 mL of double-strength TID ¶ 60 mg single dose simvastatin acid simvastatin 7 16 Grapefruit Juice § (low dose) 8 oz (about 237 mL) of single-strength # 20 mg single dose simvastatin acid simvastatin 1.3 1.9 Avoid taking with >10 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Verapamil SR 240 mg QD Days 1 to 7 then 240 mg BID on Days 8 to 10 80 mg on Day 10 simvastatin acid simvastatin 2.3 2.5 2.4 2.1 Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid simvastatin 2.69 3.1 2.69 2.88 Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6 Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid simvastatin 1.75 1.76 1.72 1.79 Avoid taking with >20 mg simvastatin, based on clinical and/or postmarketing experience [see Warnings and Precautions (5.1) ] Amlodipine 10 mg QD x 10 days 80 mg on Day 10 simvastatin acid simvastatin 1.58 1.77 1.56 1.47 Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Day 6 to 9 simvastatin acid simvastatin 2.26 1.86 2.28 1.75 No dosing adjustments required for the following: Fenofibrate 160 mg QD x 14 days 80 mg QD on Days 8 to 14 simvastatin acid simvastatin 0.64 0.89 0.89 0.83 Niacin extended-release Þ 2 g single dose 20 mg single dose simvastatin acid simvastatin 1.6 1.4 1.84 1.08 Propranolol 80 mg single dose 80 mg single dose total inhibitor active inhibitor 0.79 0.79 ↓ from 33.6 to 21.1 ng·eq/mL ↓ from 7 to 4.7 ng·eq/mL In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80 mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day. In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m 2 ), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear." ], "overdosage": [ "10 OVERDOSAGE Significant lethality was observed in mice after a single oral dose of 9 g/m 2 . No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m 2 , respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools. A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present." ] }, { "spl_product_data_elements": [ "ATORVASTATIN CALCIUM ATORVASTATIN CALCIUM ANHYDROUS LACTOSE SAND VP/VA COPOLYMER CROSCARMELLOSE SODIUM MAGNESIUM STEARATE MANNITOL CELLULOSE, MICROCRYSTALLINE SODIUM BICARBONATE SODIUM CARBONATE SODIUM LAURYL SULFATE HYDROXYPROPYL METHYLCELLULOSE TALC CI 77891 CI 77492 PEG-135 ATORVASTATIN CALCIUM TRIHYDRATE ATORVASTATIN SG;153" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Atorvastatin Calcium Tablets are indicated: To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies, or alone if such treatments are unavailable, to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia Hypertriglyceridemia Atorvastatin calcium tablet is an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): To reduce the risk of: Myocardial infarction (MI), stroke, revascularization procedures, and angina in adults with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD. MI and stroke in adults with type 2 diabetes mellitus with multiple risk factors for CHD but without clinically evident CHD. Non-fatal MI, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident CHD. As an adjunct to diet to reduce low-density lipoprotein (LDL-C) in: Adults with primary hyperlipidemia. Adults and pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). As an adjunct to other LDL-C-lowering therapies to reduce LDL-C in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia. As an adjunct to diet for the treatment of adults with: Primary dysbetalipoproteinemia. Hypertriglyceridemia." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Take orally once daily with or without food ( 2.1 ). Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust dosage if necessary ( 2.1 ). Adults ( 2.2 ): Recommended starting dosage is 10 mg or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. Patients requiring LDL-C reduction >45% may start at 40 mg once daily. Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 mg to 20 mg once daily ( 2.3 ). Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 mg to 20 mg once daily; dosage range is 10 mg to 80 mg once daily ( 2.4 ). See full prescribing information for atorvastatin calcium tablets dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage Information Take atorvastatin calcium tablets orally once daily at any time of the day, with or without food. Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating atorvastatin calcium tablets, and adjust the dosage if necessary. If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage of atorvastatin calcium tablets is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. Patients who require reduction in LDL-C greater than 45% may be started at 40 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HeFH The recommended starting dosage of atorvastatin calcium tablets is 10 mg once daily. The dosage range is 10 mg to 20 mg once daily. 2.4 Recommended Dosage in Pediatric Patients 10 Years of Age and Older with HoFH The recommended starting dosage of atorvastatin calcium tablets is 10 mg to 20 mg once daily. The dosage range is 10 mg to 80 mg once daily. 2.5 Dosage Modifications Due to Drug Interactions Concomitant use of atorvastatin calcium tablets with the following drugs requires dosage modification of atorvastatin calcium tablets [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . Anti-Viral Medications In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium 20 mg once daily. In patients taking nelfinavir, do not exceed atorvastatin calcium tablets 40 mg once daily. Select Azole Antifungals or Macrolide Antibiotics In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium tablets 20 mg once daily. For additional recommendations regarding concomitant use of atorvastatin calcium tablets with other anti-viral medications, azole antifungals or macrolide antibiotics, [see Drug Interactions (7.1) ] ." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Atorvastatin Calcium Tablets, USP: 10 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “152” on the other 20 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “153” on the other 40 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “154” on the other 80 mg of atorvastatin: yellow oval shaped biconvex, film-coated tablets with “SG” on one side and “155” on the other Tablets: 10 mg; 20 mg; 40 mg; and 80 mg of atorvastatin ( 3 )." ], "contraindications": [ "4 CONTRAINDICATIONS Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] . Hypersensitivity to atorvastatin or any excipients in atorvastatin calcium tablets. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2) ] . Acute liver failure or decompensated cirrhosis ( 4 ). Hypersensitivity to atorvastatin or any excipient in atorvastatin calcium tablets ( 4 )." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher atorvastatin calcium dosage. Discontinue atorvastatin calcium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue atorvastatin calcium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing atorvastatin calcium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 2.5 , 5.1 , 7.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. Discontinue atorvastatin calcium tablets if IMNM is suspected ( 5.2 ). Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium tablets ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Atorvastatin Calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including atorvastatin calcium. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher atorvastatin calcium dosage [see Drug Interactions (7.1) and Use in Specific Populations (8.5, 8.6) ] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Atorvastatin calcium exposure may be increased by drug interactions due to inhibition of cytochrome P450 enzyme 3A4 (CYP3A4) and/or transporters (e.g., breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended. Atorvastatin calcium dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration (2.5) ]. Cases of myopathy/rhabdomyolysis have been reported with atorvastatin co-administered with lipid modifying doses (>1 gram/day) of niacin, fibrates, colchicine, and ledipasvir plus sofosbuvir [see Adverse Reactions (6.1) ] . Consider if the benefit of use of these products outweighs the increased risk of myopathy and rhabdomyolysis [see Drug Interactions (7.1) ]. Concomitant intake of large quantities, more than 1.2 liters daily, of grapefruit juice is not recommended in patients taking atorvastatin calcium [see Drug Interactions (7.1) ]. Discontinue atorvastatin calcium if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if atorvastatin calcium is discontinued. Temporarily discontinue atorvastatin calcium in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the atorvastatin calcium dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue atorvastatin calcium if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of atorvastatin calcium [see Adverse Reactions (6.1) ]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 0.7% of patients receiving atorvastatin calcium in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin calcium. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury [see Use in Specific Populations (8.7) ]. Consider liver enzyme testing before atorvastatin calcium initiation and when clinically indicated thereafter. atorvastatin calcium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) ]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin calcium. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin calcium. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 5.5 Increased Risk of Hemorrhagic Stroke in Patients on atorvastatin calcium tablets 80 mg with Recent Hemorrhagic Stroke In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial where 2365 adult patients, without CHD who had a stroke or TIA within the preceding 6 months, were treated with atorvastatin calcium 80 mg, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin calcium vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of non-fatal hemorrhagic stroke was significantly higher in the atorvastatin calcium group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin calcium group [see Adverse Reactions (6.1) ]. Consider the risk/benefit of use of atorvastatin calcium 80 mg in patients with recent hemorrhagic stroke." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] Hepatic Dysfunction [see Warnings and Precautions (5.3) ] Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at (1-855-724-3436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8,755 Atorvastatin Calcium vs. 7,311 placebo; age range 10 years to 93 years, 39% female, 91% White, 3% Black or African American, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). Table 1 summarizes adverse reactions reported in ≥ 2% and at a rate greater than placebo in patients treated with Atorvastatin Calcium (n=8,755), from seventeen placebo-controlled trials. Table 1: Adverse Reactions Occurring in ≥ 2% in Patients Atorvastatin calcium -Treated with any Dose and Greater than Placebo Adverse Reaction % Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755 Nasopharyngitis 8.2 12.9 5.3 7.0 4.2 8.3 Arthralgia 6.5 8.9 11.7 10.6 4.3 6.9 Diarrhea 6.3 7.3 6.4 14.1 5.2 6.8 Pain in extremity 5.9 8.5 3.7 9.3 3.1 6.0 Urinary tract infection 5.6 6.9 6.4 8.0 4.1 5.7 Dyspepsia 4.3 5.9 3.2 6.0 3.3 4.7 Nausea 3.5 3.7 3.7 7.1 3.8 4.0 Musculoskeletal pain 3.6 5.2 3.2 5.1 2.3 3.8 Muscle Spasms 3.0 4.6 4.8 5.1 2.4 3.6 Myalgia 3.1 3.6 5.9 8.4 2.7 3.5 Insomnia 2.9 2.8 1.1 5.3 2.8 3.0 Pharyngolaryngeal pain 2.1 3.9 1.6 2.8 0.7 2.3 Other adverse reactions reported in placebo-controlled trials include: Body as a whole : malaise, pyrexia Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal system : musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and nutritional system : transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous system : nightmare Respiratory system: epistaxis Skin and appendages: urticaria Special senses : vision blurred, tinnitus Urogenital system: white blood cells urine positive Elevations in Liver Enzyme Tests Persistent elevations in serum transaminases, defined as more than 3 times the ULN and occurring on 2 or more occasions, occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10mg, 20mg, 40mg, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin calcium. Treating to New Targets Study (TNT) In TNT, [see Clinical Studies (14.1) ] 10,001 patients (age range 29-78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin calcium 10 mg daily (n=5,006) or atorvastatin calcium 80 mg daily (n=4,995). In the high-dose atorvastatin calcium group, there were more patients with serious adverse reactions (1.8%) and discontinuations due to adverse reactions (9.9%) as compared to the low-dose group (1.4%; 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 x ULN twice within 4-10 days) occurred in 1.3% of individuals with atorvastatin calcium 80 mg and in 0.2% of individuals with atorvastatin calcium 10 mg. Elevations of CK (≥ 10 x ULN) were higher in the high-dose atorvastatin calcium group (0.3%) compared to the low-dose atorvastatin calcium group (0.1%). Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) In SPARCL, 4731 patients (age range 21-92 years, 40% female; 93% White, 3% Black or African American, 1% Asian, 3% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months were treated with atorvastatin calcium 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years. There was a higher incidence of persistent hepatic transaminase elevations (≥ 3 x ULN twice within 4-10 days) in the atorvastatin calcium group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 x ULN) were rare, but were higher in the atorvastatin calcium group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 6.1% of subjects in the atorvastatin calcium group and 3.8% of subjects in the placebo group. In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (9.2% vs. 11.6%) and increased the incidence of hemorrhagic stroke (2.3% vs. 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Atorvastatin Calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin calcium group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% Atorvastatin calcium vs. 4% placebo). Adverse Reactions from Clinical Studies of atorvastatin calcium in Pediatric Patients with HeFH In a 26-week controlled study in pediatric patients with HeFH (ages 10 years to 17 years) (n=140, 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 mg to 20 mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Specific Populations (8.4) and Clinical Studies (14.6) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of atorvastatin calcium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: pancreatitis General disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune system disorders: anaphylaxis Injury: tendon rupture Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis. There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Nervous system disorders: dizziness, peripheral neuropathy. There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric disorders: depression Respiratory disorders: interstitial lung disease Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)" ], "adverse_reactions_table": [ "
Adverse Reaction% Placebo N=7311 % 10 mg N=3908 % 20 mg N=188 % 40 mg N=604 % 80 mg N=4055 % Any dose N=8755
Nasopharyngitis8.212.95.37.04.28.3
Arthralgia6.58.911.710.64.36.9
Diarrhea6.37.36.414.15.26.8
Pain in extremity5.98.53.79.33.16.0
Urinary tract infection5.66.96.48.04.15.7
Dyspepsia4.35.93.26.03.34.7
Nausea3.53.73.77.13.84.0
Musculoskeletal pain3.65.23.25.12.33.8
Muscle Spasms3.04.64.85.12.43.6
Myalgia3.13.65.98.42.73.5
Insomnia2.92.81.15.32.83.0
Pharyngolaryngeal pain2.13.91.62.80.72.3
" ], "drug_interactions": [ "7 DRUG INTERACTIONS See full prescribing information for details regarding concomitant use of atorvastatin calcium tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.1 ). Rifampin : May reduce atorvastatin plasma concentrations. Administer simultaneously with atorvastatin calcium tablets ( 7.2 ). Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.3 ). Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Atorvastatin calcium is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin calcium and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with Atorvastatin Calcium Tablets Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3) ]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium. Intervention: Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3) ]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium. Intervention: Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended. In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium 20 mg. In patients taking nelfinavir, do not exceed atorvastatin calcium 40 mg [see Dosage and Administration (2.5) ]. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3) ]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg [see Dosage and Administration (2.5) ]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin calcium. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin calcium. Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin calcium. Intervention: Consider if the benefit of using fibrates concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin calcium. Intervention: Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin calcium. 7.2 Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Tablets Table 3 presents drug interactions that may decrease exposure to atorvastatin calcium and instructions for preventing or managing them. Table 3: Drug Interactions that may Decrease Exposure to Atorvastatin Calcium Tablets Rifampin Clinical Impact: Concomitant administration of atorvastatin calcium with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer atorvastatin calcium and rifampin simultaneously. 7.3 Atorvastatin Calcium Tablets Effects on Other Drugs Table 4 presents atorvastatin calcium’s effect on other drugs and instructions for preventing or managing them. Table 4: Atorvastatin Calcium Tablets Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin calcium and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Intervention: Consider this when selecting an oral contraceptive for patients taking atorvastatin calcium. Digoxin Clinical Impact: When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3) ]. Intervention: Monitor patients taking digoxin appropriately." ], "drug_interactions_table": [ "
Cyclosporine or Gemfibrozil
Clinical Impact:Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3)]. Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium.
