{ "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": "2026-06-05", "results": { "skip": 0, "limit": 10, "total": 67 } }, "results": [ { "spl_product_data_elements": [ "Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID MANNITOL SODIUM ACETATE WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID MANNITOL SODIUM ACETATE WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID MANNITOL SODIUM ACETATE WATER" ], "recent_major_changes": [ "Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.5 ) 07/2024" ], "recent_major_changes_table": [ "
Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats (5.5)07/2024
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Octreotide Acetate Injection is a somatostatin analogue indicated: Acromegaly : To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. ( 1.1 ) Carcinoid Tumors : For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. ( 1.2 ) Vasoactive Intestinal Peptide Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. ( 1.3 ) Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects. ( 1.4 ) 1.1 Acromegaly Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. 1.2 Carcinoid Tumors Octreotide Acetate Injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors Octreotide Acetate Injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors. 1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Octreotide Acetate injection may be administered subcutaneously or intravenously. ( 2.1 ) Acromegaly : Recommended initial Octreotide Acetate injection dosage is 50 mcg three times daily during the initial 2 weeks of therapy. Maintenance dose 100 mcg to 500 mcg three times daily. ( 2.2 ) Carcinoid Tumors : Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy. ( 2.3 ) VIPomas : Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. ( 2.4 ) 2.1 Dosage and Administration Overview Octreotide Acetate injection may be administered subcutaneously or intravenously. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Sites should be rotated in a systematic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Octreotide Acetate injection is not compatible in Total Parenteral Nutrition solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product. Octreotide Acetate injection may be diluted in volumes of 50 mL to 200 mL and infused intravenously over 15 to 30 minutes or administered by intravenous (IV) push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus. Assess total and/or free T4 levels at baseline and periodically during chronic octreotide acetate therapy. 2.2 Recommended Dosage and Monitoring for Acromegaly The recommended initial dosage of octreotide acetate is 50 mcg three times daily to be administered subcutaneously. Increase octreotide acetate dose based upon GH or IGF-1 levels. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 levels within normal range. Monitor GH or IGF-1 every two weeks after initiating octreotide acetate therapy or with dosage change, and to guide titration. The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. Octreotide Acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, Octreotide Acetate injection therapy may be resumed. 2.3 Recommended Dosage and Monitoring for Carcinoid Tumors The recommended daily dosage of Octreotide Acetate injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in two to four divided doses given subcutaneously (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. Measurement of urinary 5-hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy. 2.4 Recommended Dosage and Monitoring for Vasoactive Intestinal Peptide Tumors Daily dosages of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required. Measurement of Plasma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy. Discard unused portion." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 50 mcg per mL, 100 mcg per mL, or 500 mcg per mL of octreotide (as acetate) as a clear solution in a single-dose vial. Injection: 50 mcg per mL, 100 mcg per mL, or 500 mcg per mL of octreotide (as acetate) in a single-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Sensitivity to this drug or any of its components. Sensitivity to this drug or any of its components. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Cardiac Function Abnormalities : Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving octreotide acetate injection intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. ( 5.1 ) Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.2 ) Glucose Metabolism : Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. ( 5.3 ) Thyroid Function : Hypothyroidism may occur. Monitor thyroid levels periodically. ( 5.4 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. ( 5.5 ) 5.1 Cardiac Function Abnormalities Complete Atrioventricular Block Patients who receive octreotide acetate injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving IV octreotide acetate injection during surgical procedures. In the majority of patients, octreotide acetate injection was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving octreotide acetate injection for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate injection intravenously. Other Cardiac Conduction Abnormalities Other cardiac conduction abnormalities have occurred during treatment with octreotide acetate injection. In acromegalic patients, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during octreotide acetate injection therapy [see Adverse Reactions (6)] . Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of octreotide acetate injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge. 5.2 Cholelithiasis and Complications of Cholelithiasis Octreotide acetate injection may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide acetate injection therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate injection for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide acetate injection therapy and died. If complications of cholelithiasis are suspected, discontinue octreotide acetate injection and treat appropriately. 5.3 Hyperglycemia and Hypoglycemia Octreotide acetate injection alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate injection therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate injection in 3% and 16% of acromegalic patients, respectively [see Adverse Reactions (6)] . Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate injection therapy was reported in one patient with no history of hyperglycemia. Monitor glucose levels during octreotide acetate injection therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly. 5.4 Thyroid Function Abnormalities Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T 4 ) is recommended during chronic therapy [see Adverse Reactions (6)] . 5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including octreotide acetate. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving octreotide acetate, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly. 5.6 Changes in Vitamin B12 Levels Depressed vitamin B 12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide acetate injection therapy, and monitoring of vitamin B 12 levels is recommended during octreotide acetate injection therapy." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Complete Atrioventricular Block [see Warnings and Precautions (5.1)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.2)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.3)] Thyroid Function Abnormalities [see Warnings and Precautions (5.4)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.5)] Changes in Vitamin B12 Levels [see Warnings and Precautions (5.6)] Most common adverse reactions (incidence > 10%) in patients with acromegaly are gallbladder abnormalities, sinus bradycardia, diarrhea, loose stools, nausea, abdominal discomfort, hyperglycemia, and hypothyroidism. In other patients, most common adverse reactions (incidence > 10%) are gallbladder abnormalities. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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, 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. Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide acetate injection therapy [see Warnings and Precautions (5.1)] . In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate injection for 1 month or less developed gallstones. Cardiac In acromegalics, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate injection therapy [see Warnings and Precautions (5.1)] . Gastrointestinal Diarrhea, loose stools, nausea, and abdominal discomfort were each seen in 34% to 61% of acromegalic patients in U.S. studies. 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5% to 10% of patients with carcinoid tumors and VIPomas. The frequency of these symptoms was not dose related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness, and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 8% and 4% required initiation of thyroid replacement therapy during octreotide acetate injection therapy [see Warnings and Precautions (5.4)] . In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6%, and dizziness in 5%. Pancreatitis was also observed [see Warnings and Precautions (5.2)] . Other Adverse Events 1% to 4% Other events, each observed in 1% to 4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance, and depression. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide acetate injection. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of octreotide acetate injection. 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. Hepatobiliary : cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy Gastrointestinal : intestinal obstruction, pancreatic exocrine insufficiency Hematologic : thrombocytopenia" ], "drug_interactions": [ "7 DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with octreotide acetate injection : cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. ( 7 ) Lutetium Lu 177 Dotatate Injection : Discontinue octreotide acetate injection at least 24 hours prior to each lutetium Lu 177 dotatate dose. ( 7.6 ) 7.1 Cyclosporine Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide acetate injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when octreotide acetate injection treatment is initiated or when the dose is altered and anti-diabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. 7.6 Lutetium Lu 177 Dotatate Injection Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue octreotide acetate injection at least 24 hours prior to each lutetium Lu 177 dotatate dose." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential : Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) 8.1 Pregnancy Risk Summary The limited data with octreotide acetate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA ( 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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide acetate injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02-1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA. 8.2 Lactation Risk Summary There is no information available on the presence of octreotide acetate injection in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for octreotide acetate injection, and any potential adverse effects on the breastfed child from octreotide acetate injection or from the underlying maternal condition. Data Following a subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at a low concentration compared to plasma (milk/plasma ratio of 0.009). 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility. 8.4 Pediatric Use Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide acetate injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month. 8.5 Geriatric Use Clinical studies of octreotide acetate injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment In patients with severe renal failure requiring dialysis, the half-life of octreotide acetate may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)] . 8.7 Hepatic Impairment-Cirrhotic Patients In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary The limited data with octreotide acetate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA ( 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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide acetate injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02-1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA." ], "pediatric_use": [ "8.4 Pediatric Use Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide acetate injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of octreotide acetate injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "overdosage": [ "10 OVERDOSAGE A limited number of accidental overdoses of octreotide acetate injection in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss. If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222." ], "description": [ "11 DESCRIPTION Octreotide Acetate Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered lactic acid solution for administration by deep subcutaneous or intravenous injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic (2 → 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. Octreotide Acetate Injection is available as sterile 1-mL vials in 3 strengths, containing 50 mcg, 100 mcg, or 500 mcg octreotide (as acetate). Each vial also contains glacial acetic acid, USP (2 mg), mannitol, USP (45 mg), sodium acetate trihydrate, USP (2 mg), water for injection, USP (quantity sufficient to 1 mL). Glacial acetic acid, USP and sodium acetate trihydrate, USP are added to provide a buffered solution, pH to 4.2 ± 0.5. The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: Structural image" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Octreotide acetate injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea). 12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)] . Octreotide suppresses secretion of TSH. 12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, IV and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (V dss ) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. In patients with acromegaly, the volume of distribution (V dss ) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of octreotide acetate injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal impairment (CL CR 40 to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR 10 to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal impairment not requiring dialysis (CL CR < 10 mL/min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. 12.6 Immunogenicity Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate injection were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients." ], "mechanism_of_action": [ "12.1 Mechanism of Action Octreotide acetate injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea)." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)] . Octreotide suppresses secretion of TSH." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, IV and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (V dss ) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. In patients with acromegaly, the volume of distribution (V dss ) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of octreotide acetate injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal impairment (CL CR 40 to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR 10 to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal impairment not requiring dialysis (CL CR < 10 mL/min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Octreotide Acetate Injection is available in 1 mL single-dose vials as follows: NDC Octreotide Acetate Injection Package Factor 71288- 566 -02 50 mcg per mL Single-Dose Vial 10 vials per carton 71288- 567 -02 100 mcg per mL Single-Dose Vial 10 vials per carton 71288- 568 -02 500 mcg per mL Single-Dose Vial 10 vials per carton Storage and Handling For prolonged storage, Octreotide Acetate Injection single-dose vials should be stored at refrigerated temperatures 2°C to 8°C (36°F to 46°F) and store in outer carton in order to protect from light. At room temperature (20°C to 30°C or 70°F to 86°F), Octreotide Acetate Injection is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. Vials should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly. Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. Sterile, Nonpyrogenic. Preservative-free. The container closure is not made with natural rubber latex." ], "how_supplied_table": [ "
NDCOctreotide Acetate InjectionPackage Factor
71288-566-02 50 mcg per mL Single-Dose Vial 10 vials per carton
71288-567-02 100 mcg per mL Single-Dose Vial 10 vials per carton
71288-568-02 500 mcg per mL Single-Dose Vial10 vials per carton
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Sterile Subcutaneous Injection Technique Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer octreotide acetate injection. Cholelithiasis and Complications of Cholelithiasis Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of cholelithiasis (e.g., cholecystitis, cholangitis, and pancreatitis) [see Warnings and Precautions (5.2)] . Steatorrhea and Malabsorption of Dietary Fats Advise patients to contact their healthcare provider if they experience new or worsening of steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss [see Warnings and Precautions (5.5)] . Pregnancy Inform female patients that treatment with octreotide acetate injection may result in unintended pregnancy [see Use in Specific Populations (8.3)] . meitheal ® Mfd. for Meitheal Pharmaceuticals Chicago, IL 60631 (USA) ©2024 Meitheal Pharmaceuticals Inc. Mfd. by Nanjing King-Friend Biochemical Pharmaceutical Co., Ltd. Nanjing, China 210061 September 2024 8S7AAM9-00" ], "package_label_principal_display_panel": [ "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 50 mcg Vial Label NDC 71288- 566 -01 Rx Only Octreotide Acetate Injection 50 mcg per mL For Subcutaneous or Intravenous Use 1 mL Single-Dose Vial PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 50 mcg Vial Label", "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 50 mcg Carton NDC 71288- 566 -02 Rx Only Octreotide Acetate Injection 50 mcg per mL For Subcutaneous or Intravenous Use 10 x 1 mL Single-Dose Vials PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 50 mcg Carton", "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 100 mcg Vial Label NDC 71288- 567 -01 Rx Only Octreotide Acetate Injection 100 mcg per mL For Subcutaneous or Intravenous Use 1 mL Single-Dose Vial PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 100 mcg Vial Label", "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 100 mcg Carton NDC 71288- 567 -02 Rx Only Octreotide Acetate Injection 100 mcg per mL For Subcutaneous or Intravenous Use 10 x 1 mL Single-Dose Vials PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 100 mcg Carton", "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 500 mcg Vial Label NDC 71288- 568 -01 Rx Only Octreotide Acetate Injection 500 mcg per mL For Subcutaneous or Intravenous Use 1 mL Single-Dose Vial PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 500 mcg Vial Label", "PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 500 mcg Carton NDC 71288- 568 -02 Rx Only Octreotide Acetate Injection 500 mcg per mL For Subcutaneous or Intravenous Use 10 x 1 mL Single-Dose Vials PACKAGE LABEL PRINCIPAL DISPLAY PANEL - Octreotide Acetate Injection 500 mcg Carton" ], "set_id": "01962c67-e551-47b6-a276-e1ae1860d2a4", "id": "a12a7206-6077-4b61-a038-4aae1170b387", "effective_time": "20250116", "version": "1", "openfda": { "application_number": [ "ANDA075957" ], "brand_name": [ "Octreotide Acetate" ], "generic_name": [ "OCTREOTIDE ACETATE" ], "manufacturer_name": [ "Meitheal Pharmaceuticals, Inc." ], "product_ndc": [ "71288-566", "71288-567", "71288-568" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS", "SUBCUTANEOUS" ], "substance_name": [ "OCTREOTIDE ACETATE" ], "rxcui": [ "312068", "312069", "312070" ], "spl_id": [ "a12a7206-6077-4b61-a038-4aae1170b387" ], "spl_set_id": [ "01962c67-e551-47b6-a276-e1ae1860d2a4" ], "package_ndc": [ "71288-566-01", "71288-566-02", "71288-567-01", "71288-567-02", "71288-568-01", "71288-568-02" ], "is_original_packager": [ true ], "unii": [ "75R0U2568I" ] } }, { "spl_product_data_elements": [ "Bromocriptine mesylate Bromocriptine mesylate BROMOCRIPTINE MESYLATE BROMOCRIPTINE ANHYDROUS LACTOSE SILICON DIOXIDE MAGNESIUM STEARATE MALEIC ACID POVIDONE K25 STARCH, CORN White to off-white bevel edged PAD;0106" ], "spl_unclassified_section": [ "Rx Only Prescribing Information", "Manufactured by Padagis Minneapolis, MN 55427 www.padagis.com 2204771 2P600 RC PH8 Rev 05-23" ], "description": [ "DESCRIPTION Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity. Each bromocriptine mesylate tablet, USP for oral administration contains 2.5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is chemically designated as Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-,(5'α)-monomethanesulfonate (salt). The structural formula is: Active Ingredient: bromocriptine mesylate, USP Inactive Ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, maleic acid, povidone and pregelatinized starch. Complies with USP dissolution test 1. Structural Formula" ], "clinical_pharmacology": [ "CLINICAL PHARMACOLOGY Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, bromocriptine mesylate significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors. Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients. Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population. Pharmacokinetics Absorption Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively. 1 Linear relationship was found between single doses of bromocriptine mesylate and C max and AUC in the dose range of 1 to 7.5 mg. 2 The pharmacokinetics of bromocriptine metabolites have not been reported. Food did not significantly affect the systemic exposure of bromocriptine following administration of bromocriptine mesylate tablets, 2.5 mg. 3 It is recommended that bromocriptine mesylate be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions. Following bromocriptine mesylate 5 mg administered twice daily for 14 days, the bromocriptine C max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively. 4 Distribution In vitro experiments showed that bromocriptine was 90%-96% bound to serum albumin. Metabolism Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway. 5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions section) . The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM. 6 Given the low therapeutic concentrations of bromocriptine in patients (C max =0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported. Excretion About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine. 5 1 Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin Pharmacol Ther; 47(6):694-7. 2 Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne, D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York, Rave Press. 3 Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81 4 Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465. 5 Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56. 6 Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14. Specific Populations Effect of Renal Impairment The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. Since parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites (see PRECAUTIONS, general) . Effect of Hepatic Impairment The effect of liver impairment on the PK of bromocriptine mesylate and its metabolites has not been evaluated. Since bromocriptine mesylate is mainly eliminated by metabolism, liver impairment may increase the plasma levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, general) . The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated. Clinical Studies In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles. Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6 to 8 weeks. However, some patients respond within a few days, and others may take up to 8 months. Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8 to 12 weeks. Some patients may fail to respond even after 12 months of therapy. In many acromegalic patients, bromocriptine mesylate produces a prompt and sustained reduction in circulating levels of serum growth hormone." ], "pharmacokinetics": [ "Pharmacokinetics Absorption Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively. 1 Linear relationship was found between single doses of bromocriptine mesylate and C max and AUC in the dose range of 1 to 7.5 mg. 2 The pharmacokinetics of bromocriptine metabolites have not been reported. Food did not significantly affect the systemic exposure of bromocriptine following administration of bromocriptine mesylate tablets, 2.5 mg. 3 It is recommended that bromocriptine mesylate be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions. Following bromocriptine mesylate 5 mg administered twice daily for 14 days, the bromocriptine C max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively. 4 Distribution In vitro experiments showed that bromocriptine was 90%-96% bound to serum albumin. Metabolism Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway. 5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions section) . The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM. 6 Given the low therapeutic concentrations of bromocriptine in patients (C max =0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported. Excretion About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine. 5 1 Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin Pharmacol Ther; 47(6):694-7. 2 Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne, D.B.,et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York, Rave Press. 3 Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81 4 Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465. 5 Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56. 6 Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14. Specific Populations Effect of Renal Impairment The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. Since parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites (see PRECAUTIONS, general) . Effect of Hepatic Impairment The effect of liver impairment on the PK of bromocriptine mesylate and its metabolites has not been evaluated. Since bromocriptine mesylate is mainly eliminated by metabolism, liver impairment may increase the plasma levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, general) . The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated." ], "clinical_studies": [ "Clinical Studies In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles. Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6 to 8 weeks. However, some patients respond within a few days, and others may take up to 8 months. Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8 to 12 weeks. Some patients may fail to respond even after 12 months of therapy. In many acromegalic patients, bromocriptine mesylate produces a prompt and sustained reduction in circulating levels of serum growth hormone." ], "indications_and_usage": [ "INDICATIONS AND USAGE Hyperprolactinemia-Associated Dysfunctions Bromocriptine mesylate tablets are indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism . Bromocriptine mesylate tablets treatment is indicated in patients with prolactin-secreting adenomas , which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine mesylate tablets therapy may be used to reduce the tumor mass prior to surgery. Acromegaly Bromocriptine mesylate tablets therapy is indicated in the treatment of acromegaly. Bromocriptine mesylate tablets therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels. Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine mesylate tablets offers potential benefit before the effects of irradiation are manifested. Parkinson's Disease Bromocriptine mesylate tablets are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson's disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine mesylate tablets therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing \"end of dose failure\" on levodopa therapy. Bromocriptine mesylate tablets therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function (\"on-off\" phenomenon). Continued efficacy of bromocriptine mesylate tablets therapy during treatment of more than 2 years has not been established. Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson's disease with bromocriptine mesylate tablets. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine mesylate-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine mesylate tablets therapy." ], "contraindications": [ "CONTRAINDICATIONS Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate tablets, uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States) . In the event that bromocriptine mesylate is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine mesylate is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine mesylate is considered to be medically contraindicated. The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period, the patient should be observed with caution." ], "warnings": [ "WARNINGS Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with bromocriptine mesylate. If pregnancy occurs during bromocriptine mesylate administration, careful observation of these patients is mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of bromocriptine mesylate treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of bromocriptine mesylate treatment during pregnancy to the mother and fetus has not been established. Bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered. Symptomatic hypotension can occur in patients treated with bromocriptine mesylate for any indication. In postpartum studies with bromocriptine mesylate, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving bromocriptine mesylate. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg. Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. While hypotension during the start of therapy with bromocriptine mesylate occurs in some patients, in rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been reported in postpartum women treated with bromocriptine mesylate for the inhibition of lactation. Hypertension has been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have also been reported both with and without the prior development of hypertension; stroke has been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing seizures (including cases of status epilepticus) and/or strokes reported developing a constant and often progressively severe headache hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness). Cases of acute myocardial infarction have also been reported. Although a causal relationship between bromocriptine mesylate administration and hypertension, seizures, strokes, and myocardial infarction in postpartum women has not been established, use of the drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States) . In the event that bromocriptine mesylate is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine mesylate is being used to treat acromegaly or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine mesylate is considered to be medically contraindicated. Because of the possibility of an interaction between bromocriptine mesylate and other ergot alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated promptly. Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the puerperium is not recommended. Among patients on bromocriptine mesylate, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine mesylate therapy should be considered. In those instances in which bromocriptine mesylate treatment was terminated, the changes slowly reverted towards normal. In a few patients on bromocriptine mesylate, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs, impaired kidney function) should be watched in this category of patients. Bromocriptine mesylate medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected." ], "precautions": [ "PRECAUTIONS General There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine mesylate, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine mesylate for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine mesylate. Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate therapy concomitantly with other medications known to lower blood pressure. The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson's disease are being treated with bromocriptine mesylate during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine. Hyperprolactinemic States Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage. The relative efficacy of bromocriptine mesylate versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy. Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with bromocriptine mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of bromocriptine mesylate treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases. Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with bromocriptine mesylate. Acromegaly Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine mesylate increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with bromocriptine mesylate. Possible tumor expansion while receiving bromocriptine mesylate therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered. Parkinson's Disease Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established. As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs. High doses of bromocriptine mesylate may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients. Bromocriptine mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine mesylate. As with levodopa, caution should be exercised when administering bromocriptine mesylate to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia. Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2 to 10 years) with bromocriptine mesylate in doses ranging from 30-140 mg daily. Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2-approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using bromocriptine mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Discontinuation of bromocriptine mesylate should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered. Information for Patients During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine mesylate should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine mesylate and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines). Patients receiving bromocriptine mesylate for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine mesylate for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms. Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine mesylate. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine mesylate [see PRECAUTIONS] . Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine mesylate or decrease the dose of bromocriptine mesylate. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see Precautions). Drug Interactions The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and C max values increased 3.7-fold and 4.6-fold, respectively). 1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%). 4 Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication). Carcinogenesis, Mutagenesis, Impairment of Fertility A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes. Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice. No mutagenic effects were obtained in any of these tests. Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg). Pregnancy Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period. Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced. No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg. Information concerning 1276 pregnancies in women taking bromocriptine mesylate has been collected. In the majority of cases, bromocriptine mesylate was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%. The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%. There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants. Nursing Mothers Bromocriptine mesylate should not be used during lactation in postpartum women. Pediatric Use The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response. The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation. Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section. Geriatric Use Clinical studies for bromocriptine mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine mesylate has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population." ], "general_precautions": [ "General There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine mesylate, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine mesylate for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine mesylate. Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate therapy concomitantly with other medications known to lower blood pressure. The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson's disease are being treated with bromocriptine mesylate during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine." ], "information_for_patients": [ "Information for Patients During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine mesylate should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine mesylate and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines). Patients receiving bromocriptine mesylate for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine mesylate for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms. Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine mesylate. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine mesylate [see PRECAUTIONS] . Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine mesylate or decrease the dose of bromocriptine mesylate. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see Precautions)." ], "drug_interactions": [ "Drug Interactions The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and C max values increased 3.7-fold and 4.6-fold, respectively). 1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%). 4 Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "Carcinogenesis, Mutagenesis, Impairment of Fertility A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes. Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice. No mutagenic effects were obtained in any of these tests. Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg)." ], "pregnancy": [ "Pregnancy Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period. Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced. No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg. Information concerning 1276 pregnancies in women taking bromocriptine mesylate has been collected. In the majority of cases, bromocriptine mesylate was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%. The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%. There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants." ], "nursing_mothers": [ "Nursing Mothers Bromocriptine mesylate should not be used during lactation in postpartum women." ], "pediatric_use": [ "Pediatric Use The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response. The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation. Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section." ], "geriatric_use": [ "Geriatric Use Clinical studies for bromocriptine mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine mesylate has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population." ], "adverse_reactions": [ "ADVERSE REACTIONS Adverse Reactions from Clinical Trials Hyperprolactinemic Indications The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%). A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to half tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine mesylate for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine mesylate for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus. Acromegaly The most frequent adverse reactions encountered in acromegalic patients treated with bromocriptine mesylate were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%). Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported. Parkinson's Disease In clinical trials in which bromocriptine mesylate was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo. Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome. Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance. Adverse Reactions from Postmarketing Experience The following adverse reactions have been reported during postapproval use of bromocriptine mesylate (All Indications Combined). Because adverse reactions from spontaneous reports 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. Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality, and impulse control/compulsive behaviors (including gambling, spending, and other intense urges). Nervous system disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep. Eye disorders: Visual disturbance, vision blurred. Ear and labyrinth disorders: Tinnitus. Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis. Vascular disorders: Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon). Respiratory, thoracic and mediastinal disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea. Gastrointestinal disorders: Nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage. Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss. Musculoskeletal and connective tissue disorders: Leg cramps. General disorders and administration site conditions: Fatigue, peripheral oedema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of bromocriptine mesylate, withdrawal symptoms (including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain) with taper or after discontinuation (see Precautions) . Adverse Events Observed in Other Conditions Postpartum Patients (see above Warnings) In postpartum studies with bromocriptine mesylate, 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of patients. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%). Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were usually of a transient nature. Reports of fainting in the puerperium may possibly be related to this effect. In postmarketing experience in the U.S., serious adverse reactions reported include 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum patients. Seizure cases were not necessarily accompanied by the development of hypertension. An unremitting and often progressively severe headache, sometimes accompanied by visual disturbance, often preceded by hours to days many cases of seizure and/or stroke. Most patients had shown no evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or pregnancy-induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to bromocriptine mesylate administration has not been established. In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with bromocriptine mesylate. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving bromocriptine mesylate. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of bromocriptine mesylate should be discontinued and the patient should be evaluated promptly. Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g., vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended. To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.", "Adverse Reactions from Clinical Trials Hyperprolactinemic Indications The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%). A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to half tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine mesylate for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine mesylate for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus. Acromegaly The most frequent adverse reactions encountered in acromegalic patients treated with bromocriptine mesylate were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%). Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported. Parkinson's Disease In clinical trials in which bromocriptine mesylate was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo. Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome. Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.", "Adverse Reactions from Postmarketing Experience The following adverse reactions have been reported during postapproval use of bromocriptine mesylate (All Indications Combined). Because adverse reactions from spontaneous reports 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. Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality, and impulse control/compulsive behaviors (including gambling, spending, and other intense urges). Nervous system disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep. Eye disorders: Visual disturbance, vision blurred. Ear and labyrinth disorders: Tinnitus. Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis. Vascular disorders: Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon). Respiratory, thoracic and mediastinal disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea. Gastrointestinal disorders: Nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage. Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss. Musculoskeletal and connective tissue disorders: Leg cramps. General disorders and administration site conditions: Fatigue, peripheral oedema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of bromocriptine mesylate, withdrawal symptoms (including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain) with taper or after discontinuation (see Precautions) ." ], "overdosage": [ "OVERDOSAGE The most commonly reported signs and symptoms associated with acute bromocriptine mesylate overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established and the drug has a very wide margin of safety. However, one death occurred in a patient who committed suicide with an unknown quantity of bromocriptine mesylate and chloroquine. Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered. There have been isolated reports of children who accidentally ingested bromocriptine mesylate. Vomiting, somnolence and fever were reported as adverse events. Patients recovered either spontaneously within a few hours or after appropriate management." ], "dosage_and_administration": [ "DOSAGE AND ADMINISTRATION General It is recommended that bromocriptine mesylate be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response. Hyperprolactinemic Indications The initial dosage of bromocriptine mesylate tablets in adults is half to one 2.5 mg scored tablet daily. An additional 2.5 mg tablet may be added to the treatment regimen as tolerated every 2 to 7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically. Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is half to one 2.5 mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas. In order to reduce the likelihood of prolonged exposure to bromocriptine mesylate tablets should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine mesylate tablets therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy. Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine mesylate therapy should be discontinued and a pregnancy test performed. Acromegaly Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine mesylate tablets also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine mesylate tablets. If, after a brief trial with bromocriptine mesylate therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered. The initial recommended dosage is half to one 2.5 mg bromocriptine mesylate tablet on retiring (with food) for 3 days. An additional half to 1 tablet should be added to the treatment regimen as tolerated every 3 to 7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine mesylate tablets varies from 20-30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day. Patients treated with pituitary irradiation should be withdrawn from bromocriptine mesylate tablets therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine mesylate tablets therapy. Usually a 4 to 8 week withdrawal period is adequate for this purpose. Recurrence of the signs/symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine mesylate tablets should be considered. Parkinson's Disease The basic principle of bromocriptine mesylate tablets therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible. The initial dose of bromocriptine mesylate is half of a 2.5 mg tablet twice daily with meals. Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may be increased every 14 to 28 days by 2.5 mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine mesylate, if increased, should be accomplished gradually in small (2.5 mg) increments. The safety of bromocriptine mesylate has not been demonstrated in dosages exceeding 100 mg/day." ], "how_supplied": [ "HOW SUPPLIED Bromocriptine Mesylate Tablets, USP are available in bottles containing 30 and 100 tablets of 2.5 mg, each bottle contains a desiccant. Bromocriptine Mesylate Tablets, USP are available containing 2.5 mg of bromocriptine (as the mesylate). The 2.5 mg tablets are white to off-white, round, bevel edged snap tablets, debossed with \"PAD\" over \"0106\" on one side and scored on the other side. Bottles of 30.........NDC 0574- 0106 -03 Bottles of 100.......NDC 0574- 0106 -01 Store at 20° to 25°C (68° to 77°F) [see USP for Controlled Room Temperature] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure." ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 30 Tablets NDC 0574-0106-03 Rx Only Bromocriptine Mesylate Tablets, USP 2.5 mg* 30 Tablets The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation. label serialization-template-1" ], "set_id": "0ee2da00-faf8-4c51-a696-9462fa4f6050", "id": "3a655bc4-d44e-4dd2-a951-211d8484f788", "effective_time": "20230531", "version": "10", "openfda": { "application_number": [ "ANDA077646" ], "brand_name": [ "Bromocriptine mesylate" ], "generic_name": [ "BROMOCRIPTINE MESYLATE" ], "manufacturer_name": [ "Padagis US LLC" ], "product_ndc": [ "0574-0106" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "BROMOCRIPTINE MESYLATE" ], "rxcui": [ "197411" ], "spl_id": [ "3a655bc4-d44e-4dd2-a951-211d8484f788" ], "spl_set_id": [ "0ee2da00-faf8-4c51-a696-9462fa4f6050" ], "package_ndc": [ "0574-0106-03", "0574-0106-01" ], "is_original_packager": [ true ], "unii": [ "FFP983J3OD" ] } }, { "spl_product_data_elements": [ "Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE" ], "recent_major_changes": [ "Indications and Usage, Carcinoid Syndrome ( 1.3 ) 09/2024 Dosage and Administration ( 2.1 ) 09/2024 Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.6 ) 07/2024" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Lanreotide Injection is a somatostatin analog indicated for: the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. ( 1.1 ) the treatment of adult patients with unresectable, well- or moderately- differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. ( 1.2 ) the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy. ( 1.3 ) 1.1 Acromegaly Lanreotide Injection is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal. 1.2 Gastroenteropancreatic Neuroendocrine Tumors Lanreotide Injection is indicated for the treatment of adult patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. 1.3 Carcinoid Syndrome Lanreotide Injection is indicated for the treatment of adults with carcinoid syndrome; when used, it reduces the frequency of short-acting somatostatin analog rescue therapy." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Administration ( 2.1 ): For deep subcutaneous injection only. Intended for administration by a healthcare provider. Administer in the superior external quadrant of the buttock. Alternate injection sites. Recommended Dosage ( 2.1 ) Acromegaly : 90 mg every 4 weeks for 3 months. Adjust thereafter based on GH and/or IGF-1 levels. See full prescribing information for titration regimen. GEP-NETs : 120 mg every 4 weeks. Carcinoid Syndrome : 120 mg every 4 weeks. If patients are already being treated with Lanreotide Injection for GEP-NET, do not administer an additional dose for carcinoid syndrome. Dosage Adjustment : See full prescribing information for dosage adjustment in patients with acromegaly and renal or hepatic impairment. ( 2.2 , 2.3 ) 2.1 Recommended Dosage Acromegaly The recommended starting dosage of Lanreotide Injection is 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months. After 3 months, the Lanreotide injection dosage may be adjusted as follows: GH greater than 1 ng/mL to less than or equal to 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain dosage at 90 mg every 4 weeks. GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase dosage to 120 mg every 4 weeks. GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce dosage to 60 mg every 4 weeks. Thereafter, the dosage should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly. Patients who are controlled on Lanreotide Injection 60 or 90 mg may be considered for an extended dosing interval of Lanreotide Injection 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patient response with dosage adjustments for biochemical and clinical symptom control, as necessary, is recommended. Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection. Carcinoid Syndrome The recommended dosage of Lanreotide Injection is 120 mg administered every 4 weeks by deep subcutaneous injection. If patients are already being treated with Lanreotide Injection for GEP-NETs, do not administer an additional dose for the treatment of carcinoid syndrome. 2.2 Dosage Adjustment in Renal Impairment Acromegaly The recommended starting dosage of Lanreotide Injection in acromegalic patients with moderate or severe renal impairment (creatinine clearance (CLcr) less than 60 mL/min) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.6 )]. 2.3 Dosage Adjustment in Hepatic Impairment Acromegaly The recommended starting dosage of Lanreotide Injection in acromegalic patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.7 )] . 2.4 Important Preparation and Administration Instructions The following instructions explain how to inject Lanreotide Injection: Read all instructions carefully before starting the injection. Follow this procedure exactly, as it may differ from your past experience. This is a single-dose pre-filled syringe with a single-use safety needle with a green needle shield (that cannot be removed) in a clear needle cap. ALL the medication must be injected SLOWLY over 20 seconds during the use. If you drop or damage the device in any way, please call 1-866-604-3268. Figure 1 The box includes the following items: Sterile needle pack containing Sterile needle Sterile Laminated pouch with sterile syringe pre-filled with LANREOTIDE INJECTION Instructions for Use Leaflet Prescribing Information Leaflet CAUTION NEVER TOUCH OR TRY TO OPEN THE GREEN NEEDLE SHIELD throughout the course of operation of the device. Green needle shield is NOT a removable cap or cover for the needle. Green needle shield will automatically activate once the injection is complete. Green needle shield is a self-operating safety lock mechanism. Needle is fully covered by green needle shield. Needle is visible only through a small window in the green needle shield. Inject medication slowly over 20 seconds. DO NOT rush the injection. Remove box from refrigerator 30 minutes prior to injecting. Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time. Stretch out the skin around injection site to make it flat and tight using your thumb and index finger. DO NOT pinch the skin around injection site. A. BEFORE YOU START Figure 2 A1. Remove LANREOTIDE INJECTION from the refrigerator 30 minutes prior to injecting (Figure 2). Do not open the sterile pouch yet. Note: Product left in its sealed pouch at room temperature (not to exceed 104° F or 40 °C) for up to 72 hours may be returned to the refrigerator for continued storage and use at a later time. Figure 3 A2. Wash your hands with soap and dry your hands thoroughly before starting (Figure 3). Follow the doctor or institution’s policy on the use of surgical gloves during the procedure Figure 4 A3. Before opening the sterile pouch, confirm that it is intact, and that the medication has not expired. The Syringe is sterile only if the pouch is sealed and undamaged. Do not use if the pouch is opened, tampered with or damaged . The expiry date is printed on the outer carton and the pouch - Do not use if the medication has expired. (Figure 4). Or Figure 5 A4. Make sure there is a clean surface for preparation. Find a clean, comfortable area for the patient to relax during procedure (Figure 5). It's important that the patient remains as still as possible during the injection. Figure 6 A5. Choose injection site - the sites are upper outer areas of the buttock as shown below It is very important that you only inject in one of the areas marked OK in the picture (Figure 6). Alternate the injection site between the right and left side each time an injection of LANREOTIDE INJECTION is administered . Figure 7 A6. Prepare the injection site by cleaning it with alcohol wipes (Figure 7) . Figure 8 A7. Tear open the sterile pouch and take out the sterile pre-filled syringe (Figure 8). B. PREPARE THE SYRINGE Figure 9 B1: Open the sterile needle cap (Figure 9) The needle is sterile only if the needle cap is sealed and undamaged. Do not use if the needle cap is opened, tampered with or damaged. Hold the clear needle cap and pull the lid off. DO NOT TOUCH THE OPEN END OF THE NEEDLE CAP TO MAINTAIN STERILITY. Figure 10 B2: Remove the cap from the sterile syringe (Figure 10) With one hand, hold the syringe barrel steady (not the plunger ). With the other hand, remove the cap by twisting it. B3: Prepare the assembly (Figure 11) Figure 11 Hold the needle cap with one hand and the syringe barrel ( not the plunger ) with the other Carefully insert the open end of the syringe into the open end of the needle cap Twist the syringe barrel clockwise until it is tight to make sure that the syringe is well connected to the safety needle. ENSURE THAT BOTH PARTS OF THE DEVICE (SYRINGE AND NEEDLE) ARE COMPLETELY CONNECTED. The assembly is fully locked when you cannot turn it any further. B4: Remove the needle from the needle cap Figure 12 Hold the syringe barrel ( not the plunger ). Pull the needle straight out from the needle cap without twisting or turning (Figure 12). Figure 13 CAUTION: NEVER TOUCH THE GREEN NEEDLE SHIELD. THERE IS A RISK OF NEEDLE STICK INJURY. (Figure 13) Green needle shield is a self-operating safety lock mechanism and is not a removable cover or cap for the needle. It will activate once the injection is complete. The needle is fully covered by the green shield and is visible only through the small round window at the end of the shield. C.PERFORM INJECTION C1: Position the syringe assembly Figure 14 Stretch out the skin around the injection site to make it flat and tight using your thumb and index finger. (Figure 14) Figure 15 DO NOT pinch the skin (Figure 15) Figure 16 Hold the assembly by the lower part of the syringe barrel ( not the plunger ) with your other hand. Position the syringe assembly at a 90-degree angle to the skin. The green collar at the bottom of the green shield should be perpendicular to the injection site (Figures 16 and 17) Figure 17 C2: Insert the needle (Figure 18) Figure 18 Holding the skin flat and tight, push the syringe assembly firmly into the skin. Do NOT pinch the skin. Keep pushing until you reach a “hard stop” and only the green collar at the end of the green needle shield remains visible. Do NOT push the plunger yet. DO NOT aspirate. Keep pressing against the skin. During this step you should not see the needle. C3: Push the top of the plunger (Figure 19) Figure 19 Keep holding your hand on the syringe barrel to maintain a 90-degree angle throughout the injection. While keeping the syringe pressed against the skin, slowly press down the plunger. You may want to use both hands while applying pressure during the injection of drug. Continue slowly pushing the plunger over 20 seconds until the Plunger top touches the syringe end . DO NOT rush the injection. The medication is thicker and harder to push than you might expect. Pushing the plunger too fast may cause discomfort to the patient. While depressing the plunger, slowly count to 20 and CONTINUE STEADY PRESSURE on the plunger. You may find it helpful to say: a “1 one-thousand” b “2 one-thousand” c “3 one-thousand” up to “20 one-thousand” During this step, as the needle is lowering, the green needle shield will retract. You should only see the green collar of the green needle shield. During this step you should not see the needle. D. REMOVE AND THROW AWAY THE SYRINGE ASSEMBLY Figure 20 D1: Remove from the skin (Figure 20) Lift the syringe straight up and away from the body. The green needle shield will return to its original position and will fully cover the needle. Figure 21 D2: Apply gentle pressure (Figure 21) Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding. Do NOT rub or massage the injection site after administration. Figure 22 D3: Check needle (Figure 22) Check through the green needle shield’s round windows that the needle was not damaged during administration. If any damage or malfunction to the needle is suspected please contact 1-866-604-3268 Figure 23 D4: Throw away / Disposal (Figure 23) DO NOT remove needle from syringe Dispose of complete product in sharps disposal container Do not dispose of the syringe or needle in the regular trash. The syringe and needle are not reusable. fig 1 fig 2 fig 3 fig 4 fig 5 fig 6 fig 7 fig 8 fig 9 fig 10 fig 11 fig 12 fig 13 fig 14 fig 15 fig 16 fig 17 fig 18 fig 19 fig 20 fig 21 fig 22 fig 23 fig 24 fig 25 fig 26 fig 27 fig 28 Fig 29" ], "dosage_and_administration_table": [ "
NEVER TOUCH OR TRY TO OPEN THE GREEN NEEDLE SHIELD throughout the course of operation of the device.Green needle shield is NOT a removable cap or cover for the needle.Green needle shield will automatically activate once the injection is complete.Green needle shield is a self-operating safety lock mechanism.Needle is fully covered by green needle shield.Needle is visible only through a small window in the green needle shield.