Intervention:Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended.
Anti-Viral Medications
Clinical Impact:Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3)]. Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium.
Intervention:Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with atorvastatin calcium is not recommended.In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with atorvastatin.In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed atorvastatin calcium 20 mg.In patients taking nelfinavir, do not exceed atorvastatin calcium 40 mg [see Dosage and Administration (2.5)]. Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with atorvastatin calcium.Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir.
Select Azole Antifungals or Macrolide Antibiotics
Clinical Impact:Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3)].
Intervention:In patients taking clarithromycin or itraconazole, do not exceed atorvastatin calcium 20 mg [see Dosage and Administration (2.5)]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin calcium. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Examples:Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.
Niacin
Clinical Impact:Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin calcium.
Intervention:Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Fibrates (other than Gemfibrozil)
Clinical Impact:Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with atorvastatin calcium.
Intervention:Consider if the benefit of using fibrates concomitantly with atorvastatin calcium outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact:Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin calcium.
Intervention:Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
Grapefruit Juice
Clinical Impact:Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis.
Intervention:Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking atorvastatin calcium.
", "
Rifampin
Clinical Impact:Concomitant administration of atorvastatin calcium with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
Intervention:Administer atorvastatin calcium and rifampin simultaneously.
", "
Oral Contraceptives
Clinical Impact:Co-administration of atorvastatin calcium and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)].
Intervention:Consider this when selecting an oral contraceptive for patients taking atorvastatin calcium.
Digoxin
Clinical Impact:When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)].
Intervention:Monitor patients taking digoxin appropriately.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ). Lactation: Breastfeeding not recommended during treatment with atorvastatin calcium tablets ( 8.2 ). 8.1 Pregnancy Risk Summary Discontinue atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin calcium use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 times and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 mg/kg/day and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20 mg/kg/day, 100 mg/kg/day, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. 8.2 Lactation Risk Summary There is no information about the presence of atorvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that atorvastatin and/or its metabolites are present in the breast milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data ) . Statins, including atorvastatin calcium, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) ] . Data Following a single oral administration of 10 mg/kg of radioactive atorvastatin to lactating rats, the concentration of total radioactivity was determined. Atorvastatin and/or its metabolites were measured in the breast milk and pup plasma at a 2:1 ratio (milk:plasma). 8.4 Pediatric Use The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of LIPITOR for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females. The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14) ] . The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH). 8.5 Geriatric Use Of the total number of atorvastatin calcium-treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (≥65 years) is a risk factor for atorvastatin calcium-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. Renal impairment does not affect the plasma concentrations of atorvastatin calcium, therefore there is no dosage adjustment in patients with renal impairment [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease. Atorvastatin Calcium is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Discontinue atorvastatin calcium when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Atorvastatin calcium decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, atorvastatin calcium may cause fetal harm when administered to pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1) ] . In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with atorvastatin calcium use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data ) . In animal reproduction studies, no adverse developmental effects were observed in pregnant rats or rabbits orally administered atorvastatin at doses that resulted in up to 30 times and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m 2 ). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development delay were observed at doses ≥ 6 times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data A Medicaid cohort linkage study of 1,152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential confounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for confounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m 2 ). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 mg/kg/day and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased. In a study in pregnant rats administered 20 mg/kg/day, 100 mg/kg/day, or 225 mg/kg/day from gestation day 7 through to lactation day 20 (weaning), there was decreased survival at birth, postnatal day 4, weaning, and post-weaning in pups of mothers dosed with 225 mg/kg/day, a dose at which maternal toxicity was observed. Pup body weight was decreased through postnatal day 21 at 100 mg/kg/day, and through postnatal day 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human exposure at the MRHD, based on AUC. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of atorvastatin calcium as an adjunct to diet to reduce LDL-C have been established pediatric patients 10 years of age and older with HeFH. Use of LIPITOR for this indication is based on a double-blind, placebo-controlled clinical trial in 187 pediatric patients 10 years of age and older with HeFH. In this limited controlled trial, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females. The safety and effectiveness of atorvastatin calcium as an adjunct to other LDL-C-lowering therapies to reduce LDL-C have been established pediatric patients 10 years of age and older with HoFH. Use of atorvastatin calcium for this indication is based on a trial without a concurrent control group in 8 pediatric patients 10 years of age and older with HoFH [see Clinical Studies (14) ] . The safety and effectiveness of atorvastatin calcium have not been established in pediatric patients younger than 10 years of age with HeFH or HoFH, or in pediatric patients with other types of hyperlipidemia (other than HeFH or HoFH)." ], "geriatric_use": [ "8.5 Geriatric Use Of the total number of atorvastatin calcium-treated patients in clinical trials, 15,813 (40%) were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these patients and younger patients. Advanced age (≥65 years) is a risk factor for atorvastatin calcium-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving atorvastatin calcium for the increased risk of myopathy [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] ." ], "overdosage": [ "10 OVERDOSAGE No specific antidotes for atorvastatin calcium are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance." ], "description": [ "11 DESCRIPTION Atorvastatin calcium is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Atorvastatin calcium, USP is [R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C 33 H 34 FN 2 O 5 ) 2 Ca•3H 2 O and its molecular weight is 1209.42. Its structural formula is: Atorvastatin calcium, USP is a white to off-white crystalline powder. Atorvastatin calcium, USP is freely soluble in methanol and insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium tablets, USP for oral administration contain 10 mg, 20 mg, 40 mg, or 80 mg atorvastatin and the following inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow. This product meets the requirements of USP Dissolution Test-2. chemical-structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles. 12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ] . 12.3 Pharmacokinetics Absorption Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Distribution Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Elimination Metabolism Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ] . In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 hours to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender Plasma concentrations of atorvastatin calcium in females differ from those in males (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between males and females. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Use in Specific Populations (8.6) ] . While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7) ]. Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosage regimen Atorvastatin Dose (mg) Ratio of AUC & Ratio of C max & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg, SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg, SD c 7.88 10.60 # , ‡ Saquinavir 400 mg BID b / ritonavir 400 mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 # Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a, * 40 mg, SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg, SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg, SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg, SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74 * * Maalox TC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (co-administered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600 mg BID b , 7 days 40 mg SD c 1.35 1.00 # Fenofibrate 160 mg QD a , 7 days 40 mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or C max (ratio of C max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Ratio based on a single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Table 6. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (mg) Ratio of AUC Ratio of C max 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months - norethindrone 1mg - ethinyl estradiol 35μg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 # See Section 7 for clinical significance. a Once daily b Twice daily c Single Dosage Atorvastatin Calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment." ], "clinical_pharmacology_table": [ "
Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosage regimenAtorvastatin
Dose (mg)Ratio of AUC &Ratio of C max&
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD afor 28 days 8.6910.66
#Tipranavir 500 mg BID b/ritonavir 200 mg BID b, 7 days 10 mg, SD c9.368.58
#Glecaprevir 400 mg QD a/pibrentasvir 120 mg QD a, 7 days 10 mg QD afor 7 days 8.2822.00
#Telaprevir 750 mg q8h f, 10 days 20 mg, SD c7.8810.60
#, ‡Saquinavir 400 mg BID b/ ritonavir 400 mg BID b, 15 days 40 mg QD afor 4 days 3.934.31
#Elbasvir 50 mg QD a/grazoprevir 200 mg QD a, 13 days 10 mg SD c1.944.34
#Simeprevir 150 mg QD a, 10 days 40 mg SD c2.121.70
#Clarithromycin 500 mg BID b, 9 days 80 mg QD afor 8 days 4.545.38
#Darunavir 300 mg BID b/ritonavir 100 mg BID b, 9 days 10 mg QD afor 4 days 3.452.25
#Itraconazole 200 mg QD a, 4 days 40 mg SD c3.321.20
#Letermovir 480 mg QD a, 10 days 20 mg SD c3.292.17
#Fosamprenavir 700 mg BID b/ritonavir 100 mg BID b, 14 days 10 mg QD afor 4 days 2.532.84
#Fosamprenavir 1400 mg BID b, 14 days 10 mg QD afor 4 days 2.304.04
#Nelfinavir 1250 mg BID b, 14 days 10 mg QD afor 28 days 1.742.22
#Grapefruit Juice, 240 mL QD a,*40 mg, SD c1.371.16
Diltiazem 240 mg QD a, 28 days 40 mg, SD c1.511.00
Erythromycin 500 mg QID e, 7 days 10 mg, SD c1.331.38
Amlodipine 10 mg, single dose80 mg, SD c1.180.91
Cimetidine 300 mg QID e, 2 weeks 10 mg QD afor 2 weeks 1.000.89
Colestipol 10 g BID b, 24 weeks 40 mg QD afor 8 weeks NA0.74 **
Maalox TC ®30 mL QID e, 17 days 10 mg QD afor 15 days 0.660.67
Efavirenz 600 mg QD a, 14 days 10 mg for 3 days0.591.01
#Rifampin 600 mg QD a, 7 days (co-administered) †40 mg SD c1.122.90
#Rifampin 600 mg QD a, 5 days (doses separated) †40 mg SD c0.200.60
#Gemfibrozil 600 mg BID b, 7 days 40 mg SD c1.351.00
#Fenofibrate 160 mg QD a, 7 days 40 mg SD c1.031.02
Boceprevir 800 mg TID d, 7 days 40 mg SD c2.322.66
", "
Table 6. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
AtorvastatinCo-administered drug and dosage regimen
Drug/Dosage (mg)Ratio of AUCRatio of C max
80 mg QD afor 15 days Antipyrine, 600 mg SD c1.030.89
80 mg QD afor 10 days #Digoxin 0.25 mg QD a, 20 days 1.151.20
40 mg QD afor 22 days Oral contraceptive QD a, 2 months - norethindrone 1mg - ethinyl estradiol 35μg 1.28 1.19 1.23 1.30
10 mg, SD cTipranavir 500 mg BID b/ritonavir 200 mg BID b, 7 days 1.080.96
10 mg QD afor 4 days Fosamprenavir 1400 mg BID b, 14 days 0.730.82
10 mg QD afor 4 days Fosamprenavir 700 mg BID b/ritonavir 100 mg BID b, 14 days 0.990.94
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Atorvastatin calcium, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ] ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by C max and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for C max and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration. Distribution Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Elimination Metabolism Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ] . In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. Excretion Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 hours to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration. Specific Populations Geriatric Plasma concentrations of atorvastatin calcium are higher (approximately 40% for C max and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Pediatric Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study. Gender Plasma concentrations of atorvastatin calcium in females differ from those in males (approximately 20% higher for C max and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between males and females. Renal Impairment Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium [see Use in Specific Populations (8.6) ] . While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins. Hepatic Impairment In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. C max and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C max and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Use in Specific Populations (8.7) ]. Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosage regimen Atorvastatin Dose (mg) Ratio of AUC & Ratio of C max & # Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD a for 28 days 8.69 10.66 # Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 10 mg, SD c 9.36 8.58 # Glecaprevir 400 mg QD a /pibrentasvir 120 mg QD a , 7 days 10 mg QD a for 7 days 8.28 22.00 # Telaprevir 750 mg q8h f , 10 days 20 mg, SD c 7.88 10.60 # , ‡ Saquinavir 400 mg BID b / ritonavir 400 mg BID b , 15 days 40 mg QD a for 4 days 3.93 4.31 # Elbasvir 50 mg QD a /grazoprevir 200 mg QD a , 13 days 10 mg SD c 1.94 4.34 # Simeprevir 150 mg QD a , 10 days 40 mg SD c 2.12 1.70 # Clarithromycin 500 mg BID b , 9 days 80 mg QD a for 8 days 4.54 5.38 # Darunavir 300 mg BID b /ritonavir 100 mg BID b , 9 days 10 mg QD a for 4 days 3.45 2.25 # Itraconazole 200 mg QD a , 4 days 40 mg SD c 3.32 1.20 # Letermovir 480 mg QD a , 10 days 20 mg SD c 3.29 2.17 # Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 10 mg QD a for 4 days 2.53 2.84 # Fosamprenavir 1400 mg BID b , 14 days 10 mg QD a for 4 days 2.30 4.04 # Nelfinavir 1250 mg BID b , 14 days 10 mg QD a for 28 days 1.74 2.22 # Grapefruit Juice, 240 mL QD a, * 40 mg, SD c 1.37 1.16 Diltiazem 240 mg QD a , 28 days 40 mg, SD c 1.51 1.00 Erythromycin 500 mg QID e , 7 days 10 mg, SD c 1.33 1.38 Amlodipine 10 mg, single dose 80 mg, SD c 1.18 0.91 Cimetidine 300 mg QID e , 2 weeks 10 mg QD a for 2 weeks 1.00 0.89 Colestipol 10 g BID b , 24 weeks 40 mg QD a for 8 weeks NA 0.74 * * Maalox TC ® 30 mL QID e , 17 days 10 mg QD a for 15 days 0.66 0.67 Efavirenz 600 mg QD a , 14 days 10 mg for 3 days 0.59 1.01 # Rifampin 600 mg QD a , 7 days (co-administered) † 40 mg SD c 1.12 2.90 # Rifampin 600 mg QD a , 5 days (doses separated) † 40 mg SD c 0.20 0.60 # Gemfibrozil 600 mg BID b , 7 days 40 mg SD c 1.35 1.00 # Fenofibrate 160 mg QD a , 7 days 40 mg SD c 1.03 1.02 Boceprevir 800 mg TID d , 7 days 40 mg SD c 2.32 2.66 & Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). # See Sections 5.1 and 7 for clinical significance. * Greater increases in AUC (ratio of AUC up to 2.5) and/or C max (ratio of C max up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). ** Ratio based on a single sample taken 8 to 16 h post dose. † Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. ‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used. a Once daily b Twice daily c Single dose d Three times daily e Four times daily f Every 8 hours Table 6. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosage regimen Drug/Dosage (mg) Ratio of AUC Ratio of C max 80 mg QD a for 15 days Antipyrine, 600 mg SD c 1.03 0.89 80 mg QD a for 10 days # Digoxin 0.25 mg QD a , 20 days 1.15 1.20 40 mg QD a for 22 days Oral contraceptive QD a , 2 months - norethindrone 1mg - ethinyl estradiol 35μg 1.28 1.19 1.23 1.30 10 mg, SD c Tipranavir 500 mg BID b /ritonavir 200 mg BID b , 7 days 1.08 0.96 10 mg QD a for 4 days Fosamprenavir 1400 mg BID b , 14 days 0.73 0.82 10 mg QD a for 4 days Fosamprenavir 700 mg BID b /ritonavir 100 mg BID b , 14 days 0.99 0.94 # See Section 7 for clinical significance. a Once daily b Twice daily c Single Dosage Atorvastatin Calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment." ], "pharmacokinetics_table": [ "
Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosage regimenAtorvastatin
Dose (mg)Ratio of AUC &Ratio of C max&
#Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD afor 28 days 8.6910.66
#Tipranavir 500 mg BID b/ritonavir 200 mg BID b, 7 days 10 mg, SD c9.368.58
#Glecaprevir 400 mg QD a/pibrentasvir 120 mg QD a, 7 days 10 mg QD afor 7 days 8.2822.00
#Telaprevir 750 mg q8h f, 10 days 20 mg, SD c7.8810.60
#, ‡Saquinavir 400 mg BID b/ ritonavir 400 mg BID b, 15 days 40 mg QD afor 4 days 3.934.31
#Elbasvir 50 mg QD a/grazoprevir 200 mg QD a, 13 days 10 mg SD c1.944.34
#Simeprevir 150 mg QD a, 10 days 40 mg SD c2.121.70
#Clarithromycin 500 mg BID b, 9 days 80 mg QD afor 8 days 4.545.38
#Darunavir 300 mg BID b/ritonavir 100 mg BID b, 9 days 10 mg QD afor 4 days 3.452.25
#Itraconazole 200 mg QD a, 4 days 40 mg SD c3.321.20
#Letermovir 480 mg QD a, 10 days 20 mg SD c3.292.17
#Fosamprenavir 700 mg BID b/ritonavir 100 mg BID b, 14 days 10 mg QD afor 4 days 2.532.84
#Fosamprenavir 1400 mg BID b, 14 days 10 mg QD afor 4 days 2.304.04
#Nelfinavir 1250 mg BID b, 14 days 10 mg QD afor 28 days 1.742.22
#Grapefruit Juice, 240 mL QD a,*40 mg, SD c1.371.16
Diltiazem 240 mg QD a, 28 days 40 mg, SD c1.511.00
Erythromycin 500 mg QID e, 7 days 10 mg, SD c1.331.38
Amlodipine 10 mg, single dose80 mg, SD c1.180.91
Cimetidine 300 mg QID e, 2 weeks 10 mg QD afor 2 weeks 1.000.89
Colestipol 10 g BID b, 24 weeks 40 mg QD afor 8 weeks NA0.74 **
Maalox TC ®30 mL QID e, 17 days 10 mg QD afor 15 days 0.660.67
Efavirenz 600 mg QD a, 14 days 10 mg for 3 days0.591.01
#Rifampin 600 mg QD a, 7 days (co-administered) †40 mg SD c1.122.90
#Rifampin 600 mg QD a, 5 days (doses separated) †40 mg SD c0.200.60
#Gemfibrozil 600 mg BID b, 7 days 40 mg SD c1.351.00
#Fenofibrate 160 mg QD a, 7 days 40 mg SD c1.031.02
Boceprevir 800 mg TID d, 7 days 40 mg SD c2.322.66
", "
Table 6. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
AtorvastatinCo-administered drug and dosage regimen
Drug/Dosage (mg)Ratio of AUCRatio of C max
80 mg QD afor 15 days Antipyrine, 600 mg SD c1.030.89
80 mg QD afor 10 days #Digoxin 0.25 mg QD a, 20 days 1.151.20
40 mg QD afor 22 days Oral contraceptive QD a, 2 months - norethindrone 1mg - ethinyl estradiol 35μg 1.28 1.19 1.23 1.30
10 mg, SD cTipranavir 500 mg BID b/ritonavir 200 mg BID b, 7 days 1.080.96
10 mg QD afor 4 days Fosamprenavir 1400 mg BID b, 14 days 0.730.82
10 mg QD afor 4 days Fosamprenavir 700 mg BID b/ritonavir 100 mg BID b, 14 days 0.990.94
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100 mg/kg/day, 200 mg/kg/day, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro , atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli , the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 mg/kg and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10 mg/kg, 40 mg/kg, or 120 mg/kg for two years." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year carcinogenicity study in rats at dose levels of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose. A 2-year carcinogenicity study in mice given 100 mg/kg/day, 200 mg/kg/day, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0 to 24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose. In vitro , atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli , the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test. In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 mg/kg and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10 mg/kg, 40 mg/kg, or 120 mg/kg for two years." ], "clinical_studies": [ "14 CLINICAL STUDIES Prevention of Cardiovascular Disease In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 patients with hypertension, 40-80 years of age (mean of 63 years; 19% female; 95% White, 3% Black or African American, 1% South Asian, 1% other), without a previous myocardial infarction and with total cholesterol (TC) levels ≤251 mg/dL. Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81%), age >55 years (85%), smoking (33%), diabetes (24%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy (14%), prior cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/albuminuria (62%). In this double-blind, placebo-controlled trial, patients were treated with anti-hypertensive therapy (goal BP <140/90 mm Hg for patients without diabetes; <130/80 mm Hg for patients with diabetes) and allocated to either atorvastatin calcium 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years. The effect of 10 mg/day of atorvastatin calcium on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3.0% for placebo), p=0.0005 (see Figure 1 )]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infraction or Coronary Heart Disease Death (in ASCOT-LLA) Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17). In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2,838 subjects (94% white, 2% Black or African American, 2% South Asian, 1% other; 68% male), ages 40 to75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and triglycerides (TG) ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the trial. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1,429) or placebo (1,411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint. Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL. The effect of atorvastatin calcium 10 mg/day on lipid levels was similar to that seen in previous clinical trials. Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 2 ). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels. Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death. There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p=0.059). Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73 mg/dL, 145 mg/dL, 128 mg/dL, 98 mg/dL, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99 mg/dL, 177 mg/dL, 152 mg/dL, 129 mg/dL, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium. Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and Table 7 ). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or sex. Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT) Table 7. Overview of Efficacy Results in TNT Endpoint Atorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HR a (95%CI) PRIMARY ENDPOINT n (%) n (%) First major cardiovascular endpoint 548 (10.9) 434 (8.7) 0.78 (0.69, 0.89) Components of the Primary Endpoint CHD death 127 (2.5) 101 (2.0) 0.80 (0.61, 1.03) Non-fatal, non-procedure related MI 308 (6.2) 243 (4.9) 0.78 (0.66, 0.93) Resuscitated cardiac arrest 26 (0.5) 25 (0.5) 0.96 (0.56, 1.67) Stroke (fatal and non-fatal) 155 (3.1) 117 (2.3) 0.75 (0.59, 0.96) SECONDARY ENDPOINTS * First CHF with hospitalization 164 (3.3) 122 (2.4) 0.74 (0.59, 0.94) First PVD endpoint 282 (5.6) 275 (5.5) 0.97 (0.83, 1.15) First CABG or other coronary revascularization procedure b 904 (18.1) 667 (13.4) 0.72 (0.65, 0.80) First documented angina endpoint b 615 (12.3) 545 (10.9) 0.88 (0.79, 0.99) All-cause mortality 282 (5.6) 284 (5.7) 1.01 (0.85, 1.19) Components of All-Cause Mortality Cardiovascular death 155 (3.1) 126 (2.5) 0.81 (0.64, 1.03) Noncardiovascular death 127 (2.5) 158 (3.2) 1.25 (0.99, 1.57) Cancer death 75 (1.5) 85 (1.7) 1.13 (0.83, 1.55) Other non-CV death 43 (0.9) 58 (1.2) 1.35 (0.91, 2.00) Suicide, homicide, and other traumatic non-CV death 9 (0.2) 15 (0.3) 1.67 (0.73, 3.82) a Atorvastatin 80 mg: atorvastatin 10 mg b Component of other secondary endpoints * Secondary endpoints not included in primary endpoint HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular disease; CABG=coronary artery bypass graft Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF. There was no significant difference between the treatment groups for all-cause mortality (Table 7). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the atorvastatin calcium 80 mg group than in the atorvastatin calcium 10 mg treatment group. Primary Hyperlipidemia in Adults Atorvastatin Calcium reduces total-C, LDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy. In two multicenter, placebo-controlled, dose-response trials in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 8.) Table 8: Dose Response in Patients with Primary Hyperlipidemia (Adjusted Mean % Change From Baseline) a Dose N TC LDL-C Apo B TG HDL-C Placebo 21 4 4 3 10 -3 10 22 -29 -39 -32 -19 6 20 20 -33 -43 -35 -26 9 40 21 -37 -50 -42 -29 6 80 23 -45 -60 -50 -37 5 a Results are pooled from 2 dose-response trials. In three multicenter, double-blind trials in patients with hyperlipidemia, atorvastatin calcium was compared to other statins. After randomization, patients were treated for 16 weeks with either atorvastatin calcium 10 mg per day or a fixed dose of the comparative agent (Table 9). Table 9: Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials) 1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference. a Significantly different from lovastatin, ANCOVA, p ≤ 0.05 b Significantly different from pravastatin, ANCOVA, p ≤ 0.05 c Significantly different from simvastatin, ANCOVA, p ≤ 0.05 Treatment (Daily Dosage) N Total-C LDL-C Apo B TG HDL-C Trial 1 Atorvastatin calcium 10 mg 707 -27 a -36 a -28 a -17 a +7 Lovastatin 20 mg 191 -19 -27 -20 -6 +7 95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 Trial 2 Atorvastatin calcium 10 mg 222 -25 b -35 b -27 b -17 b +6 Pravastatin 20 mg 77 -17 -23 -17 -9 +8 95% CI for Diff1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 Trial 3 Atorvastatin calcium 10 mg 132 -29 c -37 c -34 c -23 c +7 Simvastatin 10 mg 45 -24 -30 -30 -15 +7 95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 Table 9 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher dosages of lovastatin, pravastatin, and simvastatin. The drugs compared in the trials summarized in the table are not necessarily exchangeable. Hypertriglyceridemia in Adults The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 10). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267-1502). Table 10: Combined Patients with Isolated Elevated TG: Median (min, max) Percentage Change From Baseline Placebo (N=12) Atorvastatin Calcium 10 mg (N=37) Atorvastatin Calcium 20 mg (N=13) Atorvastatin Calcium 80 mg (N=14) TG -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3) Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8) LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2) non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3) Dysbetalipoproteinemia in Adults The results of an open-label crossover trial of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia are shown in the table below (Table 11). Table 11: Open-Label Crossover Trial of 16 Patients with Dysbetalipoproteinemia Median % Change (min, max) Median (min, max) at Baseline (mg/dL) Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31) TG 678 (273, 5990) -39 (-92, -8) -53 (-95, -30) IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8) non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36) HoFH in Adults and Pediatric Patients In a trial without a concurrent control group, 29 patients (mean age of 22 years, median age of 24 years, 31% <18 years) with HoFH received maximum daily doses of 20 mg to 80 mg of atorvastatin calcium. The mean LDL-C reduction in this trial was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%. HeFH in Pediatric Patients In a double-blind, placebo-controlled trial followed by an open-label phase, 187 males and post-menarchal females 10 years to 17 years of age (mean age 14.1 years; 31% female; 92% White, 1.6% Black or African American, 1.6% Asian, 4.8% other) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the trial required 1) a baseline LDL-C level ≥190 mg/dL or 2) a baseline LDL-C level ≥160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 219 mg/dL (range: 139 mg/dL to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 mg/dL to 325 mg/dL) in the placebo group. The dosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was >130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (56%). Atorvastatin calcium significantly decreased plasma levels of total-C, LDL-C, TG, and apolipoprotein B during the 26-week double-blind phase (see Table 12 ). Table 12: Lipid-altering Effects of Atorvastatin Calcium in Adolescent Males and Females with Heterozygous Familial Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in Intention-to-Treat Population) DOSAGE N Total-C LDL-C HDL-C TG Apolipoprotein B Placebo 47 -1.5 -0.4 -1.9 1.0 0.7 Atorvastatin Calcium 140 -31.4 -39.6 2.8 -12.0 -34.0 The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26-week double-blind phase. Atorvastatin was also studied in a three year open-label, uncontrolled trial that included 163 patients with HeFH who were 10 years to 15 years old (82 males and 81 females). All patients had a clinical diagnosis of HeFH confirmed by genetic analysis (if not already confirmed by family history). Approximately 98% were White, and less than 1% were Black, African American or Asian. Mean LDL-C at baseline was 232 mg/dL. The starting atorvastatin dosage was 10 mg once daily and doses were adjusted to achieve a target of <130 mg/dL LDL-C. The reductions in LDL-C from baseline were generally consistent across age groups within the trial as well as with previous clinical trials in both adult and pediatric placebo-controlled trials. Figure-01 Figure-02 Figure-03" ], "clinical_studies_table": [ "