Inject medication slowly over 20 seconds.DO NOT rush the injection.
Remove box from refrigerator 30 minutes prior to injecting.Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time.
Stretch out the skin around injection site to make it flat and tight using your thumb and index finger.DO NOT pinch the skin around injection site.
", "
A. BEFORE YOU START
Figure 2 A1. Remove LANREOTIDE INJECTION from the refrigerator 30 minutes prior to injecting (Figure 2). Do not open the sterile pouch yet.Note: Product left in its sealed pouch at room temperature (not to exceed 104° F or 40 °C) for up to 72 hours may be returned to the refrigerator for continued storage and use at a later time.
Figure 3 A2.Wash your hands with soap and dry your hands thoroughly before starting (Figure 3).
Follow the doctor or institution’s policy on the use of surgical gloves during the procedure
Figure 4A3. Before opening the sterile pouch, confirm that it is intact, and that the medication has not expired. The Syringe is sterile only if the pouch is sealed and undamaged. Do not use if the pouch is opened, tampered with or damaged. The expiry date is printed on the outer carton and the pouch - Do not use if the medication has expired. (Figure 4).
OrFigure 5 A4. Make sure there is a clean surface for preparation.Find a clean, comfortable area for the patient to relax during procedure (Figure 5).It's important that the patient remains as still as possible during the injection.
Figure 6A5.Choose injection site - the sites are upper outer areas of the buttock as shown belowIt is very important that you only inject in one of the areas marked OK in the picture (Figure 6).
Alternate the injection site between the right and left side each time an injection of LANREOTIDE INJECTION is administered.
Figure 7A6.Prepare the injection site by cleaning it with alcohol wipes (Figure 7).
Figure 8A7. Tear open the sterile pouch and take out the sterile pre-filled syringe (Figure 8).
B. PREPARE THE SYRINGE
Figure 9B1: Open the sterile needle cap (Figure 9)The needle is sterile only if the needle cap is sealed and undamaged. Do not use if the needle cap is opened, tampered with or damaged.Hold the clear needle cap and pull the lid off.DO NOT TOUCH THE OPEN END OF THE NEEDLE CAP TO MAINTAIN STERILITY.
Figure 10B2: Remove the cap from the sterile syringe (Figure 10)With one hand, hold the syringe barrel steady (not the plunger).With the other hand, remove the cap by twisting it.
B3: Prepare the assembly (Figure 11)Figure 11Hold the needle cap with one hand and the syringe barrel (not the plunger) with the otherCarefully insert the open end of the syringe into the open end of the needle capTwist the syringe barrel clockwise until it is tight to make sure that the syringe is well connected to the safety needle.ENSURE THAT BOTH PARTS OF THE DEVICE (SYRINGE AND NEEDLE) ARE COMPLETELY CONNECTED.The assembly is fully locked when you cannot turn it any further.
B4: Remove the needle from the needle capFigure 12Hold the syringe barrel (not the plunger).Pull the needle straight out from the needle cap without twisting or turning (Figure 12).
Figure 13CAUTION: NEVER TOUCH THE GREEN NEEDLE SHIELD. THERE IS A RISK OF NEEDLE STICK INJURY. (Figure 13)Green needle shield is a self-operating safety lock mechanism and is not a removable cover or cap for the needle. It will activate once the injection is complete.The needle is fully covered by the green shield and is visible only through the small round window at the end of the shield.
C.PERFORM INJECTION
C1: Position the syringe assemblyFigure 14Stretch out the skin around the injection site to make it flat and tight using your thumb and index finger. (Figure 14)
Figure 15DO NOT pinch the skin(Figure 15)
Figure 16Hold the assembly by the lower part of the syringe barrel (not the plunger) with your other hand.Position the syringe assembly at a 90-degree angle to the skin. The green collar at the bottom of the green shield should be perpendicular to the injection site (Figures 16 and 17)Figure 17
C2: Insert the needle (Figure 18)Figure 18Holding the skin flat and tight, push the syringe assembly firmly into the skin.Do NOT pinch the skin.Keep pushing until you reach a “hard stop” and only the green collar at the end of the green needle shield remains visible.Do NOT push the plunger yet.DO NOT aspirate.Keep pressing against the skin.During this step you should not see the needle.
C3: Push the top of the plunger (Figure 19)Figure 19Keep holding your hand on the syringe barrel to maintain a 90-degree angle throughout the injection.While keeping the syringe pressed against the skin, slowly press down the plunger. You may want to use both hands while applying pressure during the injection of drug.Continue slowly pushing the plunger over 20 seconds until the Plunger top touches the syringe end .DO NOT rush the injection. The medication is thicker and harder to push than you might expect. Pushing the plunger too fast may cause discomfort to the patient.While depressing the plunger, slowly count to 20 and CONTINUE STEADY PRESSURE on the plunger. You may find it helpful to say: a “1 one-thousand” b “2 one-thousand” c “3 one-thousand” up to “20 one-thousand”During this step, as the needle is lowering, the green needle shield will retract. You should only see the green collar of the green needle shield.During this step you should not see the needle.
D. REMOVE AND THROW AWAY THE SYRINGE ASSEMBLY
Figure 20D1: Remove from the skin (Figure 20)Lift the syringe straight up and away from the body.The green needle shield will return to its original position and will fully cover the needle.
Figure 21D2: Apply gentle pressure (Figure 21)Apply gentle pressure to the injection site with a dry cotton ball or sterile gauze to prevent any bleeding.Do NOT rub or massage the injection site after administration.
Figure 22D3: Check needle (Figure 22)Check through the green needle shield’s round windows that the needle was not damaged during administration.If any damage or malfunction to the needle is suspected please contact 1-866-604-3268
Figure 23D4: Throw away / Disposal (Figure 23)DO NOT remove needle from syringeDispose of complete product in sharps disposal containerDo not dispose of the syringe or needle in the regular trash.The syringe and needle are not reusable.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL of lanreotide in single-dose, prefilled syringes packaged with a safety needle. The prefilled syringes contain a white to pale yellow, semi-solid formulation. Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL of lanreotide in single-dose prefilled syringes ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Lanreotide Injection is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide [ see Adverse Reactions ( 6.3 )] . Hypersensitivity to lanreotide. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholthiasis are suspected. Gallstones may occur; consider periodic monitoring. ( 5.1 ) Hyperglycemia and Hypoglycemia : Glucose monitoring is recommended and antidiabetic treatment adjusted accordingly. ( 5.2 , 7.1 ) Cardiovascular Abnormalities : Decrease in heart rate may occur. Use with caution in at-risk patients. ( 5.3 ) Thyroid Function Abnormalities : Decreases in thyroid function may occur; perform tests where clinically indicated. ( 5.4 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. ( 5.6 ) 5.1 Cholelithiasis and Complications of Cholelithiasis Lanreotide Injection may reduce gallbladder motility and lead to gallstone formation; therefore, patients may need to be monitored periodically [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )] . There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, and pancreatitis, and requiring cholecystectomy in patients taking lanreotide. If complications of cholelithiasis are suspected, discontinue Lanreotide Injection and treat appropriately. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Lanreotide Injection may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when Lanreotide Injection treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions ( 6.1 )] . 5.3 Cardiovascular Abnormalities The most common overall cardiac adverse reactions observed in three pooled lanreotide injection cardiac studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%), and hypertension (12/217, 5.5%) [see Adverse Reactions ( 6.1 )]. In 81 patients with baseline heart rates of 60 beats per minute (bpm) or greater treated with lanreotide in Study 3, the incidence of heart rate less than 60 bpm was 23% (19/81) as compared to 16% (15/94) of placebo treated patients; 10 patients (12%) had documented heart rates less than 60 bpm on more than one visit. The incidence of documented episodes of heart rate less than 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia. In patients without underlying cardiac disease, Lanreotide Injection may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to Lanreotide Injection treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with Lanreotide Injection in patients with bradycardia. 5.4 Thyroid Function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (less than 1%). Thyroid function tests are recommended where clinically indicated. 5.5 Monitoring: Laboratory Tests Acromegaly : Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [see Dosage and Administration ( 2.1 )] . 5.6 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including lanreotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving Lanreotide Injection, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.2 )] Cardiovascular Abnormalities [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions ( 5.6 )] Most common adverse reactions are: Acromegaly : (>5%): diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions. ( 6.1 ) GEP-NET : (>10%): abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. ( 6.1 ) Carcinoid Syndrome : (≥5% and at least 5% greater than placebo): headache, dizziness and muscle spasm. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. Inc. at 1-866-604-3268 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, 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. The safety of Lanreotide Injection was established from adequate and well-controlled studies of another lanreotide injection product [see Clinical Studies ( 14 )] . Adverse reactions observed in these adequate and well-controlled studies are described below. Acromegaly The data described below reflect exposure to lanreotide injection in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo-controlled, run-in period, and another had an active control. The population was mainly White (329/353, 93%) with a median age of 53 years of age (range 19 to 84 years). Fifty-four subjects (13%) were age 66 to 74 and 18 subjects (4.3%) were 75 years of age and older. Patients were evenly matched for sex (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly, severity at baseline (N=265), serum GH levels were less than 10 ng/mL for 69% (183/265) of the patients and 10 ng/mL or greater for 31% (82/265) of the patients. The most commonly reported adverse reactions reported by greater than 5% of patients who received lanreotide (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis, and injection site reactions. Tables 1 and 2 present adverse reaction data from clinical studies with lanreotide in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies. Adverse Reactions in Parallel Fixed-Dose Phase of Study 1 The incidence of treatment-emergent adverse reactions for lanreotide injection 60, 90, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [see Clinical Studies ( 14.1 )] are provided in Table 1. Table 1: Adverse Reactions in Patients with Acromegaly at an Incidence of Greater than 5% with Lanreotide Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose A patient is counted only once for each body system and preferred term. Dictionary = WHOART. Placebo-Controlled Double-Blind Phase Weeks 0 to 4 Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20 Body System Preferred Term Placebo (N=25) Lanreotide Overall (N=83) Lanreotide 60 mg (N=34) Lanreotide 90 mg (N=36) Lanreotide 120 mg (N=37) Lanreotide Overall (N=107) N (%) N (%) N (%) N (%) N (%) N (%) Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%) Diarrhea Abdominal pain Flatulence 0 1 (4%) 0 26 (31%) 6 (7%) 5 (6%) 9 (26%) 3 (9%) 0 (0%) 15 (42%) 6 (17%) 3 (8%) 24 (65%) 7 (19%) 5 (14%) 48 (45%) 16 (15%) 8 (7%) Application Site Disorders (Injection site mass/ pain/ reaction/ inflammation) 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%) Liver and Biliary System Disorders 1 (4%) 3 (4%) 9 (26%) 7 (19%) 4 (11%) 20 (19%) Cholelithiasis 0 2 (2%) 5 (15%) 6 (17%) 3 (8%) 14 (13%) Heart Rate & Rhythm Disorders 0 8 (10%) 7 (21%) 2 (6%) 5 (14%) 14 (13%) Bradycardia 0 7 (8%) 6 (18%) 2 (6%) 2 (5%) 10 (9%) Red Blood Cell Disorders 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Anemia 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Metabolic & Nutritional Disorders 3 (12%) 13 (16%) 8 (24%) 9 (25%) 4 (11%) 21 (20%) Weight decrease 0 7 (8%) 3 (9%) 4 (11%) 2 (5%) 9 (8%) In Study 1, the adverse reactions of diarrhea, abdominal pain, and flatulence increased in incidence with increasing dose of lanreotide injection . Adverse Reactions in Long-Term Clinical Trials Table 2 provides the most common adverse reactions (greater than 5%) that occurred in 416 acromegalic patients treated with lanreotide injection pooled from 7 studies compared to those patients from the 2 efficacy studies (Studies 1 and 2). Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout [see Clinical Studies ( 14.1 )] . Table 2: Adverse Reactions in Lanreotide -Treated Patients with Acromegaly at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2 Dictionary = MedDRA 7.1 System Organ Class Number and Percentage of Patients Studies 1 & 2 (N=170) Overall Pooled Data (N=416) N % N % Patients with any Adverse Reactions 157 92 356 86 Gastrointestinal disorders 121 71 235 57 Diarrhea 81 48 155 37 Abdominal pain 34 20 79 19 Nausea 15 9 46 11 Constipation 9 5 33 8 Flatulence 12 7 30 7 Vomiting 8 5 28 7 Loose stools 16 9 23 6 Hepatobiliary disorders 53 31 99 24 Cholelithiasis 45 27 85 20 General disorders and administration site conditions 51 30 91 22 (Injection site pain /mass /induration/ nodule/pruritus) 28 17 37 9 Musculoskeletal and connective tissue disorders 44 26 70 17 Arthralgia 17 10 30 7 Nervous system disorders 34 20 80 19 Headache 9 5 30 7 In addition to the adverse reactions listed in Table 2, the following reactions were also seen: Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies. Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies. Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies. Gastrointestinal Adverse Reactions In the pooled clinical studies of lanreotide therapy, a variety of gastrointestinal (GI) reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with lanreotide in the pooled clinical studies discontinued treatment because of gastrointestinal reactions. Pancreatitis was reported in less than 1% of patients. Gallbladder Adverse Reactions In clinical studies involving 416 acromegalic patients treated with lanreotide, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with lanreotide who underwent routine evaluation with gallbladder ultrasound, 17% had gallstones at baseline. New cholelithiasis was reported in 12% of patients. Cholelithiasis may be related to dose or duration of exposure [see Warnings and Precautions ( 5.1 )] . Injection Site Reactions In the pooled clinical studies, injection site pain (4%) and injection site mass (2%) were the most frequently reported local adverse drug reactions that occurred with the administration of lanreotide. In a specific analysis, 20 of 413 patients (5%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects. Glucose Metabolism Adverse Reactions In the clinical studies in acromegalic patients treated with lanreotide, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients [see Warnings and Precautions ( 5.2 )] . Cardiac Adverse Reactions In the pooled clinical studies, sinus bradycardia (3%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in less than 1% of patients. The relationship of these events to lanreotide could not be established because many of these patients had underlying cardiac disease [see Warnings and Precautions ( 5.3 )] . A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the 2 treatments over 1 year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study. Other Adverse Reactions For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain, and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups. Gastroenteropancreatic Neuroendocrine Tumors The safety of lanreotide injection 120 mg for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated in Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 were randomized to receive lanreotide (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks. The data below reflect exposure to lanreotide in 101 patients with GEP-NETs, including 87 patients exposed for at least 6 months and 72 patients exposed for at least 1 year (median duration of exposure 22 months). Patients treated with lanreotide had a median age of 64 years (range 30 to 83 years), 53% were men and 96% were White. Eighty-one percent of patients (83/101) in the lanreotide arm and 82% of patients (82/103) in the placebo arm did not have disease progression within 6 months of enrollment and had not received prior therapy for GEP-NETs. The rates of discontinuation due to treatment-emergent adverse reactions were 5% (5/101 patients) in the lanreotide arm and 3% (3/103 patients) in the placebo arm. Table 3 compares the adverse reactions reported with an incidence of 5% and greater in patients receiving lanreotide injection 120 mg administered every 4 weeks and reported more commonly than placebo. Table 3: Adverse Reactions Occurring in 5% and Greater of Lanreotide -Treated Patients with GEP-NETs and at a Higher Rate Than in Placebo -Treated Patients in Study 3 1 Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 2 Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 3 Includes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling 4 Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 5 Includes preferred terms of hypertension, hypertensive crisis 6 Includes preferred terms of depression, depressed mood * Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed. ** Defined as hazardous to well-being, significant impairment of function or incapacitation Adverse Reaction Lanreotide 120 mg N=101 Placebo N=103 Any (%) Severe** (%) Any (%) Severe** (%) Any Adverse Reactions 88 26 90 31 Abdominal pain 1 34* 6* 24* 4 Musculoskeletal pain 2 19* 2* 13* 2 Vomiting 19* 2* 9* 2* Headache 16 0 11 1 Injection site reaction 3 15 0 7 0 Hyperglycemia 4 14* 0 5 0 Hypertension 5 14* 1* 5 0 Cholelithiasis 14* 1* 7 0 Dizziness 9 0 2* 0 Depression 6 7 0 1 0 Dyspnea 6 0 1 0 Carcinoid Syndrome The safety of lanreotide injection 120 mg in patients with histopathologically confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) was evaluated in Study 4, a double-blind, placebo-controlled trial. Patients were randomized to receive lanreotide injection (N=59) or placebo (N=56) administered by deep subcutaneous injection once every 4 weeks. Patients in both arms of Study 4 had access to subcutaneous octreotide as rescue medication for symptom control. Adverse reactions reported in Study 4 were generally similar to those reported in Study 3 for the GEP-NETs population shown in Table 3 above. Adverse reactions occurring in Study 4 in 5% and greater of lanreotide-treated patients and occurring at least 5% more than in placebo-treated patients were headache (12% vs 5%, respectively), dizziness (7% vs 0%, respectively), and muscle spasm (5% vs 0%, respectively) by week 16. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of lanreotide. 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: pancreatic exocrine insufficiency Hepatobiliary: steatorrhea; cholecystitis, cholangitis, pancreatitis, which have sometimes required cholecystectomy Hypersensitivity: angioedema and anaphylaxis Injection site reactions : injection site abscess" ], "adverse_reactions_table": [ "
Table 1: Adverse Reactions in Patients with Acromegaly at an Incidence of Greater than 5% with Lanreotide Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose
A patient is counted only once for each body system and preferred term. Dictionary = WHOART.
Placebo-Controlled Double-Blind Phase Weeks 0 to 4Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20
Body System Preferred TermPlacebo (N=25)Lanreotide Overall (N=83)Lanreotide 60 mg (N=34)Lanreotide 90 mg (N=36)Lanreotide 120 mg (N=37)Lanreotide Overall (N=107)
N (%)N (%)N (%)N (%)N (%)N (%)
Gastrointestinal System Disorders1 (4%)30 (36%)12 (35%)21 (58%)27 (73%)60 (56%)
Diarrhea Abdominal pain Flatulence0 1 (4%) 026 (31%) 6 (7%) 5 (6%)9 (26%) 3 (9%) 0 (0%)15 (42%) 6 (17%) 3 (8%)24 (65%) 7 (19%) 5 (14%)48 (45%) 16 (15%) 8 (7%)
Application Site Disorders (Injection site mass/ pain/ reaction/ inflammation)0 (0%)5 (6%)3 (9%)4 (11%)8 (22%)15 (14%)
Liver and Biliary System Disorders1 (4%)3 (4%)9 (26%)7 (19%)4 (11%)20 (19%)
Cholelithiasis02 (2%)5 (15%)6 (17%)3 (8%)14 (13%)
Heart Rate & Rhythm Disorders08 (10%)7 (21%)2 (6%)5 (14%)14 (13%)
Bradycardia07 (8%)6 (18%)2 (6%)2 (5%)10 (9%)
Red Blood Cell Disorders06 (7%)2 (6%)5 (14%)2 (5%)9 (8%)
Anemia06 (7%)2 (6%)5 (14%)2 (5%)9 (8%)
Metabolic & Nutritional Disorders3 (12%)13 (16%)8 (24%)9 (25%)4 (11%)21 (20%)
Weight decrease07 (8%)3 (9%)4 (11%)2 (5%)9 (8%)
", "
Table 2: Adverse Reactions in Lanreotide -Treated Patients with Acromegaly at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2
Dictionary = MedDRA 7.1
System Organ ClassNumber and Percentage of Patients
Studies 1 & 2 (N=170)Overall Pooled Data (N=416)
N%N%
Patients with any Adverse Reactions1579235686
Gastrointestinal disorders1217123557
Diarrhea814815537
Abdominal pain34207919
Nausea1594611
Constipation95338
Flatulence127307
Vomiting85287
Loose stools169236
Hepatobiliary disorders53319924
Cholelithiasis45278520
General disorders and administration site conditions51309122
(Injection site pain /mass /induration/ nodule/pruritus)2817379
Musculoskeletal and connective tissue disorders44267017
Arthralgia1710307
Nervous system disorders34208019
Headache95307
", "
Table 3: Adverse Reactions Occurring in 5% and Greater of Lanreotide -Treated Patients with GEP-NETs and at a Higher Rate Than in Placebo -Treated Patients in Study 3
1Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 2 Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 3 Includes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling 4 Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 5 Includes preferred terms of hypertension, hypertensive crisis 6 Includes preferred terms of depression, depressed mood * Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed.** Defined as hazardous to well-being, significant impairment of function or incapacitation
Adverse ReactionLanreotide 120 mg N=101Placebo N=103
Any (%)Severe** (%)Any (%)Severe** (%)
Any Adverse Reactions88269031
Abdominal pain134*6*24*4
Musculoskeletal pain219*2*13*2
Vomiting19*2*9*2*
Headache160111
Injection site reaction315070
Hyperglycemia414*050
Hypertension514*1*50
Cholelithiasis14*1*70
Dizziness902*0
Depression67010
Dyspnea6010
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Cyclosporine : Lanreotide Injection may decrease the absorption of cyclosporine. Dosage adjustment of cyclosporine may be needed. ( 7.2 ) Bromocriptine : Lanreotide Injection may increase the absorption of bromocriptine. ( 7.3 ) Bradycardia-Inducing Drugs (e.g., beta-blockers) : Lanreotide Injection may decrease heart rate. Dosage adjustment of the coadministered drug may be necessary. ( 7.3 ) 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Lanreotide Injection treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Warnings and Precautions ( 5.2 )] . 7.2 Cyclosporine Concomitant administration of cyclosporine with Lanreotide Injection may decrease the absorption of cyclosporine, and therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic drug concentrations. [see Clinical Pharmacology ( 12.3 )] 7.3 Bromocriptine Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the absorption of bromocriptine [see Clinical Pharmacology ( 12.3 )] . 7.4 Bradycardia-Inducing Drugs Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dosage adjustments of concomitant drugs may be necessary. 7.5 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that Lanreotide Injection may have this effect, avoid other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine). Drugs metabolized by the liver may be metabolized more slowly during Lanreotide Injection treatment and dose reductions of the concomitantly administered medications should be considered [see Clinical Pharmacology ( 12.3 )] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed during treatment and for 6 months after the last dose. ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data based on post-marketing case reports with lanreotide use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5- and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively ( see Data) The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Animal Data A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.2 Lactation Risk Summary There is no information available on the presence of lanreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that lanreotide administered subcutaneously passes into the milk of lactating rats; however, due to specifies-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk . Because of the potential for serious adverse reactions in breastfed infants from Lanreotide Injection, including effects on glucose metabolism and bradycardia, advise women not to breastfeed during treatment with Lanreotide Injection and for 6 months (6 half-lives) following the last dose. 8.3 Females and Males of Reproductive Potential Infertility Females Based on results from animal studies conducted in female rats, Lanreotide Injection may reduce fertility in females of reproductive potential [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use The safety and effectiveness of Lanreotide Injection in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients 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. Studies 3 and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Acromegaly Lanreotide has been studied in patients with end-stage renal function on dialysis, but has not been studied in patients with mild, moderate, or severe renal impairment. It is recommended that patients with moderate or severe renal impairment receive a starting dose of Lanreotide Injection of 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Lanreotide Injection 120 mg every 6 or 8 weeks [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] . Neuroendocrine Tumors (NET) – Gastroenteropancreatic Neuroendocrine Tumors No effect was observed in total clearance of lanreotide in patients with mild to moderate renal impairment receiving lanreotide injection 120 mg. Patients with severe renal impairment were not studied [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Acromegaly It is recommended that patients with moderate or severe hepatic impairment receive a starting dose of Lanreotide Injection 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Lanreotide Injection 120 mg every 6 or 8 weeks [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )] . Neuroendocrine Tumors (NET) – Gastroenteropancreatic Neuroendocrine Tumors Lanreotide has not been studied in patients with hepatic impairment." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited available data based on post-marketing case reports with lanreotide use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5- and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively ( see Data) The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Animal Data A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of Lanreotide Injection in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients 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. Studies 3 and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "description": [ "11 DESCRIPTION Lanreotide Injection 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL is a prolonged-release formulation for deep subcutaneous injection. It contains the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, water for injection and acetic acid (for pH adjustment). Lanreotide Injection is available as sterile, ready-to-use, single-dose prefilled syringes containing lanreotide acetate supersaturated bulk solution of 24.6% w/w lanreotide base. Each syringe contains: Lanreotide Injection 60 mg/0.2 mL Lanreotide Injection 90 mg/0.3 mL Lanreotide Injection 120 mg/0.5 mL Lanreotide acetate 89.9 mg 123.2 mg 156.6 mg Acetic Acid q.s. q.s. q.s. Water for injection 236.4 mg 324.1 mg 411.6 mg Total Weight 328.9 mg 450.9 mg 572.8 mg Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D­ alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is: The Lanreotide Injection in the prefilled syringe is a white to pale yellow, semi-solid formulation. Chemical Structure" ], "description_table": [ "
Each syringe contains:Lanreotide Injection 60 mg/0.2 mLLanreotide Injection 90 mg/0.3 mLLanreotide Injection 120 mg/0.5 mL
Lanreotide acetate89.9 mg123.2 mg156.6 mg
Acetic Acidq.s.q.s.q.s.