Figure 1: Effect of Atorvastatin Calcium 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infraction or Coronary Heart Disease Death (in ASCOT-LLA)
", "
Figure 2: Effect of Atorvastatin Calcium 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS
", "
Figure 3: Effect of Atorvastatin Calcium 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
", "
Table 7. Overview of Efficacy Results in TNT
EndpointAtorvastatin 10 mg (N=5006) Atorvastatin 80 mg (N=4995) HR a(95%CI)
PRIMARY ENDPOINTn(%)n(%)
First major cardiovascular endpoint548(10.9)434(8.7)0.78 (0.69, 0.89)
Components of the Primary Endpoint
CHD death127(2.5)101(2.0)0.80 (0.61, 1.03)
Non-fatal, non-procedure related MI308(6.2)243(4.9)0.78 (0.66, 0.93)
Resuscitated cardiac arrest26(0.5)25(0.5)0.96 (0.56, 1.67)
Stroke (fatal and non-fatal)155(3.1)117(2.3)0.75 (0.59, 0.96)
SECONDARY ENDPOINTS*
First CHF with hospitalization164(3.3)122(2.4)0.74 (0.59, 0.94)
First PVD endpoint282(5.6)275(5.5)0.97 (0.83, 1.15)
First CABG or other coronary revascularization procedure b904(18.1)667(13.4)0.72 (0.65, 0.80)
First documented angina endpoint b615(12.3)545(10.9)0.88 (0.79, 0.99)
All-cause mortality282(5.6)284(5.7)1.01 (0.85, 1.19)
Components of All-Cause Mortality
Cardiovascular death155(3.1)126(2.5)0.81 (0.64, 1.03)
Noncardiovascular death127(2.5)158(3.2)1.25 (0.99, 1.57)
Cancer death75(1.5)85(1.7)1.13 (0.83, 1.55)
Other non-CV death43(0.9)58(1.2)1.35 (0.91, 2.00)
Suicide, homicide, and other traumatic non-CV death9(0.2)15(0.3)1.67 (0.73, 3.82)
", "
DoseNTCLDL-CApo BTGHDL-C
Placebo2144310-3
1022-29-39-32-196
2020-33-43-35-269
4021-37-50-42-296
8023-45-60-50-375
", "
1A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference. aSignificantly different from lovastatin, ANCOVA, p ≤ 0.05 bSignificantly different from pravastatin, ANCOVA, p ≤ 0.05 cSignificantly different from simvastatin, ANCOVA, p ≤ 0.05
Treatment (Daily Dosage) NTotal-CLDL-CApo BTGHDL-C
Trial 1
Atorvastatin calcium 10 mg707-27 a-36 a-28 a-17 a+7
Lovastatin 20 mg191-19-27-20-6+7
95% CI for Diff1-9.2, -6.5-10.7, -7.1-10.0, -6.5-15.2, -7.1-1.7, 2.0
Trial 2
Atorvastatin calcium 10 mg222-25 b-35 b-27 b-17 b+6
Pravastatin 20 mg77-17-23-17-9+8
95% CI for Diff1-10.8, -6.1-14.5, -8.2-13.4, -7.4-14.1, -0.7-4.9, 1.6
Trial 3
Atorvastatin calcium 10 mg132-29 c-37 c-34 c-23 c+7
Simvastatin 10 mg45-24-30-30-15+7
95% CI for Diff1-8.7, -2.7-10.1, -2.6-8.0, -1.1-15.1, -0.7-4.3, 3.9
", "
Placebo (N=12) Atorvastatin Calcium 10 mg (N=37) Atorvastatin Calcium 20 mg (N=13) Atorvastatin Calcium 80 mg (N=14)
TG-12.4 (-36.6, 82.7)-41.0 (-76.2, 49.4)-38.7 (-62.7, 29.5)-51.8 (-82.8, 41.3)
Total-C-2.3 (-15.5, 24.4)-28.2 (-44.9, -6.8)-34.9 (-49.6, -15.2)-44.4 (-63.5, -3.8)
LDL-C3.6 (-31.3, 31.6)-26.5 (-57.7, 9.8)-30.4 (-53.9, 0.3)-40.5 (-60.6, -13.8)
HDL-C3.8 (-18.6, 13.4)13.8 (-9.7, 61.5)11.0 (-3.2, 25.2)7.5 (-10.8, 37.2)
non-HDL-C-2.8 (-17.6, 30.0)-33.0 (-52.1, -13.3)-42.7 (-53.7, -17.4)-51.5 (-72.9, -4.3)
", "
Median % Change (min, max)
Median (min, max) at Baseline (mg/dL) Atorvastatin Calcium 10 mg Atorvastatin Calcium 80 mg
Total-C442 (225, 1320)-37 (-85, 17)-58 (-90, -31)
TG678 (273, 5990)-39 (-92, -8)-53 (-95, -30)
IDL-C + VLDL-C215 (111, 613)-32 (-76, 9)-63 (-90, -8)
non-HDL-C411 (218, 1272)-43 (-87, -19)-64 (-92, -36)
", "
DOSAGENTotal-CLDL-CHDL-CTGApolipoprotein B
Placebo47-1.5-0.4-1.91.00.7
Atorvastatin Calcium140-31.4-39.62.8-12.0-34.0
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-6604" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Myopathy and Rhabdomyolysis Advise patients that atorvastatin calcium may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication or consuming large quantities of grapefruit juice and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ]. Hepatic Dysfunction Inform patients that atorvastatin calcium may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3) ] . Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with atorvastatin calcium. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4) ] . Pregnancy Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if atorvastatin calcium should be discontinued [see Use in Specific Populations (8.1) ] . Lactation Advise patients that breastfeeding is not recommended during treatment with atorvastatin calcium [see Use in Specific Populations (8.2) ]. Missed Doses If a dose is missed, advise patients not to take the missed dose and resume with the next scheduled dose. Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 USA Dispense the Patient Information available at: https://sciegenpharm.com/medication-guide/ Rev: 8/2025" ], "spl_patient_package_insert": [ "Patient Information Atorvastatin Calcium Tablets, USP (a tor″ va stat′ in kal′ see um) for oral use What is Atorvastatin Calcium Tablet? Atorvastatin calcium tablets is a prescription medicine that contains a cholesterol lowering medicine (statin) called atorvastatin calcium. Atorvastatin calcium tablets is used: to reduce the risk of: heart attack, stroke, certain types of heart surgery and chest pain in adults who do not have heart disease but have other multiple risk factors for heart disease. heart attack and stroke in adults with type 2 diabetes mellitus who do not have heart disease but have other multiple risk factors. heart attack that does not cause death, stroke, certain types of heart surgery, hospitalization for congestive heart failure, and chest pain in adults with heart disease. along with diet to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol: in adults with primary hyperlipidemia. in adults and children aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). This is an inherited condition that causes high levels of bad cholesterol. along with other cholesterol lowering treatments or alone if such treatments are unavailable in adults and children aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). This is an inherited condition that causes high levels of bad cholesterol. along with diet for the treatment of adults with: primary dysbetalipoproteinemia (an inherited condition that causes high levels of cholesterol and fat). hypertriglyceridemia. It is not known if atorvastatin calcium tablets are safe and effective in children younger than 10 years of age with HeFH or HoFH or in children with other types of hyperlipidemias (other than HeFH or HoFH). Do not take Atorvastatin Calcium Tablets if you: have liver problems (acute liver failure or decompensated cirrhosis) are allergic to atorvastatin or any of the ingredients in atorvastatin calcium tablets. Stop using atorvastatin calcium tablets and get medical help right away if you have symptoms of a serious allergic reaction including: swelling of your face, lips, tongue or throat problems breathing or swallowing fainting or feeling dizzy very rapid heartbeat severe skin rash or itching flu-like symptoms including fever, sore throat, cough, tiredness, and joint pain See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets. Before you take Atorvastatin Calcium Tablets, tell your healthcare provider about all of your medical conditions, including if you: have unexplained muscle aches or weakness drink more than 2 glasses of alcohol daily have diabetes have thyroid problems have kidney problems had a stroke are pregnant or plan to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you become pregnant, stop taking atorvastatin calcium tablets and call your healthcare provider right away. are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take atorvastatin calcium tablets or breastfeed. You should not do both. Talk to your healthcare provider about the best way to feed your baby if you take atorvastatin calcium tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your healthcare provider if you take medicines for: your immune system (cyclosporine) cholesterol (gemfibrozil) infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole) birth control pills heart failure (digoxin) gout (colchicine) niacin fibrates treating HIV, AIDS, or hepatitis C (anti-virals) tipranavir plus ritonavir ledipasvir plus sofosbuvir saquinavir plus ritonavir fosamprenavir elbasvir plus grazoprevir nelfinavir glecaprevir plus pibrentasvir simeprevir darunavir plus ritonavir fosamprenavir plus ritonavir letermovir Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take Atorvastatin Calcium Tablets? Take atorvastatin calcium tablets exactly as your healthcare provider tells you to take it. Do not change your dose or stop atorvastatin calcium tablets without talking to your healthcare provider. Your healthcare provider may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets. Your dose of atorvastatin calcium tablets may be changed based on these blood test results. Take atorvastatin calcium tablets each day at any time of day. Atorvastatin calcium tablets can be taken with or without food. Your healthcare provider may start you on a cholesterol lowering diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets. If you miss a dose of atorvastatin calcium tablets, wait and take the next dose at your regular time. Do not take 2 doses of atorvastating calcium tablets at the same time. If you take too much atorvastatin calcium tablets or overdose, call your healthcare provider or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away. What should I avoid while taking Atorvastatin Calcium Tablets? Avoid drinking more than 1.2 liters of grapefruit juice each day. What are the possible side effects of Atorvastatin Calcium Tablets? atorvastatin calcium tablets may cause serious side effects including: Muscle pain, tenderness and weakness (myopathy). Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death. Tell your healthcare provider right away if you have: unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take atorvastatin calcium tablets. muscle problems that do not go away after your healthcare provider has told you to stop taking atorvastatin calcium tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems. Your chances of getting muscle problems are higher if you: are taking certain other medicines while you take atorvastatin calcium tablets drink large amounts of grapefruit juice are 65 years of age or older have thyroid problems (hypothyroidism) that are not controlled have kidney problems are taking higher doses of atorvastatin calcium tablets Liver problems. Your healthcare provider should do blood tests to check your liver before you start taking atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feel tired or weak nausea or vomiting loss of appetite upper belly pain dark amber colored urine yellowing of your skin or the whites of your eyes Increase in blood sugar level. Your blood sugar level may increase while you are taking atorvastatin calcium tablets. Exercise regularly and make healthy food choices to maintain healthy body weight. The most common side effects of atorvastatin calcium tablets include: nasal congestion, sore throat, runny nose diarrhea urinary tract infection nausea muscle spasms throat pain muscle and joint pain pain in extremity upset stomach musculoskeletal pain trouble sleeping Talk to your healthcare provider or pharmacist if you have side effects that bother you or that will not go away. These are not all the side effects of atorvastatin calcium tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store Atorvastatin Calcium Tablets? Store atorvastatin calcium tablets at room temperature between 68°F to 77°F (20°C to 25°C). Do not keep medicine that is out of date or that you no longer need. Keep atorvastatin calcium tablets and all medicines out of the reach of children. General information about the safe and effective use of Atorvastatin Calcium Tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about atorvastatin calcium tablets, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about atorvastatin calcium tablets that is written for health professionals. What are the ingredients in Atorvastatin Calcium Tablets, USP? Active ingredient: atorvastatin calcium, USP Inactive ingredients: anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow. Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 USA Dispense the Patient Information available at: https://sciegenpharm.com/medication-guide/ Rev: 5/2024" ], "spl_patient_package_insert_table": [ "
Patient Information Atorvastatin Calcium Tablets, USP (a tor″ va stat′ in kal′ see um) for oral use
What is Atorvastatin Calcium Tablet?
Atorvastatin calcium tablets is a prescription medicine that contains a cholesterol lowering medicine (statin) called atorvastatin calcium. Atorvastatin calcium tablets is used:
to reduce the risk of: heart attack, stroke, certain types of heart surgery and chest pain in adults who do not have heart disease but have other multiple risk factors for heart disease.heart attack and stroke in adults with type 2 diabetes mellitus who do not have heart disease but have other multiple risk factors.heart attack that does not cause death, stroke, certain types of heart surgery, hospitalization for congestive heart failure, and chest pain in adults with heart disease.along with diet to reduce low density lipoprotein cholesterol (LDL-C) or bad cholesterol: in adults with primary hyperlipidemia.in adults and children aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH). This is an inherited condition that causes high levels of bad cholesterol.along with other cholesterol lowering treatments or alone if such treatments are unavailable in adults and children aged 10 years and older with homozygous familial hypercholesterolemia (HoFH). This is an inherited condition that causes high levels of bad cholesterol.along with diet for the treatment of adults with: primary dysbetalipoproteinemia (an inherited condition that causes high levels of cholesterol and fat).hypertriglyceridemia.
It is not known if atorvastatin calcium tablets are safe and effective in children younger than 10 years of age with HeFH or HoFH or in children with other types of hyperlipidemias (other than HeFH or HoFH).
Do not take Atorvastatin Calcium Tablets if you:
have liver problems (acute liver failure or decompensated cirrhosis)are allergic to atorvastatin or any of the ingredients in atorvastatin calcium tablets. Stop using atorvastatin calcium tablets and get medical help right away if you have symptoms of a serious allergic reaction including: swelling of your face, lips, tongue or throatproblems breathing or swallowingfainting or feeling dizzyvery rapid heartbeatsevere skin rash or itchingflu-like symptoms including fever, sore throat, cough, tiredness, and joint pain
See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets.
Before you take Atorvastatin Calcium Tablets, tell your healthcare provider about all of your medical conditions, including if you:have unexplained muscle aches or weaknessdrink more than 2 glasses of alcohol dailyhave diabeteshave thyroid problemshave kidney problemshad a strokeare pregnant or plan to become pregnant. Atorvastatin calcium tablets may harm your unborn baby. If you become pregnant, stop taking atorvastatin calcium tablets and call your healthcare provider right away.are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take atorvastatin calcium tablets or breastfeed. You should not do both. Talk to your healthcare provider about the best way to feed your baby if you take atorvastatin calcium tablets.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. Atorvastatin calcium tablets and certain other medicines can increase the risk of muscle problems or other side effects. Especially tell your healthcare provider if you take medicines for: your immune system (cyclosporine)cholesterol (gemfibrozil)infections (erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole)birth control pillsheart failure (digoxin)gout (colchicine)niacinfibratestreating HIV, AIDS, or hepatitis C (anti-virals)
tipranavir plus ritonavirledipasvir plus sofosbuvirsaquinavir plus ritonavirfosamprenavirelbasvir plus grazoprevirnelfinavirglecaprevir plus pibrentasvirsimeprevirdarunavir plus ritonavirfosamprenavir plus ritonavirletermovir
Ask your healthcare provider or pharmacist for a list of medicines if you are not sure. Know all the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take Atorvastatin Calcium Tablets?
Take atorvastatin calcium tablets exactly as your healthcare provider tells you to take it.Do not change your dose or stop atorvastatin calcium tablets without talking to your healthcare provider.Your healthcare provider may do blood tests to check your cholesterol levels during your treatment with atorvastatin calcium tablets.Your dose of atorvastatin calcium tablets may be changed based on these blood test results.Take atorvastatin calcium tablets each day at any time of day. Atorvastatin calcium tablets can be taken with or without food.Your healthcare provider may start you on a cholesterol lowering diet before giving you atorvastatin calcium tablets. Stay on this low-fat diet when you take atorvastatin calcium tablets.If you miss a dose of atorvastatin calcium tablets, wait and take the next dose at your regular time. Do not take 2 doses of atorvastating calcium tablets at the same time.If you take too much atorvastatin calcium tablets or overdose, call your healthcare provider or Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.
What should I avoid while taking Atorvastatin Calcium Tablets?
Avoid drinking more than 1.2 liters of grapefruit juice each day.
What are the possible side effects of Atorvastatin Calcium Tablets? atorvastatin calcium tablets may cause serious side effects including:
Muscle pain, tenderness and weakness (myopathy).Muscle problems, including muscle breakdown, can be serious in some people and, rarely, cause kidney damage that can lead to death. Tell your healthcare provider right away if you have:unexplained muscle pain, tenderness, or weakness, especially if you also have a fever or feel more tired than usual while you take atorvastatin calcium tablets.muscle problems that do not go away after your healthcare provider has told you to stop taking atorvastatin calcium tablets. Your healthcare provider may do further tests to diagnose the cause of your muscle problems.Your chances of getting muscle problems are higher if you:are taking certain other medicines while you take atorvastatin calcium tabletsdrink large amounts of grapefruit juiceare 65 years of age or olderhave thyroid problems (hypothyroidism) that are not controlledhave kidney problemsare taking higher doses of atorvastatin calcium tabletsLiver problems.Your healthcare provider should do blood tests to check your liver before you start taking atorvastatin calcium tablets and if you have symptoms of liver problems while you take atorvastatin calcium tablets. Call your healthcare provider right away if you have the following symptoms of liver problems: feel tired or weaknausea or vomitingloss of appetiteupper belly paindark amber colored urineyellowing of your skin or the whites of your eyesIncrease in blood sugar level.Your blood sugar level may increase while you are taking atorvastatin calcium tablets. Exercise regularly and make healthy food choices to maintain healthy body weight. The most common side effects of atorvastatin calcium tablets include:
nasal congestion, sore throat, runny nosediarrheaurinary tract infectionnauseamuscle spasmsthroat painmuscle and joint painpain in extremityupset stomachmusculoskeletal paintrouble sleeping
Talk to your healthcare provider or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of atorvastatin calcium tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How do I store Atorvastatin Calcium Tablets?
Store atorvastatin calcium tablets at room temperature between 68°F to 77°F (20°C to 25°C).Do not keep medicine that is out of date or that you no longer need.Keep atorvastatin calcium tablets and all medicines out of the reach of children.
General information about the safe and effective use of Atorvastatin Calcium Tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about atorvastatin calcium tablets, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about atorvastatin calcium tablets that is written for health professionals.
What are the ingredients in Atorvastatin Calcium Tablets, USP?
Active ingredient:atorvastatin calcium, USP
Inactive ingredients:anhydrous lactose, NF; colloidal silicon dioxide, NF; copovidone, NF; croscarmellose sodium, NF; magnesium stearate, NF; mannitol, USP; silicified microcrystalline cellulose, NF; sodium bicarbonate, USP; sodium carbonate anhydrous, NF; sodium lauryl sulfate, NF; hypromellose, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow.
Manufactured by: ScieGen Pharmaceuticals, Inc. Hauppauge, NY 11788 USA
Dispense the Patient Information available at: https://sciegenpharm.com/medication-guide/ Rev: 5/2024
" ], "package_label_principal_display_panel": [ "ATORVASTATIN CALCIUM Label Image" ], "set_id": "012cfe0f-d5d9-4b54-a4ab-bb4f113bc554", "id": "24486739-6af9-44e4-a8fd-669ce67cddb6", "effective_time": "20250917", "version": "3", "openfda": {} }, { "spl_product_data_elements": [ "Pravastatin Sodium Pravastatin Sodium CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS CROSCARMELLOSE SODIUM SODIUM LAURYL SULFATE POVIDONE ALCOHOL FERRIC OXIDE RED FERRIC OXIDE YELLOW SILICON DIOXIDE MAGNESIUM STEARATE PRAVASTATIN SODIUM PRAVASTATIN Light Brown FL15 Pravastatin Sodium Pravastatin Sodium CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS CROSCARMELLOSE SODIUM SODIUM LAURYL SULFATE POVIDONE ALCOHOL FERRIC OXIDE RED FERRIC OXIDE YELLOW SILICON DIOXIDE MAGNESIUM STEARATE PRAVASTATIN SODIUM PRAVASTATIN Light Brown FL16 Pravastatin Sodium Pravastatin Sodium CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS CROSCARMELLOSE SODIUM SODIUM LAURYL SULFATE POVIDONE ALCOHOL FERRIC OXIDE RED FERRIC OXIDE YELLOW SILICON DIOXIDE MAGNESIUM STEARATE PRAVASTATIN SODIUM PRAVASTATIN Light Brown FL17 Pravastatin Sodium Pravastatin Sodium CROSCARMELLOSE SODIUM SODIUM LAURYL SULFATE POVIDONE ALCOHOL FERRIC OXIDE RED FERRIC OXIDE YELLOW SILICON DIOXIDE MAGNESIUM STEARATE PRAVASTATIN SODIUM PRAVASTATIN CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS Light Brown FL18" ], "recent_major_changes": [ "Contraindications, Pregnancy and Lactation Removed ( 4 ) 05/2022 Warnings and Precautions, Immune-Mediated Necrotizing Myopathy Updated ( 5.2 ) 05/2022" ], "indications_and_usage": [ "1 INDICATIONS & USAGE Pravastatin sodium tablets is indicated: • To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). • To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. • As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. • As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). • As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia. Pravastatin sodium tablets are an HMG-CoA reductase inhibitor (statin) indicated ( 1 ): · To reduce the risk of myocardial infarction, myocardial revascularization procedures, and cardiovascular mortality in adults with elevated low-density lipoprotein cholesterol (LDL-C) without clinically evident coronary heart disease (CHD). · To reduce the risk of coronary death, myocardial infarction, myocardial revascularization procedures, stroke or transient ischemic attack, and slow the progression of coronary atherosclerosis in adults with clinically evident CHD. · As an adjunct to diet to reduce LDL-C in adults with primary hyperlipidemia. · As an adjunct to diet to reduce LDL-C in pediatric patients ages 8 years and older with heterozygous familial hypercholesterolemia (HeFH). · As an adjunct to diet for the treatment of adults with: o Primary dysbetalipoproteinemia. o Hypertriglyceridemia." ], "dosage_and_administration": [ "2 DOSAGE & ADMINISTRATION · Take orally once daily at any time of the day, with or without food ( 2.1 ). · For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving Pravastatin sodium tablets 80 mg daily, prescribe alternative LDL- C-lowering treatment ( 2.1 ). · Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating Pravastatin sodium tablets, and adjust the dosage if necessary ( 2.1 ). · Adults: recommended starting dosage is Pravastatin sodium tablets 40 mg to 80 mg once daily. ( 2.2 ) · Pediatric Patients ( 2.3 ): o aged 8 to 13 years, the recommended dosage is 20 mg once daily. o aged 14 to 18 years, the recommended starting dosage is 40 mg once daily. · Severe renal impairment: recommended starting dosage is pravastatin sodium 10 mg once daily. Recommended maximum Pravastatin sodium tablets dosage is 40mg once daily. ( 2.4 ) · See full prescribing information for dosage modifications due to drug interactions ( 2.5 , 7 ). 2.1 Important Dosage and Administration Information · Take Pravastatin sodium tablets orally once daily as a single dose at any time of the day, with or without food. · For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving Pravastatin sodium tablets 80 mg daily, prescribe alternative LDL-C-lowering treatment. · Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating Pravastatin sodium tablets, and adjust the dosage if necessary. 2.2 Recommended Dosage in Adult Patients The recommended starting dosage is Pravastatin sodium tablets 40 mg to 80 mg once daily. 2.3 Recommended Dosage in Pediatric Patients 8 Years of Age and Older with HeFH · In pediatric patients aged 8 to 13 years, the recommended dosage is Pravastatin sodium tablets 20 mg once daily. · In pediatric patients aged 14 to 18 years, the recommended starting dosage is Pravastatin sodium tablets 40 mg once daily. 2.4 Recommended Dosage in Patients with Renal Impairment · In patients with severe renal impairment, the recommended starting dosage is pravastatin sodium 10 mg once daily. Pravastatin sodium tablets is available in a 10 mg strength. The maximum recommended dosage of Pravastatin sodium tablets in patients with severe renal impairment is 40 mg once daily [ see Clinical Pharmacology ( 12.3 )]. · The recommended dosage of Pravastatin sodium tablets for patients with mild or moderate renal impairment is the same as patients with normal renal function. 2.5 Dosage and Administration Modifications Due to Drug Interactions · In patients taking a bile acid sequestrant, administer Pravastatin sodium tablets at least 1 hour before or 4 hours after the bile acid sequestrant [ See Drug Interactions (7.2) ]. · Concomitant use of Pravastatin sodium tablets with the following drugs requires dosage modifications of Pravastatin sodium tablets [ see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] : o Cyclosporine In patients taking cyclosporine, the recommended starting dosage is pravastatin sodium 10 mg once daily. Pravastatin sodium tablets is available in a 10 mg strength. The maximum recommended dosage of Pravastatin sodium tablets in patients taking cyclosporine is 20 mg once daily. o Clarithromycin and Erythromycin The maximum recommended dosage is Pravastatin sodium tablets 40 mg once daily." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS & STRENGTHS Pravastatin sodium tablets, USP are supplied as: 10 mg tablets: light brown, mottled, round tablets, debossed with FL15 on one side and plain on the other side. 20 mg tablets: light brown, mottled, round tablets, debossed with FL16 on one side and plain on the other side. 40 mg tablets: light brown, mottled, round tablets, debossed with FL17 on one side and plain on the other side. 80 mg tablets: light brown, mottled, capsule shape, unscored tablets, debossed with FL18 on one side and plain on other side. · Tablets: 10 mg, 20 mg, 40 mg and 80 mg of pravastatin sodium. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS · Acute liver failure or decompensated cirrhosis [ see Warnings and Precautions (5.3) ]. · Hypersensitivity to any pravastatin or any excipients in Pravastatin sodium tablets. · Hypersensitivity to pravastatin or any excipient in Pravastatin sodium tablets ( 4 ) · Acute liver failure or decompensated cirrhosis ( 4 , 5.3 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS · Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher Pravastatin sodium tablets dosage. Discontinue Pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue Pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing Pravastatin sodium tablets dosage. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. ( 5.1 , 7.1 , 8.5 , 8.6 ) · Immune-Mediated Necrotizing Myopathy (IMNM): Rare reports of IMNM, an autoimmune myopathy, have been reported. Discontinue Pravastatin sodium tablets if IMNM is suspected ( 5.2 ). · Hepatic Dysfunction: Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ( 5.3 ). 