Water for injection236.4 mg324.1 mg411.6 mg
Total Weight328.9 mg450.9 mg572.8 mg
" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lanreotide, the active component of Lanreotide Injection, is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin. 12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies ( 14.1 )] . In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days. In Study 4, patients with carcinoid syndrome treated with lanreotide injection 120 mg every 4 weeks had reduced levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) compared with placebo [see Clinical Studies ( 14.3 )]. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [see Warnings and Precautions ( 5.1 )] . In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21-day) of lanreotide, serum glucose concentrations were temporarily decreased by 20% to 30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [see Warnings and Precautions ( 5.2) ] . Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis [see Warnings and Precautions ( 5. 4 )] . 12.3 Pharmacokinetics Lanreotide Injection is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream. After a single, deep subcutaneous administration, the mean absolute bioavailability of lanreotide in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax and showed high inter-subject variability. Lanreotide showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion. Acromegaly In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of lanreotide between 60 and 120 mg, linear pharmacokinetics were observed in acromegalic patients. At steady state, mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7, and 7.7 ± 2.5 ng/mL, increasing linearly with dose. The mean accumulation ratio index was 2.7, which is in line with the range of values for the half-life of lanreotide. The steady- state trough serum lanreotide concentrations in patients receiving lanreotide every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60 mg, 90 mg, and 120 mg doses, respectively. A limited initial burst effect and a low peak-to-trough fluctuation (81% to 108%) of the serum concentration at the plateau were observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1, and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of lanreotide injection 120 mg demonstrated mean steady-state, Cmin values between 1.6 and 2.3 ng/mL for the 8- and 6-week treatment interval, respectively. Gastroenteropancreatic Neuroendocrine Tumors In patients with GEP-NETs treated with lanreotide 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL. Specific Populations Lanreotide Injection has not been studied in specific populations. However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Geriatric Patients Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects. Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged 65 to 85 years with neuroendocrine tumors. Patients with Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2­fold increase in half-life and AUC was observed [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with lanreotide. GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied. Patients with Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.7 )]. The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of Lanreotide Injection or of other lanreotide products. Acromegaly Laboratory investigations of acromegalic patients treated with lanreotide injection in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (less than 1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of lanreotide injection. GEP-NETs In Study 3, development of anti-lanreotide antibodies was assessed using a radioimmunoprecipitation assay. In patients with GEP-NETs receiving lanreotide injection, the incidence of anti-lanreotide antibodies was 4% (3 of 82) at 24 weeks, 10% (7 of 67) at 48 weeks, 11% (6 of 57) at 72 weeks, and 10% (8 of 84) at 96 weeks. Assessment for neutralizing antibodies was not conducted. Carcinoid Syndrome In Study 4, less than 2% (2 of 108) of the patients treated with lanreotide injection developed anti-lanreotide antibodies." ], "mechanism_of_action": [ "12.1 Mechanism of Action Lanreotide, the active component of Lanreotide Injection, is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies ( 14.1 )] . In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of lanreotide, plasma GH levels fall rapidly and are maintained for at least 28 days. In Study 4, patients with carcinoid syndrome treated with lanreotide injection 120 mg every 4 weeks had reduced levels of urinary 5-hydroxyindoleacetic acid (5-HIAA) compared with placebo [see Clinical Studies ( 14.3 )]. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [see Warnings and Precautions ( 5.1 )] . In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21-day) of lanreotide, serum glucose concentrations were temporarily decreased by 20% to 30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [see Warnings and Precautions ( 5.2) ] . Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis [see Warnings and Precautions ( 5. 4 )] ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Lanreotide Injection is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream. After a single, deep subcutaneous administration, the mean absolute bioavailability of lanreotide in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax and showed high inter-subject variability. Lanreotide showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion. Acromegaly In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of lanreotide between 60 and 120 mg, linear pharmacokinetics were observed in acromegalic patients. At steady state, mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7, and 7.7 ± 2.5 ng/mL, increasing linearly with dose. The mean accumulation ratio index was 2.7, which is in line with the range of values for the half-life of lanreotide. The steady- state trough serum lanreotide concentrations in patients receiving lanreotide every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60 mg, 90 mg, and 120 mg doses, respectively. A limited initial burst effect and a low peak-to-trough fluctuation (81% to 108%) of the serum concentration at the plateau were observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1, and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of lanreotide injection 120 mg demonstrated mean steady-state, Cmin values between 1.6 and 2.3 ng/mL for the 8- and 6-week treatment interval, respectively. Gastroenteropancreatic Neuroendocrine Tumors In patients with GEP-NETs treated with lanreotide 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL. Specific Populations Lanreotide Injection has not been studied in specific populations. However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Geriatric Patients Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects. Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged 65 to 85 years with neuroendocrine tumors. Patients with Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2­fold increase in half-life and AUC was observed [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )]. Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with lanreotide. GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied. Patients with Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.7 )]. The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide at 0.5, 1.5, 5, 10, and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30 mg/kg/day resulting in exposures 3 times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5 mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. In a fertility study conducted with lanreotide in rats, reduced female fecundity was observed at estimated exposure corresponding to approximately 10-fold the plasma exposure at the MRHD of 120 mg. The fertility of male rats was unaffected by the treatment up to an estimated exposure corresponding to approximately 11-fold the plasma exposure at the MRHD of 120 mg." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide at 0.5, 1.5, 5, 10, and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30 mg/kg/day resulting in exposures 3 times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5 mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. In a fertility study conducted with lanreotide in rats, reduced female fecundity was observed at estimated exposure corresponding to approximately 10-fold the plasma exposure at the MRHD of 120 mg. The fertility of male rats was unaffected by the treatment up to an estimated exposure corresponding to approximately 11-fold the plasma exposure at the MRHD of 120 mg." ], "clinical_studies": [ "14 CLINICAL STUDIES The safety and efficacy of Lanreotide Injection have been established based on adequate and well-controlled studies of another lanreotide injection product. Below is a description of the results of these adequate and well-controlled studies of lanreotide injection in these conditions. 14.1 Acromegaly The effect of lanreotide on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in 2 long-term, multiple-dose, randomized, multicenter studies. Study 1 This 1-year study included a 4-week, double-blind, placebo-controlled phase; a 16-week single-blind, fixed-dose phase; and a 32-week, open-label, dose-titration phase. Patients with active acromegaly, based on biochemical tests and medical history, entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist. Upon entry, patients were randomly allocated to receive a single, deep subcutaneous injection of lanreotide 60, 90, or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of lanreotide followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels. A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist or had stopped treatment for at least 3 months prior to their participation in the study, and were required to have a mean GH level greater than 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were required to have a mean GH concentration greater than 3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication. One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase, and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4). In the double-blind phase of Study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a greater than 50% decrease in mean GH from baseline to Week 4, including 52%, 44%, and 90% of patients in the 60, 90, and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of greater than 50%, including 68% (23/34), 64% (23/36), and 84% (31/37) of patients in the 60, 90, and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 4). Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Patients with Acromegaly in Study 1 1 n=105, 2 n=102, 3 Age-adjusted *Last Observation Carried Forward Baseline N=107 Before Titration 1 (16 weeks) N=107 Before Titration 2 (32 weeks) N=105 Last Value Available* N=107 IGH ≤5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%) ≤2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%) ≤1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%) Median GH ng/mL 10.27 2.53 2.20 2.43 GH Reduction Median % Reduction - 75.5 78.2 75.5 IGF-1 Normal 3 Number of Responders (%) 9 (8%) 58 (54%) 57 (54%) 62 (58%) Median IGF-1 ng/mL 775.0 332.0 1 316.5 2 326.0 IGF-1 Reduction Median % Reduction -- 52.3 1 54.5 2 55.4 IGF-1 Normal 3 + GH ≤2.5 ng/m L Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%) Study 2 This was a 48-week, open-label, uncontrolled, multicenter study that enrolled patients who had an IGF-1 concentration 1.3 times or greater than the upper limit of the normal age- adjusted range. Patients receiving treatment with a somatostatin analog (other than lanreotide) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months. Patients were initially enrolled in a 4-month, fixed-dose phase where they received 4 deep subcutaneous injections of lanreotide 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of lanreotide was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again. A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48 weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1). After 48 weeks of treatment with lanreotide at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations less than 2.5 ng/mL increased significantly from 35% to 77% after the fixed- dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of less than or equal to 2.5 ng/mL (see Table 5) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of less than 1 ng/mL. Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Patients with Acromegaly in Study 2 1 Age-adjusted, 2 N= 62, * Last Observation Carried Forward Baseline N=63 Before Titration 1 (12 wks) N=63 Before Titration 2 (28 wks) N=59 Last Value Available* N=63 IGF-1 Normal1 Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%) Median IGF-1 ng/mL 689.0 382.0 334.0 317.0 IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3 GH ≤5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%) ≤2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86%) ≤1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%) Median GH ng/Ml 3.71 1.65 1.48 1.13 GH Reduction Median % Reduction -- 63.2 66.7 78.6 2 IGF-1 normal 1 + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%) Examination of age and gender subgroups did not identify differences in response to lanreotide among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of lanreotide in these subgroups. 14.2 Gastroenteropancreatic Neuroendocrine Tumors The efficacy of lanreotide was established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, GEP-NETs. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive lanreotide injection 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity, or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) or death. The median patient age was 63 years (range 30 to 92 years) and 95% were White. Disease progression was present in nine of 204 patients (4.4%) in the 6 months prior to enrollment and 29 patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Baseline prognostic characteristics were similar between arms with one exception: there were 39% of patients in the lanreotide arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of greater than 25%. Patients in the lanreotide arm had a statistically significant improvement in PFS compared to patients receiving placebo (see Table 6 and Figure 1). Table 6: Efficacy Results in Patients with GEP-NETs in Study 3 1 NE = not reached at 22 months 2 Hazard Ratio is derived from a Cox stratified proportional hazards model Lanreotide Placebo n=101 n=103 Number of Events (%) 32 (31.7%) 60 (58.3%) Median PFS (months)(95% CI) NE 1 (NE, NE) 16.6 (11.2, 22.1) HR (95% CI) 0.47 (0.30, 0.73) 2 Log-rank p-value <0.001 Figure 1: Kaplan-Meier Curves of Progression-Free Survival in Patients with GEP-NETs in Study 3 Figure 30.jpg 14.3 Carcinoid Syndrome Study 4 was a multicenter, randomized, 16-week, double-blind, placebo-controlled trial in 115 patients with histopathologically-confirmed neuroendocrine tumors and a history of carcinoid syndrome (flushing and/or diarrhea) who were treatment naïve or stable on another somatostatin analog and who were randomized 1:1 to receive lanreotide injection 120 mg (n=59) or placebo (n=56) by deep subcutaneous injection every 4 weeks. Patients were instructed to self-administer a short-acting somatostatin analog (octreotide) as rescue medication as needed for symptom control. The use of rescue therapy and the severity and frequency of diarrhea and flushing symptoms were reported daily in electronic patient diaries. During the 16 week double-blind phase, the primary efficacy outcome measure was the percentage of days in which patients administered at least one injection of rescue medication for symptom control. Average daily frequencies of diarrhea and flushing events were assessed secondarily. The patient population had a mean age of 59 years (range 27 to 85 years), 58% were female and 77% were White. Patients in the lanreotide arm experienced 15% fewer days on rescue medication compared to patients in the placebo arm (34% vs. 49% of days, respectively; p=0.02). The average daily frequencies of diarrhea and flushing events in patients treated with lanreotide (and rescue medication) were numerically lower relative to patients treated with placebo (and rescue medication), but were not statistically significantly different via hierarchical testing." ], "clinical_studies_table": [ "
Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Patients with Acromegaly in Study 1
1n=105, 2n=102, 3Age-adjusted *Last Observation Carried Forward
Baseline N=107Before Titration 1 (16 weeks) N=107Before Titration 2 (32 weeks) N=105Last Value Available* N=107
IGH
≤5.0 ng/mLNumber of Responders (%)20 (19%)72 (67%)76 (72%)74 (69%)
≤2.5 ng/mLNumber of Responders (%)0 (0%)52 (49%)59 (56%)55 (51%)
≤1.0 ng/mLNumber of Responders (%)0 (0%)15 (14%)18 (17%)17 (16%)
Median GHng/mL10.272.532.202.43
GH ReductionMedian % Reduction-75.578.275.5
IGF-1
Normal3Number of Responders (%)9 (8%)58 (54%)57 (54%)62 (58%)
Median IGF-1ng/mL775.0332.01316.52326.0
IGF-1 ReductionMedian % Reduction--52.3154.5255.4
IGF-1 Normal3 + GH ≤2.5 ng/mLNumber of Responders (%)0 (0%)41 (38%)46 (44%)44 (41%)
", "
Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Patients with Acromegaly in Study 2
1Age-adjusted, 2N= 62, * Last Observation Carried Forward
Baseline N=63Before Titration 1 (12 wks) N=63Before Titration 2 (28 wks) N=59Last Value Available* N=63
IGF-1
Normal1Number of Responders (%)0 (0%)17 (27%)22 (37%)27 (43%)
Median IGF-1ng/mL689.0382.0334.0317.0
IGF-1 ReductionMedian % Reduction--41.051.050.3
GH
≤5.0 ng/mLNumber of Responders (%)40 (64%)59 (94%)57 (97%)62 (98%)
≤2.5 ng/mLNumber of Responders (%)21 (33%)47 (75%)47 (80%)54 (86%)
≤1.0 ng/mLNumber of Responders (%)8 (13%)19 (30%)18 (31%)28 (44%)
Median GHng/Ml3.711.651.481.13
GH ReductionMedian % Reduction--63.266.778.62
IGF-1 normal1 + GH ≤2.5 ng/mLNumber of Responders (%)0 (0%)14 (22%)20 (34%)24 (38%)
", "
Table 6: Efficacy Results in Patients with GEP-NETs in Study 3
1NE = not reached at 22 months 2Hazard Ratio is derived from a Cox stratified proportional hazards model
LanreotidePlacebo
n=101n=103
Number of Events (%)32 (31.7%)60 (58.3%)
Median PFS (months)(95% CI)NE1 (NE, NE)16.6 (11.2, 22.1)
HR (95% CI)0.47 (0.30, 0.73)2
Log-rank p-value<0.001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Lanreotide Injection is supplied in strengths of 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL lanreotide as a white to pale yellow, semi-solid formulation in a single-dose, sterile, prefilled, ready-to-use, polypropylene syringe and a safety needle device. The safety needle device is a sterile, single use needle system consisting of a needle (1.2 mm x 20 mm, stainless steel) held in protective plastic safety housing. The single-dose prefilled syringe is contained in a plastic tray and is packed in a triple-layered aluminium pouch. The sterile safety needle is co-packaged along with the sealed aluminium pouch in the kit carton box and is attached to the former at the point of use. NDC 69097-880-67 60 mg/0.2 mL lanreotide, sterile, prefilled syringe NDC 69097-890-67 90 mg/0.3 mL lanreotide, sterile, prefilled syringe NDC 69097-870-67 120 mg/0.5 mL lanreotide, sterile, prefilled syringe Storage and Handling Store Lanreotide Injection in the refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the original package. Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 72 hours may be returned to the refrigerator for continued storage and usage at a later time." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypersensitivity Reactions Advise patients to immediately contact their healthcare provider if they experience serious hypersensitivity reactions, such as angioedema or anaphylaxis [see Contraindications ( 4 )] . Cholelithiasis and Complications of Cholelithiasis Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, or pancreatitis) [see Warnings and Precautions ( 5.1 )]. Hyperglycemia and Hypoglycemia Advise patients to immediately contact their healthcare provider if they experience signs or symptoms of hyper- or hypoglycemia [see Warnings and Precautions ( 5.2 )] . Cardiovascular Abnormalities Advise patients to immediately contact their healthcare provider if they experience bradycardia [see Warnings and Precautions ( 5.3 )]. Thyroid Function Abnormalities Advise patients to contact their healthcare provider if they experience signs or symptoms of hypothyroidism [see Warnings and Precautions ( 5.4 )]. Laboratory Tests Advise patients with acromegaly that response to Lanreotide Injection should be monitored by periodic measurements of GH and IGF-1 levels, with a goal of decreasing these levels to the normal range [see Dosage and Administration ( 2.1 )]. Steatorrhea and Malabsorption of Dietary Fats Advise patients to contact their healthcare provider if they experience new or worsening symptoms of steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss [see Warnings and Precautions ( 5.6 )]. Lactation Advise women not to breastfeed during treatment with Lanreotide Injection and for 6 months after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility Advise females of reproductive potential of the potential for reduced fertility from Lanreotide Injection [see Use in Specific Populations ( 8.3 )]. Manufactured by: Pharmathen International S.A. Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, Greece Manufactured for: Cipla USA Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059" ], "information_for_patients_table": [ "
Manufactured by: Pharmathen International S.A. Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, GreeceManufactured for: Cipla USA Inc. 10 Independence Boulevard, Suite 300 Warren, NJ 07059
" ], "spl_patient_package_insert": [ "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 09/2024 PATIENT INFORMATION Lanreotide (lan-REE-oh-tide) Injection for subcutaneous use Read this Patient Information before you receive your first Lanreotide injection and before each injection. 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 is Lanreotide injection? Lanreotide injection is a prescription medicine used for: the long-term treatment of people with acromegaly when: ⚬ surgery or radiotherapy have not worked well enough or ⚬ they are not able to have surgery or radiotherapy. the treatment of adults with a type of cancer known as neuroendocrine tumors, from the gastrointestinal tract or the pancreas (GEP-NETs) that has spread or cannot be removed by surgery. the treatment of adults with carcinoid syndrome to reduce the need for the use of short-acting somatostatin medicine It is not known if Lanreotide injection is safe and effective in children. Who should not receive Lanreotide injection? Do not receive Lanreotide injection if you are allergic to lanreotide. What should I tell my healthcare provider before receiving Lanreotide injection? Before you receive Lanreotide injection , tell your healthcare provider about all of your medical conditions, including if you: have gallbladder problems. have diabetes. have heart problems. have thyroid problems. have kidney problems. have liver problems. are pregnant or plan to become pregnant. It is not known if Lanreotide injection will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if Lanreotide injection passes into your breast milk. You should not breastfeed if you receive Lanreotide injection and for 6 months after your last dose of Lanreotide injection. are a person who can become pregnant. Lanreotide injection may affect fertility and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you. Tell your healthcare provider about all the medicines you take, including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Lanreotide injection and other medicines may affect each other, causing side effects. Lanreotide injection may affect the way other medicines work, and other medicines may affect how Lanreotide injection works. Your dose of Lanreotide injection or your other medicines may need to be changed. Especially tell your healthcare provider if you take: insulin or other diabetes medicines. cyclosporine (Gengraf, Neoral, or Sandimmune). medicines that lower your heart rate such as beta blockers. How will I receive Lanreotide injection ? You will receive a Lanreotide injection dose every 4 weeks in your healthcare provider’s office. Your healthcare provider may change your dose of Lanreotide injection or the length of time between your injections. Your healthcare provider will tell you how long you need to receive Lanreotide injection. Lanreotide injection is injected deep under the skin of the upper outer area of your buttock. Your injection site should change (alternate) between your right and left buttock from one injection of Lanreotide injection to the next. During your treatment with Lanreotide injection for acromegaly, your healthcare provider may do certain blood tests to see if Lanreotide injection is working. What should I avoid while receiving Lanreotide injection ? Lanreotide injection can cause dizziness. If you have dizziness, do not drive a car or operate machinery. What are the possible side effects of Lanreotide injection ? Lanreotide injection may cause serious side effects, including: Gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are a serious but common side effect in people who take Lanreotide injection and have acromegaly and GEP-NET. Your healthcare provider may check your gallbladder before and during treatment with Lanreotide injection. Possible complications of gallstones include inflammation and infection of the gallbladder and pancreatitis. Tell your healthcare provider if you get any symptoms of gallstones, including: ⚬ sudden pain in your upper right stomach area (abdomen) ⚬ yellowing of your skin and whites of your eyes ⚬ nausea ⚬ sudden pain in your right shoulder between your shoulder blades ⚬ fever with chills Changes in your blood sugar (high blood sugar or low blood sugar). If you have diabetes, test your blood sugar as your healthcare provider tells you to. Your healthcare provider may change your dose of diabetes medicine especially when you first start receiving Lanreotide injection or if your dose of Lanreotide injection changes. High blood sugar is a common side effect in people with GEP-NET. Tell your healthcare provider right away if you have any signs or symptoms of high blood sugar or low blood sugar. Signs and symptoms of high blood sugar may include: ⚬ increased thirst ⚬ increased appetite ⚬ nausea ⚬ weakness or tiredness ⚬ urinating more often than normal ⚬ your breath smells like fruit Signs and symptoms of low blood sugar may include: ⚬ dizziness or lightheadedness ⚬ sweating ⚬ confusion ⚬ headache ⚬ blurred vision ⚬ slurred speech ⚬ shakiness ⚬ fast heartbeat ⚬ irritability or mood changes ⚬ hunger Slow heart rate . Tell your healthcare provider right away if you have slowing of your heart rate or if you have symptoms of a slow heart rate, including: ⚬ dizziness or lightheadedness ⚬ fainting or near-fainting ⚬ chest pain ⚬ shortness of breath ⚬ confusion or memory ⚬ weakness, extreme tiredness High blood pressure. High blood pressure can happen in people who receive Lanreotide injection and is a common side effect in people with GEP-NET. Changes in thyroid function. Lanreotide injection can cause the thyroid gland to not make enough thyroid hormones that the body needs (hypothyroidism) in people who have acromegaly. Tell your healthcare provider if you have signs and symptoms of low thyroid hormones levels, including: ⚬ fatigue ⚬ weight gain ⚬ a puffy face ⚬ being cold all of the time ⚬ constipation ⚬ dry skin ⚬ thinning, dry hair ⚬ decreased sweating ⚬ depression Fatty stool. Lanreotide injection may cause your body to have issues absorbing dietary fats. Tell your healthcare provider if you have any new or worsening symptoms including fatty or oily stools, changes in the color of your stools, loose stools, stomach (abdominal) bloating or weight loss. The most common side effects of Lanreotide injection in people with acromegaly include: • diarrhea • stomach area (abdominal) pain • nausea • pain, itching, or a lump at the injection site The most common side effects of Lanreotide injection in people with GEP-NET include: • stomach area (abdominal) pain • muscle and joint aches • vomiting • headache • pain, itching, or a lump at the injection site The most common side effects of Lanreotide Injection in people with carcinoid syndrome include: • headache • dizziness • muscle spasm Tell your healthcare provider right away if you have signs of an allergic reaction after receiving Lanreotide injection, including: • swelling of your face, lips, mouth or tongue • breathing problems • fainting, dizziness, feeling lightheaded (low blood pressure) • itching • flushing or redness of your skin • rash • hives These are not all the possible side effects of Lanreotide injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Lanreotide injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not receive Lanreotide injection for a condition for which it was not prescribed. You can ask your healthcare provider for information about Lanreotide injection that is written for health professionals. What are the ingredients in Lanreotide injection? Active ingredient: lanreotide acetate Inactive ingredients: water for injection and acetic acid (for pH adjustment) Manufactured by: Pharmathen International S.A., Rodopi, Greece Manufactured for: Cipla USA, Inc., 10 Independence Boulevard, Suite 300, Warren, NJ 07059 SAP Code: 99353071 For more information, go to www.ciplausa.com or call 1-886-604-3268." ], "spl_patient_package_insert_table": [ "
This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 09/2024
PATIENT INFORMATIONLanreotide (lan-REE-oh-tide) Injection for subcutaneous use
Read this Patient Information before you receive your first Lanreotide injection and before each injection. 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 is Lanreotide injection?Lanreotide injection is a prescription medicine used for:the long-term treatment of people with acromegaly when: ⚬ surgery or radiotherapy have not worked well enough or ⚬ they are not able to have surgery or radiotherapy.the treatment of adults with a type of cancer known as neuroendocrine tumors, from the gastrointestinal tract or the pancreas (GEP-NETs) that has spread or cannot be removed by surgery.the treatment of adults with carcinoid syndrome to reduce the need for the use of short-acting somatostatin medicineIt is not known if Lanreotide injection is safe and effective in children.
Who should not receive Lanreotide injection?Do not receive Lanreotide injection if you are allergic to lanreotide.
What should I tell my healthcare provider before receiving Lanreotide injection?Before you receive Lanreotide injection, tell your healthcare provider about all of your medical conditions, including if you:have gallbladder problems.have diabetes.have heart problems.have thyroid problems.have kidney problems.have liver problems.are pregnant or plan to become pregnant. It is not known if Lanreotide injection will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if Lanreotide injection passes into your breast milk. You should not breastfeed if you receive Lanreotide injection and for 6 months after your last dose of Lanreotide injection.are a person who can become pregnant. Lanreotide injection may affect fertility and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.Tell your healthcare provider about all the medicines you take, including prescription and over­ the-counter medicines, vitamins, and herbal supplements. Lanreotide injection and other medicines may affect each other, causing side effects. Lanreotide injection may affect the way other medicines work, and other medicines may affect how Lanreotide injection works. Your dose of Lanreotide injection or your other medicines may need to be changed.Especially tell your healthcare provider if you take:insulin or other diabetes medicines.cyclosporine (Gengraf, Neoral, or Sandimmune).medicines that lower your heart rate such as beta blockers.
How will I receive Lanreotide injection?You will receive a Lanreotide injection dose every 4 weeks in your healthcare provider’s office.Your healthcare provider may change your dose of Lanreotide injection or the length of time between your injections. Your healthcare provider will tell you how long you need to receive Lanreotide injection.Lanreotide injection is injected deep under the skin of the upper outer area of your buttock. Your injection site should change (alternate) between your right and left buttock from one injection of Lanreotide injection to the next.During your treatment with Lanreotide injection for acromegaly, your healthcare provider may do certain blood tests to see if Lanreotide injection is working.
What should I avoid while receiving Lanreotide injection?Lanreotide injection can cause dizziness. If you have dizziness, do not drive a car or operate machinery.
What are the possible side effects of Lanreotide injection? Lanreotide injection may cause serious side effects, including:Gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are a serious but common side effect in people who take Lanreotide injection and have acromegaly and GEP-NET. Your healthcare provider may check your gallbladder before and during treatment with Lanreotide injection. Possible complications of gallstones include inflammation and infection of the gallbladder and pancreatitis. Tell your healthcare provider if you get any symptoms of gallstones, including:
⚬ sudden pain in your upper right stomach area (abdomen) ⚬ yellowing of your skin and whites of your eyes ⚬ nausea ⚬ sudden pain in your right shoulder between your shoulder blades ⚬ fever with chills
Changes in your blood sugar (high blood sugar or low blood sugar). If you have diabetes, test your blood sugar as your healthcare provider tells you to. Your healthcare provider may change your dose of diabetes medicine especially when you first start receiving Lanreotide injection or if your dose of Lanreotide injection changes. High blood sugar is a common side effect in people with GEP-NET.Tell your healthcare provider right away if you have any signs or symptoms of high blood sugar or low blood sugar.Signs and symptoms of high blood sugar may include:
⚬ increased thirst ⚬ increased appetite ⚬ nausea ⚬ weakness or tiredness ⚬ urinating more often than normal ⚬ your breath smells like fruit
Signs and symptoms of low blood sugar may include:
⚬ dizziness or lightheadedness ⚬ sweating ⚬ confusion ⚬ headache ⚬ blurred vision ⚬ slurred speech ⚬ shakiness ⚬ fast heartbeat ⚬ irritability or mood changes ⚬ hunger
Slow heart rate. Tell your healthcare provider right away if you have slowing of your heart rate or if you have symptoms of a slow heart rate, including:
⚬ dizziness or lightheadedness ⚬ fainting or near-fainting ⚬ chest pain ⚬ shortness of breath ⚬ confusion or memory ⚬ weakness, extreme tiredness
High blood pressure. High blood pressure can happen in people who receive Lanreotide injection and is a common side effect in people with GEP-NET.Changes in thyroid function. Lanreotide injection can cause the thyroid gland to not make enough thyroid hormones that the body needs (hypothyroidism) in people who have acromegaly. Tell your healthcare provider if you have signs and symptoms of low thyroid hormones levels, including:
⚬ fatigue ⚬ weight gain ⚬ a puffy face ⚬ being cold all of the time ⚬ constipation ⚬ dry skin ⚬ thinning, dry hair ⚬ decreased sweating ⚬ depression
Fatty stool. Lanreotide injection may cause your body to have issues absorbing dietary fats. Tell your healthcare provider if you have any new or worsening symptoms including fatty or oily stools, changes in the color of your stools, loose stools, stomach (abdominal) bloating or weight loss.
The most common side effects of Lanreotide injection in people with acromegaly include:
• diarrhea • stomach area (abdominal) pain • nausea • pain, itching, or a lump at the injection site
The most common side effects of Lanreotide injection in people with GEP-NET include:
• stomach area (abdominal) pain • muscle and joint aches • vomiting • headache • pain, itching, or a lump at the injection site
The most common side effects of Lanreotide Injection in people with carcinoid syndrome include: • headache • dizziness • muscle spasm Tell your healthcare provider right away if you have signs of an allergic reaction after receiving Lanreotide injection, including:
• swelling of your face, lips, mouth or tongue • breathing problems • fainting, dizziness, feeling lightheaded (low blood pressure) • itching • flushing or redness of your skin • rash • hives
These are not all the possible side effects of Lanreotide injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Lanreotide injection.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not receive Lanreotide injection for a condition for which it was not prescribed. You can ask your healthcare provider for information about Lanreotide injection that is written for health professionals.