5.1 Myopathy and Rhabdomyolysis Pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including Pravastatin sodium tablets. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CK) to greater than 10 times the upper limit of normal (ULN), occurred <0.1% in Pravastatin sodium tablets-treated patients in clinical trials. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid-lowering therapies), and higher Pravastatin sodium tablets dosage [ see Drug Interactions (7.1) ]. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Pravastatin sodium tablets is not recommended in patients taking gemfibrozil [ see Drug Interactions (7) ]. There are Pravastatin sodium tablets dosage restrictions for patients taking cyclosporin and select macrolide antibiotics [ see Dosage and Administration (2.5) ]. The following drugs when used concomitantly with Pravastatin sodium tablets may also increase the risk of myopathy and rhabdomyolysis: niacin, fibrates, and colchicine [ see Drug Interactions (7) ]. Discontinue Pravastatin sodium tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if Pravastatin sodium tablets is discontinued. Temporarily discontinue Pravastatin sodium tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Pravastatin sodium tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum creatine kinase that persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue Pravastatin sodium tablets if IMNM is suspected. 5.3 Hepatic Dysfunction Increases in serum transaminases have been reported with use of Pravastatin sodium tablets [see Adverse Reactions (6.1)]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1% of patients receiving either Pravastatin sodium tablets or placebo in clinical studies. Marked persistent increases of hepatic transaminases have also occurred with Pravastatin sodium tablets. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Pravastatin sodium tablets. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before Pravastatin sodium tablets initiation and when clinically indicated thereafter. Pravastatin sodium tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue Pravastatin sodium tablets. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including Pravastatin sodium tablets. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: · Myopathy and Rhabdomyolysis [ see Warnings and Precautions (5.1)] · Immune-Mediated Necrotizing Myopathy [ see Warnings and Precautions (5.2)] · Hepatic Dysfunction [ see Warnings and Precautions (5.3)] · Increases in HbA1c and Fasting Serum Glucose Levels [ see Warnings and Precautions (5.4)] In short-term clinical trials, the most commonly reported adverse reactions (≥2% and greater than placebo) were: musculoskeletal pain, nausea/vomiting, upper respiratory infection, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact APNAR PHARMA LP at 1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In Pravastatin sodium tablets placebo-controlled clinical trials, 1313 patients (age range 20 to 76 years, 32% women, 93.5% White, 5% Black, 0.9% Hispanic, 0.4% Asian, 0.2% Other) with a median treatment duration of 14 weeks, 3.3% of patients on Pravastatin sodium tablets and 1.2% patients on placebo discontinued due to adverse reactions (regardless of causality). The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: hepatic transaminase elevations, nausea, anxiety/depression, and dizziness. Adverse reactions (regardless of causality) reported in ≥2% of Pravastatin sodium tablets-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1: Table 1: Adverse Reactions in ≥ 2% of Patients Treated with Pravastatin (Any Dose) and at an Incidence Greater Than Placebo in Short-Term Placebo-Controlled Trials % Placebo N=411 % Any Dose N=902 Nausea/Vomiting 7.1 7.4 Diarrhea 5.6 6.7 Headache 4.6 6.3 Upper Respiratory Infection 5.8 5.9 Angina Pectoris 3.4 4.5 Rash 1.4 4.5 CPK Increased 3.6 4.1 Dizziness 3.4 3.5 ALT Increased 1.2 2.9 Chest Pain 1.9 2.7 Cough 1.7 2.5 Myalgia 1.2 2.3 Influenza 0.7 2.0 g-GT Increased 1.2 2.0 The safety and tolerability of Pravastatin sodium tablets at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Pravastatin sodium tablets at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin. In Pravastatin sodium tablets placebo-controlled clinical trials, 21,483 patients (age range 24-75 years, 10.3% women, 52.3% White, 0.8% Black, 0.5% Hispanic, 0.1% Asian, 0.1% Other, 46.1% not recorded) had a median treatment duration of 261 weeks. Adverse reactions (regardless of causality) were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Pravastatin in Ischemic Disease study [LIPID]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with Pravastatin sodium tablets 40 mg and 10,719 patients treated with placebo. Patients weres exposed to Pravastatin sodium tablets for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. Adverse reactions (regardless of causality) occurring in ≥5% of patients treated with Pravastatin sodium tablets in these studies are identified in Table 2: Table 2: Adverse Reactions in ≥ 5% of Patients Treated with Pravastatin 40 mg and at an Incidence Greater than Placebo in Long-Term Placebo-Controlled Trials Placebo (N=10,719) % of patients Pravastatin sodium tablets (N=10,764) % of patients Musculoskeletal Pain 24.4 24.9 Upper Respiratory Tract Infection 20.2 21.2 Musculoskeletal Traumatism 9.6 10.2 Chest Pain 9.8 10.0 Influenza 9.0 9.2 Fatigue 7.8 8.4 Cough 7.4 8.2 Dizziness 6.6 7.3 Rash (including dermatitis) 7.1 7.2 Sinus Abnormality 6.7 7.0 Muscle Cramp 4.6 5.1 No new adverse reactions were identified in a study of pediatric patients with HeFH. Laboratory Abnormalities Increases in ALT, AST values and CK have been observed. Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Pravastatin sodium tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: myopathy, rhabdomyolysis, tendon disorder, polymyositis, immune-mediated necrotizing myopathy associated with statin use. Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy. Rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). Hypersensitivity : anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome). Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure. Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails), lichen planus. Renal: urinary abnormality (including dysuria, frequency, nocturia). Respiratory: dyspnea, interstitial lung disease. Psychiatric: nightmare. Reproductive: gynecomastia. Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities." ], "adverse_reactions_table": [ "
% Placebo N=411% Any Dose N=902
Nausea/Vomiting7.17.4
Diarrhea5.66.7
Headache4.66.3
Upper Respiratory Infection5.85.9
Angina Pectoris3.44.5
Rash 1.44.5
CPK Increased3.64.1
Dizziness3.43.5
ALT Increased1.22.9
Chest Pain1.92.7
Cough1.72.5
Myalgia1.22.3
Influenza0.72.0
g-GT Increased1.22.0
", "
Placebo (N=10,719) % of patients Pravastatin sodium tablets (N=10,764) % of patients
Musculoskeletal Pain24.424.9
Upper Respiratory Tract Infection20.221.2
Musculoskeletal Traumatism9.610.2
Chest Pain9.810.0
Influenza9.09.2
Fatigue7.88.4
Cough7.48.2
Dizziness6.67.3
Rash (including dermatitis)7.17.2
Sinus Abnormality6.77.0
Muscle Cramp4.65.1
" ], "drug_interactions": [ "7 DRUG INTERACTIONS · See full prescribing information for details regarding concomitant use of Pravastatin sodium tablets with other drugs that increase the risk of myopathy and rhabdomyolysis. ( 2.5 , 7.1 ) · Bile Acid Sequestrants: in patients taking a bile acid sequestrant, administer Pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant ( 7.2 ) 7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin sodium tablets Pravastatin sodium tablets is a substrate of the transport protein OATP1B1. Pravastatin sodium tablets plasma levels can be significantly increased with concomitant administration of inhibitors of OATP1B1. Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with Pravastatin sodium tabletsand instructions for preventing or managing them [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Table 3: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Pravastatin sodium tablets Gemfibrozil Clinical Impact: There is an increased risk of myopathy/rhabdomyolysis when Pravastatin sodium tablets is administered with gemfibrozil Intervention: Avoid concomitant use of gemfibrozil with Pravastatin sodium tablets. Cyclosporine Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with Pravastatin sodium tablets. Intervention: Initiate with a dosage of pravastatin sodium 10 mg once daily. Pravastatin sodium tablets is available in a 10 mg strength. Do not exceed Pravastatin sodium tablets 20 mg once daily [ see Dosage and Administration(2.5) ]. Select Macrolide Antibiotics Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with Pravastatin sodium tablets. Other macrolides (e.g., azithromycin)have the potential to increase Pravastatin sodium tablets exposures and increase the risk of myopathy and rhabdomyolysis when used concomintantly. Intervention: For patients taking erythromycin or clarithromycin, do not exceed 40mg Pravastatin sodium tablets once daily [ see Dosage and Administration (2.5) ]. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with Pravastatin sodium tablets. Intervention: Consider if the benefit of using niacin concomitantly with Pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitorpatientsforsignsandsymptomsofmyopathy,particularlyduringinitiation of therapy and during upward dose titration of either drug. Fibrates(other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysisisincreasedwithconcomitantuseoffibrateswithPravastatin sodium tablets. Intervention: Consider if the benefit of using fibrates concomitantly with Pravastatin sodium tablets outweighstheincreasedriskofmyopathyandrhabdomyolysis.Ifconcomitantuseis decided,monitorpatientsforsignsandsymptomsofmyopathy,particularlyduring initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Casesofmyopathyandrhabdomyolysishavebeenreportedwithconcomitantuseof colchicine with Pravastatin sodium tablets. Intervention: Consider if the benefit of using colchicine concomitantly with Pravastatin sodium tablets outweighstheincreasedriskofmyopathyandrhabdomyolysis.Ifconcomitantuseis decided,monitorpatientsforsignsandsymptomsofmyopathy,particularlyduring initiation of therapy and during upward dose titration of either drug. 7.2 Drug Interactions that Decrease the Efficacy of Pravastatin sodium tablets Table 4 presents drug interactions that may decrease the efficacy of Pravastatin sodium tablets and instructions for preventing or managing them. Table 4: Drug Interactions that Decrease the Efficacy of Pravastatin sodium tablets Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [ see Clinical Pharmacology (12.3) ]. Intervention: In patients taking a bile acid sequestrant, administer Pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant [ see Dosage and Administration (2.5) ]." ], "drug_interactions_table": [ "
Gemfibrozil
Clinical Impact:There is an increased risk of myopathy/rhabdomyolysis when Pravastatin sodium tablets is administered with gemfibrozil
Intervention:Avoid concomitant use of gemfibrozil with Pravastatin sodium tablets.
Cyclosporine
Clinical Impact:The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine with Pravastatin sodium tablets.
Intervention:Initiate with a dosage of pravastatin sodium 10 mg once daily. Pravastatin sodium tablets is available in a 10 mg strength. Do not exceed Pravastatin sodium tablets 20 mg once daily [ see Dosage and Administration(2.5)].
Select Macrolide Antibiotics
Clinical Impact:The risk of myopathy and rhabdomyolysis is increased by concomitant use of clarithromycin or erythromycin with Pravastatin sodium tablets. Other macrolides (e.g., azithromycin)have the potential to increase Pravastatin sodium tablets exposures and increase the risk of myopathy and rhabdomyolysis when used concomintantly.
Intervention:For patients taking erythromycin or clarithromycin, do not exceed 40mg Pravastatin sodium tablets once daily [ see Dosage and Administration (2.5)].
Niacin
Clinical Impact:Cases of myopathy and rhabdomyolysis have been observed with concomitant use of niacin with Pravastatin sodium tablets.
Intervention:Consider if the benefit of using niacin concomitantly with Pravastatin sodium tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitorpatientsforsignsandsymptomsofmyopathy,particularlyduringinitiation of therapy and during upward dose titration of either drug.
Fibrates(other than Gemfibrozil)
Clinical Impact:Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysisisincreasedwithconcomitantuseoffibrateswithPravastatin sodium tablets.
Intervention:Consider if the benefit of using fibrates concomitantly with Pravastatin sodium tablets outweighstheincreasedriskofmyopathyandrhabdomyolysis.Ifconcomitantuseis decided,monitorpatientsforsignsandsymptomsofmyopathy,particularlyduring initiation of therapy and during upward dose titration of either drug.
Colchicine
Clinical Impact:Casesofmyopathyandrhabdomyolysishavebeenreportedwithconcomitantuseof colchicine with Pravastatin sodium tablets.
Intervention:Consider if the benefit of using colchicine concomitantly with Pravastatin sodium tablets outweighstheincreasedriskofmyopathyandrhabdomyolysis.Ifconcomitantuseis decided,monitorpatientsforsignsandsymptomsofmyopathy,particularlyduring initiation of therapy and during upward dose titration of either drug.
", "
Bile Acid Sequestrants
Clinical Impact:Concomitant cholestyramine or colestipol administration decreased the mean exposure of pravastatin approximately 51% and 47%, respectively [ see ClinicalPharmacology (12.3)].
Intervention:In patients taking a bile acid sequestrant, administer Pravastatin sodium tablets at least 1 hour before or at least 4 hours after the bile acid sequestrant [ see Dosage and Administration (2.5)].
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS · Pregnancy: May cause fetal harm ( 8.1 ) · Lactation: Breastfeeding not recommended during treatment with Pravastatin sodium tablets ( 8.2 ) 8.1 Pregnancy Risk Summary Discontinue Pravastatin sodium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pravastatin sodium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, Pravastatin sodium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [ see Clinical Pharmacology (12.1) ]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid- lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with Pravastatin sodium tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m2). An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary Based on one lactation study in published literature, pravastatin is present in human milk. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Statins, including Pravastatin sodium tablets, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant. Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with Pravastatin sodium tablets [ see Use in Specific Populations (8.1) , Clinical Pharmacology (12.1) ]. 8.4 Pediatric Use The safety and effectiveness of Pravastatin sodium tablets as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of Pravastatin sodium tablets for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population. The safety and effectiveness of Pravastatin sodium tablets have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH). 8.5 Geriatric Use In clinical studies, 4,797 (36.4%) Pravastatin sodium tablets-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Mean pravastatin AUCs are 25%-50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [ see Clinical Pharmacology (12.3) ]. Advanced age (≥65 years) is a risk factor for Pravastatin sodium tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving Pravastatin sodium tablets for the increased risk of myopathy [ see Warnings and Precautions (5.1) ]. 8.6 Renal Impairment Renal impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all patients with renal impairment for development of myopathy. In patients with severe renal impairment, the recommended starting dose is pravastatin sodium 10 mg once daily. Pravastatin sodium tablets is available in a 10 mg strength. The maximum recommended dosage in patients with severe renal impairment is Pravastatin sodium tablets 40 mg once daily. The recommended dosage for patients with mild or moderate renal impairment is the same as patients with normal renal function. [ see Dosage and Administration( 2.4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Pravastatin sodium tablets shows a large inter-subject variability in pharmacokinetics in patients with liver cirrhosis [ Clinical Pharmacology (12.3) ] . Pravastatin sodium tablets is contraindicated in patients with acute liver failure or decompensated cirrhosis [ see Contraindications (4) , Warnings and Precautions (5.3) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Discontinue Pravastatin sodium tablets when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Pravastatin sodium tablets decreases synthesis of cholesterol and possibly other biologically active substances derived from cholesterol; therefore, Pravastatin sodium tablets may cause fetal harm when administered to pregnant patients based on the mechanism of action [ see Clinical Pharmacology (12.1) ]. In addition, treatment of hyperlipidemia is not generally necessary during pregnancy. Atherosclerosis is a chronic process and the discontinuation of lipid- lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Available data from case series and prospective and retrospective observational cohort studies over decades of use with statins in pregnant women have not identified a drug-associated risk of major congenital malformations. Published data from prospective and retrospective observational cohort studies with Pravastatin sodium tablets use in pregnant women are insufficient to determine if there is a drug-associated risk of miscarriage (see Data). In animal reproduction studies, no evidence of fetal malformations was seen in pregnant rats or rabbits orally administered pravastatin during the period of organogenesis at doses that resulted in 10 times and 120 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg/day, based on body surface area (mg/m2). An imbalance in some fetal skeletal variations, increased offspring mortality, and developmental delays occurred when pregnant rats were exposed to 10 times to 12 times the MRHD during organogenesis to parturition (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data A Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to 886,996 controls did not find a significant teratogenic effect from maternal use of statins in the first trimester of pregnancy, after adjusting for potential cofounders – including maternal age, diabetes mellitus, hypertension, obesity, and alcohol and tobacco use – using propensity score-based methods. The relative risk of congenital malformations between the group with statin use and the group with no statin use in the first trimester was 1.07 (95% confidence interval 0.85 to 1.37) after controlling for confounders, particularly pre-existing diabetes mellitus. There were also no statistically significant increases in any of the organ-specific malformations assessed after accounting for cofounders. In the majority of pregnancies, statin treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. Study limitations include reliance on physician coding to define the presence of a malformation, lack of control for certain confounders such as body mass index, use of prescription dispensing as verification for the use of a statin, and lack of information on non-live births. Animal Data Embryofetal and neonatal mortality was observed in rats given pravastatin during the period of organogenesis or during organogenesis continuing through weaning. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at ≥100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In other studies, no teratogenic effects were observed when pravastatin was dosed orally during organogenesis in rabbits (gestation days 6 through 18) up to 50 mg/kg/day or in rats (gestation days 7 through 17) up to 1000 mg/kg/day. Exposures were 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day MRHD based on body surface area (mg/m 2 ). In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), developmental delays were observed at ≥100 mg/kg/day systemic exposure, corresponding to 12 times the human exposure at 80 mg/day MRHD, based on body surface area (mg/m 2 ). In pregnant rats, pravastatin crosses the placenta and is found in fetal tissue at 30% of the maternal plasma levels following administration of a single dose of 20 mg/day orally on gestation day 18, which corresponds to exposure 2 times the MRHD of 80 mg daily based on body surface area (mg/m 2 )." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of Pravastatin sodium tablets as an adjunct to diet to reduce LDL-C have been established in pediatric patients 8 years of age and older with HeFH. Use of Pravastatin sodium tablets for this indication is based on a double-blind, placebo-controlled clinical study in 214 pediatric patients (100 males and 114 females) 8 years of age and older with HeFH. Doses greater than 40 mg daily have not been studied in this population. The safety and effectiveness of Pravastatin sodium tablets have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH)." ], "geriatric_use": [ "8.5 Geriatric Use In clinical studies, 4,797 (36.4%) Pravastatin sodium tablets-treated patients were aged 65 and older and 110 (0.8%) were aged 75 and older. No significant differences in efficacy or safety were observed between geriatric patients and younger patients. Mean pravastatin AUCs are 25%-50% higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [ see Clinical Pharmacology (12.3) ]. Advanced age (≥65 years) is a risk factor for Pravastatin sodium tablets-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving Pravastatin sodium tablets for the increased risk of myopathy [ see Warnings and Precautions (5.1) ]." ], "overdosage": [ "10 OVERDOSAGE No specific antidotes for Pravastatin sodium tablets are known. Contact Poison Control (1-800-222-1222) for latest recommendations." ], "description": [ "11 DESCRIPTION Pravastatin sodium tablets is a statin, an inhibitor of 3-hydroxy-3-methylglutaryl- coenzyme A (HMG-CoA) reductase. Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula: Pravastatin sodium is an odorless, white to off-white, fine or crystalline powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7. It is soluble in methanol and water (>300 mg/mL), slightly soluble in isopropanol, and practically insoluble in acetone, acetonitrile, chloroform, and ether. Pravastatin sodium tablets for oral use contain 10 mg, 20 mg, 40 mg, and 80 mg pravastatin sodium, which is equivalent to 9.46, 18.97, 37.94 and 75.88 mg of pravastatin, respectively. Inactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, dehydrated alcohol, dibasic sodium phosphate anhydrous, ferric oxide brown, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol. 12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of Pravastatin sodium tablets is usually achieved by 4 weeks and is maintained after that. 12.3 Pharmacokinetics Absorption Pravastatin sodium tablets is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin Cmax and AUC follwing a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of Pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for pravastatin is 1.8 hours in humans and the elimination half-life (t½) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations (8.6)]. Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations (8.6)]. Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, Cmax, Tmax, and t½ values were similar in older and younger subjects [See Use in Specific Populations (8.5).] Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [See Use in Specific Populations (8.4).] Drug-Drug Interactions Table 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ¯47% ¯53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ¯40% ↑12% ¯12% ¯39% ↑30% ¯6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ¯51% ¯38% ¯18% ↑4.9% ↑23% ¯33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ¯34% ¯16% ¯33% ¯16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑33% ↑26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ¯28% ¯24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ¯13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ¯7.0% ¯20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ¯3.6% ¯8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 20 mg single dose ¯1.8% ↑3.7% BID = twice daily; OD = once daily; QID = four times daily Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17% ↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0% ↑1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change BID = twice daily; OD = once daily" ], "clinical_pharmacology_table": [ "
Coadministered Drug and Dosing RegimenPravastatin
Dose (mg)Change in AUCChange in C max
Cyclosporine 5 mg/kg single dose40 mg single dose↑282%↑327%
Clarithromycin 500 mg BID for 9 days40 mg OD for 8 days↑110%↑128%
Boceprevir 800 mg TID for 6 days40 mg single dose↑63%↑49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days40 mg single dose↑81%↑63%
Colestipol 10 g single dose20 mg single dose¯47%¯53%
Cholestyramine 4 g single doseAdministered simultaneouslyAdministered 1 hour prior to cholestyramineAdministered 4 hours after cholestyramine20 mg single dose¯40%↑12%¯12%¯39%↑30%¯6.8%
Cholestyramine 24 g OD for 4 weeks20 mg BID for 8 weeks5 mg BID for 8 weeks 10 mg BID for 8 weeks ¯51%¯38%¯18%↑4.9%↑23%¯33%
Fluconazole200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV20 mg PO+10 mg IV¯34%¯16%¯33%¯16%
Kaletra 400 mg/100 mg BID for 14 days20 mg OD for 4 days↑33%↑26%
Verapamil IR 120 mg for 1 day andVerapamil ER 480 mg for 3 days40 mg single dose↑31%↑42%
Cimetidine 300 mg QID for 3 days20 mg single dose↑30%↑9.8%
Antacids 15 mL QID for 3 days20 mg single dose¯28%¯24%
Digoxin 0.2 mg OD for 9 days20 mg OD for 9 days↑23%↑26%
Probucol 500 mg single dose20 mg single dose↑14%↑24%
Warfarin 5 mg OD for 6 days20 mg BID for 6 days¯13%↑6.7%
Itraconazole 200 mg OD for 30 days40 mg OD for 30 days↑11% (compared to Day 1)↑17% (compared to Day 1)
Gemfibrozil 600 mg single dose20 mg single dose¯7.0%¯20%
Aspirin 324 mg single dose20 mg single dose↑4.7%↑8.9%
Niacin 1 g single dose20 mg single dose¯3.6%¯8.2%
Diltiazem20 mg single dose↑2.7%↑30%
Grapefruit juice20 mg single dose¯1.8%↑3.7%
", "
Pravastatin Dosing RegimenName and DoseChange in AUCChange in C max
20 mg BID for 6 daysWarfarin 5 mg OD for 6 days Change in mean prothrombin time↑17%↑0.4 sec↑15%
20 mg OD for 9 daysDigoxin 0.2 mg OD for 9 days↑4.6%↑5.3%
20 mg BID for 4 weeks10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose↑3.0%↑1.6%↑ Less than 1%Not Reported
20 mg OD for 4 daysKaletra 400 mg/100 mg BID for 14 daysNo changeNo change
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Pravastatin is a reversible inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Inhibition of HMG-CoA reductase by pravastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of Pravastatin sodium tablets is usually achieved by 4 weeks and is maintained after that." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption Pravastatin sodium tablets is administered orally in the active form. Peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces area under the concentration-time curve (AUC) and C max by 31% and 49%, respectively, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals. Pravastatin plasma concentrations, including AUC, C max , and steady-state minimum (C min ), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose. The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin Cmax and AUC follwing a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively. Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of Pravastatin sodium tablets. Distribution Approximately 50% of the circulating drug is bound to plasma proteins. Elimination Metabolism The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66). Excretion Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation). Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for pravastatin is 1.8 hours in humans and the elimination half-life (t½) for total radioactivity (pravastatin plus metabolites) is 77 hours. Specific Populations Renal Impairment A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945) [see Use in Specific Populations (8.6)]. Hepatic Impairment In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects [see Use in Specific Populations (8.6)]. Geriatric In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, Cmax, Tmax, and t½ values were similar in older and younger subjects [See Use in Specific Populations (8.5).] Pediatric After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for pediatric patients 8 to 11 years (N=14) and 12 to 16 years (N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for pediatric patients 8 to 11 years and 12 to 16 years, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability [See Use in Specific Populations (8.4).] Drug-Drug Interactions Table 5: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Coadministered Drug and Dosing Regimen Pravastatin Dose (mg) Change in AUC Change in C max Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ¯47% ¯53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ¯40% ↑12% ¯12% ¯39% ↑30% ¯6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ¯51% ¯38% ¯18% ↑4.9% ↑23% ¯33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ¯34% ¯16% ¯33% ¯16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑33% ↑26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ¯28% ¯24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ¯13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ¯7.0% ¯20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ¯3.6% ¯8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 20 mg single dose ¯1.8% ↑3.7% BID = twice daily; OD = once daily; QID = four times daily Table 6: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17% ↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0% ↑1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change BID = twice daily; OD = once daily" ], "pharmacokinetics_table": [ "