What are the ingredients in Lanreotide injection?Active ingredient: lanreotide acetateInactive ingredients: water for injection and acetic acid (for pH adjustment) Manufactured by: Pharmathen International S.A., Rodopi, GreeceManufactured for: Cipla USA, Inc., 10 Independence Boulevard, Suite 300, Warren, NJ 07059 SAP Code: 99353071 For more information, go to www.ciplausa.com or call 1-886-604-3268.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 60 mg/0.2 mL Carton Label NDC 69097-880-67 Rx Only Lanreotide Injection 60 mg*/0.2 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. Cipla 60 mg/0.2 mL Carton Label", "PRINCIPAL DISPLAY PANEL - 90 mg/0.3 mL Carton Label NDC 69097-890-67 Rx Only Lanreotide Injection 90 mg*/0.3 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. Cipla 90 mg/0.3 mL Carton Label", "PRINCIPAL DISPLAY PANEL - 120 mg/0.5 mL Carton Label NDC 69097-870-67 Rx Only Lanreotide Injection 120 mg*/0.5 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. Cipla 120 mg/0.5 mL Carton Label" ], "set_id": "11da176a-99bc-4ada-8b3f-6bd2b37a6313", "id": "fd205110-15eb-4707-82b2-185e5bbf616b", "effective_time": "20240901", "version": "7", "openfda": { "application_number": [ "NDA215395" ], "brand_name": [ "Lanreotide Acetate" ], "generic_name": [ "LANREOTIDE ACETATE" ], "manufacturer_name": [ "Cipla USA Inc." ], "product_ndc": [ "69097-870", "69097-880", "69097-890" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "SUBCUTANEOUS" ], "substance_name": [ "LANREOTIDE ACETATE" ], "rxcui": [ "749811", "749814", "749817" ], "spl_id": [ "fd205110-15eb-4707-82b2-185e5bbf616b" ], "spl_set_id": [ "11da176a-99bc-4ada-8b3f-6bd2b37a6313" ], "package_ndc": [ "69097-880-67", "69097-890-67", "69097-870-67" ], "is_original_packager": [ true ], "unii": [ "IEU56G3J9C" ] } }, { "spl_product_data_elements": [ "Bromocriptine Mesylate Bromocriptine Mesylate BROMOCRIPTINE MESYLATE BROMOCRIPTINE SILICON DIOXIDE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MALEIC ACID STARCH, CORN POVIDONE K30 Off-white E280;25 Bromocriptine Mesylate Bromocriptine Mesylate BROMOCRIPTINE MESYLATE BROMOCRIPTINE SILICON DIOXIDE STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE MALEIC ACID GELATIN FERRIC OXIDE RED TITANIUM DIOXIDE WATER FERROSOFERRIC OXIDE BUTYL ALCOHOL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL SHELLAC caramel opaque cap white opaque body 102;PARLODEL5mg" ], "description": [ "DESCRIPTION Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity. Each bromocriptine mesylate tablet for oral administration contains 2.5 mg bromocriptine (as the mesylate) and each capsule contains 5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is chemically designated as Ergotaman-3′, 6′, 18-trione, 2-bromo-12′-hydroxy-2′-(1-methylethyl) -5′-(2-methylpropyl)-, (5′α)-monomethanesulfonate (salt). The structural formula is: 2.5 mg Tablets Active Ingredient: bromocriptine mesylate, USP Inactive Ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, maleic acid, povidone, and corn starch. Meets USP Dissolution Test 1. 5 mg Capsules Active Ingredient: bromocriptine mesylate, USP Inactive Ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, and maleic acid. The hard gelatin capsule contains gelatin, iron oxide red, titanium dioxide and purified water. The imprinting ink contains black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol and shellac. structure" ], "clinical_pharmacology": [ "CLINICAL PHARMACOLOGY Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, bromocriptine mesylate significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces long-lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors. Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients. Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population. Pharmacokinetics Absorption Following single dose administration of bromocriptine mesylate tablets, 2 x 2.5 mg to 5 healthy volunteers under fasted conditions, the mean peak plasma levels of bromocriptine, time to reach peak plasma concentrations and elimination half-life were 465 pg/mL ± 226, 2.5 hrs ± 2 and 4.85 hr, respectively. 1 Linear relationship was found between single doses of bromocriptine mesylate and C max and AUC in the dose range of 1 to 7.5 mg. 2 The pharmacokinetics of bromocriptine metabolites have not been reported. Food did not significantly affect the systemic exposure of bromocriptine following administration of bromocriptine mesylate tablets, 2.5 mg. 3 It is recommended that bromocriptine mesylate be taken with food because of the high percentage of subjects who vomit upon receiving bromocriptine under fasting conditions. Following bromocriptine mesylate 5 mg administered twice daily for 14 days, the bromocriptine C max and AUC at steady-state were 628 ± 375 pg/mL and 2377 ± 1186 pg*hr/mL, respectively. 4 Distribution In vitro experiments showed that bromocriptine was 90% - 96% bound to serum albumin. Metabolism Bromocriptine undergoes extensive first-pass biotransformation, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. In vitro studies using human liver microsomes showed that bromocriptine has a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constituted a main metabolic pathway. 5 Inhibitors and/or potent substrates for CYP3A4 might therefore inhibit the clearance of bromocriptine and lead to increased levels. (see PRECAUTIONS, drug interactions section) . The participation of other major CYP enzymes such as 2D6, 2C8, and 2C19 on the metabolism of bromocriptine has not been evaluated. Bromocriptine is also an inhibitor of CYP3A4 with a calculated IC50 value of 1.69 μM. 6 Given the low therapeutic concentrations of bromocriptine in patients (C max =0.82 nM), a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected. The potential effect of bromocriptine and its metabolites to act as inducers of CYP enzymes has not been reported. Excretion About 82% and 5.6 % of the radioactive dose orally administered was recovered in feces and urine, respectively. Bromolysergic acid and bromoisolysergic acid accounted for half of the radioactivity in urine. 5 1 Nelson, M. et. al. (1990). Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine. Clin Pharmacol Ther; 47(6):694-7. 2 Schran, H.F., Bhuta, S.I., Schwartz, et al. (1980). The pharmacokinetics of bromocriptine in man. In: Golstein, M. Calne, D.B., et. Al (eds). Ergot compound and brain function: Neuroendocrine and neuropsychiatric aspects, pp. 125-139, New York, Rave Press. 3 Kopitar, Z., Vrhovac, B., Povsic, L., Plavsic, F., Francetic, I., Urbancic, J. (1991). The effect of food and metoclopramide on the pharmacokinetics and side effects of bromocriptine. Eur J Drug Metab Pharmacokinet; 16(3):177-81 4 Flogstad, A.K., Halse, J., Grass, P., Abisch, E., Djoseland, O., Kutz, K., Bodd, E., and Jervell, J., (1994). A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology & Metabolism; Vol 79, 461-465 5 Peyronneau MA, Delaforge M, Riviere R et al. 1994. High affinity of ergopeptides for CYP P450 3A. Importance of their peptide moiety for P450 recognition and hydroxylation of bromocriptine. Eur J Biochem 223:947-56. 6 Wynalda, M.A., Wienkers, L.C. (1997). Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos; 25:1211-14. Specific Populations Effect of Renal Impairment The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. Since parent drug and metabolites are almost completely excreted via metabolism, and only 6% eliminated via the kidney, renal impairment may not have a significant impact on the PK of bromocriptine and its metabolites (see PRECAUTIONS, general) . Effect of Hepatic Impairment The effect of liver impairment on the PK of bromocriptine mesylate and its metabolites has not been evaluated. Since bromocriptine mesylate is mainly eliminated by metabolism, liver impairment may increase the plasma levels of bromocriptine, therefore, caution may be necessary (see PRECAUTIONS, general) . The effect of age, race, and gender on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated. Clinical Studies In about 75% of cases of amenorrhea and galactorrhea, bromocriptine mesylate therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles. Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6 to 8 weeks. However, some patients respond within a few days, and others may take up to 8 months. Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8 to 12 weeks. Some patients may fail to respond even after 12 months of therapy. In many acromegalic patients, bromocriptine mesylate produces a prompt and sustained reduction in circulating levels of serum growth hormone." ], "indications_and_usage": [ "INDICATIONS & USAGE Hyperprolactinemia-Associated Dysfunctions Bromocriptine mesylate is indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine mesylate treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine mesylate therapy may be used to reduce the tumor mass prior to surgery. Acromegaly Bromocriptine mesylate therapy is indicated in the treatment of acromegaly. Bromocriptine mesylate therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels. Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine mesylate offers potential benefit before the effects of irradiation are manifested. Parkinson’s Disease Bromocriptine mesylate tablets or capsules are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine mesylate therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose failure” on levodopa therapy. Bromocriptine mesylate therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function (“on-off” phenomenon). Continued efficacy of bromocriptine mesylate therapy during treatment of more than 2 years has not been established. Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease with bromocriptine mesylate. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine mesylate-treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine mesylate therapy." ], "contraindications": [ "CONTRAINDICATIONS Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate, uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States) . In the event that bromocriptine mesylate is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine mesylate is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine mesylate is considered to be medically contraindicated. The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period, the patient should be observed with caution." ], "warnings": [ "WARNINGS Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with bromocriptine mesylate. If pregnancy occurs during bromocriptine mesylate administration, careful observation of these patients is mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of bromocriptine mesylate treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of bromocriptine mesylate treatment during pregnancy to the mother and fetus has not been established. Bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered. Symptomatic hypotension can occur in patients treated with bromocriptine mesylate for any indication. In postpartum studies with bromocriptine mesylate, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving bromocriptine mesylate. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg. Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. While hypotension during the start of therapy with bromocriptine mesylate occurs in some patients, in rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, have been reported in postpartum women treated with bromocriptine mesylate for the inhibition of lactation. Hypertension have been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have also been reported both with and without the prior development of hypertension; stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing seizures (including cases of status epilepticus) and/or strokes reported developing a constant and often progressively severe headache hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness). Cases of acute myocardial infarction have also been reported. Although a causal relationship between bromocriptine mesylate administration and hypertension, seizures, strokes, and myocardial infarction in postpartum women has not been established, use of the drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended. In patients being treated for hyperprolactinemia, bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States) . In the event that bromocriptine mesylate is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine mesylate must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine mesylate is being used to treat acromegaly or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine mesylate is considered to be medically contraindicated. Because of the possibility of an interaction between bromocriptine mesylate and other ergot alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated promptly. Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the puerperium is not recommended. Among patients on bromocriptine mesylate, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine mesylate therapy should be considered. In those instances in which bromocriptine mesylate treatment was terminated, the changes slowly reverted towards normal. In a few patients on bromocriptine mesylate, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs, impaired kidney function) should be watched in this category of patients. Bromocriptine mesylate medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected." ], "precautions": [ "PRECAUTIONS GENERAL There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine mesylate, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine mesylate for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine mesylate. Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate therapy concomitantly with other medications known to lower blood pressure. The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with bromocriptine mesylate during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine. Hyperprolactinemic States Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage. The relative efficacy of bromocriptine mesylate versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy. Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with bromocriptine mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets or capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of bromocriptine mesylate treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases. Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with bromocriptine mesylate. Acromegaly Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine mesylate increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with bromocriptine mesylate. Possible tumor expansion while receiving bromocriptine mesylate therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered. Parkinson’s Disease Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established. As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs. High doses of bromocriptine mesylate may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients. Bromocriptine mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine mesylate. As with levodopa, caution should be exercised when administering bromocriptine mesylate to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia. Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2 to 10 years) with bromocriptine mesylate in doses ranging from 30-140 mg daily. Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2-approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using bromocriptine mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Discontinuation of bromocriptine mesylate should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered. INFORMATION FOR PATIENTS During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine mesylate should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine mesylate and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines). Patients receiving bromocriptine mesylate for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine mesylate for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms. Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine mesylate. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine mesylate [see PRECAUTIONS]. Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine mesylate or decrease the dose of bromocriptine mesylate. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see Precautions). DRUG INTERACTIONS The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and C max values increased 3.7-fold and 4.6-fold, respectively). 1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%). 4 Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication). CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes. Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice. No mutagenic effects were obtained in any of these tests. Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg). PREGNANCY Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period. Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced. No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg. Information concerning 1276 pregnancies in women taking bromocriptine mesylate has been collected. In the majority of cases, bromocriptine mesylate was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11% - 25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%. The incidence of birth defects in the population at large ranges from 2% - 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%. There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants. NURSING MOTHERS Bromocriptine mesylate should not be used during lactation in postpartum women. PEDIATRIC USE The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response. The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation. Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section. GERIATRIC USE Clinical studies for bromocriptine mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine mesylate has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population." ], "general_precautions": [ "GENERAL There have been reports of patients experiencing intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including bromocriptine mesylate, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with bromocriptine mesylate for Parkinson’s disease or hyperprolactinemia-associated dysfunctions. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking bromocriptine mesylate. Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine mesylate therapy concomitantly with other medications known to lower blood pressure. The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with bromocriptine mesylate during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine. Hyperprolactinemic States Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine mesylate leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases, the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage. The relative efficacy of bromocriptine mesylate versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy. Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with bromocriptine mesylate. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with bromocriptine mesylate tablets or capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of bromocriptine mesylate treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases. Cerebrospinal fluid rhinorrhea has been observed in some patients with prolactin-secreting adenomas treated with bromocriptine mesylate. Acromegaly Cold-sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine mesylate. The response, should it occur, can be reversed by reducing the dose of bromocriptine mesylate and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine mesylate increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with bromocriptine mesylate. Possible tumor expansion while receiving bromocriptine mesylate therapy has been reported in a few patients. Since the natural history of growth hormone-secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered. Parkinson’s Disease Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established. As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs. High doses of bromocriptine mesylate may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients. Bromocriptine mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine mesylate is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine mesylate. As with levodopa, caution should be exercised when administering bromocriptine mesylate to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia. Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2 to 10 years) with bromocriptine mesylate in doses ranging from 30-140 mg daily. Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2-approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using bromocriptine mesylate for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Discontinuation of bromocriptine mesylate should be undertaken gradually whenever possible, even if the patient is to remain on levodopa. A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy. Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including bromocriptine mesylate. These symptoms generally do not respond to levodopa. Prior to discontinuation of bromocriptine mesylate, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation of bromocriptine mesylate. In case of severe withdrawal symptoms, re-administration of a dopamine agonist at the lowest effective dose may be considered." ], "information_for_patients": [ "INFORMATION FOR PATIENTS During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine mesylate therapy. In postmarketing reports, bromocriptine mesylate has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine mesylate should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine mesylate and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines). Patients receiving bromocriptine mesylate for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine mesylate for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms. Patients and their caregivers should be alerted to the possibility that patients may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges and other intense urges and the inability to control these urges while taking bromocriptine mesylate. Advise patients and their caregivers to inform their healthcare provider if they develop new or increased uncontrolled spending, gambling urges, sexual urges, or other urges while being treated with bromocriptine mesylate [see PRECAUTIONS]. Especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery. Advise patients to contact their healthcare provider if they wish to discontinue bromocriptine mesylate or decrease the dose of bromocriptine mesylate. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as fever, muscular rigidity, altered consciousness, apathy, anxiety, depression, fatigue, insomnia, sweating, or pain (see Precautions)." ], "drug_interactions": [ "DRUG INTERACTIONS The risk of using bromocriptine mesylate in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine mesylate. Bromocriptine mesylate may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine mesylate: phenothiazines, haloperidol, metoclopramide, and pimozide. Bromocriptine is a substrate of CYP3A4. Caution should therefore be used when co-administering drugs which are strong inhibitors of this enzyme (such as azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine (mean AUC and C max values increased 3.7-fold and 4.6-fold, respectively). 1 The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine (bromocriptine AUC increased about 38%). 4 Concomitant use of bromocriptine mesylate with other ergot alkaloids is not recommended. Dose adjustment may be necessary in those cases where high doses of bromocriptine are being used (such as Parkinson’s disease indication)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes. Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice. No mutagenic effects were obtained in any of these tests. Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg)." ], "pregnancy": [ "PREGNANCY Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6 to 15 postcoitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6 to 15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or postnatal period. Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced. No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg. Information concerning 1276 pregnancies in women taking bromocriptine mesylate has been collected. In the majority of cases, bromocriptine mesylate was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1276 pregnancies, there were 1088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11% - 25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%. The incidence of birth defects in the population at large ranges from 2% - 4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%. There is no suggestion that bromocriptine mesylate contributed to the type or incidence of birth defects in this group of infants." ], "nursing_mothers": [ "NURSING MOTHERS Bromocriptine mesylate should not be used during lactation in postpartum women." ], "pediatric_use": [ "PEDIATRIC USE The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year-old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response. The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation. Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section." ], "geriatric_use": [ "GERIATRIC USE Clinical studies for bromocriptine mesylate did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine mesylate has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population." ], "adverse_reactions": [ "ADVERSE REACTIONS Adverse Reactions from Clinical Trials Hyperprolactinemic Indications The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%). A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ bromocriptine mesylate tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine mesylate for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine mesylate for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus. Acromegaly The most frequent adverse reactions encountered in acromegalic patients treated with bromocriptine mesylate were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%). Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported. Parkinson’s Disease In clinical trials in which bromocriptine mesylate was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo. Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome. Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance. Adverse Reactions from Postmarketing Experience The following adverse reactions have been reported during postapproval use of bromocriptine mesylate (All Indications Combined). Because adverse reactions from spontaneous reports 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. Psychiatric disorders: Confusion, psychomotor agitation/excitation, hallucinations, psychotic disorders, insomnia, libido increase, hypersexuality, and impulse control/compulsive behaviors (including gambling, spending, and other intense urges). Nervous system disorders: Headache, drowsiness, dizziness, dyskinaesia, somnolence, paraesthesia, excess daytime somnolence, sudden onset of sleep. Eye disorders: Visual disturbance, vision blurred. Ear and labyrinth disorders: Tinnitus. Cardiac disorders: Pericardial effusion, constrictive pericarditis, tachycardia, bradycardia, arrhythmia, cardiac valve fibrosis. Vascular disorders: Hypotension, orthostatic hypotension (very rarely leading to syncope), reversible pallor of fingers and toes induced by cold (especially in patients with history of Raynaud's phenomenon). Respiratory, thoracic and mediastinal disorders: Nasal congestion, pleural effusion, pleural fibrosis, pleurisy, pulmonary fibrosis, dyspnoea. Gastrointestinal disorders: Nausea, constipation, vomiting, dry mouth, diarrhea, abdominal pain, retroperitoneal fibrosis, gastrointestinal ulcer, gastrointestinal hemorrhage. Skin and subcutaneous tissue disorders: Allergic skin reactions, hair loss. Musculoskeletal and connective tissue disorders: Leg cramps. General disorders and administration site conditions: Fatigue, peripheral oedema, a syndrome resembling Neuroleptic Malignant Syndrome on abrupt withdrawal of bromocriptine mesylate, withdrawal symptoms (including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain) with taper or after discontinuation (see Precautions) . Adverse Events Observed in Other Conditions Postpartum Patients (see above Warnings) In postpartum studies with bromocriptine mesylate, 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of patients. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%). Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were usually of a transient nature. Reports of fainting in the puerperium may possibly be related to this effect. In postmarketing experience in the U.S., serious adverse reactions reported include 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum patients. Seizure cases were not necessarily accompanied by the development of hypertension. An unremitting and often progressively severe headache, sometimes accompanied by visual disturbance, often preceded by hours to days many cases of seizure and/or stroke. Most patients had shown no evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or pregnancy-induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to bromocriptine mesylate administration has not been established. In rare cases serious adverse events, including hypertension, myocardial infarction, seizures, stroke, or psychic disorders have been reported in postpartum women treated with bromocriptine mesylate. In some patients the development of seizures or stroke was preceded by severe headache and/or transient visual disturbances. Although the causal relationship of these events to the drug is uncertain, periodic monitoring of blood pressure is advisable in postpartum women receiving bromocriptine mesylate. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbances), or evidence of CNS toxicity develop, the administration of bromocriptine mesylate should be discontinued and the patient should be evaluated promptly. Particular caution is required in patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure, e.g., vasoconstrictors such as sympathomimetics or ergot alkaloids including ergometrine or methylergometrine and their concomitant use in the puerperium is not recommended. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." ], "overdosage": [ "OVERDOSAGE The most commonly reported signs and symptoms associated with acute bromocriptine mesylate overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established and the drug has a very wide margin of safety. However, one death occurred in a patient who committed suicide with an unknown quantity of bromocriptine mesylate and chloroquine. Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered. There have been isolated reports of children who accidentally ingested bromocriptine mesylate. Vomiting, somnolence and fever were reported as adverse events. Patients recovered either spontaneously within a few hours or after appropriate management." ], "dosage_and_administration": [ "DOSAGE & ADMINISTRATION General It is recommended that bromocriptine mesylate be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response. Hyperprolactinemic Indications The initial dosage of bromocriptine mesylate tablets in adults is one ½ to one 2½ mg scored tablet daily. An additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2 to 7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically. Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is one ½ to one 2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas. In order to reduce the likelihood of prolonged exposure to bromocriptine mesylate should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine mesylate therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy. Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine mesylate therapy should be discontinued and a pregnancy test performed. Acromegaly Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine mesylate also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine mesylate. If, after a brief trial with bromocriptine mesylate therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered. The initial recommended dosage is one ½ to one 2½ mg bromocriptine mesylate tablet on retiring (with food) for 3 days. An additional one ½ to 1 bromocriptine mesylate tablet should be added to the treatment regimen as tolerated every 3 to 7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine mesylate varies from 20-30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day. Patients treated with pituitary irradiation should be withdrawn from bromocriptine mesylate therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine mesylate therapy. Usually a 4 to 8 week withdrawal period is adequate for this purpose. Recurrence of the signs/symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine mesylate should be considered. Parkinson’s Disease The basic principle of bromocriptine mesylate therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible. The initial dose of bromocriptine mesylate is one ½ of a 2½ mg bromocriptine mesylate tablet twice daily with meals. Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may be increased every 14 to 28 days by 2½ mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine mesylate, if increased, should be accomplished gradually in small (2½ mg) increments. The safety of bromocriptine mesylate has not been demonstrated in dosages exceeding 100 mg/day." ], "how_supplied": [ "HOW SUPPLIED Bromocriptine Mesylate Tablets, USP 2.5 mg Bromocriptine mesylate tablets are available in bottles containing 30 and 100 tablets of 2.5 mg, each bottle contains a desiccant. Off-white, round, flat-faced, beveled-edge tablets, debossed “E” above the score and “280” below the score on one side and debossed “2.5” on the other side, each containing 2.5 mg bromocriptine (as the mesylate). Bottles of 30: NDC 70954-978-10 Bottles of 100: NDC 70954-978-20 Bromocriptine Mesylate Capsules, USP 5 mg Bromocriptine mesylate capsules are available in bottles containing 30 and 100 capsules of 5 mg. Hard gelatin capsule size 3 with caramel opaque cap imprinted “102” on the cap and white opaque body, imprinted with “PARLODEL” over “5 mg” on the body, each containing 5 mg bromocriptine (as the mesylate). Bottles of 30: NDC 70954-951-10 Bottles of 100: NDC 70954-951-20 Store and Dispense Store at 68ºF to 77ºF (20ºC to 25ºC); excursions permitted to 59ºF to 86ºF (15ºC to 30ºC) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container. Manufactured by: Esjay Pharma Private Limited, India Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 P3374/00/25 Rev. 07/2025 logo" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Bromocriptine Mesylate Tablets, USP 2.5 mg NDC 70954-978-10 Bottle of 30 tablets NDC 70954-978-20 Bottle of 100 tablets Bromocriptine Mesylate Capsules, USP 5 mg NDC 70954-951-10 Bottle of 30 capsules NDC 70954-951-20 Bottle of 100 capsules container one container two bromo-caps-1 bromo-caps-2" ], "set_id": "17f3a343-1782-4799-95ba-31dfe93be2cf", "id": "45243870-6592-4cdf-a2a1-2e8ea48a47d8", "effective_time": "20260406", "version": "2", "openfda": { "application_number": [ "NDA017962" ], "brand_name": [ "Bromocriptine Mesylate" ], "generic_name": [ "BROMOCRIPTINE MESYLATE" ], "manufacturer_name": [ "ANI Pharmaceuticals, Inc." ], "product_ndc": [ "70954-951", "70954-978" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "BROMOCRIPTINE MESYLATE" ], "rxcui": [ "197411", "197412" ], "spl_id": [ "45243870-6592-4cdf-a2a1-2e8ea48a47d8" ], "spl_set_id": [ "17f3a343-1782-4799-95ba-31dfe93be2cf" ], "package_ndc": [ "70954-978-10", "70954-978-20", "70954-951-10", "70954-951-20" ], "is_original_packager": [ true ], "upc": [ "0370954978107", "0370954978206" ], "unii": [ "FFP983J3OD" ] } }, { "effective_time": "20171220", "recent_major_changes": [ "Contraindications ( 4 )" ], "drug_interactions": [ "7 DRUG INTERACTIONS Hypoglycemia agents: Hypo- and/or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment adjusted accordingly ( 7.1 ) Cyclosporine: Somatuline may decrease the bioavailability of cyclosporine. Cyclosporine dose may need to be adjusted ( 7.2 ) Drugs affecting heart rate: Somatuline may decrease heart rate. Dose adjustment of coadministered drugs that decrease heart rate may be necessary ( 7.3 ) 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly. 7.2 Cyclosporine Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels. 7.3 Other Concomitant Drug Therapy The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine. Concomitant administration of bradycardia inducing drugs (e.g. beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary. Vitamin K absorption was not affected when concomitantly administered with lanreotide. 7.4 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered." ], "spl_unclassified_section_table": [ "
" ], "geriatric_use": [ "8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients compared with younger patients, and the 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. It is not necessary to alter the starting dose in elderly patients as expected lanreotide serum concentrations in the elderly are well within the range of serum concentrations safely tolerated in healthy young subjects. Similarly, it is not necessary to alter the titration or maintenance doses of Somatuline Depot as dose selection is based on therapeutic response [ see Dosage and Administration (2) and Clinical Pharmacology (12.3) ]." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [ see Clinical Studies (14) ]. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [ see Warnings and Precautions (5) ]. In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [ see Warnings and Precautions (5) ]. Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis." ], "spl_patient_package_insert": [ "Patient Information Somatuline® Depot (So-mah-tu-leen Dee-Poh ) (lanreotide) Injection Read this Patient Information before you receive your first Somatuline® Depot injection and before each injection. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is Somatuline® Depot? Somatuline® Depot is a prescription medicine used for the long-term treatment of people with acromegaly when: surgery or radiotherapy have not worked well enough or they are not able to have surgery or radiotherapy It is not known if Somatuline® Depot is safe and effective in children. What should I tell my doctor before receiving Somatuline® Depot? Before you receive Somatuline® Depot, tell your doctor if you have: gallbladder problems diabetes thyroid problems heart problems kidney problems liver problems are allergic to latex or natural dry rubber. The pre-filled syringe needle cover contains rubber. are pregnant or plan to become pregnant. It is not known if Somatuline® Depot will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. are breast-feeding or plan to breast-feed. It is not known if Somatuline® Depot passes into your breast milk. Talk to your doctor about the best way to feed your baby if you receive Somatuline® Depot. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Somatuline® Depot and other medicines may affect each other causing side effects. Somatuline® Depot may affect the way other medicines work, and other medicines may affect how Somatuline® Depot works. Your dose of Somatuline® Depot or your other medicines may need to be adjusted. Especially tell your doctor if you take: insulin or other diabetes medicines a cyclosporine (Gengraf, Neoral, or Sandimmune) a medicine called bromocriptine (Parlodel) medicines that lower your heart rate such as beta blockers Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How will I receive Somatuline® Depot? You will receive a Somatuline® Depot injection every 4 weeks as directed by your doctor. Your doctor may change your dose of Somatuline® Depot or the length of time between your injections. Your doctor will tell you how long you need to receive Somatuline® Depot. Somatuline® Depot is injected deep under the skin of the upper outer area of your buttock. Your injection site should change (alternate) between your right and left buttock each time you receive an injection of Somatuline® Depot. During your treatment with Somatuline ® Depot, your doctor may do certain blood tests to see if Somatuline® Depot is working. Your doctor may change your dose, or length between your Somatuline® Depot injections as needed. What are the possible side effects of Somatuline® Depot? Somatuline® Depot may cause serious side effects, including: gallstones. Tell your doctor if you have any of these symptoms: sudden pain in your upper right stomach area (abdomen) sudden pain in your right shoulder or between your shoulder blades yellowing of your skin and whites of your eyes fever with chills nausea changes in your blood sugar (high blood sugar or low blood sugar). If you have diabetes, test your blood sugar as your doctor tells you to. Your doctor may change your dose of diabetes medicine especially when you first start receiving Somatuline® Depot or if your dose of Somatuline® Depot changes. slow heart rate high blood pressure The most common side effects of Somatuline® Depot include: diarrhea stomach area (abdominal) pain nausea pain, itching or a lump at the injection site Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Somatuline® Depot. For more information ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Somatuline® Depot. Medicines are sometimes prescribed for conditions other than those listed in the patient leaflet. This Patient Information leaflet summarizes the most important information about Somatuline® Depot. If you would like more information about Somatuline® Depot talk with your doctor. You can ask your pharmacist or doctor for information about Somatuline® Depot that is written for health professionals. For more information, go to www.somatulinedepot.com or call Ipsen Biopharmaceuticals, Inc. at 1-866-837-2422. Issued August 2007 Revised February 2012 Somatuline® Depot is manufactured by Ipsen Pharma Biotech SAS BP, 707 Signes, 83030 Toulon Cedex 9, France for Ipsen Pharma SAS, 65 quai Georges Gorse, 92650, Boulogne Billancourt Cedex, France" ], "description": [ "11 DESCRIPTION Somatuline Depot (lanreotide) Injection 60, 90 and 120 mg is a prolonged-release formulation for deep subcutaneous injection containing the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, and water for injection. Somatuline Depot is available as sterile, ready-to-use, pre-filled syringes containing lanreotide supersaturated bulk solution of 24.6% w/w lanreotide base. Each syringe contains: Somatuline Depot 60 mg Somatuline Depot 90 mg Somatuline Depot 120 mg Lanreotide acetate 79.8 mg 116.4 mg 155.5 mg Water for injection 186.2mg 271.6 mg 363 mg Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is: For appearance of the formulation, see Dosage Forms and Strengths (3) . Chemical Structure" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m 2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 60, 90 and 120 mg sterile, single-use, pre-filled syringes. The pre-filled syringes contain a white to pale yellow, semi-solid formulation. Single use syringe: 60, 90 and 120 mg ( 3 )" ], "storage_and_handling": [ "Storage and Handling Somatuline Depot must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light in its original package. Thirty (30) minutes prior to injection, remove sealed pouch of Somatuline Depot from refrigerator and allow it to come to room temperature. Keep pouch sealed until injection. Each syringe is intended for single use. Do not use beyond the expiration date on the packaging." ], "mechanism_of_action": [ "12.1 Mechanism of Action Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream. After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg. In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of Somatuline Depot 120 mg demonstrated mean steady state, C min values between 1.6 and 2.3 ng/mL for the 8 and 6 week treatment interval, respectively. Specific Populations Somatuline Depot has not been studied in specific populations. The pharmacokinetics of lanreotide in renal impaired, hepatic impaired and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC was observed. Patients with moderate to severe renal impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. Geriatric Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects. Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion." ], "clinical_studies_table": [ "
Table 3 Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1
Baseline N=107 Before Titration 1 (16 weeks) N=107 Before Titration 2 (32 weeks) N=105 Last Value AvailableLast Observation Carried Forward N=107
GH
≤5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%)
≤2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%)
≤1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%)
Median GH ng/mL 10.27 2.53 2.20 2.43
GH Reduction Median % Reduction -- 75.5 78.2 75.5
IGF-1
NormalAge-adjusted, Number of Responders (%) 9 (8%) 58 (54%) 57 (54%) 62 (58%)
Median IGF-1 ng/mL 775.0 332.0n=105, 316.5n=102, 326.0
IGF-1 Reduction Median % Reduction -- 52.3 54.5 55.4
IGF-1 Normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%)
", "
Table 4 Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2
Baseline N=63 Before Titration 1 (12 wks) N=63 Before Titration 2 (28 wks) N=59 Last Value Available Last Observation Carried Forward N=63
IGF-1
NormalAge-adjusted, Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%)
Median IGF-1 ng/mL 689.0 382.0 334.0 317.0
IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3
GH
≤5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%)
≤2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86 %)
≤1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%)
Median GH ng/mL 3.71 1.65 1.48 1.13
GH Reduction Median % Reduction -- 63.2 66.7 78.6N= 62,
IGF-1 normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%)
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Somatuline Depot (lanreotide) Injection 60 mg, 90 mg and 120 mg is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal. Somatuline Depot (lanreotide) Injection is a somatostatin analog indicated for: the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy ( 1 )" ], "set_id": "18281cb0-e1bf-4db6-b009-eb6ea96a4f64", "id": "60d7e1aa-bd80-44bc-a44b-e3cb1b09df3e", "description_table": [ "
Each syringe contains: Somatuline Depot 60 mg Somatuline Depot 90 mg Somatuline Depot 120 mg
Lanreotide acetate 79.8 mg 116.4 mg 155.5 mg
Water for injection 186.2mg 271.6 mg 363 mg
" ], "teratogenic_effects": [ "Pregnancy Category C Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established." ], "contraindications": [ "4 CONTRAINDICATIONS Somatuline Depot should not be prescribed to patients with hypersensitivity to lanreotide or related peptides [see Adverse Reactions (6.2) ] Hypersensitivity to lanreotide or related peptides ( 4 )" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category C Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions in animals and potential in nursing infants from Somatuline, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother." ], "spl_product_data_elements": [ "Somatuline Depot lanreotide acetate lanreotide acetate lanreotide Water Somatuline Depot lanreotide acetate lanreotide acetate lanreotide Water Somatuline Depot lanreotide acetate lanreotide acetate lanreotide Water" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Gallbladder: Gallstones may occur; consider periodic monitoring ( 5.1 ) Glucose Metabolism: Hypo- and/or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment adjusted accordingly ( 5.2 ) Cardiac Function: Decrease in heart rate may occur. Use with caution in at-risk patients ( 5.4 ) 5.1 Cholelithiasis and Gallbladder Sludge Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically [ see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ]. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Somatuline Depot may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [ see Adverse Reactions (6.1) ]. 5.3 Thyroid function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated. 5.4 Cardiovascular Abnormalities The most common overall cardiac adverse reactions observed in three pooled Somatuline Depot Cardiac Studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%) and hypertension (12/217, 5.5%) [ see Adverse Reactions (6.1) ]. In patients without underlying cardiac disease, lanreotide may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia. 5.5 Drug Interactions The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs. Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant administration of Somatuline Depot and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels [ see Drug Interactions (7.2) ]. 5.6 Monitoring: Laboratory Tests Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [ see Dosage and Administration (2) ]." ], "adverse_reactions_table": [ "
Table 1 Adverse Reactions at an Incidence > 5% Lanreotide Overall and Occurring at Higher Rate in Drug than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 by Dose
Placebo-Controlled Double-Blind Phase Weeks 0 to 4 Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20
Body System Preferred Term Placebo (N=25) N (%) Lanreotide Overall (N=83) N (%) Lanreotide 60 mg (N=34) N (%) Lanreotide 90 mg (N=36) N (%) Lanreotide 120 mg (N=37) N (%) Lanreotide Overall (N=107) N (%)
A patient is counted only once for each body system and preferred term.
Dictionary = WHOART.
Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%)
Diarrhea 0 26 (31%) 9 (26%) 15 (42%) 24 (65%) 48 (45%)
Abdominal pain 1 (4%) 6 (7%) 3 (9%) 6 (17%) 7 (19%) 16 (15%)
Flatulence 0 5 (6%) 0 (0%) 3 (8%) 5 (14%) 8 (7%)
Application Site Disorders 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%)
(Injection site mass/ pain/ reaction/ inflammation)
Liver and Biliary System Disorders 1 (4%) 3 (4%) 9 (26%) 7 (19%) 4 (11%) 20 (19%)
Cholelithiasis 0 2 (2%) 5 (15%) 6 (17%) 3 (8%) 14 (13%)
Heart Rate & Rhythm Disorders 0 8 (10%) 7 (21%) 2 (6%) 5 (14%) 14 (13%)
Bradycardia 0 7 (8%) 6 (18%) 2 (6%) 2 (5%) 10 (9%)
Red Blood Cell Disorders 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%)
Anemia 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%)
Metabolic & Nutritional Disorders 3 (12%) 13 (16%) 8 (24%) 9 (25%) 4 (11%) 21 (20%)
Weight decrease 0 7 (8%) 3 (9%) 4 (11%) 2 (5%) 9 (8%)
", "
Table 2 Adverse Reactions at an Incidence > 5.0% in Overall Group Reported in Clinical Studies
System Organ Class Number and Percentage of Patients
Studies 1 & 2 Overall Pooled Data
(N = 170) (N = 416)
N % N %
Dictionary - MedDRA 7.1
Patients with any Adverse Reactions 157 92 356 86
Gastrointestinal disorders 121 71 235 57
Diarrhea 81 48 155 37
Abdominal pain 34 20 79 19
Nausea 15 9 46 11
Constipation 9 5 33 8
Flatulence 12 7 30 7
Vomiting 8 5 28 7
Loose stools 16 9 23 6
Hepatobiliary disorders 53 31 99 24
Cholelithiasis 45 27 85 20
General disorders and administration site conditions 51 30 91 22
(Injection site pain /mass / induration /nodule /pruritus) 28 17 37 9
Musculoskeletal and connective tissue disorders 44 26 70 17
Arthralgia 17 10 30 7
Nervous system disorders 34 20 80 19
Headache 9 5 30 7
" ], "openfda": {}, "version": "8", "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Patients should begin treatment with Somatuline Depot 90 mg given via the deep subcutaneous route, at 4 week intervals for 3 months. After 3 months dosage may be adjusted as follows: GH >1 to ≤ 2.5 ng/mL, IGF-1 normal and clinical symptoms controlled: maintain Somatuline Depot dose at 90 mg every 4 weeks. GH > 2.5 ng/mL, IGF-1 elevated and/or clinical symptoms uncontrolled, increase Somatuline Depot dose to 120 mg every 4 weeks. GH ≤ 1 ng/mL, IGF-1 normal and clinical symptoms controlled: reduce Somatuline Depot dose to 60 mg every 4 weeks. Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in serum GH and /or IGF-1 levels; and/or changes in symptoms of acromegaly. Patients who are controlled on Somatuline Depot 60 mg or 90 mg may be considered for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patients response with dose adjustments for biochemical and clinical symptom control, as necessary, is recommended. Somatuline Depot should be injected via the deep subcutaneous route in the superior external quadrant of the buttock. The skin should not be folded and the needle should be inserted perpendicular to the skin, rapidly and to its full length. The injection site should alternate between the right and left side. The starting dose in patients with moderate and severe renal or moderate and severe hepatic impairment should be 60 mg via the deep subcutaneous route, at 4 week intervals for 3 months followed by dose adjustment as described above [ see Clinical Pharmacology (12.3) ]. Dose range of 60 mg to 120 mg every 4 weeks ( 2 ) Recommended dose is 90 mg every 4 weeks for 3 months. Adjust thereafter based on GH and/or IGF-1 levels ( 2 ) Renal and Hepatic Impairment: Initial dose is 60 mg every 4 weeks for 3 months in moderate and severe renal or hepatic impairment. Adjust thereafter based on GH and/or IGF-1 levels. ( 2 , 12.3 ) Injected in the superior external quadrant of the buttock. Injection site should be alternated ( 2 ) Store at 2-8°C (36-46 °F) in the original package ( 16 )" ], "adverse_reactions": [ "6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, 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. Most common adverse reactions are diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-866-837-2422 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience The data described below reflect exposure to Somatuline Depot in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo controlled run-in period and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53.0 years of age (range 19-84 years). Fifty-four subjects (13%) were age 66-74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients were evenly matched for gender (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly severity at baseline (N=265), serum GH levels were < 10 ng/mL for 69% (183/265) of the patients and ≥ 10 ng/mL for 31% (82/265) of the patients. The most commonly reported adverse reactions reported by > 5% of patients who received Somatuline Depot (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis and injection site reactions. Tables 1 and 2 present adverse reaction data from clinical studies with Somatuline Depot in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies. Adverse Reactions in Parallel Fixed-Dose Phase of Study 1: The incidence of treatment-emergent adverse reactions for Somatuline Depot 60 mg, 90 mg, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [ see Clinical Studies (14) ], are provided in Table 1. Table 1 Adverse Reactions at an Incidence > 5% Lanreotide Overall and Occurring at Higher Rate in Drug than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 by Dose Placebo-Controlled Double-Blind Phase Weeks 0 to 4 Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20 Body System Preferred Term Placebo (N=25) N (%) Lanreotide Overall (N=83) N (%) Lanreotide 60 mg (N=34) N (%) Lanreotide 90 mg (N=36) N (%) Lanreotide 120 mg (N=37) N (%) Lanreotide Overall (N=107) N (%) A patient is counted only once for each body system and preferred term. Dictionary = WHOART. Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%) Diarrhea 0 26 (31%) 9 (26%) 15 (42%) 24 (65%) 48 (45%) Abdominal pain 1 (4%) 6 (7%) 3 (9%) 6 (17%) 7 (19%) 16 (15%) Flatulence 0 5 (6%) 0 (0%) 3 (8%) 5 (14%) 8 (7%) Application Site Disorders 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%) (Injection site mass/ pain/ reaction/ inflammation) Liver and Biliary System Disorders 1 (4%) 3 (4%) 9 (26%) 7 (19%) 4 (11%) 20 (19%) Cholelithiasis 0 2 (2%) 5 (15%) 6 (17%) 3 (8%) 14 (13%) Heart Rate & Rhythm Disorders 0 8 (10%) 7 (21%) 2 (6%) 5 (14%) 14 (13%) Bradycardia 0 7 (8%) 6 (18%) 2 (6%) 2 (5%) 10 (9%) Red Blood Cell Disorders 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Anemia 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Metabolic & Nutritional Disorders 3 (12%) 13 (16%) 8 (24%) 9 (25%) 4 (11%) 21 (20%) Weight decrease 0 7 (8%) 3 (9%) 4 (11%) 2 (5%) 9 (8%) In Study 1, the adverse reactions of diarrhea, abdominal pain and flatulence increased in incidence with increasing dose of Somatuline Depot. Adverse Reactions in Long-Term Clinical Trials: Table 2 provides the most common adverse reactions that occurred in 416 acromegalic patients treated with Somatuline Depot in seven studies. The analysis of safety compares adverse reaction rates of patients at baseline from the two efficacy studies, to the overall pooled data from seven studies. Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout [ see Clinical Studies (14) ]. Table 2 Adverse Reactions at an Incidence > 5.0% in Overall Group Reported in Clinical Studies System Organ Class Number and Percentage of Patients Studies 1 & 2 Overall Pooled Data (N = 170) (N = 416) N % N % Dictionary - MedDRA 7.1 Patients with any Adverse Reactions 157 92 356 86 Gastrointestinal disorders 121 71 235 57 Diarrhea 81 48 155 37 Abdominal pain 34 20 79 19 Nausea 15 9 46 11 Constipation 9 5 33 8 Flatulence 12 7 30 7 Vomiting 8 5 28 7 Loose stools 16 9 23 6 Hepatobiliary disorders 53 31 99 24 Cholelithiasis 45 27 85 20 General disorders and administration site conditions 51 30 91 22 (Injection site pain /mass / induration /nodule /pruritus) 28 17 37 9 Musculoskeletal and connective tissue disorders 44 26 70 17 Arthralgia 17 10 30 7 Nervous system disorders 34 20 80 19 Headache 9 5 30 7 In addition to the adverse reactions listed in Table 2, the following reactions were also seen: Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies. Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies. Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies. Gastrointestinal Adverse Reactions In the pooled clinical studies of Somatuline Depot therapy, a variety of gastrointestinal reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with Somatuline Depot in the pooled clinical studies discontinued treatment because of gastrointestinal reactions. Pancreatitis was reported in < 1% of patients. Gallbladder Adverse Reactions In clinical studies involving 416 acromegalic patients treated with Somatuline Depot, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with Somatuline Depot who underwent routine evaluation with gallbladder ultrasound, 17.4% had gallstones at baseline. New cholelithiasis was reported in 12.0% of patients. Cholelithiasis may be related to dose or duration of exposure [ see Cholelithiasis and Gallbladder Sludge (5.1) ]. Injection Site Reactions In the pooled clinical studies, injection site pain (4.1%) and injection site mass (1.7%) were the most frequently reported local adverse drug reactions that occurred with the administration of Somatuline Depot. In a specific analysis 20 of 413 patients (4.8%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects. Glucose Metabolism Adverse Reactions In the clinical studies in acromegalic patients treated with Somatuline Depot, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients [ see Hyperglycemia and Hypoglycemia (5.2) ]. Cardiac Adverse Reactions In the pooled clinical studies, sinus bradycardia (3.1%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in < 1% of patients. The relationship of these events to Somatuline Depot could not be established because many of these patients had underlying cardiac disease [ see Cardiovascular Abnormalities (5.4) ]. A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the two treatments over one year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study. Other Adverse Reactions For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups. Laboratory investigations of acromegalic patients treated with Somatuline Depot in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (<1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of Somatuline Depot. 6.2 Postmarketing Experience As adverse reactions experienced post approval use 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. The profile of reported adverse reactions for Somatuline Depot was consistent with that observed for treatment-related adverse reactions in the clinical studies. Those reported most frequently being gastrointestinal disorders (abdominal pain, diarrhea, and steatorrhea), hepatobiliary disorders (cholecystitis), and general disorders and administration site conditions (injection site reactions). Occasional cases of pancreatitis have also been observed. A small number of allergic reactions associated with lanreotide (including angioedema, anaphylaxis, and hypersensitivity) have been reported in the postmarketing environment." ], "spl_unclassified_section": [ "Manufactured by: Ipsen Pharma Biotech 83870 Signes, France Distributed by: Ipsen Biopharmaceuticals, Inc. Basking Ridge, NJ 07920 USA" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Renal Impairment: Start dose is 60 mg in moderate and severe renal impairment ( 2 , 8.6 , 12.3 ) Hepatic Impairment: Start dose is 60 mg in moderate and severe hepatic impairment ( 2 , 8.7 , 12.3 ) 8.1 Pregnancy Pregnancy Category C Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.3 Nursing Mothers It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions in animals and potential in nursing infants from Somatuline, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients compared with younger patients, and the 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. It is not necessary to alter the starting dose in elderly patients as expected lanreotide serum concentrations in the elderly are well within the range of serum concentrations safely tolerated in healthy young subjects. Similarly, it is not necessary to alter the titration or maintenance doses of Somatuline Depot as dose selection is based on therapeutic response [ see Dosage and Administration (2) and Clinical Pharmacology (12.3) ]. 8.6 Renal Impairment Lanreotide has been studied in patients with end-stage renal function on dialysis, but has not been studied in patients with mild, moderate and severe renal impairment. It is recommended that patients with moderate and severe renal impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks [ see Dosage and Administration (2) and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment It is recommended that patients with moderate and severe hepatic impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks [ see Dosage and Administration (2) and Clinical Pharmacology (12.3) ]." ], "how_supplied_table": [ "
NDC 15054-0060-1 60-mg, sterile, pre-filled syringe
NDC 15054-0090-1 90-mg, sterile, pre-filled syringe
NDC 15054-0120-1 120-mg, sterile, pre-filled syringe
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Somatuline Depot is supplied in strengths of 60 mg, 90 mg and 120 mg in a single, sterile, pre-filled, ready-to-use, polypropylene syringe fitted with a 20 mm needle covered by a dry natural rubber sheath. Each pre-filled syringe is sealed in a laminated pouch and packed in a carton. NDC 15054-0060-1 60-mg, sterile, pre-filled syringe NDC 15054-0090-1 90-mg, sterile, pre-filled syringe NDC 15054-0120-1 120-mg, sterile, pre-filled syringe Storage and Handling Somatuline Depot must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light in its original package. Thirty (30) minutes prior to injection, remove sealed pouch of Somatuline Depot from refrigerator and allow it to come to room temperature. Keep pouch sealed until injection. Each syringe is intended for single use. Do not use beyond the expiration date on the packaging." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION The physician should provide a copy of the FDA-Approved Patient Labeling and review the contents with the patient. Patients should be advised to inform their doctor or pharmacist if they develop any unusual symptoms, or if any known symptom persists or worsens. Patients should be advised that response to Somatuline Depot should be monitored by periodic measurements of GH and IGF-1 levels, with a goal of decreasing these levels to the normal range." ], "clinical_studies": [ "14 CLINICAL STUDIES The effect of Somatuline Depot on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in two long-term, multiple-dose, randomized multicenter studies. Study 1 This one-year study included a 4-week double-blind, placebo-controlled phase, a 16-week single-blind, fixed-dose phase, and a 32-week open-label dose-titration phase. Patients with active acromegaly based on biochemical tests and medical history entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist. Upon entry, patients were randomly allocated to receive a single deep subcutaneous injection of Somatuline Depot 60, 90 or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of Somatuline Depot followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels. A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level > 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were to have a mean GH concentration >3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication. One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4). In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4 including 52%, 44% and 90% of patients in the 60, 90 and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50% including 68% (23/34), 64% (23/36) and 84% (31/37) of patients in the 60, 90 and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 3 ). Table 3 Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1 Baseline N=107 Before Titration 1 (16 weeks) N=107 Before Titration 2 (32 weeks) N=105 Last Value Available Last Observation Carried Forward N=107 GH ≤5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%) ≤2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%) ≤1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%) Median GH ng/mL 10.27 2.53 2.20 2.43 GH Reduction Median % Reduction -- 75.5 78.2 75.5 IGF-1 Normal Age-adjusted, Number of Responders (%) 9 (8%) 58 (54%) 57 (54%) 62 (58%) Median IGF-1 ng/mL 775.0 332.0 n=105, 316.5 n=102, 326.0 IGF-1 Reduction Median % Reduction -- 52.3 54.5 55.4 IGF-1 Normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%) Study 2 This was a 48-week, open-label, uncontrolled multicenter study which enrolled patients who had an IGF-1 concentration ≥ 1.3 times the upper limit of the age-adjusted normal range. Patients receiving treatment with a somatostatin analog (other than Somatuline Depot) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months. Patients were initially enrolled in a 4-month fixed-dose phase where they received four deep subcutaneous injections of Somatuline Depot, 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of Somatuline Depot was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again. A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48-weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1). After 48 weeks of treatment with Somatuline Depot at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations < 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of ≤ 2.5 ng/mL (see Table 4 ) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of <1 ng/mL. Table 4 Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2 Baseline N=63 Before Titration 1 (12 wks) N=63 Before Titration 2 (28 wks) N=59 Last Value Available Last Observation Carried Forward N=63 IGF-1 Normal Age-adjusted, Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%) Median IGF-1 ng/mL 689.0 382.0 334.0 317.0 IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3 GH ≤5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%) ≤2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86 %) ≤1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%) Median GH ng/mL 3.71 1.65 1.48 1.13 GH Reduction Median % Reduction -- 63.2 66.7 78.6 N= 62, IGF-1 normal + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%) Examination of age and gender subgroups did not identify differences in response to Somatuline Depot among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of Somatuline Depot in these subgroups." ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 60 mg/0.2 ml Syringe Carton NDC 15054 0060 1 Somatuline ® Depot (lanreotide) Injection 60 mg/0.2 ml For deep subcutaneous injection Rx only. For single use only. Sterile. Warning: Needle Sheath Contains Dry Natural Rubber CONTENTS: This box contains one (1) pre-filled syringe. Each syringe contains lanreotide acetate corresponding to 60 mg of lanreotide base per 0.2 ml solution, which is the equivalent of 60 mg lanreotide per syringe. 60 mg IPSEN PRINCIPAL DISPLAY PANEL - 60 mg/0.2 ml Syringe Carton", "PRINCIPAL DISPLAY PANEL - 90 mg/0.3 ml Syringe Carton NDC 15054 0090 1 Somatuline ® Depot (lanreotide) Injection 90 mg/0.3 ml For deep subcutaneous injection Rx only. For single use only. Sterile. Warning: Needle Sheath Contains Dry Natural Rubber CONTENTS: This box contains one (1) pre-filled syringe. Each syringe contains lanreotide acetate corresponding to 90 mg of lanreotide base per 0.3 ml solution, which is the equivalent of 90 mg lanreotide per syringe. 90 mg IPSEN PRINCIPAL DISPLAY PANEL - 90 mg/0.3 ml Syringe Carton", "PRINCIPAL DISPLAY PANEL - 120 mg/0.5 ml Syringe Carton NDC 15054 0120 1 Somatuline ® Depot (lanreotide) Injection 120 mg/0.5 ml For deep subcutaneous injection Rx only. For single use only. Sterile. Warning: Needle Sheath Contains Dry Natural Rubber CONTENTS: This box contains one (1) pre-filled syringe. Each syringe contains lanreotide acetate corresponding to 120 mg of lanreotide base per 0.5 ml solution, which is the equivalent of 120 mg lanreotide per syringe. 120 mg IPSEN PRINCIPAL DISPLAY PANEL - 120 mg/0.5 ml Syringe Carton" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin. 12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [ see Clinical Studies (14) ]. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [ see Warnings and Precautions (5) ]. In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [ see Warnings and Precautions (5) ]. Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis. 12.3 Pharmacokinetics Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream. After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg. In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of Somatuline Depot 120 mg demonstrated mean steady state, C min values between 1.6 and 2.3 ng/mL for the 8 and 6 week treatment interval, respectively. Specific Populations Somatuline Depot has not been studied in specific populations. The pharmacokinetics of lanreotide in renal impaired, hepatic impaired and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC was observed. Patients with moderate to severe renal impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. Geriatric Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects. Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenicity, Mutagenicity, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m 2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate." ], "overdosage": [ "10 OVERDOSAGE If overdose occurs, symptomatic management is indicated. There are no confirmed postmarketing cases of overdose with lanreotide that were serious or led to an adverse reaction. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at phone number 1-800-222-1222." ] }, { "spl_product_data_elements": [ "Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE Lanreotide Acetate lanreotide acetate LANREOTIDE ACETATE LANREOTIDE" ], "recent_major_changes": [ "Warnings and Precautions, Cholelithiasis and Complications of Cholelithiasis ( 5.1 ) 4/2019" ], "recent_major_changes_table": [ "
Warnings and Precautions, Cholelithiasis and Complications of Cholelithiasis (5.1)4/2019
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Lanreotide injection is a somatostatin analog indicated for: the long-term treatment of acromegalic patients who have had an inadequate response to or cannot be treated with surgery and/or radiotherapy. ( 1.1 ) the treatment of adult patients with unresectable, well- or moderately- differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival. ( 1.2 ) 1.1 Acromegaly Lanreotide Injection is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option. The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal. 1.2 Gastroenteropancreatic Neuroendocrine Tumors Lanreotide Injection is indicated for the treatment of adult patients with unresectable, well or moderately differentiated, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to improve progression-free survival." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Administration ( 2.1 ): For deep subcutaneous injection only. Intended for administration by a healthcare provider. Administer in the superior external quadrant of the buttock. Alternate injection sites. Recommended Dosage ( 2.1 ) Acromegaly: 90 mg every 4 weeks for 3 months. Adjust thereafter based on GH and/or IGF-1 levels. See full prescribing information for titration regimen. GEP-NETs: 120 mg every 4 weeks. Dosage Adjustment: See full prescribing information for dosage adjustment in patients with acromegaly and renal or hepatic impairment. ( 2.3 , 2.4 ) 2.1 Important Administration Instructions For deep subcutaneous injection only. Lanreotide injection is intended for administration by a healthcare provider. Preparation Remove Lanreotide injection from the refrigerator 30 minutes prior to administration and allow to come to room temperature. Keep pouch sealed until just prior to injection. Product left in its sealed pouch at room temperature (not to exceed 104°F or 40°C) for up to 24 hours may be returned to the refrigerator for continued storage and use at a later time. Prior to administration, inspect the Lanreotide injection syringe visually for particulate matter and discoloration. Do not administer if particulate matter or discoloration is observed. The content of the prefilled syringe is a semi-solid phase having a gel-like appearance, with viscous characteristics and a color varying from white to pale yellow. The supersaturated solution can also contain micro bubbles that can clear up during injection. These differences are normal and do not interfere with the quality of the product. Administration Administer as a deep subcutaneous injection in the superior external quadrant of the buttock. Alternate the injection site between the right and left sides from one injection to the next. 2.2 Recommended Dosage Acromegaly The recommended starting dosage of Lanreotide injection is 90 mg given via the deep subcutaneous route, at 4-week intervals for 3 months. After 3 months, the dosage may be adjusted as follows: GH greater than 1 ng/mL to less than or equal to 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain Lanreotide injection dosage at 90 mg every 4 weeks. GH greater than 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled: increase Lanreotide injection dosage to 120 mg every 4 weeks. GH less than or equal to 1 ng/mL, IGF-1 normal, and clinical symptoms controlled: reduce Lanreotide injection dosage to 60 mg every 4 weeks. Thereafter, the dosage should be adjusted according to the response of the patient as judged by a reduction in serum GH and/or IGF-1 levels; and/or changes in symptoms of acromegaly. Patients who are controlled on Lanreotide injection 60 or 90 mg may be considered for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response. Continued monitoring of patient response with dosage adjustments for biochemical and clinical symptom control, as necessary, is recommended. Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) The recommended dosage of Lanreotide injection is 120 mg administered every 4 weeks by deep subcutaneous injection. 2.3 Dosage Adjustment in Renal Impairment Acromegaly The recommended starting dosage of Lanreotide injection in acromegalic patients with moderate or severe renal impairment (creatinine clearance less than 60 mL/min) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.6 )] . 2.4 Dosage Adjustment in Hepatic Impairment Acromegaly The recommended starting dosage of Lanreotide injection in acromegalic patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) is 60 mg via the deep subcutaneous route at 4-week intervals for 3 months followed by dosage adjustment [see Dosage and Administration ( 2.2 ), Use in Specific Populations ( 8.7 )]." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL sterile, single-dose, prefilled syringes fitted with an automatic needle guard. The prefilled syringes contain a white to pale yellow, semi-solid formulation. Injection: 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL single-dose prefilled syringes ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Lanreotide injection is contraindicated in patients with history of a hypersensitivity to lanreotide. Allergic reactions (including angioedema and anaphylaxis) have been reported following administration of lanreotide [see Adverse Reactions ( 6.3 )] . Hypersensitivity to lanreotide. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholelithiasis are suspected. Gallstones may occur; consider periodic monitoring. ( 5.1 ) Hyperglycemia and Hypoglycemia : Glucose monitoring is recommended and antidiabetic treatment adjusted accordingly. ( 5.2 , 7.1 ) Cardiovascular Abnormalities : Decrease in heart rate may occur. Use with caution in at-risk patients. ( 5.3 ) Thyroid Function Abnormalities : Decreases in thyroid function may occur; perform tests where clinically indicated. ( 5.4 ) 5.1 Cholelithiasis and Complications of Cholelithiasis Lanreotide injection may reduce gallbladder motility and lead to gallstone formation; therefore, patients may need to be monitored periodically [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )] . There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, and pancreatitis, and requiring cholecystectomy in patients taking Lanreotide injection. If complications of cholelithiasis are suspected, discontinue Lanreotide injection and treat appropriately. 5.2 Hyperglycemia and Hypoglycemia Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Lanreotide injection may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions ( 6.1 )] . 5.3 Cardiovascular Abnormalities The most common overall cardiac adverse reactions observed in three pooled Lanreotide injection cardiac studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%), and hypertension (12/217, 5.5%) [see Adverse Reactions ( 6.1 )] . In 81 patients with baseline heart rates of 60 beats per minute (bpm) or greater treated with Lanreotide injection in Study 3, the incidence of heart rate less than 60 bpm was 23% (19/81) as compared to 16% (15/94) of placebo treated patients; 10 patients (12%) had documented heart rates less than 60 bpm on more than one visit. The incidence of documented episodes of heart rate less than 50 bpm as well as the incidence of bradycardia reported as an adverse event was 1% in each treatment group. Initiate appropriate medical management in patients who develop symptomatic bradycardia. In patients without underlying cardiac disease, Lanreotide injection may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to Lanreotide injection treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with Lanreotide injection in patients with bradycardia. 5.4 Thyroid Function Abnormalities Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (less than 1%). Thyroid function tests are recommended where clinically indicated. 5.5 Monitoring: Laboratory Tests Acromegaly : Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [see Dosage and Administration ( 2.2 )] ." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following adverse reactions to Lanreotide injection are discussed in greater detail in other sections of the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.1 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.2 )] Cardiovascular Abnormalities [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Most common adverse reactions are: Acromegaly (>5%): diarrhea, cholelithiasis, abdominal pain, nausea and injection site reactions. ( 6.1 ) GEP-NET (>10%): abdominal pain, musculoskeletal pain, vomiting, headache, injection site reaction, hyperglycemia, hypertension, and cholelithiasis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exelan Pharmaceuticals, Inc. at 1-866-604-3268 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, 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. Acromegaly The data described below reflect exposure to Lanreotide injection in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo-controlled, run-in period, and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53 years of age (range 19 to 84 years). Fifty-four subjects (13%) were age 66 to 74 and 18 subjects (4.3%) were 75 years of age and older. Patients were evenly matched for sex (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly, severity at baseline (N=265), serum GH levels were less than 10 ng/mL for 69% (183/265) of the patients and 10 ng/mL or greater for 31% (82/265) of the patients. The most commonly reported adverse reactions reported by greater than 5% of patients who received Lanreotide injection (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis, and injection site reactions. Tables 1 and 2 present adverse reaction data from clinical studies with Lanreotide injection in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies. Adverse Reactions in Parallel Fixed-Dose Phase of Study 1 The incidence of treatment-emergent adverse reactions for Lanreotide injection 60, 90, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [see Clinical Studies ( 14.1 )] are provided in Table 1 . Table 1: Adverse Reactions at an Incidence of Greater than 5% with Lanreotide Acetate Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose A patient is counted only once for each body system and preferred term. Dictionary = WHOART. Placebo-Controlled Double-Blind Phase Weeks 0 to 4 Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20 Body System Preferred Term Placebo (N=25) LANREOTIDE ACETATE Overall (N=83) LANREOTIDE ACETATE 60 mg (N=34) LANREOTIDE ACETATE 90 mg (N=36) LANREOTIDE ACETATE 120 mg (N=37) LANREOTIDE ACETATE Overall (N=107) N (%) N (%) N (%) N (%) N (%) N (%) Gastrointestinal System Disorders 1 (4%) 30 (36%) 12 (35%) 21 (58%) 27 (73%) 60 (56%) Diarrhea Abdominal pain Flatulence 0 1 (4%) 0 26 (31%) 6 (7%) 5 (6%) 9 (26%) 3 (9%) 0 (0%) 15 (42%) 6 (17%) 3 (8%) 24 (65%) 7 (19%) 5 (14%) 48 (45%) 16 (15%) 8 (7%) Application Site Disorders (Injection site mass/ pain/ reaction/ inflammation) 0 (0%) 5 (6%) 3 (9%) 4 (11%) 8 (22%) 15 (14%) Liver and Biliary System Disorders 1 (4%) 3 (4%) 9 (26%) 7 (19%) 4 (11%) 20 (19%) Cholelithiasis 0 2 (2%) 5 (15%) 6 (17%) 3 (8%) 14 (13%) Heart Rate & Rhythm Disorders 0 8 (10%) 7 (21%) 2 (6%) 5 (14%) 14 (13%) Bradycardia 0 7 (8%) 6 (18%) 2 (6%) 2 (5%) 10 (9%) Red Blood Cell Disorders 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Anemia 0 6 (7%) 2 (6%) 5 (14%) 2 (5%) 9 (8%) Metabolic & Nutritional Disorders 3 (12%) 13 (16%) 8 (24%) 9 (25%) 4 (11%) 21 (20%) Weight decrease 0 7 (8%) 3 (9%) 4 (11%) 2 (5%) 9 (8%) In Study 1, the adverse reactions of diarrhea, abdominal pain, and flatulence increased in incidence with increasing dose of Lanreotide injection. Adverse Reactions in Long-Term Clinical Trials Table 2 provides the most common adverse reactions (greater than 5%) that occurred in 416 acromegalic patients treated with Lanreotide injection pooled from 7 studies compared to those patients from the 2 efficacy studies (Studies 1 and 2). Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout [see Clinical Studies ( 14.1 )] . Table 2: Adverse Reactions in Lanreotide Acetate -Treated Patients at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2 Dictionary = MedDRA 7.1 System Organ Class Number and Percentage of Patients Studies 1 & 2 (N=170) Overall Pooled Data (N=416) N % N % Patients with any Adverse Reactions 157 92 356 86 Gastrointestinal disorders 121 71 235 57 Diarrhea 81 48 155 37 Abdominal pain 34 20 79 19 Nausea 15 9 46 11 Constipation 9 5 33 8 Flatulence 12 7 30 7 Vomiting 8 5 28 7 Loose stools 16 9 23 6 Hepatobiliary disorders 53 31 99 24 Cholelithiasis 45 27 85 20 General disorders and administration site conditions 51 30 91 22 (Injection site pain /mass /induration/ nodule/pruritus) 28 17 37 9 Musculoskeletal and connective tissue disorders 44 26 70 17 Arthralgia 17 10 30 7 Nervous system disorders 34 20 80 19 Headache 9 5 30 7 In addition to the adverse reactions listed in Table 2 , the following reactions were also seen: Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies. Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies. Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies. Gastrointestinal Adverse Reactions In the pooled clinical studies of Lanreotide injection therapy, a variety of gastrointestinal (GI) reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with Lanreotide injection in the pooled clinical studies discontinued treatment because of gastrointestinal reactions. Pancreatitis was reported in less than 1% of patients. Gallbladder Adverse Reactions In clinical studies involving 416 acromegalic patients treated with Lanreotide injection, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with Lanreotide injection who underwent routine evaluation with gallbladder ultrasound, 17% had gallstones at baseline. New cholelithiasis was reported in 12% of patients. Cholelithiasis may be related to dose or duration of exposure [see Warnings and Precautions ( 5.1 )] . Injection Site Reactions In the pooled clinical studies, injection site pain (4%) and injection site mass (2%) were the most frequently reported local adverse drug reactions that occurred with the administration of Lanreotide injection. In a specific analysis, 20 of 413 patients (5%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects. Glucose Metabolism Adverse Reactions In the clinical studies in acromegalic patients treated with Lanreotide injection, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients [see Warnings and Precautions ( 5.2 )] . Cardiac Adverse Reactions In the pooled clinical studies, sinus bradycardia (3%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in less than 1% of patients. The relationship of these events to Lanreotide injection could not be established because many of these patients had underlying cardiac disease [see Warnings and Precautions ( 5.3 )] . A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the 2 treatments over 1 year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study. Other Adverse Reactions For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain, and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups. Gastroenteropancreatic Neuroendocrine Tumors The safety of Lanreotide injection 120 mg for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) was evaluated in Study 3, a double-blind, placebo-controlled trial. Patients in Study 3 were randomized to receive Lanreotide injection (N=101) or placebo (N=103) administered by deep subcutaneous injection once every 4 weeks. The data below reflect exposure to Lanreotide injection in 101 patients with GEP-NETs, including 87 patients exposed for at least 6 months and 72 patients exposed for at least 1 year (median duration of exposure 22 months). Patients treated with Lanreotide injection had a median age of 64 years (range 30 to 83 years), 53% were men and 96% were Caucasian. Eighty-one percent of patients (83/101) in the Lanreotide injection arm and 82% of patients (82/103) in the placebo arm did not have disease progression within 6 months of enrollment and had not received prior therapy for GEP-NETs. The rates of discontinuation due to treatment-emergent adverse reactions were 5% (5/101 patients) in the Lanreotide injection arm and 3% (3/103 patients) in the placebo arm. Table 3 compares the adverse reactions reported with an incidence of 5% and greater in patients receiving Lanreotide injection 120 mg administered every 4 weeks and reported more commonly than placebo. Table 3: Adverse Reactions Occurring in 5% and Greater of Lanreotide Acetate -Treated Patients and at a Higher Rate Than in Placebo- Treated Patients in Study 3 Adverse Reaction LANREOTIDE ACETATE 120 mg N=101 Placebo N=103 Any (%) Severe Includes preferred terms of depression, depressed mood (%) Any (%) Severe (%) Any Adverse Reactions 88 26 90 31 Abdominal pain Defined as hazardous to well-being, significant impairment of function or incapacitation 34 Includes preferred terms of hypertension, hypertensive crisis 6 24 4 Musculoskeletal pain Includes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort 19 2 13 2 Vomiting 19 2 9 2 Headache 16 0 11 1 Injection site reaction Includes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed. 15 0 7 0 Hyperglycemia Includes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain 14 0 5 0 Hypertension Includes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling 14 1 5 0 Cholelithiasis 14 1 7 0 Dizziness 9 0 2 0 Depression Includes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus 7 0 1 0 Dyspnea 6 0 1 0 6.2 Immunogenicity As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to lanreotide in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Laboratory investigations of acromegalic patients treated with Lanreotide injection in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (less than 1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of Lanreotide injection. In Study 3, development of anti-lanreotide antibodies was assessed using a radioimmunoprecipitation assay. In patients with GEP NETs receiving Lanreotide injection , the incidence of anti-lanreotide antibodies was 4% (3 of 82) at 24 weeks, 10% (7 of 67) at 48 weeks, 11% (6 of 57) at 72 weeks, and 10% (8 of 84) at 96 weeks. Assessment for neutralizing antibodies was not conducted. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Lanreotide injection. 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. Hepatobiliary: steatorrhea; cholecystitis, cholangitis, pancreatitis, which have sometimes required cholecystectomy Hypersensitivity: angioedema and anaphylaxis Injection site reactions : injection site abscess" ], "adverse_reactions_table": [ "
Table 1: Adverse Reactions at an Incidence of Greater than 5% with Lanreotide Acetate Overall and Occurring at Higher Rate than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 By Dose
A patient is counted only once for each body system and preferred term. Dictionary = WHOART.
Placebo-Controlled Double-Blind Phase Weeks 0 to 4Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20
Body System Preferred TermPlacebo (N=25)LANREOTIDE ACETATE Overall (N=83)LANREOTIDE ACETATE 60 mg (N=34)LANREOTIDE ACETATE 90 mg (N=36)LANREOTIDE ACETATE 120 mg (N=37)LANREOTIDE ACETATE Overall (N=107)
N (%)N (%)N (%)N (%)N (%)N (%)
Gastrointestinal System Disorders1 (4%)30 (36%)12 (35%)21 (58%)27 (73%)60 (56%)
Diarrhea Abdominal pain Flatulence 0 1 (4%) 026 (31%) 6 (7%) 5 (6%)9 (26%) 3 (9%) 0 (0%)15 (42%) 6 (17%) 3 (8%)24 (65%) 7 (19%) 5 (14%)48 (45%) 16 (15%) 8 (7%)
Application Site Disorders (Injection site mass/ pain/ reaction/ inflammation) 0 (0%)5 (6%)3 (9%)4 (11%)8 (22%)15 (14%)
Liver and Biliary System Disorders1 (4%)3 (4%)9 (26%)7 (19%)4 (11%)20 (19%)
Cholelithiasis02 (2%)5 (15%)6 (17%)3 (8%)14 (13%)
Heart Rate & Rhythm Disorders08 (10%)7 (21%)2 (6%)5 (14%)14 (13%)
Bradycardia07 (8%)6 (18%)2 (6%)2 (5%)10 (9%)
Red Blood Cell Disorders06 (7%)2 (6%)5 (14%)2 (5%)9 (8%)
Anemia0 6 (7%)2 (6%)5 (14%)2 (5%)9 (8%)
Metabolic & Nutritional Disorders3 (12%)13 (16%)8 (24%)9 (25%)4 (11%)21 (20%)
Weight decrease 07 (8%)3 (9%)4 (11%)2 (5%)9 (8%)
", "
Table 2: Adverse Reactions in Lanreotide Acetate -Treated Patients at an Incidence Greater than 5% in Overall Group Versus Adverse Reactions Reported in Studies 1 and 2
Dictionary = MedDRA 7.1
System Organ ClassNumber and Percentage of Patients
Studies 1 & 2 (N=170)Overall Pooled Data (N=416)
N%N%
Patients with any Adverse Reactions1579235686
Gastrointestinal disorders1217123557
Diarrhea814815537
Abdominal pain34207919
Nausea1594611
Constipation95338
Flatulence127307
Vomiting85287
Loose stools169236
Hepatobiliary disorders53319924
Cholelithiasis45278520
General disorders and administration site conditions51309122
(Injection site pain /mass /induration/ nodule/pruritus) 2817379
Musculoskeletal and connective tissue disorders44267017
Arthralgia1710307
Nervous system disorders34208019
Headache95307
", "
Table 3: Adverse Reactions Occurring in 5% and Greater of Lanreotide Acetate -Treated Patients and at a Higher Rate Than in Placebo- Treated Patients in Study 3
Adverse ReactionLANREOTIDE ACETATE 120 mg N=101Placebo N=103
Any (%)SevereIncludes preferred terms of depression, depressed mood (%)Any (%)Severe (%)
Any Adverse Reactions88269031
Abdominal painDefined as hazardous to well-being, significant impairment of function or incapacitation34Includes preferred terms of hypertension, hypertensive crisis6244
Musculoskeletal painIncludes preferred terms of abdominal pain, abdominal pain upper/lower, abdominal discomfort192132
Vomiting19292
Headache160111
Injection site reactionIncludes one or more serious adverse events (SAEs) defined as any event that results in death, is life threatening, results in hospitalization or prolongation of hospitalization, results in persistent or significant disability, results in congenital anomaly/birth defect, or may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed.15070
HyperglycemiaIncludes preferred terms of myalgia, musculoskeletal discomfort, musculoskeletal pain, back pain14050
HypertensionIncludes preferred terms of infusion site extravasation, injection site discomfort, injection site granuloma, injections site hematoma, injection site hemorrhage, injection site induration, injection site mass, injections site nodule, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling14150
Cholelithiasis14170
Dizziness9020
DepressionIncludes preferred terms of diabetes mellitus, glucose tolerance impaired, hyperglycemia, type 2 diabetes mellitus7010
Dyspnea6010
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Cyclosporine : Lanreotide injection may decrease the absorption of cyclosporine. Dosage adjustment of cyclosporine may needed. ( 7.2 ) Bromocriptine : Lanreotide injection may increase the absorption of bromocriptine. ( 7.3 ) Bradycardia-Inducing Drugs (e.g., beta-blockers) : Lanreotide injection may decrease heart rate. Dosage adjustment of the coadministered drug may be necessary. ( 7.3 ) 7.1 Insulin and Oral Hypoglycemic Drugs Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when Lanreotide injection treatment is initiated or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Warnings and Precautions ( 5.2 )]. 7.2 Cyclosporine Concomitant administration of cyclosporine with Lanreotide injection may decrease the absorption of cyclosporine, and therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic drug concentrations. [see Clinical Pharmacology ( 12.3 )] 7.3 Bromocriptine Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the absorption of bromocriptine [see Clinical Pharmacology ( 12.3 )] . 7.4 Bradycardia-Inducing Drugs Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dosage adjustments of concomitant drugs may be necessary. 7.5 Drug Metabolism Interactions The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that Lanreotide injection may have this effect, avoid other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine). Drugs metabolized by the liver may be metabolized more slowly during Lanreotide injection treatment and dose reductions of the concomitantly administered medications should be considered [see Clinical Pharmacology ( 12.3 )] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed during treatment and for 6 months after the last dose. ( 8.2 ) 8.1 Pregnancy Risk Summary Limited available data based on postmarketing case reports with Lanreotide injection use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5- and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Animal Data A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities. 8.2 Lactation Risk Summary There is no information available on the presence of lanreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that lanreotide injection administered subcutaneously passes into the milk of lactating rats; however, due to specifies-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Because of the potential for serious adverse reactions in breastfed infants from Lanreotide injection, including effects on glucose metabolism and bradycardia, advise women not to breastfeed during treatment with Lanreotide injection and for 6 months (6 half-lives) following the last dose. 8.3 Females and Males of Reproductive Potential Infertility Females Based on results from animal studies conducted in female rats, Lanreotide injection may reduce fertility in females of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of Lanreotide injection in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients 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. Studies 3 and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment Acromegaly Lanreotide has been studied in patients with end-stage renal function on dialysis, but has not been studied in patients with mild, moderate, or severe renal impairment. It is recommended that patients with moderate or severe renal impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks [see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] . Neuroendocrine Tumors (NET) – Gastroenteropancreatic Neuroendocrine Tumors No effect was observed in total clearance of lanreotide in patients with mild to moderate renal impairment receiving Lanreotide injection 120 mg. Patients with severe renal impairment were not studied [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Acromegaly It is recommended that patients with moderate or severe hepatic impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks [see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] . Neuroendocrine Tumors (NET) – Gastroenteropancreatic Neuroendocrine Tumors Lanreotide injection has not been studied in patients with hepatic impairment." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited available data based on postmarketing case reports with Lanreotide injection use in pregnant women are not sufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, decreased embryo/fetal survival was observed in pregnant rats and rabbits at subcutaneous doses 5- and 2-times the maximum recommended human dose (MRHD) of 120 mg, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Animal Data A reproductive study in pregnant rats given 30 mg/kg of lanreotide by subcutaneous injection every 2 weeks (5 times the human dose, based on body surface area comparisons) resulted in decreased embryo/fetal survival. A study in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day (2 times the human therapeutic exposures at the maximum recommended dose of 120 mg, based on comparisons of relative body surface area) shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of Lanreotide injection in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use No overall differences in safety or effectiveness were observed between elderly patients with acromegaly compared with younger patients 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. Studies 3 and 4, conducted in patients with neuroendocrine tumors, did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "description": [ "11 DESCRIPTION Lanreotide (lanreotide) injection 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL is a prolonged-release formulation for deep subcutaneous injection. It contains the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, water for injection and acetic acid (for pH adjustment). Lanreotide injection is available as sterile, ready-to-use, single-dose prefilled syringes containing lanreotide acetate supersaturated bulk solution of 24.6% w/w lanreotide base. Each syringe contains: LANREOTIDE ACETATE 60 mg/0.2 mL LANREOTIDE ACETATE 90 mg/0.3 mL LANREOTIDE ACETATE 120 mg/0.5 mL Lanreotide acetate 89.9 mg 123.2 mg 156.6 mg Acetic Acid q.s. q.s. q.s. Water for injection 236.4 mg 324.1 mg 411.6 mg Total Weight 328.9 mg 450.9 mg 572.8 mg Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-D­ alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is: The Lanreotide Injection in the prefilled syringe is a white to pale yellow, semi-solid formulation. Chemical Structure" ], "description_table": [ "
Each syringe contains:LANREOTIDE ACETATE 60 mg/0.2 mLLANREOTIDE ACETATE 90 mg/0.3 mLLANREOTIDE ACETATE 120 mg/0.5 mL
Lanreotide acetate89.9 mg123.2 mg156.6 mg
Acetic Acidq.s.q.s.q.s.