Coadministered Drug and Dosing RegimenPravastatin
Dose (mg)Change in AUCChange in C max
Cyclosporine 5 mg/kg single dose40 mg single dose↑282%↑327%
Clarithromycin 500 mg BID for 9 days40 mg OD for 8 days↑110%↑128%
Boceprevir 800 mg TID for 6 days40 mg single dose↑63%↑49%
Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days40 mg single dose↑81%↑63%
Colestipol 10 g single dose20 mg single dose¯47%¯53%
Cholestyramine 4 g single doseAdministered simultaneouslyAdministered 1 hour prior to cholestyramineAdministered 4 hours after cholestyramine20 mg single dose¯40%↑12%¯12%¯39%↑30%¯6.8%
Cholestyramine 24 g OD for 4 weeks20 mg BID for 8 weeks5 mg BID for 8 weeks 10 mg BID for 8 weeks ¯51%¯38%¯18%↑4.9%↑23%¯33%
Fluconazole200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV20 mg PO+10 mg IV¯34%¯16%¯33%¯16%
Kaletra 400 mg/100 mg BID for 14 days20 mg OD for 4 days↑33%↑26%
Verapamil IR 120 mg for 1 day andVerapamil ER 480 mg for 3 days40 mg single dose↑31%↑42%
Cimetidine 300 mg QID for 3 days20 mg single dose↑30%↑9.8%
Antacids 15 mL QID for 3 days20 mg single dose¯28%¯24%
Digoxin 0.2 mg OD for 9 days20 mg OD for 9 days↑23%↑26%
Probucol 500 mg single dose20 mg single dose↑14%↑24%
Warfarin 5 mg OD for 6 days20 mg BID for 6 days¯13%↑6.7%
Itraconazole 200 mg OD for 30 days40 mg OD for 30 days↑11% (compared to Day 1)↑17% (compared to Day 1)
Gemfibrozil 600 mg single dose20 mg single dose¯7.0%¯20%
Aspirin 324 mg single dose20 mg single dose↑4.7%↑8.9%
Niacin 1 g single dose20 mg single dose¯3.6%¯8.2%
Diltiazem20 mg single dose↑2.7%↑30%
Grapefruit juice20 mg single dose¯1.8%↑3.7%
", "
Pravastatin Dosing RegimenName and DoseChange in AUCChange in C max
20 mg BID for 6 daysWarfarin 5 mg OD for 6 days Change in mean prothrombin time↑17%↑0.4 sec↑15%
20 mg OD for 9 daysDigoxin 0.2 mg OD for 9 days↑4.6%↑5.3%
20 mg BID for 4 weeks10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose↑3.0%↑1.6%↑ Less than 1%Not Reported
20 mg OD for 4 daysKaletra 400 mg/100 mg BID for 14 daysNo changeNo change
" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC. In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors. No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No adverse effects were seen in juvenile rats dosed with 5 mg/kg/day pravastatin (5 times plasma exposure at the maximum recommended human dose [MRHD] of 80 mg based on AUC) in a study of pravastatin administered from postnatal days (PND) 4 through 80 at 5, 15 and 45 mg/kg/day. A PND 4 rat is generally comparable to a 3rd trimester human fetus with regards to neurologic development/myelination. At ≥ 15 mg/kg/day (≥ 20 times the MRHD), decreased body-weight gain was observed during the pre-weaning period and slight thinning of the corpus callosum was observed at the end of the drug-free recovery period (PND 132). Thinning of the corpus callosum was not associated with any inflammatory or degenerative changes in the brain. Impacts on neurobehavioral and learning endpoints were detected only at very high exposures (43 times the MRHD). No thinning of the corpus callosum was observed in rats dosed with pravastatin for 3 months beginning on PND 35 at ≥ 250 mg/kg/day. PND 35 in a rat is approximately equivalent to an 8 to 12-year-old human child." ], "clinical_studies": [ "14 CLINICAL STUDIES Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), the effect of Pravastatin sodium tablets on fatal and nonfatal CHD was assessed in 6595 male patients 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL. In this randomized, double-blind, placebo- controlled study, patients were treated with standard care, including dietary advice, and either Pravastatin sodium tablets 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25 th , 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36.0, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively. Pravastatin sodium tablets significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the Pravastatin sodium tablets group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with Pravastatin sodium tablets was similar across the age range studied and throughout the range of baseline LDL cholesterol levels. Pravastatin sodium tablets also decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients).Cardiovascular deaths were decreased by 32% (73 vs 50) and there was no increase in death from non-cardiovascular causes. Secondary Prevention of Cardiovascular Events In the LIPID study, the effect of Pravastatin sodium tablets, 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 patients ≥65 years; 782 patients with diabetes) who had experienced either an MI (5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total- C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with Pravastatin sodium tablets significantly reduced the risk for total mortality by reducing coronary death (see Table 7). The risk reduction due to treatment with Pravastatin sodium tablets on CHD mortality was consistent regardless of age. Pravastatin sodium tablets significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 7: LIPID - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin sodium tablets 40 mg (N=4512) Placebo (N=4502) Risk Reduction p -value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE study, the effect of Pravastatin sodium tablets, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with Pravastatin sodium tablets significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 8). Table 8: CARE - Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin sodium tablets 40 mg (N=2081) Placebo (N=2078) Risk Reduction p -value Primary Endpoint CHD mortality or nonfatal MI a 212 (10.2) 274 (13.2) 24% 0.003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% <0.001 Stroke or TIA 93 (4.5) 124 (6.0) 26% 0.029 a The risk reduction due to treatment with Pravastatin sodium tablets was consistent in both sexes. Primary Hyperlipidemia In multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with Pravastatin sodium tablets in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, and TG (see Table 9). In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hyperlipidemia, treatment with Pravastatin sodium tablets at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25 th and 75 th percentile changes from baseline in LDL-C for Pravastatin sodium tablets 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 9). Table 9: Primary Hyperlipidemia Trials: Dose Response of Pravastatin sodium tablets Once Daily Administration Dose Total- C LDL- C HDL- C TG Mean Percent Changes From Baseline After 8 Weeks a Placebo (N=36) −3% −4% +1% −4% 10 mg (N=18) −16% −22% +7% −15% 20 mg (N=19) −24% −32% +2% −11% 40 mg (N=18) −25% −34% +12% −24% Mean Percent Changes From Baseline After 6 Weeks b Placebo (N=162) 0% −1% −1% +1% 80 mg (N=277) −27% −37% +3% −19% a A multicenter, double-blind, placebo-controlled study. b Pooled analysis of 2 multicenter, double-blind, placebo-controlled studies. Hypertriglyceridemia The response to Pravastatin sodium tablets in patients with hypertriglyceridemia (baseline TG >200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients from the CARE study. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246.0 (200.5, 349.5) mg/dL (see Table 10). Table 10: Patients with Hypertriglyceridemia Median (25 th , 75 th percentile) % Change from Baseline Pravastatin 40 mg (N=429) Placebo (N=430) TG −21.1 (−34.8, 1.3) −6.3 (−23.1, 18.3) Total-C −22.1 (−27.1, −14.8) 0.2 (−6.9, 6.8) LDL-C −31.7 (−39.6, −21.5) 0.7 (−9.0, 10.0) HDL-C 7.4 (−1.2, 17.7) 2.8 (−5.7, 11.7) Non-HDL-C −27.2 (−34.0, −18.5) −0.8 (−8.2, 7.0) Dysbetalipoproteinemia The response to Pravastatin sodium tablets in two double-blind crossover studies of 46 patients with genotype E2/E2 and dysbetalipoproteinemia is shown in Table 11. Table 11: Patients with Dysbetalipoproteinemia Median (min, max) % Change from Baseline Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=20) Study 1 Total-C 386.5 (245.0, 672.0) −32.7 (−58.5, 4.6) TG 443.0 (275.0, 1299.0) −23.7 (−68.5, 44.7) VLDL-C a 206.5 (110.0, 379.0) −43.8 (−73.1, −14.3) LDL-C a 117.5 (80.0, 170.0) −40.8 (−63.7, 4.6) HDL-C 30.0 (18.0, 88.0) 6.4 (−45.0, 105.6) Non-HDL-C 344.5 (215.0, 646.0) −36.7 (−66.3, 5.8) a N=14 Median (min, max) at Baseline (mg/dL) Median % Change (min, max) Pravastatin 40 mg (N=26) Study 2 Total-C 340.3 (230.1, 448.6) −31.4 (−54.5, −13.0) TG 343.2 (212.6, 845.9) −11.9 (−56.5, 44.8) VLDL-C 145.0 (71.5, 309.4) −35.7 (−74.7, 19.1) LDL-C 128.6 (63.8, 177.9) −30.3 (−52.2, 13.5) HDL-C 38.7 (27.1, 58.0) 5.0 (−17.7, 66.7) Non-HDL-C 295.8 (195.3, 421.5) −35.5 (−81.0, −13.5) HeFH in Pediatric Patients Aged 8 Years and Above A double-blind, placebo-controlled study in 214 pedatric patients (100 males and 114 females) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The pediatric patients aged 8 to 13 years were randomized to placebo (N=63) or 20 mg of Pravastatin sodium tablets daily (N=65) and the pediatric patients aged 14 to 18 years were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151-405 mg/dL) and placebo (range: 154-375 mg/dL) groups, respectively. Pravastatin sodium tablets significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both pediatric age groups (see Table 12). The effect of Pravastatin sodium tablets treatment in the 2 age groups was similar. Table 12: Lipid-Lowering Effects of Pravastatin sodium tablets in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a Pravastatin 20 mg (Aged 8-13 years) N=65 Pravastatin 40 mg (Aged 14-18 years) N=41 Combined Pravastatin (Aged 8-18 years) N=106 Combined Placebo (Aged 8-18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo LDL-C −26.04 b −21.07 b −24.07 b −1.52 (−26.74, −18.86) TC −20.75 b −13.08 b −17.72 b −0.65 (−20.40, −13.83) HDL-C 1.04 13.71 5.97 3.13 (−1.71, 7.43) TG −9.58 −0.30 −5.88 −3.27 (−13.95, 10.01) ApoB −23.16 b −18.08 b −21.11 b −0.97 (−24.29, −16.18) (N) (61) (39) (100) (106) a The above least-squares mean values were calculated based on log-transformed lipid values. b Significant at p≤0.0001 when compared with placebo. The mean achieved LDL-C was 186 mg/dL (range: 67-363 mg/dL) in the Pravastatin sodium tablets group k to 236 mg/dL (range: 105-438 mg/dL) in the placebo group. graph-1" ], "clinical_studies_table": [ "
Number (%) of Subjects
EventPravastatin sodium tablets 40 mg (N=4512)Placebo (N=4502)Risk Reduction p-value
Primary Endpoint
CHD mortality287 (6.4)373 (8.3)24%0.0004
Secondary Endpoints
Total mortality498 (11.0)633 (14.1)23%<0.0001
CHD mortality or nonfatal MI557 (12.3)715 (15.9)24%<0.0001
Myocardial revascularization procedures (CABG or PTCA)584 (12.9)706 (15.7)20%<0.0001
Stroke
All-cause169 (3.7)204 (4.5)19%0.0477
Non-hemorrhagic154 (3.4)196 (4.4)23%0.0154
Cardiovascular mortality331 (7.3)433 (9.6)25%<0.0001
", "
Number (%) of Subjects
EventPravastatin sodium tablets 40 mg (N=2081)Placebo (N=2078)Risk Reduction p-value
Primary Endpoint
CHD mortality or nonfatal MI a212 (10.2)274 (13.2)24%0.003
Secondary Endpoints
Myocardial revascularization procedures (CABG or PTCA)294 (14.1)391 (18.8)27%<0.001
Stroke or TIA93 (4.5)124 (6.0)26%0.029
", "
DoseTotal-CLDL-CHDL-CTG
Mean Percent Changes From Baseline After 8 Weeks a
Placebo (N=36)−3%−4%+1%−4%
10 mg (N=18)−16%−22%+7%−15%
20 mg (N=19)−24%−32%+2%−11%
40 mg (N=18)−25%−34%+12%−24%
Mean Percent Changes From Baseline After 6 Weeks b
Placebo (N=162)0%−1%−1%+1%
80 mg (N=277)−27%−37%+3%−19%
", "
Pravastatin 40 mg (N=429)Placebo (N=430)
TG−21.1 (−34.8, 1.3)−6.3 (−23.1, 18.3)
Total-C−22.1 (−27.1, −14.8)0.2 (−6.9, 6.8)
LDL-C−31.7 (−39.6, −21.5)0.7 (−9.0, 10.0)
HDL-C7.4 (−1.2, 17.7)2.8 (−5.7, 11.7)
Non-HDL-C−27.2 (−34.0, −18.5)−0.8 (−8.2, 7.0)
", "
Median (min, max) at Baseline (mg/dL)Median % Change (min, max) Pravastatin 40 mg (N=20)
Study 1
Total-C386.5 (245.0, 672.0)−32.7 (−58.5, 4.6)
TG443.0 (275.0, 1299.0)−23.7 (−68.5, 44.7)
VLDL-C a206.5 (110.0, 379.0)−43.8 (−73.1, −14.3)
LDL-C a117.5 (80.0, 170.0)−40.8 (−63.7, 4.6)
HDL-C30.0 (18.0, 88.0)6.4 (−45.0, 105.6)
Non-HDL-C344.5 (215.0, 646.0)−36.7 (−66.3, 5.8)
", "
Median (min, max) at Baseline (mg/dL)Median % Change (min, max) Pravastatin 40 mg (N=26)
Study 2
Total-C340.3 (230.1, 448.6)−31.4 (−54.5, −13.0)
TG343.2 (212.6, 845.9)−11.9 (−56.5, 44.8)
VLDL-C145.0 (71.5, 309.4)−35.7 (−74.7, 19.1)
LDL-C128.6 (63.8, 177.9)−30.3 (−52.2, 13.5)
HDL-C38.7 (27.1, 58.0)5.0 (−17.7, 66.7)
Non-HDL-C295.8 (195.3, 421.5)−35.5 (−81.0, −13.5)
", "
Pravastatin 20 mg (Aged 8-13 years) N=65Pravastatin 40 mg (Aged 14-18 years) N=41Combined Pravastatin (Aged 8-18 years) N=106Combined Placebo (Aged 8-18 years) N=10895% CI of the Difference Between Combined Pravastatin and Placebo
LDL-C−26.04 b−21.07 b−24.07 b−1.52(−26.74, −18.86)
TC−20.75 b−13.08 b−17.72 b−0.65(−20.40, −13.83)
HDL-C1.0413.715.973.13(−1.71, 7.43)
TG−9.58−0.30−5.88−3.27(−13.95, 10.01)
ApoB−23.16 b−18.08 b−21.11 b−0.97(−24.29, −16.18)
(N)(61)(39)(100)(106)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Pravastatin sodium tablets, USP are supplied as: 10 mg tablets: light brown, mottled, round tablets, debossed with FL15 on one side and plain on the other side. NDC 24689-140-01, bottle of 30 tablets NDC 24689-140-02, bottle of 90 tablets NDC 24689-140-03, bottle of 100 tablets NDC 24689-140-04, bottle of 500 tablets 20 mg tablets: light brown, mottled, round tablets, debossed with FL16 on one side and plain on the other side. NDC 24689-141-01, bottle of 30 tablets NDC 24689-141-02, bottle of 90 tablets NDC 24689-141-03, bottle of 100 tablets NDC 24689-141-04, bottle of 500 tablets NDC 24689-141-05, bottle of 1000 tablets 40 mg tablets: light brown, mottled, round tablets, debossed with FL17 on one side and plain on the other side. NDC 24689-142-01, bottle of 30 tablets NDC 24689-142-02, bottle of 90 tablets NDC 24689-142-03, bottle of 100 tablets NDC 24689-142-04, bottle of 500 tablets NDC 24689-142-05, bottle of 1000 tablets 80 mg tablets: light brown, mottled, capsule shape, unscored tablets, debossed with FL18 on one side and plain on other side.. NDC 24689-143-01, bottle of 90 tablets NDC 24689-143-02, bottle of 100 tablets NDC 24689-143-03, bottle of 500 tablets Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Myopathy and Rhabdomyolysis Advise patients that Pravastatin sodium tablets may cause myopathy and rhabdomyolysis. Inform patients that the risk is increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever [ see Warnings and Precautions (5.1) , Drug Interactions (7.1) ]. Hepatic Dysfunction Inform patients that Pravastatin sodium tablets may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [ see Warnings and Precautions (5.3) ]. Increases in HbA1c and Fasting Serum Glucose Levels Inform patients that increases in HbA1c and fasting serum glucose levels may occur with Pravastatin sodium tablets. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [ see Warnings and Precautions (5.4) ]. Pregnancy Advise pregnant patients and patients who may become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if Pravastatin sodium tablets should be discontinued [ see Use in Specific Populations (8.1) ] . Lactation Advise patients that breastfeeding is not recommended during treatment with Pravastatin sodium tablets [ see Use in Specific Populations (8.2) ] . Manufactured for: Apnar Pharma LP CHINO, CA, USA 91710 Rev. 06/2022" ], "package_label_principal_display_panel": [ "Specimen label for batches packed at Apnar Pharma Private Limited NDC 24689-140-02 Pravastatin Sodium Tablets, USP 10 mg Rx 90 Tablets NDC 24689-141-02 Pravastatin Sodium Tablets, USP 20 mg Rx 90 Tablets NDC 24689-141-05 Pravastatin Sodium Tablets, USP 20 mg Rx 1000 Tablets NDC 24689-142-02 Pravastatin Sodium Tablets, USP 40 mg Rx 90 Tablets NDC 24689-142-05 Pravastatin Sodium Tablets, USP 40 mg Rx 1000 Tablets NDC 24689-143-01 Pravastatin Sodium Tablets, USP 80 mg Rx 90 Tablets 10mg_90ct 20mg_90ct 20mg_1000ct 40mg_90ct 40mg_1000ct 80mg_90ct" ], "set_id": "0158f4f6-ffe6-4c93-892b-5e4ac39d98fb", "id": "74107490-e051-4381-b181-05831b6c821d", "effective_time": "20260510", "version": "5", "openfda": {} } ] }