Water for injection236.4 mg324.1 mg411.6 mg
Total Weight328.9 mg450.9 mg572.8 mg
" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lanreotide, the active component of Lanreotide acetate is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin. 12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies ( 14.1 )] . In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Lanreotide acetate, plasma GH levels fall rapidly and are maintained for at least 28 days. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [see Warnings and Precautions ( 5.1 )] . In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21-day) of lanreotide, serum glucose concentrations were temporarily decreased by 20% to 30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [see Warnings and Precautions ( 5.2 )] . Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis [see Warnings and Precautions ( 5.4 )] . 12.3 Pharmacokinetics Lanreotide acetate is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream. After a single, deep subcutaneous administration, the mean absolute bioavailability of Lanreotide acetate in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively. Mean C max values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and C max , and showed high inter-subject variability. Lanreotide acetate showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion. Acromegaly In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Lanreotide acetate between 60 and 120 mg, linear pharmacokinetics were observed in acromegalic patients. At steady state, mean C max values were 3.8 ± 0.5, 5.7 ± 1.7, and 7.7 ± 2.5 ng/mL, increasing linearly with dose. The mean accumulation ratio index was 2.7, which is in line with the range of values for the half-life of Lanreotide acetate. The steady- state trough serum lanreotide concentrations in patients receiving Lanreotide acetate every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60 mg, 90 mg, and 120 mg doses, respectively. A limited initial burst effect and a low peak-to-trough fluctuation (81% to 108%) of the serum concentration at the plateau were observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1, and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of Lanreotide injection 120 mg demonstrated mean steady-state, C min values between 1.6 and 2.3 ng/mL for the 8- and 6-week treatment interval, respectively. Gastroenteropancreatic Neuroendocrine Tumors In patients with GEP-NETs treated with Lanreotide injection 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL. Specific Populations Lanreotide injection has not been studied in specific populations. However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Geriatric Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or C max of lanreotide in elderly as compared to healthy young subjects. Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged 65 to 85 years with neuroendocrine tumors. Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2­-fold increase in half-life and AUC was observed. Patients with acromegaly and with moderate to severe renal impairment should begin treatment with Lanreotide injection 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks. Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with Lanreotide injection. GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied. Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with acromegaly and with moderate to severe hepatic impairment should begin treatment with Lanreotide injection 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks. The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET." ], "mechanism_of_action": [ "12.1 Mechanism of Action Lanreotide, the active component of Lanreotide acetate is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine, and paracrine functions. The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies ( 14.1 )] . In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Lanreotide acetate, plasma GH levels fall rapidly and are maintained for at least 28 days. Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits postprandial secretion of pancreatic polypeptide, gastrin, and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in postprandial insulin secretion, resulting in transient, mild glucose intolerance. Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity. Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [see Warnings and Precautions ( 5.1 )] . In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide. In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21-day) of lanreotide, serum glucose concentrations were temporarily decreased by 20% to 30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [see Warnings and Precautions ( 5.2 )] . Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis [see Warnings and Precautions ( 5.4 )] ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Lanreotide acetate is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the bloodstream. After a single, deep subcutaneous administration, the mean absolute bioavailability of Lanreotide acetate in healthy subjects was 73.4, 69.0, and 78.4% for the 60 mg, 90 mg, and 120 mg doses, respectively. Mean C max values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and C max , and showed high inter-subject variability. Lanreotide acetate showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL at 60 mg. In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion. Acromegaly In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Lanreotide acetate between 60 and 120 mg, linear pharmacokinetics were observed in acromegalic patients. At steady state, mean C max values were 3.8 ± 0.5, 5.7 ± 1.7, and 7.7 ± 2.5 ng/mL, increasing linearly with dose. The mean accumulation ratio index was 2.7, which is in line with the range of values for the half-life of Lanreotide acetate. The steady- state trough serum lanreotide concentrations in patients receiving Lanreotide acetate every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60 mg, 90 mg, and 120 mg doses, respectively. A limited initial burst effect and a low peak-to-trough fluctuation (81% to 108%) of the serum concentration at the plateau were observed. For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1, and 4.0 ± 1.4 ng/mL, respectively). Pharmacokinetic data from studies evaluating extended dosing use of Lanreotide injection 120 mg demonstrated mean steady-state, C min values between 1.6 and 2.3 ng/mL for the 8- and 6-week treatment interval, respectively. Gastroenteropancreatic Neuroendocrine Tumors In patients with GEP-NETs treated with Lanreotide injection 120 mg every 4 weeks, steady state concentrations were reached after 4 to 5 injections and the mean trough serum lanreotide concentrations at steady state ranged from 5.3 to 8.6 ng/mL. Specific Populations Lanreotide injection has not been studied in specific populations. However, the pharmacokinetics of lanreotide in renal impaired, hepatic impaired, and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose. Geriatric Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or C max of lanreotide in elderly as compared to healthy young subjects. Age has no effect on clearance of lanreotide based on population PK analysis in patients with GEP-NET which included 122 patients aged 65 to 85 years with neuroendocrine tumors. Renal Impairment An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2­-fold increase in half-life and AUC was observed. Patients with acromegaly and with moderate to severe renal impairment should begin treatment with Lanreotide injection 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks. Mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment has no effect on clearance of lanreotide in patients with GEP-NET based on population PK analysis which included 106 patients with mild and 59 patients with moderate renal impairment treated with Lanreotide injection. GEP-NET patients with severe renal impairment (CLcr < 30 mL/min) were not studied. Hepatic Impairment In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with acromegaly and with moderate to severe hepatic impairment should begin treatment with Lanreotide injection 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Lanreotide injection 120 mg every 6 or 8 weeks. The effect of hepatic impairment on clearance of lanreotide has not been studied in patients with GEP-NET." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide at 0.5, 1.5, 5, 10, and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30 mg/kg/day resulting in exposures 3 times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5 mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. In a fertility study conducted with lanreotide in rats, reduced female fecundity was observed at estimated exposure corresponding to approximately 10-fold the plasma exposure at the MRHD of 120 mg. The fertility of male rats was unaffected by the treatment up to an estimated exposure corresponding to approximately 11-fold the plasma exposure at the MRHD of 120 mg." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide at 0.5, 1.5, 5, 10, and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30 mg/kg/day resulting in exposures 3 times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5 mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant. Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay. In a fertility study conducted with lanreotide in rats, reduced female fecundity was observed at estimated exposure corresponding to approximately 10-fold the plasma exposure at the MRHD of 120 mg. The fertility of male rats was unaffected by the treatment up to an estimated exposure corresponding to approximately 11-fold the plasma exposure at the MRHD of 120 mg." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Acromegaly The effect of Lanreotide injection on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in 2 long-term, multiple-dose, randomized, multicenter studies. Study 1 This 1-year study included a 4-week, double-blind, placebo-controlled phase; a 16-week single-blind, fixed-dose phase; and a 32-week, open-label, dose-titration phase. Patients with active acromegaly, based on biochemical tests and medical history, entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist. Upon entry, patients were randomly allocated to receive a single, deep subcutaneous injection of Lanreotide injection 60, 90, or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of Lanreotide injection followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels. A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level greater than 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were required to have a mean GH concentration greater than 3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication. One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase, and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4). In the double-blind phase of Study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a greater than 50% decrease in mean GH from baseline to Week 4, including 52%, 44%, and 90% of patients in the 60, 90, and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of greater than 50%, including 68% (23/34), 64% (23/36), and 84% (31/37) of patients in the 60, 90, and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 4 ). Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1 1 n=105, 2 n=102, 3 Age-adjusted Baseline N=107 Before Titration 1 (16 weeks) N=107 Before Titration 2 (32 weeks) N=105 Last Value Available Last Observation Carried Forward N=107 GH ≤5.0 ng/mL Number of Responders (%) 20 (19%) 72 (67%) 76 (72%) 74 (69%) ≤2.5 ng/mL Number of Responders (%) 0 (0%) 52 (49%) 59 (56%) 55 (51%) ≤1.0 ng/mL Number of Responders (%) 0 (0%) 15 (14%) 18 (17%) 17 (16%) Median GH ng/mL 10.27 2.53 2.20 2.43 GH Reduction Median % Reduction -- 75.5 78.2 75.5 IGF-1 Normal 3 Number of Responders (%) 9 (8%) 58 (54%) 57 (54%) 62 (58%) Median IGF-1 ng/mL 775.0 332.0 1 316.5 2 326.0 IGF-1 Reduction Median % Reduction -- 52.3 1 54.5 2 55.4 IGF-1 Normal 3 + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 41 (38%) 46 (44%) 44 (41%) Study 2 This was a 48-week, open-label, uncontrolled, multicenter study that enrolled patients who had an IGF-1 concentration 1.3 times or greater than the upper limit of the normal age-adjusted range. Patients receiving treatment with a somatostatin analog (other than Lanreotide injection) or a dopaminergic agonist had to attain this IGF-1 concentration after a washout period of up to 3 months. Patients were initially enrolled in a 4-month, fixed-dose phase where they received 4 deep subcutaneous injections of Lanreotide injection 90 mg, at 4-week intervals. Patients then entered a dose-titration phase where the dose of Lanreotide injection was adjusted based on GH and IGF-1 levels at the beginning of the dose-titration phase and, if necessary, again after another 4 injections. Patients titrated up to the maximum dose (120 mg) were not allowed to titrate down again. A total of 63 patients (38 males, 25 females) entered the fixed-dose phase of the trial and 57 patients completed 48 weeks of treatment. Six patients withdrew due to adverse reactions (3), other reasons (2), or lack of efficacy (1). After 48 weeks of treatment with Lanreotide injection at 4-week intervals, 43% (27/63) of the acromegalic patients in this study achieved normal age-adjusted IGF-1 concentrations. Mean IGF-1 concentrations after treatment completion were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The reduction in IGF-1 concentrations over time correlated with a corresponding marked decrease in mean GH concentrations. The proportion of patients with mean GH concentrations less than 2.5 ng/mL increased significantly from 35% to 77% after the fixed-dose phase and 85% at the end of the study. At the end of treatment, 24/63 (38%) of patients had both normal IGF-1 concentrations and a GH concentration of less than or equal to 2.5 ng/mL (see Table 5 ) and 17/63 patients (27%) had both normal IGF-1 concentrations and a GH concentration of less than 1 ng/mL. Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2 1 Age-adjusted, 2 N= 62, Baseline N=63 Before Titration 1 (12 wks) N=63 Before Titration 2 (28 wks) N=59 Last Value Available Last Observation Carried Forward N=63 IGF-1 Normal 1 Number of Responders (%) 0 (0%) 17 (27%) 22 (37%) 27 (43%) Median IGF-1 ng/mL 689.0 382.0 334.0 317.0 IGF-1 Reduction Median % Reduction -- 41.0 51.0 50.3 GH ≤5.0 ng/mL Number of Responders (%) 40 (64%) 59 (94%) 57 (97%) 62 (98%) ≤2.5 ng/mL Number of Responders (%) 21 (33%) 47 (75%) 47 (80%) 54 (86 %) ≤1.0 ng/mL Number of Responders (%) 8 (13%) 19 (30%) 18 (31%) 28 (44%) Median GH ng/Ml 3.71 1.65 1.48 1.13 GH Reduction Median % Reduction -- 63.2 66.7 78.6 2 IGF-1 normal 1 + GH ≤2.5 ng/mL Number of Responders (%) 0 (0%) 14 (22%) 20 (34%) 24 (38%) Examination of age and gender subgroups did not identify differences in response to Lanreotide injection among these subgroups. The limited number of patients in the different racial subgroups did not raise any concerns regarding efficacy of Lanreotide injection in these subgroups. 14.2 Gastroenteropancreatic Neuroendocrine Tumors The efficacy of Lanreotide injection was established in a multicenter, randomized, double-blind, placebo-controlled trial of 204 patients with unresectable, well or moderately differentiated, metastatic or locally advanced, gastroenteropancreatic neuroendocrine tumors. Patients were required to have non-functioning tumors without hormone-related symptoms. Patients were randomized 1:1 to receive Lanreotide injection 120 mg (n=101) or placebo (n=103) every 4 weeks until disease progression, unacceptable toxicity, or a maximum of 96 weeks of treatment. Randomization was stratified by the presence or absence of prior therapy and by the presence or absence of disease progression within 6 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS), defined as time to disease progression as assessed by central independent radiological review using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) or death. The median patient age was 63 years (range 30 to 92 years) and 95% were Caucasian. Disease progression was present in nine of 204 patients (4.4%) in the 6 months prior to enrollment and 29 patients (14%) received prior chemotherapy. Ninety-one patients (45%) had primary sites of disease in the pancreas, with the remainder originating in the midgut (35%), hindgut (7%), or unknown primary location (13%). The majority (69%) of the study population had grade 1 tumors. Baseline prognostic characteristics were similar between arms with one exception; there were 39% of patients in the Lanreotide injection arm and 27% of patients in the placebo arm who had hepatic involvement by tumor of greater than 25%. Patients on the Lanreotide injection arm had a statistically significant improvement in PFS compared to patients receiving placebo (see Table 6 and Figure 1 ). Table 6: Efficacy Results in Study 3 1 NE = not reached at 22 months 2 Hazard Ratio is derived from a Cox stratified proportional hazards model LANREOTIDE ACETATE Placebo n=101 n=103 Number of Events (%) 32 (31.7%) 60 (58.3%) Median PFS (months)(95% CI) NE 1 (NE, NE) 16.6 (11.2, 22.1) HR (95% CI) 0.47 (0.30, 0.73) 2 Log-rank p-value <0.001 Figure 1: Kaplan-Meier Curves of Progression-Free Survival Figure 1" ], "clinical_studies_table": [ "
Table 4: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1
1 n=105, 2n=102, 3Age-adjusted
Baseline N=107 Before Titration 1 (16 weeks) N=107Before Titration 2 (32 weeks) N=105Last Value Available Last Observation Carried Forward N=107
GH
≤5.0 ng/mLNumber of Responders (%)20 (19%)72 (67%)76 (72%)74 (69%)
≤2.5 ng/mLNumber of Responders (%)0 (0%)52 (49%)59 (56%)55 (51%)
≤1.0 ng/mLNumber of Responders (%)0 (0%)15 (14%)18 (17%)17 (16%)
Median GHng/mL10.272.532.202.43
GH ReductionMedian % Reduction--75.578.275.5
IGF-1
Normal3Number of Responders (%)9 (8%)58 (54%)57 (54%)62 (58%)
Median IGF-1ng/mL775.0332.01316.52326.0
IGF-1 ReductionMedian % Reduction--52.3154.5255.4
IGF-1 Normal3 + GH ≤2.5 ng/mL Number of Responders (%)0 (0%)41 (38%)46 (44%)44 (41%)
", "
Table 5: Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 2
1 Age-adjusted, 2N= 62,
Baseline N=63 Before Titration 1 (12 wks) N=63Before Titration 2 (28 wks) N=59Last Value AvailableLast Observation Carried Forward N=63
IGF-1
Normal1Number of Responders (%)0 (0%)17 (27%)22 (37%)27 (43%)
Median IGF-1ng/mL689.0382.0334.0317.0
IGF-1 ReductionMedian % Reduction--41.051.050.3
GH
≤5.0 ng/mLNumber of Responders (%)40 (64%)59 (94%)57 (97%)62 (98%)
≤2.5 ng/mLNumber of Responders (%)21 (33%)47 (75%)47 (80%)54 (86 %)
≤1.0 ng/mLNumber of Responders (%)8 (13%)19 (30%)18 (31%)28 (44%)
Median GHng/Ml3.711.651.481.13
GH ReductionMedian % Reduction--63.266.778.62
IGF-1 normal1 + GH ≤2.5 ng/mL Number of Responders (%)0 (0%)14 (22%)20 (34%)24 (38%)
", "
Table 6: Efficacy Results in Study 3
1 NE = not reached at 22 months 2 Hazard Ratio is derived from a Cox stratified proportional hazards model
LANREOTIDE ACETATEPlacebo
n=101n=103
Number of Events (%)32 (31.7%)60 (58.3%)
Median PFS (months)(95% CI)NE1 (NE, NE)16.6 (11.2, 22.1)
HR (95% CI)0.47 (0.30, 0.73)2
Log-rank p-value<0.001
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Lanreotide injection is supplied in strengths of 60 mg/0.2 mL, 90 mg/0.3 mL, and 120 mg/0.5 mL as a white to pale yellow, semi-solid formulation in a single, sterile, prefilled, ready-to-use, polypropylene syringe (fitted with an automatic needle guard) fitted with a 20 mm needle covered by a sheath. Each prefilled syringe is sealed in a laminated pouch and packed in a carton. NDC 76282-709-67 60 mg/0.2 mL, sterile, prefilled syringe NDC 76282-710-67 90 mg/0.3 mL, sterile, prefilled syringe NDC 76282-711-67 120 mg/0.5 mL, sterile, prefilled syringe Storage and Handling Store Lanreotide injection in the refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the original package." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Hypersensitivity Reactions Advise patients to immediately contact their healthcare provider if they experience serious hypersensitivity reactions, such as angioedema or anaphylaxis [see Contraindications ( 4 )] . Cholelithiasis and Complications of Cholelithiasis Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, or pancreatitis) [see Warnings and Precautions ( 5.1 )] . Hyperglycemia and Hypoglycemia Advise patients to immediately contact their healthcare provider if they experience signs or symptoms of hyper- or hypoglycemia [see Warnings and Precautions ( 5.2 )] . Cardiovascular Abnormalities Advise patients to immediately contact their healthcare provider if they experience bradycardia [see Warnings and Precautions ( 5.3 )] . Thyroid Function Abnormalities Advise patients to contact their healthcare provider if they experience signs or symptoms of hypothyroidism [see Warnings and Precautions ( 5.4 )] . Laboratory Tests Advise patients with acromegaly that response to Lanreotide injection should be monitored by periodic measurements of GH and IGF-1 levels, with a goal of decreasing these levels to the normal range [see Dosage and Administration ( 2.2 )] . Lactation Advise women not to breastfeed during treatment with Lanreotide injection and for 6 months after the last dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise females of reproductive potential of the potential for reduced fertility from Lanreotide injection [see Use in Specific Populations ( 8.3 )] . Manufactured by: Pharmathen International S.A. Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, Greece Manufactured for: Exelan Pharmaceuticals, Inc. Boca Raton, FL 33432 Issued: 08/2023" ], "information_for_patients_table": [ "
Manufactured by: Pharmathen International S.A. Industrial Park Sapes, Rodopi Prefecture, Block No 5, Rodopi 69300, GreeceManufactured for: Exelan Pharmaceuticals, Inc. Boca Raton, FL 33432
" ], "spl_patient_package_insert": [ "Patient Information LANREOTIDE (lan-REE-oh-tide) (lanreotide) injection Read this Patient Information before you receive your first Lanreotide injection and before each injection. 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 is Lanreotide injection? Lanreotide injection is a prescription medicine used for: the long-term treatment of people with acromegaly when: surgery or radiotherapy have not worked well enough or they are not able to have surgery or radiotherapy the treatment of adults with a type of cancer known as neuroendocrine tumors, from the gastrointestinal tract or the pancreas (GEP-NETs) that has spread or cannot be removed by surgery It is not known if Lanreotide injection is safe and effective in children. Who should not receive Lanreotide injection? Do not receive Lanreotide injection if you are allergic to lanreotide. What should I tell my healthcare provider before receiving Lanreotide injection? Before you receive Lanreotide injection , tell your healthcare provider about all of your medical conditions, including if you: have gallbladder problems have diabetes have heart problems have thyroid problems have kidney problems have liver problems are pregnant or plan to become pregnant. It is not known if Lanreotide injection will harm your unborn baby are breastfeeding or plan to breastfeed. It is not known if Lanreotide injection passes into your breast milk. You should not breastfeed if you receive Lanreotide injection and for 6 months after your last dose of Lanreotide injection are a female who can become pregnant. Lanreotide injection may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you Tell your healthcare provider about all the medicines you take, including prescription and over­- the-counter medicines, vitamins, and herbal supplements. Lanreotide injection and other medicines may affect each other, causing side effects. Lanreotide injection may affect the way other medicines work, and other medicines may affect how Lanreotide injection works. Your dose of Lanreotide injection or your other medicines may need to be changed. Especially tell your healthcare provider if you take: insulin or other diabetes medicines cyclosporine (Gengraf, Neoral, or Sandimmune) medicines that lower your heart rate such as beta blockers How will I receive Lanreotide injection? You will receive a Lanreotide injection every 4 weeks in your healthcare provider’s office Your healthcare provider may change your dose of Lanreotide injection or the length of time between your injections. Your healthcare provider will tell you how long you need to receive Lanreotide injection Lanreotide injection is injected deep under the skin of the upper outer area of your buttock. Your injection site should change (alternate) between your right and left buttock from one injection of Lanreotide injection to the next During your treatment with Lanreotide injection for acromegaly, your healthcare provider may do certain blood tests to see if Lanreotide injection is working What should I avoid while receiving Lanreotide injection? Lanreotide injection can cause dizziness. If you have dizziness, do not drive a car or operate machinery. What are the possible side effects of Lanreotide injection? Lanreotide injection may cause serious side effects, including: Gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are a serious but common side effect in people who take Lanreotide injection and have acromegaly and GEP-NET. Your healthcare provider may check your gallbladder before and during treatment with Lanreotide injection. Possible complications of gallstones include inflammation and infection of the gall bladder, and pancreatitis. Tell your healthcare provider if you get any symptoms of gallstones, including: ⚬ sudden pain in your upper right stomach area (abdomen) ⚬ yellowing of your skin and whites of your eyes ⚬ nausea ⚬ sudden pain in your right shoulder or between your shoulder blades ⚬ fever with chills Changes in your blood sugar (high blood sugar or low blood sugar). If you have diabetes, test your blood sugar as your healthcare provider tells you to. Your healthcare provider may change your dose of diabetes medicine especially when you first start receiving Lanreotide injection or if your dose of Lanreotide injection changes. High blood sugar is a common side effect in people with GEP-NET. Tell your healthcare provider right away if you have any signs or symptoms of high blood sugar or low blood sugar. Signs and symptoms of high blood sugar may include: ⚬ increased thirst ⚬ increased appetite ⚬ nausea ⚬ weakness or tiredness ⚬ urinating more often than normal ⚬ your breath smells like fruit Signs and symptoms of low blood sugar may include: ⚬ dizziness or lightheadedness ⚬ sweating ⚬ confusion ⚬ headache ⚬ blurred vision ⚬ slurred speech ⚬ shakiness ⚬ fast heartbeat ⚬ irritability or mood changes ⚬ hunger Slow heart rate. Tell your healthcare provider right away if you have slowing of your heart rate or if you have symptoms of a slow heart rate, including: ⚬ dizziness or lightheadedness ⚬ fainting or near-fainting ⚬ chest pain ⚬ shortness of breath ⚬ confusion or memory problems ⚬ weakness, extreme tiredness High blood pressure. High blood pressure can happen in people who receive Lanreotide injection and is a common side effect in people with GEP-NET. Changes in thyroid function. Lanreotide injection can cause the thyroid gland to not make enough thyroid hormones that the body needs (hypothyroidism) in people who have acromegaly. Tell your healthcare provider if you have signs and symptoms of low thyroid hormones levels, including: ⚬ fatigue ⚬ weight gain ⚬ a puffy face ⚬ being cold all of the time ⚬ constipation ⚬ dry skin ⚬ thinning, dry hair ⚬ decreased sweating ⚬ depression The most common side effects of Lanreotide injection in people with acromegaly include: • diarrhea • stomach area (abdominal) pain • nausea • pain, itching, or a lump at the injection site The most common side effects of Lanreotide injection in people with GEP-NET include: • stomach area (abdominal) pain • muscle and joint aches • vomiting • headache • pain, itching, or a lump at the injection site Tell your healthcare provider right away if you have signs of an allergic reaction after receiving Lanreotide injection, including: • swelling of your face, lips, mouth or tongue • breathing problems • fainting, dizziness, feeling lightheaded (low blood pressure) • itching • flushing or redness of your skin • rash • hives These are not all the possible side effects of Lanreotide injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Lanreotide injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not receive Lanreotide injection for a condition for which it was not prescribed. You can ask your healthcare provider for information about Lanreotide injection that is written for health professionals. What are the ingredients in Lanreotide injection? Active ingredient: lanreotide acetate Inactive ingredients: water for injection and acetic acid (for pH adjustment) Manufactured by: Pharmathen International S.A., Rodopi, Greece Manufactured for: Exelan Pharmaceuticals, Inc. Boca Raton, FL 33432 For more information, contact Exelan Pharmaceuticals, Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Issued: 08/2023" ], "spl_patient_package_insert_table": [ "
Patient InformationLANREOTIDE (lan-REE-oh-tide) (lanreotide) injection
Read this Patient Information before you receive your first Lanreotide injection and before each injection. 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 is Lanreotide injection?Lanreotide injection is a prescription medicine used for:the long-term treatment of people with acromegaly when:surgery or radiotherapy have not worked well enough orthey are not able to have surgery or radiotherapythe treatment of adults with a type of cancer known as neuroendocrine tumors, from the gastrointestinal tract or the pancreas (GEP-NETs) that has spread or cannot be removed by surgeryIt is not known if Lanreotide injection is safe and effective in children.
Who should not receive Lanreotide injection?Do not receive Lanreotide injection if you are allergic to lanreotide.
What should I tell my healthcare provider before receiving Lanreotide injection?Before you receive Lanreotide injection, tell your healthcare provider about all of your medical conditions, including if you:have gallbladder problemshave diabeteshave heart problemshave thyroid problemshave kidney problemshave liver problemsare pregnant or plan to become pregnant. It is not known if Lanreotide injection will harm your unborn babyare breastfeeding or plan to breastfeed. It is not known if Lanreotide injection passes into your breast milk. You should not breastfeed if you receive Lanreotide injection and for 6 months after your last dose of Lanreotide injectionare a female who can become pregnant. Lanreotide injection may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for youTell your healthcare provider about all the medicines you take, including prescription and over­- the-counter medicines, vitamins, and herbal supplements. Lanreotide injection and other medicines may affect each other, causing side effects. Lanreotide injection may affect the way other medicines work, and other medicines may affect how Lanreotide injection works. Your dose of Lanreotide injection or your other medicines may need to be changed. Especially tell your healthcare provider if you take:insulin or other diabetes medicinescyclosporine (Gengraf, Neoral, or Sandimmune)medicines that lower your heart rate such as beta blockers
How will I receive Lanreotide injection?You will receive a Lanreotide injection every 4 weeks in your healthcare provider’s officeYour healthcare provider may change your dose of Lanreotide injection or the length of time between your injections. Your healthcare provider will tell you how long you need to receive Lanreotide injectionLanreotide injection is injected deep under the skin of the upper outer area of your buttock. Your injection site should change (alternate) between your right and left buttock from one injection of Lanreotide injection to the nextDuring your treatment with Lanreotide injection for acromegaly, your healthcare provider may do certain blood tests to see if Lanreotide injection is working
What should I avoid while receiving Lanreotide injection?Lanreotide injection can cause dizziness. If you have dizziness, do not drive a car or operate machinery.
What are the possible side effects of Lanreotide injection?Lanreotide injection may cause serious side effects, including:Gallstones (cholelithiasis) and complications that can happen if you have gallstones. Gallstones are a serious but common side effect in people who take Lanreotide injection and have acromegaly and GEP-NET. Your healthcare provider may check your gallbladder before and during treatment with Lanreotide injection. Possible complications of gallstones include inflammation and infection of the gall bladder, and pancreatitis. Tell your healthcare provider if you get any symptoms of gallstones, including:
⚬ sudden pain in your upper right stomach area (abdomen) ⚬ yellowing of your skin and whites of your eyes ⚬ nausea ⚬ sudden pain in your right shoulder or between your shoulder blades ⚬ fever with chills
Changes in your blood sugar (high blood sugar or low blood sugar). If you have diabetes, test your blood sugar as your healthcare provider tells you to. Your healthcare provider may change your dose of diabetes medicine especially when you first start receiving Lanreotide injection or if your dose of Lanreotide injection changes. High blood sugar is a common side effect in people with GEP-NET.Tell your healthcare provider right away if you have any signs or symptoms of high blood sugar or low blood sugar.Signs and symptoms of high blood sugar may include:
⚬ increased thirst ⚬ increased appetite ⚬ nausea ⚬ weakness or tiredness ⚬ urinating more often than normal ⚬ your breath smells like fruit
Signs and symptoms of low blood sugar may include:
⚬ dizziness or lightheadedness ⚬ sweating ⚬ confusion ⚬ headache ⚬ blurred vision ⚬ slurred speech ⚬ shakiness ⚬ fast heartbeat ⚬ irritability or mood changes ⚬ hunger
Slow heart rate. Tell your healthcare provider right away if you have slowing of your heart rate or if you have symptoms of a slow heart rate, including:
⚬ dizziness or lightheadedness ⚬ fainting or near-fainting ⚬ chest pain ⚬ shortness of breath ⚬ confusion or memory problems ⚬ weakness, extreme tiredness
High blood pressure. High blood pressure can happen in people who receive Lanreotide injection and is a common side effect in people with GEP-NET.Changes in thyroid function. Lanreotide injection can cause the thyroid gland to not make enough thyroid hormones that the body needs (hypothyroidism) in people who have acromegaly. Tell your healthcare provider if you have signs and symptoms of low thyroid hormones levels, including:
⚬ fatigue ⚬ weight gain ⚬ a puffy face ⚬ being cold all of the time ⚬ constipation ⚬ dry skin ⚬ thinning, dry hair ⚬ decreased sweating ⚬ depression
The most common side effects of Lanreotide injection in people with acromegaly include:
• diarrhea • stomach area (abdominal) pain • nausea • pain, itching, or a lump at the injection site
The most common side effects of Lanreotide injection in people with GEP-NET include:
• stomach area (abdominal) pain • muscle and joint aches • vomiting • headache • pain, itching, or a lump at the injection site
Tell your healthcare provider right away if you have signs of an allergic reaction after receiving Lanreotide injection, including:
• swelling of your face, lips, mouth or tongue • breathing problems • fainting, dizziness, feeling lightheaded (low blood pressure) • itching • flushing or redness of your skin • rash • hives
These are not all the possible side effects of Lanreotide injection. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Lanreotide injection.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not receive Lanreotide injection for a condition for which it was not prescribed. You can ask your healthcare provider for information about Lanreotide injection that is written for health professionals.
What are the ingredients in Lanreotide injection?Active ingredient: lanreotide acetateInactive ingredients: water for injection and acetic acid (for pH adjustment)Manufactured by: Pharmathen International S.A., Rodopi, GreeceManufactured for: Exelan Pharmaceuticals, Inc. Boca Raton, FL 33432For more information, contact Exelan Pharmaceuticals, Inc. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Issued: 08/2023
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 60 mg/0.2 mL Carton Label NDC 76282-709-67 Rx Only Lanreotide Injection 60 mg*/0.2 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. EXELAN PHARMACEUTICALS, INC. 60 mg/0.2 mL Carton Label", "PRINCIPAL DISPLAY PANEL - 90 mg/0.3 mL Carton Label NDC 76282-710-67 Rx Only Lanreotide Injection 90 mg*/0.3 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. EXELAN PHARMACEUTICALS, INC. 90 mg/0.3 mL Carton Label", "PRINCIPAL DISPLAY PANEL - 120 mg/0.5 mL Carton Label NDC 76282-711-67 Rx Only Lanreotide Injection 120 mg*/0.5 mL For deep subcutaneous injection Single dose only. Discard unused portion. Lanreotide Injection should be administered by a healthcare professional. Leave at room temperature for 30 minutes before administration. CONTENTS: This box contains one (1) pre-filled syringe and one (1) safety needle. EXELAN PHARMACEUTICALS, INC. 120 mg/0.5 mL Carton Label" ], "set_id": "1c3dc59e-5469-488b-98bd-ec1cd9172c0f", "id": "b1660088-3928-45d3-8140-08bd77d73fbc", "effective_time": "20230818", "version": "2", "openfda": {} }, { "spl_product_data_elements": [ "Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID SODIUM ACETATE MANNITOL WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID SODIUM ACETATE MANNITOL WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID SODIUM ACETATE MANNITOL WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID SODIUM ACETATE PHENOL MANNITOL WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE ACETIC ACID SODIUM ACETATE PHENOL MANNITOL WATER" ], "description": [ "DESCRIPTION Octreotide Acetate Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered acetate solution for administration by deep subcutaneous (intrafat) or intravenous (IV) injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic (2→7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. Octreotide Acetate Injection is available as sterile 1-mL single-dose vials in 3 strengths, containing 50 mcg, 100 mcg, or 500 mcg octreotide (as acetate), and sterile 5 mL multiple-dose vials in 2 strengths, containing 200 mcg/mL and 1000 mcg/mL of octreotide (as acetate). Each single-dose vial also contains: Glacial acetic acid, USP………….. 2 mg Sodium acetate trihydrate, USP…... 2 mg Mannitol, USP……………………. 45 mg Water for injection, USP…………. qs to 1 mL Each mL of the multiple-dose vials also contains: Glacial acetic acid, USP………….. 2 mg Sodium acetate trihydrate, USP…... 2 mg Phenol liquefied, USP……………... 5 mg Mannitol, USP……………………. 45 mg Water for injection, USP…………. qs to 1 mL Glacial acetic acid, USP and sodium acetate trihydrate, USP are added to provide a buffered solution, pH to 4.2 ± 0.5. The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: Chemical Structure" ], "clinical_pharmacology": [ "CLINICAL PHARMACOLOGY Octreotide Acetate Injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone (GH), glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide (VIP), secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea). Octreotide substantially reduces GH and/or insulin growth factor-1 (IGF-1; somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased (see WARNINGS ). Octreotide suppresses secretion of thyroid stimulating hormone (TSH). Pharmacokinetics After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous (IV) and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In healthy volunteers, the distribution of octreotide from plasma was rapid (tα 1/2 = 0.2 h), the volume of distribution (V dss ) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of Octreotide Acetate Injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the pharmacokinetics differs somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (V dss ) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals. In patients with renal impairment, the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (CL CR 40 to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR 10 to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (CL CR < 10 mL/min) t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr." ], "indications_and_usage": [ "INDICATIONS AND USAGE Acromegaly Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. The goal is to achieve normalization of GH and IGF-1 (somatomedin C) levels (see DOSAGE AND ADMINISTRATION ). In patients with acromegaly, Octreotide Acetate Injection reduces GH to within normal ranges in 50% of patients and reduces IGF-1 (somatomedin C) to within normal ranges in 50% to 60% of patients. Since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with Octreotide Acetate Injection to reduce blood levels of GH and IGF-1 (somatomedin C) offers potential benefit before the effects of irradiation are manifested. Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects. Carcinoid Tumors Octreotide Acetate Injection is indicated for the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. Octreotide Acetate Injection studies were not designed to show an effect on the size, rate of growth, or development of metastases. Vasoactive Intestinal Peptide Tumors (VIPomas) Octreotide Acetate Injection is indicated for the treatment of the profuse watery diarrhea associated with VIP-secreting tumors. Octreotide Acetate Injection studies were not designed to show an effect on the size, rate of growth, or development of metastases." ], "contraindications": [ "CONTRAINDICATIONS Sensitivity to this drug or any of its components." ], "warnings": [ "WARNINGS Cholelithiasis and Complications of Cholelithiasis Single doses of Octreotide Acetate Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate for 1 month or less developed gallstones. The incidence of gallstones did not appear related to age, sex, or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide acetate therapy or following its withdrawal. One patient developed ascending cholangitis during octreotide acetate therapy and died. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications requiring cholecystectomy. If complications of cholelithiasis are suspected, discontinue octreotide acetate and treat appropriately. Complete Atrioventricular Block Patients who receive Octreotide Acetate Injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving intravenous Octreotide Acetate Injection during surgical procedures. In majority of patients, Octreotide Acetate Injection was given at higher than recommended doses and/or as a continuous intravenous infusion. The safety of continuous intravenous infusion has not been established in patients receiving Octreotide Acetate Injection for the approved indications. Consider cardiac monitoring in patients receiving Octreotide Acetate Injection intravenously." ], "precautions": [ "PRECAUTIONS General Octreotide Acetate Injection alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone (GH), which may result in hypoglycemia or hyperglycemia. Octreotide acetate also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with octreotide acetate. However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development of diabetes mellitus, hypothyroidism, and cardiovascular disease. Although the degree to which these abnormalities are related to octreotide acetate therapy is not clear, new abnormalities of glycemic control, thyroid function, and electrocardiogram (ECG) developed during octreotide acetate therapy, as described below. Risk of Pregnancy with Normalization of Insulin Growth Factor-1 (IGF-1; somatomedin C) and Growth Hormone (GH) Although acromegaly may lead to infertility, there are reports of pregnancy in acromegalic women. In women with active acromegaly who have been unable to become pregnant, normalization of GH and IGF-1 (somatomedin C) may restore fertility. Female patients of child-bearing potential should be advised to use adequate contraception during treatment with octreotide. Hyperglycemia and Hypoglycemia The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate in 3% and 16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate therapy was reported in one patient with no history of hyperglycemia. In patients with concomitant Type I diabetes mellitus, Octreotide Acetate Injection may affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients. In nondiabetics and Type II diabetics with partially intact insulin reserves, Octreotide Acetate Injection administration may result in decreases in plasma insulin levels and hyperglycemia. It is therefore recommended that glucose tolerance and anti-diabetic treatment be periodically monitored during therapy with these drugs. Thyroid Function Abnormalities In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving octreotide acetate. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T 4 ) is recommended during chronic therapy. Cardiac Function Abnormalities [see WARNINGS; Complete Atrioventricular Block ] In acromegalics, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during octreotide acetate therapy. Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of octreotide acetate therapy resulted in worsening of congestive heart failure with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge. Pancreatitis Several cases of pancreatitis have been reported in patients receiving octreotide acetate therapy. Dietary fats malabsorption Octreotide acetate may alter absorption of dietary fats in some patients. Decreased vitamin B12 levels and Abnormal Schilling’s Tests Depressed vitamin B 12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide acetate therapy, and monitoring of vitamin B 12 levels is recommended during chronic octreotide acetate therapy. Increased half-life of octreotide acetate in patients with renal failure on dialysis In patients with severe renal failure requiring dialysis, the half-life of octreotide acetate may be increased, necessitating adjustment of the maintenance dosage. Information for Patients Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer Octreotide Acetate Injection. Inform patients that cholelithiasis has been reported with the use of Octreotide Acetate Injection. Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, and pancreatitis). Laboratory Tests Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy: Acromegaly: Growth hormone (GH), insulin growth factor-1 (IGF-1; somatomedin C) Responsiveness to octreotide acetate may be evaluated by determining GH levels at 1 to 4 hour intervals for 8 to 12 hours post dose. Alternatively, a single measurement of IGF-1 (somatomedin C) level may be made two weeks after drug initiation or dosage change. Carcinoid: urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin, plasma Substance P VIPoma: plasma vasoactive intestinal peptide (VIP) Baseline and periodic total and/or free T 4 measurements should be performed during chronic therapy (see PRECAUTIONS, General ). Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Octreotide Acetate Injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may require dose adjustments of these therapeutic agents. Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone (GH). Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue Octreotide Acetate Injection at least 24 hours prior to each lutetium Lu 177 dotatate dose. Drug/Laboratory Test Interactions No known interference exists with clinical laboratory tests, including amine or peptide determinations. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on body surface area). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on body surface area) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide acetate did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7x the human exposure based on body surface area. There are no adequate and well-controlled studies of octreotide use in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of Octreotide Acetate Injection or 20 to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Nursing Mothers It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Octreotide Acetate Injection is administered to a nursing woman. Pediatric Use Safety and efficacy of Octreotide Acetate Injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Octreotide Acetate Injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of Octreotide Acetate Injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean BMI increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 to 30 mg once a month. Geriatric Use Clinical studies of Octreotide Acetate Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "general_precautions": [ "General Octreotide Acetate Injection alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone (GH), which may result in hypoglycemia or hyperglycemia. Octreotide acetate also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with octreotide acetate. However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development of diabetes mellitus, hypothyroidism, and cardiovascular disease. Although the degree to which these abnormalities are related to octreotide acetate therapy is not clear, new abnormalities of glycemic control, thyroid function, and electrocardiogram (ECG) developed during octreotide acetate therapy, as described below." ], "information_for_patients": [ "Information for Patients Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer Octreotide Acetate Injection. Inform patients that cholelithiasis has been reported with the use of Octreotide Acetate Injection. Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of gallstones (e.g., cholecystitis, cholangitis, and pancreatitis)." ], "laboratory_tests": [ "Laboratory Tests Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy: Acromegaly: Growth hormone (GH), insulin growth factor-1 (IGF-1; somatomedin C) Responsiveness to octreotide acetate may be evaluated by determining GH levels at 1 to 4 hour intervals for 8 to 12 hours post dose. Alternatively, a single measurement of IGF-1 (somatomedin C) level may be made two weeks after drug initiation or dosage change. Carcinoid: urinary 5-hydroxyindole acetic acid (5-HIAA), plasma serotonin, plasma Substance P VIPoma: plasma vasoactive intestinal peptide (VIP) Baseline and periodic total and/or free T 4 measurements should be performed during chronic therapy (see PRECAUTIONS, General )." ], "drug_interactions": [ "Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Octreotide Acetate Injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may require dose adjustments of these therapeutic agents. Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone (GH). Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue Octreotide Acetate Injection at least 24 hours prior to each lutetium Lu 177 dotatate dose." ], "drug_and_or_laboratory_test_interactions": [ "Drug/Laboratory Test Interactions No known interference exists with clinical laboratory tests, including amine or peptide determinations." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on body surface area). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on body surface area) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide acetate did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7x the human exposure based on body surface area. There are no adequate and well-controlled studies of octreotide use in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of Octreotide Acetate Injection or 20 to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported." ], "nursing_mothers": [ "Nursing Mothers It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when Octreotide Acetate Injection is administered to a nursing woman." ], "pediatric_use": [ "Pediatric Use Safety and efficacy of Octreotide Acetate Injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Octreotide Acetate Injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of Octreotide Acetate Injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean BMI increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 to 30 mg once a month." ], "geriatric_use": [ "Geriatric Use Clinical studies of Octreotide Acetate Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "adverse_reactions": [ "ADVERSE REACTIONS Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic Octreotide Acetate Injection therapy (see WARNINGS ). Cardiac In acromegalics, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate therapy (see PRECAUTIONS, General ). Gastrointestinal Diarrhea, loose stools, nausea, and abdominal discomfort were each seen in 34% to 61% of acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5% to 10% of patients with other disorders. The frequency of these symptoms was not dose related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness, and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 6% during octreotide acetate therapy (see PRECAUTIONS, General ). In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Pancreatitis was also observed (see WARNINGS and PRECAUTIONS ). Other Adverse Events 1% to 4% Other events (relationship to drug not established), each observed in 1% to 4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance, and depression. Other Adverse Events Less Than 1% Events reported in less than 1% of patients and for which relationship to Octreotide Acetate Injection is not established are listed: Gastrointestinal (GI): hepatitis, jaundice, increase in liver enzymes, GI bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary: rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint effusion, muscle pain, Raynaud's phenomenon; Cardiovascular: chest pain, shortness of breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease, syncope, tremor, seizure, vertigo, Bell's Palsy, paranoia, pituitary apoplexy, increased intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus, gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital: nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous: otitis, allergic reaction, increased CK, weight loss. Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide acetate. Postmarketing Experience The following adverse reactions have been identified during the postapproval use of octreotide acetate. 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. Hepatobiliary: cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy Gastrointestinal: intestinal obstruction Hematologic: thrombocytopenia To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ." ], "overdosage": [ "OVERDOSAGE A limited number of accidental overdoses of Octreotide Acetate Injection in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss. Octreotide Acetate Injection given in intravenous (IV) boluses of 1 mg (1,000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222. Drug Abuse and Dependence There is no indication that octreotide acetate has potential for drug abuse or dependence. Octreotide acetate levels in the central nervous system are negligible, even after doses up to 30,000 mcg." ], "drug_abuse_and_dependence": [ "Drug Abuse and Dependence There is no indication that octreotide acetate has potential for drug abuse or dependence. Octreotide acetate levels in the central nervous system are negligible, even after doses up to 30,000 mcg." ], "dosage_and_administration": [ "DOSAGE AND ADMINISTRATION Octreotide Acetate Injection may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of Octreotide Acetate Injection for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination. Octreotide Acetate Injection is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product. Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50 to 200 mL and infused intravenously over 15 to 30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus. The initial dosage is usually 50 mcg administered twice or 3 times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows. Acromegaly Dosage may be initiated at 50 mcg 3 times a day. Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses. Insulin growth factor-1 (IGF-1; somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone (GH) levels at 0 to 8 hours after Octreotide Acetate Injection administration permit more rapid titration of dose. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 (somatomedin C) levels less than 1.9 unit/mL in males and less than 2.2 unit/mL in females. The dose most commonly found to be effective is 100 mcg 3 times a day, but some patients require up to 500 mcg 3 times a day for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-1 (somatomedin C) or GH levels should be reevaluated at 6-month intervals. Octreotide Acetate Injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 (somatomedin C) levels increase and signs and symptoms recur, Octreotide Acetate Injection therapy may be resumed. Carcinoid Tumors The suggested daily dosage of Octreotide Acetate Injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. VIPomas Daily dosages of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range, 150 to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required." ], "how_supplied": [ "HOW SUPPLIED Octreotide Acetate Injection is available in 1 mL single-dose vials and 5 mL multiple-dose vials as follows: NDC Number Octreotide Acetate Injection Vial/Package Size 0703-3301-04 50 mcg/mL 1 mL single-dose vial 25 per shelf tray 0703-3311-04 100 mcg/mL 1 mL single-dose vial 25 per shelf tray 0703-3321-04 500 mcg/mL 1 mL single-dose vial 25 per shelf tray 0703-3333-01 200 mcg/mL 5 mL multiple-dose vial packaged individually 0703-3343-01 1000 mcg/mL 5 mL multiple-dose vial packaged individually Storage For prolonged storage, Octreotide Acetate Injection single-dose vials and multiple-dose vials should be stored at refrigerated temperatures 2°C to 8°C (36°F to 46°F) and protected from light. At room temperature (20°C to 30°C or 70°F to 86°F), Octreotide Acetate is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Single-dose vials should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly." ], "how_supplied_table": [ "
NDC NumberOctreotide Acetate InjectionVial/Package Size
0703-3301-0450 mcg/mL1 mL single-dose vial 25 per shelf tray
0703-3311-04100 mcg/mL1 mL single-dose vial 25 per shelf tray
0703-3321-04500 mcg/mL1 mL single-dose vial 25 per shelf tray
0703-3333-01200 mcg/mL5 mL multiple-dose vial packaged individually
0703-3343-011000 mcg/mL5 mL multiple-dose vial packaged individually
" ], "storage_and_handling": [ "Storage For prolonged storage, Octreotide Acetate Injection single-dose vials and multiple-dose vials should be stored at refrigerated temperatures 2°C to 8°C (36°F to 46°F) and protected from light. At room temperature (20°C to 30°C or 70°F to 86°F), Octreotide Acetate is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Single-dose vials should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly." ], "spl_unclassified_section": [ "Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. I 2/2023" ], "package_label_principal_display_panel": [ "Package/Label Display Panel NDC 0703-3301-04 Octreotide Acetate Injection 50 mcg/mL For Subcutaneous or Intravenous Use Rx only 1 mL Single-Dose Vial 25 Vials 1", "Package/Label Display Panel NDC 0703-3311-04 Octreotide Acetate Injection 100 mcg/mL For Subcutaneous or Intravenous Use Rx only 1 mL Single-Dose Vial 25 Vials 2", "Package/Label Display Panel NDC 0703-3321-04 Octreotide Acetate Injection 500 mcg/mL For Subcutaneous or Intravenous Use Rx only 1 mL Single-Dose Vial 25 Vials 3", "Package/Label Display Panel NDC 0703-3333-01 Octreotide Acetate Injection 1000 mcg/5 mL (200 mcg/mL) For Subcutaneous or Intravenous Use STORE REFRIGERATED AT 2ºC to 8ºC (36ºF to 46ºF); PROTECT FROM LIGHT. AFTER INITIAL USE, DISCARD WITHIN 14 DAYS Rx only 5 mL Multiple-Dose Vial 4", "Package/Label Display Panel NDC 0703-3343-01 Octreotide Acetate Injection 5000 mcg/5 mL (1000 mcg/mL) For Subcutaneous or Intravenous Use STORE REFRIGERATED AT 2ºC to 8ºC (36ºF to 46ºF); PROTECT FROM LIGHT. AFTER INITIAL USE, DISCARD WITHIN 14 DAYS Rx only 5 mL Multiple-Dose Vial 5" ], "set_id": "20917b50-512f-45c9-a446-1e8a509f3687", "id": "b41326b8-8138-4e6c-b294-ae005aa697b9", "effective_time": "20230228", "version": "12", "openfda": {} }, { "spl_product_data_elements": [ "BYNFEZIA Pen octreotide acetate OCTREOTIDE ACETATE OCTREOTIDE LACTIC ACID MANNITOL PHENOL SODIUM BICARBONATE WATER" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE BYNFEZIA PEN is a s o matostatin analogue indicated: Acromegaly : To reduce blood levels of growth hormone (GH) and insulin growth factor 1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. (1 .1) Carcinoid Tumors : For the symptomatic treatment of patients with m eta static c a rcinoid t u mo rs where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. (1 .2) Vasoactive Intestinal Peptide Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors . (1 .3) Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide injection; these trials were not optimally designed to detect such effects. (1.4) 1.1 Acromegaly BYNFEZIA PEN is indicated to reduce blood levels of growth hormone (GH) and insulin gro wth factor-1 (I GF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. 1.2 Carcinoid Tumors BYNFEZIA PEN is indicated for treat ment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors BYNFEZIA PEN is indicated for the treat ment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tu mors. 1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide injection; these trials were not optimally designed to detect such effects." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • BYNFEZIA PEN is administered subcutaneously; alternate injection site periodically (2.1) • Acromegaly: Recommended initial BYNFEZIA dosage is 50 mcg three times daily during the initial 2 weeks of therapy. Maintenance dose 100 mcg to 500 mcg three times daily. (2.2) • Carcinoid Tumors: Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.3) • VIPomas: Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.4) 2.1 Dosage and Administration Overview Inspect visually for particulate matter and discoloration. Only use BYNFEZIA PEN if the solution appears colorless with no visible particles. BYNFEZIA PEN should be at room temperature before injecting to reduce potential injection site reactions. Administer BYNFEZIA PEN by subcutaneous injection into the abdomen, the front of the middle thighs, or the back/outer area of the upper arms. Rotate injection sites so that the same site is not used repeatedly. Injection sites should be at least 2 inches away from your last injection site. Provide proper training to patients and/or caregivers on the administration of BYNFEZIA PEN prior to use according to the “Instructions for Use”. 2.2 Recommended Dosage and Monitoring for Acromegaly The recommended initial dosage of BYNFEZIA PEN is 50 mcg three times daily to be administered subcutaneously . Increase BYNFEZIA dose based upon GH or IGF-1 levels. The goal is to achieve GH levels less than 5 ng/mL or IGF-I levels within normal range. Monitor GH or IGF-1 every two weeks after initiating BYNFEZIA PEN therapy or with dosage change, and to guide titration. The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. BYNFEZIA PEN should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-I levels increase and signs and symptoms recur, BYNFEZIA PEN therapy may be resumed. 2.3 Recommended Dosage and Monitoring for Carcinoid Tumors The recommended daily dosage of BYNFEZIA PEN during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in two to four divided doses given subcutaneously (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1,500 mcg/day. However, experience with doses above 750 mcg/day is limited. Measurement of urinary 5-hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy. 2.4 Recommended Dosage and Monitoring for Vasoactive Intestinal Peptide Tumors Daily dosage of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response; but usually doses above 450 mcg/day are not required. Measurement of Plas ma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS BYNFEZIA PEN is available as: Injection: 7,000 mcg/2.8 mL (2,500 mcg/mL) octreotide (as acetate) as a clear, colorless solution in a single-patient-use prefilled pen. Injection: 7,000 mcg/2.8 mL (2,500 mcg/mL) octreotide (as acetate) in a 2.8 mL single-patient-use prefilled pen (3)" ], "contraindications": [ "4 CONTRAINDICATIONS Sensitivity to this drug or any of its co mponents. Sensitivity to this drug or any of the components (4)" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Cardiac Conduction Abnormalities: Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. (5.1) • Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected. (5.2) • Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. (5.3) • Thyroid Function: Hypothyroidism may occur. Monitor thyroid levels periodically. (5.4) • Steatorrhea and Malabsorption of Dietary Fats: New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. (5.5) 5.1 Cardiac Conduction Abnormalities Cardiac conduction abnormalities have occurred during treatment with octreotide. In acromegalic patients, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during octreotide therapy [see Adverse Reactions (6)] . Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of octreotide therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge. 5.2 Cholelithiasis and Complications of Cholelithiasis BYNFEZIA PEN may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide for 12 months or longer was 52%. Less than 2% of patients treated with octreotide for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide therapy and died. If complications of cholelithiasis are suspected, discontinue BYNFEZIA PEN and treat appropriately. 5.3 Hyperglycemia and Hypoglycemia BYNFEZIA PEN alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide in 3% and 16% of acromegalic patients, respectively [ see Adverse Reactions (6)] . Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide therapy was reported in one patient with no history of hyperglycemia. Monitor glucose levels during BYNFEZIA PEN therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly. 5.4 Thyroid Function Abnormalities Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T4) is recommended during chronic therapy [see Adverse Reactions (6)] . 5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including octreotide. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving octreotide, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly. 5.6 Changes in Vitamin B12 Levels Depressed vitamin B 12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide therapy and monitoring of vitamin B 12 levels is recommended during BYNFEZIA PEN therapy." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiac Conduction Abnormalities [Warnings and Precautions (5.1)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.2)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.3)] Thyroid Function Abnormalities [see Warnings and Precautions (5.4)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.5)] Changes in Vitamin B 12 Levels [see Warnings and Precautions (5.6)] Most common adverse reactions (> 10%): (6.1) Acromegaly: Gallbladder abnormalities, sinus bradycardia, diarrhea, loose stools nausea, abdominal discomfort, hyperglycemia, and hypothyroidism. Carcinoid Tumors and VIPomas: Gallbladder abnormalities. To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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, 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. The safety of BYNFEZIA PEN has been established based on clinical studies of octreotide acetate injection. Below is a description of the adverse reactions from the clinical studies. Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide therapy [see Warnings and Precautions (5.1)] . In clinical trials (primarily patients with acromegaly or psoriasis) (BYNFEZIA PEN is not indicated for the treatment of psoriasis)], the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide for 12 months or longer was 52%. Less than 2% of patients treated with octreotide for 1 month or less developed gallstones. Cardiac In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide therapy [ see Warnings and Precautions (5.1)] . Gastrointestinal Diarrhea, loose stools, nausea, and abdominal discomfort were each seen in 34% to 61% of acromegalic patients in U.S. studies. 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5% to 10% of patients with carcinoid tumors and VIPomas. The frequency of these symptoms was not dose related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness, and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 8% and 4% required initiation of thyroid replacement therapy during octreotide therapy [see Warnings and Precautions (5.4)] . In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6%, and dizziness in 5%. Pancreatitis was also observed [see Warnings and Precautions (5.2)] . Other Adverse Events 1% to 4% Other events, each observed in 1% to 4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance, and depression. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of octreotide acetate injection. 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. Hepatobiliary: cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy Gastrointestinal: intestinal obstruction, pancreatic exocrine insufficiency Hematologic: thrombocytopenia" ], "drug_interactions": [ "7 DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with BYNFEZIA PEN : cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. (7) Lutetium Lu 177 Dotatate Injection : Discontinue BYNFEZIA PEN at least 24 hours prior to each lutetium Lu 177 dotatate dose. (7.6) 7.1 Cyclosporine Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of BYNFEZIA PEN with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when BYNFEZIA PEN treatment is initiated or when the dose is altered and anti-diabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Li mited published data indicate that so matostatin analogs might decrease the metabolic clearance of co mpounds known to be metabolized by cytochro me P450 enzy mes, which may be due to the suppression of GH. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. 7.6 Lutetium Lu 177 Dotatate Injection Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue BYNFEZIA PEN at least 24 hours prior to each lutetium Lu 177 dotatate dose." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) 8.1 Pregnancy Risk Summary The limited data with octreotide acetate in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7 and 13 times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA ( 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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7 and 13 times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02–1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA. 8.2 Lactation Risk Summary There is no information available on the presence of octreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYNFEZIA PEN, and any potential adverse effects on the breastfed child from BYNFEZIA PEN or from the underlying maternal condition. Data Following a subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at a low concentration compared to plasma (milk/plasma ratio of 0.009). 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility. 8.4 Pediatric Use Safety and efficacy of octreotide injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide injection in pediatric patients under age 6 years. In post-marketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month. 8.5 Geriatric Use Clinical studies of octreotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment In patients with severe renal failure requiring dialysis, the half-life of octreotide may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment-Cirrhotic Patients In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary The limited data with octreotide acetate in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7 and 13 times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA ( 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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7 and 13 times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02–1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA." ], "labor_and_delivery": [ "8.2 Lactation Risk Summary There is no information available on the presence of octreotide in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYNFEZIA PEN, and any potential adverse effects on the breastfed child from BYNFEZIA PEN or from the underlying maternal condition. Data Following a subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at a low concentration compared to plasma (milk/plasma ratio of 0.009)." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility." ], "pediatric_use": [ "8.4 Pediatric Use Safety and efficacy of octreotide injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide injection in pediatric patients under age 6 years. In post-marketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of octreotide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "overdosage": [ "10 OVERDOSAGE A limited number of accidental overdoses of octreotide in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss. If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222." ], "description": [ "11 DESCRIPTION BYNFEZIA PEN ( octreotide acetate) injection contains octreotide as its acetate salt. Octreotide is a somatostatin analogue. Octreotide acetate known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2→7)-disulfide; [R-(R*, R*)] acetate salt. The molecular formula of octreotide free base is C 49 H 66 N 10 O 10 S 2 and its molecular weight is 1019.3 and its structural formula as acetate salt is: BYNFEZIA PEN (octreotide acetate) injection is available as a disposable single-patient-use prefilled pen containing 7,000 mcg of octreotide (as acetate)/2.8 mL. Each milliliter of octreotide acetate injection contains 2,500 mcg octreotide (present as octreotide acetate, USP), 3.4 mg lactic acid, 22.5 mg mannitol, 5 mg phenol, and Water for Injection (q.s.). The pH of the solution is adjusted to 4.2 ± 0.3 by the addition of aqueous sodium bicarbonate solution. spl-octreotide-structure.jpg" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action BYNFEZIA PEN (octreotide acetate) exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea). 12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-I (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)] . Octreotide suppresses secretion of TSH. 12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and co mpletely from the injection site. Peak concentrations of 5.2 ng/ mL (100 mcg dose) were reached 0.4 hours after dosing. Peak concentrations and area under the curve (AUC) values were dose proportional after subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plas ma was rapid (t α1/2 = 0.2 h), the volu me of distribution (Vd ss ) was esti mated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plas ma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albu min. In patients with acromegaly, the volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The eli mination of octreotide from plas ma had an apparent half-life of 1.7 to 1.9 hours co m pared with 1 to 3 minutes with the natural hor mone. The duration of action of octreotide injection is variable but extends up to 12 hours depending upon the type of tu mor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal i mpair ment (C L CR 40 to 60 m L/ min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate i mpair ment (CL CR 10 to 39 m L/ min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal i mpairment not requiring dialysis (CL CR <10 m L/ min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. 12.6 Immunogenicity Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide injection were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients." ], "mechanism_of_action": [ "12.1 Mechanism of Action BYNFEZIA PEN (octreotide acetate) exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea)." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-I (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)] . Octreotide suppresses secretion of TSH." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and co mpletely from the injection site. Peak concentrations of 5.2 ng/ mL (100 mcg dose) were reached 0.4 hours after dosing. Peak concentrations and area under the curve (AUC) values were dose proportional after subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100 mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plas ma was rapid (t α1/2 = 0.2 h), the volu me of distribution (Vd ss ) was esti mated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plas ma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albu min. In patients with acromegaly, the volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The eli mination of octreotide from plas ma had an apparent half-life of 1.7 to 1.9 hours co m pared with 1 to 3 minutes with the natural hor mone. The duration of action of octreotide injection is variable but extends up to 12 hours depending upon the type of tu mor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal i mpair ment (C L CR 40 to 60 m L/ min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate i mpair ment (CL CR 10 to 39 m L/ min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal i mpairment not requiring dialysis (CL CR <10 m L/ min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7 times the human exposure based on BSA." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7 times the human exposure based on BSA." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied BYNFEZIA PEN ( octreotide acetate) injection, 7,000 mcg/2.8 mL (2,500 mcg /mL) octreotide is a clear colorless solution and it is available as: Dosage Unit Package Size NDC # 2.8 mL single -patient-use prefilled pen Carton of 1 NDC 62756-452-36 2.8 mL single -patient-use prefilled pen Carton of 2 NDC 62756-452-37 Dispense in the original sealed carton with the enclosed Instructions for Use. Storage and Handling Before first use, store BYNFEZIA PEN in the refrigerator between 2°C to 8°C (36°F to 46°F) and store in outer carton in order to protect from light. After first use, store pens at controlled room temperature between 20°C to 25°C (68°F to 77°F). Excursions between 15°C (59°F) and 30°C (86°F) are allowed for up to 28 days. Discard the pen 28 days after first use. Do not freeze." ], "how_supplied_table": [ "
Dosage Unit Package Size NDC #
2.8 mL single -patient-use prefilled pen Carton of 1 NDC 62756-452-36
2.8 mL single -patient-use prefilled pen Carton of 2 NDC 62756-452-37
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise patient and/or caregivers to read the FDA-approved patient labeling (Instructions for Use). Sterile Subcutaneous Injection Technique Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer BYNFEZIA PEN. Cholelithiasis and Complications of Cholelithiasis Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of cholelithiasis (e.g., cholecystitis, cholangitis, and pancreatitis) [see Warnings and Precautions (5.2)]. Steatorrhea and Malabsorption of Dietary Fats Advise patients to contact their healthcare provider if they experience new or worsening of steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss [see Warnings and Precautions (5.5)]. Pregnancy Inform female patients that treatment with BYNFEZIA PEN may result in unintended pregnancy [see Use in Specific Populations (8.3)]. All trademarks are the property of their respective owners. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd., India At M/s. OneSource Specialty Pharma Limited Plot No. 2-D1, Obadenahalli, Doddaballapura, 3rd Phase, Industrial Area, Doddaballapura Taluk, Bengaluru Rural, 561203, Karnataka INDIA" ], "spl_unclassified_section": [ "INSTRUCTIONS FOR USE BYNFEZIA PEN ® (ben-FEZ-ee-uh PEN) (octreotide acetate) Prefilled Pen Read these instructions before you start using the BYNFEZIA PEN. It is important that you understand and follow these instructions to use the pen correctly. BYNFEZIA PEN is a prefilled pen that you or your caregiver can use to give more than 1 dose of medicine. Ask your healthcare provider about your dose of BYNFEZIA PEN and how to inject BYNFEZIA PEN the right way before you inject it for the first time. If your healthcare provider decides that you or your caregiver can give your BYNFEZIA PEN at home, you or your caregiver should receive training on how to use the pen. Contact your healthcare provider if you or your caregiver have any questions. Important • Do not use a pen for more than 28 days after first use. After 28 days throw away (dispose of) the pen, even if the pen still has medicine in it. • Do not place the pen in water or any other liquid. • Keep your pen and needles out of the reach of children. • Do not use if any part of your pen appears broken or damaged. • If you drop your pen, prime it before you use it again to make sure the pen still works correctly (see step 3. Prime Your Pen ). • Do not take BYNFEZIA PEN solution out of the pen and put it into a syringe. • Do not share your pen or needles with another person. You may give an infection to them or get an infection from them. • Do not remove the outer needle cover or inner needle cover until you are ready to inject. • Do not press the injection button unless a needle is attached to the pen. How should I store my BYNFEZIA PEN ? Before First Use: • Store new unused pens in the refrigerator between 36°F to 46°F (2°C to 8°C) and store in the outer carton in order to protect from light. • Do not freeze. Throw away (dispose of) the pen if it has been frozen. • Do not store the pen in direct sunlight. After First Use or During Use: • Store the pen at room temperature between 68°F to 77°F (20°C to 25°C) for up to 28 days. • Store the pen with the pen cap on. • Throw away (dispose of) the pen 28 days after first use in a sharps container, even if the pen still has medicine in it (see step 6. Additional Disposal Information ). • Do not store a pen with a needle attached. How do I give a dose larger than 200 mcg (more than 1 injection)? 1. Turn the dose set knob to 200 mcg (highest dose setting) and give the first injection. Choose a different injection site for each injection at least 2 inches from the area you used for your last injection. 2. Calculate the remaining dose by subtracting 200 mcg from the prescribed dose. 3. Turn the dose set knob to the line for your remaining dose up to the highest dose setting of 200 mcg. Give the second injection at least 2 inches away from the first injection. 4. You may need more injections to give your total prescribed dose (see examples below). See the following examples to give a total dose larger than 200 mcg: Example Dose Steps to give a total dose larger than 200 mcg Number of injections needed to give the total dose For example, if your total dose is 300 mcg Turn the dose set knob to 200 mcg for your first injection. Your remaining dose is 100 mcg. For the second injection, turn your dose set knob to 100 mcg to give the remaining dose. 2 For example, if your total dose is 450 mcg Turn the dose set knob to 200 mcg for your first injection. Your remaining dose is 250 mcg. Turn the dose set knob to 200 mcg for your second injection. Your remaining dose is 50 mcg. For the third injection, turn your dose set knob to 50 mcg to give the remaining dose. 3 1. Check the Pen A. Wash your hands with soap and water (Figure A). B. Check the expiration (EXP) date (Figure B). Check the pen label to make sure the expiration date has not passed. Do not use if the expiration date has passed. C. Pull the pen cap straight o­ff the pen (Figure C). D. Check the medicine (Figure D). The medicine should be clear and colorless. You may see small air bubbles in the pen, which is normal and will not affect the dose. Do not use if the medicine looks cloudy, colored, or has lumps or particles in it. The pen cartridge may look empty because the medicine is clear and colorless. Make sure you have enough medicine left in the pen to inject the full dose. When the plunger moves pass the thick line, your pen is almost empty (Figure E). If the dose set knob does not let you dial your prescribed dose, this means there is not enough medicine left in your pen. Throw away (dispose of) the pen and use a new pen for the injection. E. Allow the pen to reach room temperature. If the pen was not stored at room temperature between 68°F to 77°F (20°C to 25°C), allow it to reach room temperature for 20 to 30 minutes before injecting. This will reduce the chance of getting a reaction at the injection site. Do not try to warm the pen by using a heat source such as hot water or microwave. See the section \"How should I store my BYNFEZIA PEN ?\" for more information. 2. Attach a Needle A. Gather the following additional supplies (Figure F): 2 alcohol swabs new pen needle sharps container cotton ball Note: These supplies are not included with the pen. B. Wipe the rubber seal on the pen with an alcohol swab (Figure G). C. Attach a new needle. Use only 31 gauge, 5 mm length disposable pen needles. If you have questions about which needle to use, ask your healthcare provider. Peel off­ the paper tab from the needle (Figure H). Push the needle with cap straight down onto the pen and screw it on to the pen by turning to the right (clockwise) until the needle feels secure (Figure I). Do not overtighten the needle. This will make it hard to remove after the injection. D. Remove the outer needle cover and set it aside (Figure J). Save the outer needle cover for use when you remove the needle in step 6. E. Remove the inner needle cover and throw it away (Figure K). Are you using a new pen? If Yes, complete step 3. If No, skip step 3 and go to step 4. 3. Prime Your Pen Note: The following steps are only needed if you are using a new pen for the first time or if you drop the pen. To prime the pen, follow the steps below to dial the pen to 100 mcg and press the injection button until a stream of medicine comes from the needle tip. If you have already primed the pen, go to step 4 to prepare and give the injection. Do not prime the pen before each dose. This will waste medicine. A. Turn the dose set knob to dial the pen to 100 mcg (Figure L). B. Hold the pen with the needle pointing up. C. Press the injection button all the way in until it stops and the dose display window returns to “0” (Figure M). D. A stream of medicine should be seen coming from the needle tip (Figure N). If you do not see a stream of medicine coming from the needle tip , repeat the priming steps. If you still do not see a stream of medicine coming from the needle tip after you repeat the priming steps 3 times, the pen may be damaged. Throw away (dispose of) the pen and use a new pen. Call Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or your healthcare provider for help or to get a new pen. 4. Prepare the Injection A. Choose an injection site (see Figure O) for injection under the skin (subcutaneous). When giving yourself the injection: Inject into the stomach at least 2 inches away from the belly button (navel) or inject into the front of the middle thighs (Figure O). When giving someone else the injection: you may also inject into the back outer area of the upper arms (Figure O). Always change (rotate) the injection site with each injection. Your injection site should be at least 2 inches away from your last injection site. Do not inject into moles, scars, birthmarks, or areas where the skin is tender, bruised, red, or hard. B. Clean your injection site with an alcohol swab (Figure P). Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose. C. Dial your dose (Figure Q). Turn the dose set knob until you see the prescribed dose in the dose display window. The dose number and black line should line up with the pointer. The pen can be used to deliver 50 mcg, 100 mcg, 150 mcg and 200 mcg doses. If your prescribed dose is more than 200 mcg, see the section “How should I give a dose larger than 200 mcg (more than 1 injection)?” in these instructions. It is normal to hear a “clicking” sound as you turn the dose set knob. If you accidentally dial past the prescribed dose, turn the dose set knob back down to the correct dose. Note: The pen cannot be dialed past the number of micrograms (mcgs) of medicine left in the pen. If the pen does not have enough medicine to give the full dose, throw away (dispose of) the pen and use a new one. 5. Give the Injection A. Insert the needle straight into the injection site (Figure R). B. Deliver your dose. Deliver your dose by slowly pressing the injection button all the way down until it stops. The number in the dose display window will go back to “0” when the injection is complete (Figure S). C. Continue to hold the injection button down and slowly count to 10 to make sure the full dose of medicine is given (Figure T). D. Remove the pen from the injection site. Lift the pen straight up from the injection site (Figure U). If you see 1 or 2 drops of medicine on the needle tip, this is normal and will not a­ffect your dose. If you see more than 2 drops of medicine on the needle tip, or you see liquid around the injection site after your injection, you may not have received your full dose. If this happens: Do not inject another dose. Contact your healthcare provider for help. Next time you inject, make sure to keep the pen needle in your skin and continue to hold the injection button down while slowly counting to 10 (see Figure T). Note: As the pen is used, a plunger will appear in the cartridge and move towards the thick line. 6. After the Injection A. Carefully place the outer needle cover back onto the needle. Place the outer needle cover on a flat surface. Hold the syringe with the needle attached in 1 hand and carefully slip the needle into the outer needle cover without using the other hand. Push the outer needle cover completely on (Figure V). Do not recap with the inner needle cover. B. Unscrew and remove the covered needle (Figure W). Squeeze the lower part of the covered needle while turning it to the left (counter clockwise). Keep turning until the covered needle lifts away from the pen. It may take several turns for the covered needle to lift away from the pen. C. Throw away (dispose of) the covered needle in a FDA-cleared sharps container (Figure X). D. Put the pen cap back on the pen (Figure Y) and store the pen. After use, store pens with the cap on at room temperature between 68°F to 77°F (20°C to 25°C) or in the refrigerator between 36°F to 46°F (2°C to 8°C) for up to 28 days. See the section \"How should I store my BYNFEZIA PEN ?\" for more information on storing your pen. E. Treat the injection site. If needed, press the injection site lightly with a cotton ball or an alcohol swab. Do not rub the area. Cleaning the Pen Wipe the outside of the pen with a clean, damp cloth. White particles may appear on the outside tip of the cartridge during normal use. You may remove them with an alcohol swab. Do not put the pen in water or any other liquid. Additional Disposal Information Put used pens and needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) pens and needles in the household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. Always keep the sharps disposal container out of the reach of children and pets. This Instructions for Use has been approved by the U.S. Food and Drug Administration. All trademarks are the property of their respective owners. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Ltd., India At M/s. OneSource Specialty Pharma Limited Plot No. 2-D1, Obadenahalli, Doddaballapura, 3rd Phase, Industrial Area, Doddaballapura Taluk, Bengaluru Rural, 561203, Karnataka INDIA For more information, call 1-800-818-4555. Issued: 10/2024 spl-octreotide-figure1 spl-octreotide-figure2 spl-octreotide-figure3 spl-octreotide-figure4 spl-octreotide-figure5 spl-octreotide-figure6 spl-octreotide-figure7 spl-octreotide-figure8 spl-octreotide-figure9 spl-octreotide-figure10 spl-octreotide-figure11 spl-octreotide-figure12 spl-octreotide-figure13 spl-octreotide-figure14 spl-octreotide-figure15 spl-octreotide-figure16 spl-octreotide-figure17 spl-octreotide-figure18 spl-octreotide-figure19 spl-octreotide-figure20 spl-octreotide-figure21 spl-octreotide-figure22 spl-octreotide-figure23 spl-octreotide-figure24 spl-octreotide-figure25 spl-octreotide-figure26" ], "spl_unclassified_section_table": [ "
Important
• Do not use a pen for more than 28 days after first use. After 28 days throw away (dispose of) the pen, even if the pen still has medicine in it. • Do not place the pen in water or any other liquid. • Keep your pen and needles out of the reach of children. • Do not use if any part of your pen appears broken or damaged. • If you drop your pen, prime it before you use it again to make sure the pen still works correctly (see step 3. Prime Your Pen). • Do not take BYNFEZIA PEN solution out of the pen and put it into a syringe. • Do not share your pen or needles with another person. You may give an infection to them or get an infection from them. • Do not remove the outer needle cover or inner needle cover until you are ready to inject. • Do not press the injection button unless a needle is attached to the pen.
How should I store my BYNFEZIA PEN?
Before First Use: • Store new unused pens in the refrigerator between 36°F to 46°F (2°C to 8°C) and store in the outer carton in order to protect from light. • Do not freeze. Throw away (dispose of) the pen if it has been frozen. • Do not store the pen in direct sunlight. After First Use or During Use: • Store the pen at room temperature between 68°F to 77°F (20°C to 25°C) for up to 28 days. • Store the pen with the pen cap on. • Throw away (dispose of) the pen 28 days after first use in a sharps container, even if the pen still has medicine in it (see step 6. Additional Disposal Information). • Do not store a pen with a needle attached.
How do I give a dose larger than 200 mcg (more than 1 injection)?
1. Turn the dose set knob to 200 mcg (highest dose setting) and give the first injection. Choose a different injection site for each injection at least 2 inches from the area you used for your last injection. 2. Calculate the remaining dose by subtracting 200 mcg from the prescribed dose. 3. Turn the dose set knob to the line for your remaining dose up to the highest dose setting of 200 mcg. Give the second injection at least 2 inches away from the first injection. 4. You may need more injections to give your total prescribed dose (see examples below). See the following examples to give a total dose larger than 200 mcg:
Example DoseSteps to give a total dose larger than 200 mcgNumber of injections needed to give the total dose
For example, if your total dose is 300 mcg Turn the dose set knob to 200 mcg for your first injection.Your remaining dose is 100 mcg.For the second injection, turn your dose set knob to 100 mcg to give the remaining dose. 2
For example, if your total dose is 450 mcg Turn the dose set knob to 200 mcg for your first injection.Your remaining dose is 250 mcg.Turn the dose set knob to 200 mcg for your second injection.Your remaining dose is 50 mcg.For the third injection, turn your dose set knob to 50 mcg to give the remaining dose. 3
1. Check the Pen
A. Wash your hands with soap and water (Figure A).
B. Check the expiration (EXP) date (Figure B). Check the pen label to make sure the expiration date has not passed. Do not use if the expiration date has passed.
C. Pull the pen cap straight o­ff the pen (Figure C).
D. Check the medicine (Figure D). The medicine should be clear and colorless. You may see small air bubbles in the pen, which is normal and will not affect the dose. Do not use if the medicine looks cloudy, colored, or has lumps or particles in it. The pen cartridge may look empty because the medicine is clear and colorless. Make sure you have enough medicine left in the pen to inject the full dose. When the plunger moves pass the thick line, your pen is almost empty (Figure E). If the dose set knob does not let you dial your prescribed dose, this means there is not enough medicine left in your pen. Throw away (dispose of) the pen and use a new pen for the injection.
E. Allow the pen to reach room temperature. If the pen was not stored at room temperature between 68°F to 77°F (20°C to 25°C), allow it to reach room temperature for 20 to 30 minutes before injecting. This will reduce the chance of getting a reaction at the injection site.Do not try to warm the pen by using a heat source such as hot water or microwave. See the section "How should I store my BYNFEZIA PEN ?" for more information.
2. Attach a Needle
A. Gather the following additional supplies (Figure F): 2 alcohol swabsnew pen needlesharps containercotton ballNote: These supplies are not included with the pen.
B. Wipe the rubber seal on the pen with an alcohol swab (Figure G).
C. Attach a new needle. Use only 31 gauge, 5 mm length disposable pen needles. If you have questions about which needle to use, ask your healthcare provider.Peel off­ the paper tab from the needle (Figure H).Push the needle with cap straight down onto the pen and screw it on to the pen by turning to the right (clockwise) until the needle feels secure (Figure I).Do not overtighten the needle. This will make it hard to remove after the injection.
D. Remove the outer needle cover and set it aside (Figure J). Save the outer needle cover for use when you remove the needle in step 6.
E. Remove the inner needle cover and throw it away (Figure K).
Are you using a new pen? If Yes, complete step 3.If No, skip step 3 and go to step 4.
3. Prime Your Pen
Note: The following steps are only needed if you are using a new pen for the first time or if you drop the pen. To prime the pen, follow the steps below to dial the pen to 100 mcg and press the injection button until a stream of medicine comes from the needle tip. If you have already primed the pen, go to step 4 to prepare and give the injection.Do not prime the pen before each dose. This will waste medicine.
A. Turn the dose set knob to dial the pen to 100 mcg (Figure L).
B. Hold the pen with the needle pointing up.
C. Press the injection button all the way in until it stops and the dose display window returns to “0” (Figure M).
D. A stream of medicine should be seen coming from the needle tip (Figure N). If you do not see a stream of medicine coming from the needle tip, repeat the priming steps. If you still do not see a stream of medicine coming from the needle tip after you repeat the priming steps 3 times, the pen may be damaged. Throw away (dispose of) the pen and use a new pen. Call Sun Pharmaceutical Industries, Inc. at 1-800-818-4555or your healthcare provider for help or to get a new pen.
4. Prepare the Injection
A. Choose an injection site (see Figure O) for injection under the skin (subcutaneous). When giving yourself the injection: Inject into the stomach at least 2 inches away from the belly button (navel) or inject into the front of the middle thighs (Figure O).When giving someone else the injection: you may also inject into the back outer area of the upper arms (Figure O).Always change (rotate) the injection site with each injection. Your injection site should be at least 2 inches away from your last injection site.Do not inject into moles, scars, birthmarks, or areas where the skin is tender, bruised, red, or hard.
B. Clean your injection site with an alcohol swab (Figure P). Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.
C. Dial your dose (Figure Q). Turn the dose set knob until you see the prescribed dose in the dose display window. The dose number and black line should line up with the pointer. The pen can be used to deliver 50 mcg, 100 mcg, 150 mcg and 200 mcg doses. If your prescribed dose is more than 200 mcg, see the section “How should I give a dose larger than 200 mcg (more than 1 injection)?” in these instructions. It is normal to hear a “clicking” sound as you turn the dose set knob.If you accidentally dial past the prescribed dose, turn the dose set knob back down to the correct dose.
Note: The pen cannot be dialed past the number of micrograms (mcgs) of medicine left in the pen. If the pen does not have enough medicine to give the full dose, throw away (dispose of) the pen and use a new one.
5. Give the Injection
A. Insert the needle straight into the injection site (Figure R).
B. Deliver your dose. Deliver your dose by slowly pressing the injection button all the way down until it stops. The number in the dose display window will go back to “0” when the injection is complete (Figure S).
C. Continue to hold the injection button down and slowly count to 10 to make sure the full dose of medicine is given (Figure T).
D. Remove the pen from the injection site. Lift the pen straight up from the injection site (Figure U).If you see 1 or 2 drops of medicine on the needle tip, this is normal and will not a­ffect your dose.If you see more than 2 drops of medicine on the needle tip, or you see liquid around the injection site after your injection, you may not have received your full dose.If this happens: Do not inject another dose. Contact your healthcare provider for help. Next time you inject, make sure to keep the pen needle in your skin and continue to hold the injection button down while slowly counting to 10 (see Figure T). Note: As the pen is used, a plunger will appear in the cartridge and move towards the thick line.
6. After the Injection
A. Carefully place the outer needle cover back onto the needle. Place the outer needle cover on a flat surface. Hold the syringe with the needle attached in 1 hand and carefully slip the needle into the outer needle cover without using the other hand. Push the outer needle cover completely on (Figure V).Do not recap with the inner needle cover.
B. Unscrew and remove the covered needle (Figure W). Squeeze the lower part of the covered needle while turning it to the left (counter clockwise).Keep turning until the covered needle lifts away from the pen. It may take several turns for the covered needle to lift away from the pen.
C. Throw away (dispose of) the covered needle in a FDA-cleared sharps container (Figure X).
D. Put the pen cap back on the pen (Figure Y) and store the pen. After use, store pens with the cap on at room temperature between 68°F to 77°F (20°C to 25°C) or in the refrigerator between 36°F to 46°F (2°C to 8°C) for up to 28 days.See the section "How should I store my BYNFEZIA PEN?" for more information on storing your pen.
E. Treat the injection site. If needed, press the injection site lightly with a cotton ball or an alcohol swab. Do not rub the area.
Cleaning the Pen
Wipe the outside of the pen with a clean, damp cloth.White particles may appear on the outside tip of the cartridge during normal use. You may remove them with an alcohol swab.Do not put the pen in water or any other liquid.
Additional Disposal Information
Put used pens and needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) pens and needles in the household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic,can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this.Do not recycle your used sharps disposal container.Always keep the sharps disposal container out of the reach of children and pets.
" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Rx only NDC 62756-452-37 Bynfezia Pen ® (octreotide acetate Injection) 7,000 mcg/2.8mL (2,500 mcg/mL) Two 2.8 mL disposable single-patient-use prefilled pens Subcutaneous use only For doses of 50 mcg, 100 mcg, 150 mcg, and 200 mcg of octreotide per injection. For Single Patient Use Only Dispense in this sealed carton SUN PHARMA spl-octreotide-carton.jpg" ], "set_id": "20ed4e79-ad4c-426f-859d-83790c00439b", "id": "ee3c8bae-88f0-4b76-80af-98a3e3312585", "effective_time": "20250221", "version": "5", "openfda": { "application_number": [ "NDA213224" ], "brand_name": [ "BYNFEZIA Pen" ], "generic_name": [ "OCTREOTIDE ACETATE" ], "manufacturer_name": [ "Sun Pharmaceutical Industries, Inc." ], "product_ndc": [ "62756-452" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "SUBCUTANEOUS" ], "substance_name": [ "OCTREOTIDE ACETATE" ], "rxcui": [ "2360543", "2360548" ], "spl_id": [ "ee3c8bae-88f0-4b76-80af-98a3e3312585" ], "spl_set_id": [ "20ed4e79-ad4c-426f-859d-83790c00439b" ], "package_ndc": [ "62756-452-37", "62756-452-36" ], "is_original_packager": [ true ], "unii": [ "75R0U2568I" ] } }, { "spl_product_data_elements": [ "SOMAVERT pegvisomant SOMAVERT pegvisomant PEGVISOMANT PEGVISOMANT GLYCINE MANNITOL SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE STERILE WATER Water WATER SOMAVERT pegvisomant SOMAVERT pegvisomant PEGVISOMANT PEGVISOMANT GLYCINE MANNITOL SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE STERILE WATER Water WATER SOMAVERT pegvisomant SOMAVERT pegvisomant PEGVISOMANT PEGVISOMANT GLYCINE MANNITOL SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE STERILE WATER Water WATER SOMAVERT pegvisomant SOMAVERT pegvisomant PEGVISOMANT PEGVISOMANT GLYCINE MANNITOL SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE STERILE WATER Water WATER SOMAVERT pegvisomant SOMAVERT pegvisomant PEGVISOMANT PEGVISOMANT GLYCINE MANNITOL SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE STERILE WATER Water WATER" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE SOMAVERT is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1) levels. SOMAVERT is a growth hormone receptor antagonist indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1) levels. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • Administer a 40 mg loading dose subcutaneously under physician supervision ( 2.1 ) • After proper injection instruction, on day after loading dose, patients or caregivers begin daily subcutaneous injections of 10 mg ( 2.1 ) • Adjust dosage in 5 mg increments or decrements until serum IGF-1 concentrations are maintained within age-adjusted normal range. Do not adjust dosage based on growth hormone (GH) levels or signs or symptoms of acromegaly ( 2.1 ) • Dosage range is 10 mg to 30 mg once daily ( 2.1 ) • Perform liver tests prior to first dosage and if greater than 3 times upper limit of normal should work-up prior to SOMAVERT administration ( 2.2 ) • Follow reconstitution and injection procedures ( 2.3 , 2.4 ) 2.1 Dosage Information The recommended loading dose of SOMAVERT is 40 mg given subcutaneously, under healthcare provider supervision. Provide proper training in subcutaneous injection technique to patients or their caregivers so they can receive once daily subcutaneous injections. On the next day following the loading dose, instruct patients or their caregivers to begin daily subcutaneous injections of 10 mg of SOMAVERT. Titrate the dosage to normalize serum IGF-1 concentrations (serum IGF-1 concentrations should be measured every four to six weeks). The dosage should not be based on growth hormone (GH) concentrations or signs and symptoms of acromegaly. It is unknown whether patients who remain symptomatic while achieving normalized IGF-1 concentrations would benefit from increased SOMAVERT dosage. • Increase the dosage by 5 mg increments every 4–6 weeks if IGF-1 concentrations are elevated. • Decrease the dosage by 5 mg decrements every 4–6 weeks if IGF-1 concentrations are below the normal range. • IGF-1 levels should also be monitored when a SOMAVERT dose given in multiple injections is converted to a single daily injection [see Clinical Pharmacology (12) ] . The recommended dosage range is between 10 mg to 30 mg given subcutaneously once daily and the maximum daily dosage is 30 mg given subcutaneously once daily. 2.2 Assess Liver Tests Prior to Initiation of SOMAVERT Prior to the start of SOMAVERT, patients should have an assessment of baseline levels of liver tests [serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP)]. For recommendations regarding initiation of SOMAVERT based on baseline liver tests and recommendations for monitoring of liver tests while on SOMAVERT, refer to Table 1 in Warning and Precautions (5.2) . 2.3 Loading Dose Injection Procedure The following instructions are for the healthcare provider to reconstitute and prepare the 40 mg loading dose. The healthcare provider will need to reconstitute 1 vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant with supplied diluent (two vials of lyophilized powder and two vials of diluent will be needed for the 40 mg loading dose). The healthcare provider will also need to inject the reconstituted SOMAVERT solution twice into the patient's upper arm, upper thigh, abdomen, or buttocks (each injection in a different area). a) Before administering the loading dose, remove the first package (1 vial of lyophilized powder of SOMAVERT containing 20 mg of pegvisomant and 1 vial containing the diluent) from the refrigerator about 10 minutes prior to the planned injection time. b) Withdraw 1 mL of the supplied diluent (Sterile Water for Injection) and inject slowly onto the sides of the vial containing lyophilized powder of SOMAVERT. Do not inject the diluent directly on the powder. c) Do not invert the vial or shake the solution as this may cause denaturation of the pegvisomant protein. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If foaming of the reconstituted SOMAVERT solution is seen, the solution is likely damaged and therefore inappropriate to inject. d) Visually inspect the reconstituted SOMAVERT solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear. If the solution is cloudy, do not use it. Once reconstituted, the solution will contain 20 mg of pegvisomant in 1 mL of solution. e) Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered within 6 hours of reconstitution. f) Inject the first reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle. g) Repeat steps (a) to (e) to reconstitute the second SOMAVERT dose of 20mg. h) Finally, inject the second reconstituted SOMAVERT solution (20 mg/mL) subcutaneously into the patient's upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle (different area than the first injection). 2.4 Maintenance Dose Injection Procedure For patient or caregiver instructions for reconstitution and administration of daily doses (10 mg to 30 mg), see the Patient's Instructions for Use . a) Before administering the dose, remove one package (1 vial of lyophilized powder of SOMAVERT containing 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant and 1 vial containing the diluent) from the refrigerator about 10 minutes prior to the planned injection time. b) Withdraw 1 mL of the supplied 5 mL diluent (Sterile Water for Injection) and inject slowly onto the sides of the vial containing lyophilized powder of SOMAVERT. Do not inject the diluent directly on the powder. c) Do not invert the vial or shake the solution as this may cause denaturation of the pegvisomant protein. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. If foaming of the reconstituted SOMAVERT solution is seen, the solution is likely damaged and therefore inappropriate to inject. d) Visually inspect the reconstituted SOMAVERT solution for particulate matter and discoloration prior to administration. The reconstituted solution should be clear. If the solution is cloudy, do not use it. Once reconstituted, the solution will contain 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant in 1 mL of solution. e) Withdraw the 1 mL reconstituted SOMAVERT solution. The solution must be administered within 6 hours of reconstitution. f) Inject the reconstituted SOMAVERT solution subcutaneously into the upper arm, upper thigh, abdomen, or buttocks using a 90-degree angle." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS For injection: 10 mg, 15 mg, 20 mg, 25 mg or 30 mg white lyophilized powder in a single-dose vial for reconstitution, each supplied with Sterile Water for Injection, USP in a separate glass vial to be used as diluent. For injection: 10 mg, 15 mg, 20 mg, 25 mg or 30 mg lyophilized powder in a single-dose vial for reconstitution supplied with a single-dose vial containing diluent (Sterile Water for Injection, USP) ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS None. None ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Hypoglycemia : Monitor blood glucose in patients with diabetes mellitus and reduce anti-diabetic drug therapy as necessary ( 5.1 ) • Liver Toxicity: Should have more frequent liver tests and/or discontinue SOMAVERT ( 5.2 ) • Systemic Hypersensitivity : Monitor closely when re-initiating SOMAVERT in patients with systemic hypersensitivity ( 5.5 ) 5.1 Hypoglycemia Associated With GH Lowering in Patients With Diabetes Mellitus GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus. 5.2 Liver Toxicity Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs). Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in <2% of subjects among two open-label trials (with a total of 147 patients). These reports were not associated with an increase in bilirubin. Transaminase elevations normalized with time, most often after suspending treatment. Postmarketing reports have identified elevations in serum hepatic transaminases up to greater than 20 times ULN associated with elevation in total bilirubin greater than 2 times ULN. In many of these cases, discontinuation of SOMAVERT therapy resulted in improvement or resolution of hepatic laboratory abnormalities. SOMAVERT should be used in accordance with the information presented in Table 2 with respect to liver test abnormalities while on SOMAVERT treatment. Table 1. Recommendations of Initiating SOMAVERT Based on Baseline LTs and Periodic Monitoring of LTs During SOMAVERT Treatment Baseline LT Levels Recommendations Normal • May treat with SOMAVERT. • Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months and then bi-annually for the next year. Elevated, but less than or equal to 3 times ULN May treat with SOMAVERT; however, monitor LTs monthly for at least one year after initiation of therapy and then bi-annually for the next year. Greater than 3 times ULN • Do not treat with SOMAVERT until a comprehensive workup establishes the cause of the patient's liver dysfunction. • Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs. • Based on the workup, consider initiation of therapy with SOMAVERT. • If the decision is to treat, LTs and clinical symptoms should be monitored very closely. If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT, the following patient management is recommended (Table 2). Table 2. Clinical Recommendations Based on Liver Test Results While on SOMAVERT LT Levels and Clinical Signs/Symptoms Recommendations Greater than or equal to 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL) • May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below). • Perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present. At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury) • Discontinue SOMAVERT immediately. • Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal. • If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious re-initiation of therapy with SOMAVERT, with frequent LT monitoring. Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability) • Immediately perform a comprehensive hepatic workup. • If liver injury is confirmed, SOMAVERT should be discontinued. 5.3 Cross-Reactivity With GH Assays SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated. 5.4 Lipohypertrophy There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection). 5.5 Systemic Hypersensitivity In patients with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating SOMAVERT therapy [see Adverse Reactions (6.2) ] ." ], "warnings_and_cautions_table": [ "May treat with SOMAVERT.Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months and then bi-annually for the next year.Do not treat with SOMAVERT until a comprehensive workup establishes the cause of the patient's liver dysfunction.Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs.Based on the workup, consider initiation of therapy with SOMAVERT.If the decision is to treat, LTs and clinical symptoms should be monitored very closely.
Table 1. Recommendations of Initiating SOMAVERT Based on Baseline LTs and Periodic Monitoring of LTs During SOMAVERT Treatment
Baseline LT LevelsRecommendations
Normal
••
Elevated, but less than or equal to 3 times ULNMay treat with SOMAVERT; however, monitor LTs monthly for at least one year after initiation of therapy and then bi-annually for the next year.
Greater than 3 times ULN
••••
", "May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below).Perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.Discontinue SOMAVERT immediately.Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal.If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious re-initiation of therapy with SOMAVERT, with frequent LT monitoring.Immediately perform a comprehensive hepatic workup.If liver injury is confirmed, SOMAVERT should be discontinued.
Table 2. Clinical Recommendations Based on Liver Test Results While on SOMAVERT
LT Levels and Clinical Signs/SymptomsRecommendations
Greater than or equal to 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL)
••
At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)
•••
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability)
••
" ], "adverse_reactions": [ "6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other section of the labeling include: • Hypoglycemia Associated with GH Lowering in Patients with Diabetes Mellitus [see Warnings and Precautions (5.1) ] • Liver Toxicity [see Warnings and Precautions (5.2) ] • Cross-Reactivity with GH Assays [see Warnings and Precautions (5.3) ] • Lipohypertrophy [see Warnings and Precautions (5.4) ] • Systemic Hypersensitivity [see Warnings and Precautions (5.5) ] Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two patients (0.8%) exposed to SOMAVERT in pre-approval clinical studies. One patient was rechallenged with SOMAVERT, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug. Elevations in ALT and AST levels were not associated with increased levels of TBIL and ALP, with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of SOMAVERT administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors. Most common reported adverse reactions (>6%) are infection, pain, nausea, diarrhea, abnormal liver tests, flu syndrome, injection site reaction ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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, 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 a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily [see Clinical Studies (14) ] . A total of 108 subjects (30 placebo, 78 SOMAVERT) completed 12 weeks of study treatment. Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. Table 3. Adverse Reactions in a 12-week Placebo-Controlled Study in Patients with Acromegaly Table includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo. Placebo n=32 SOMAVERT 10 mg/day n=26 15 mg/day n=26 20 mg/day N=28 Infection The 6 events coded as \"infection\" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1). The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1). 2 (6%) 6 (23%) 0 0 Pain 2 (6%) 2 (8%) 1 (4%) 4 (14%) Nausea 1 (3%) 0 2 (8%) 4 (14%) Diarrhea 1 (3%) 1 (4%) 0 4 (14%) Abnormal liver function tests 1 (3%) 3 (12%) 1 (4%) 1 (4%) Flu syndrome 0 1 (4%) 3 (12%) 2 (7%) Injection site reaction 0 2 (8%) 1 (4%) 3 (11%) Dizziness 2 (6%) 2 (8%) 1 (4%) 1 (4%) Accidental injury 1 (3%) 2 (8%) 1 (4%) 0 Back pain 1 (3%) 2 (8%) 0 1 (4%) Sinusitis 1 (3%) 2 (8%) 0 1 (4%) Chest pain 0 1 (4%) 2 (8%) 0 Peripheral edema 0 2 (8%) 0 1 (4%) Hypertension 0 0 2 (8%) 0 Paresthesia 2 (6%) 0 0 2 (7%) 6.2 Postmarketing Experience Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of SOMAVERT. 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. Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use. Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge [see Warnings and Precautions (5.5) ] . Adverse Reactions from an Observational Study ACROSTUDY was an international observational registry that captured long term safety data in 2221 patients with acromegaly treated with SOMAVERT for a mean treatment duration of 8.5 years. Patients could also receive other therapy for acromegaly during the registry period. Treatment dose and schedule were at the discretion of each treating healthcare provider. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. Of the 1327 patients who had a normal AST and ALT at baseline, 20 (1.5%) patients had elevated tests >3-5 times ULN, and 22 (1.7%) patients had elevated tests >5 times ULN. Lipohypertrophy was reported in 35 (1.6%) patients. Of the 1795 patients who had a MRI reported at baseline and at least once during follow up in the study, MRI results showed that 128 (7.1%) were reported to have an increase, 310 (17.3%) were reported to have a decrease, 81 (4.5%) had both increase and decrease, and 1276 (71.1%) had no change." ], "adverse_reactions_table": [ "
Table 3. Adverse Reactions in a 12-week Placebo-Controlled Study in Patients with AcromegalyTable includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo.
Placebo n=32SOMAVERT
10 mg/day n=2615 mg/day n=2620 mg/day N=28
InfectionThe 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1). The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1).2 (6%)6 (23%)00
Pain2 (6%)2 (8%)1 (4%)4 (14%)
Nausea1 (3%)02 (8%)4 (14%)
Diarrhea1 (3%)1 (4%)04 (14%)
Abnormal liver function tests1 (3%)3 (12%)1 (4%)1 (4%)
Flu syndrome01 (4%)3 (12%)2 (7%)
Injection site reaction02 (8%)1 (4%)3 (11%)
Dizziness2 (6%)2 (8%)1 (4%)1 (4%)
Accidental injury1 (3%)2 (8%)1 (4%)0
Back pain1 (3%)2 (8%)01 (4%)
Sinusitis1 (3%)2 (8%)01 (4%)
Chest pain01 (4%)2 (8%)0
Peripheral edema02 (8%)01 (4%)
Hypertension002 (8%)0
Paresthesia2 (6%)002 (7%)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS • Insulin and/or Oral hypoglycemic Agents: Patients with acromegaly and with diabetes mellitus may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents ( 5.2 , 7.1 ) • Opioids: Patients on opioids may need higher SOMAVERT doses to achieve appropriate IGF-1 suppression ( 7.2 ) 7.1 Insulin and/or Oral Hypoglycemic Agents After initiation of SOMAVERT, patients with acromegaly and diabetes mellitus treated with insulin and/or oral hypoglycemic agents may require dose reductions of insulin and/or oral hypoglycemic agents [see Warnings and Precautions (5.1) ] . 7.2 Opioids In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-1 concentrations compared with patients not receiving opioids. The mechanism of this interaction is not known." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 ) 8.1 Pregnancy Risk Summary Postmarketing reports of SOMAVERT use in pregnant women are insufficient to establish a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Acromegaly may improve during pregnancy (see Clinical Considerations ). In animal reproduction studies, fetotoxicity was observed at a dose that was 6 times the maximum recommended human dose based on body surface area following subcutaneous administration of pegvisomant during organogenesis or during the preimplantation period ( 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Published data from case reports, case series, and a small interventional study in pregnant women with acromegaly have demonstrated that acromegaly may improve or stabilize without treatment during pregnancy, particularly if acromegaly is treated before pregnancy. In rare cases, acromegaly may worsen during pregnancy. Since IGF-1 levels may change physiologically during pregnancy and interpreting IGF-1 and growth hormone levels in pregnant women with acromegaly may be unreliable, clinical monitoring is recommended. Data Animal Data The effects of pegvisomant on early embryonic development and embryo-fetal development were evaluated in two separate studies, which were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant administration during organogenesis. At the 10 mg/kg/day dose (6 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies. 8.2 Lactation Risk Summary Limited information from a case report in published literature reported that the level of pegvisomant in human milk was below the level of detection. There is no information available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SOMAVERT and any potential adverse effects on the breastfed child from SOMAVERT or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with pegvisomant may lead to improved fertility. 8.4 Pediatric Use The safety and effectiveness of SOMAVERT in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment SOMAVERT was not studied in patients with renal impairment and the safety and efficacy in these patients is not known." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Postmarketing reports of SOMAVERT use in pregnant women are insufficient to establish a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. Acromegaly may improve during pregnancy (see Clinical Considerations ). In animal reproduction studies, fetotoxicity was observed at a dose that was 6 times the maximum recommended human dose based on body surface area following subcutaneous administration of pegvisomant during organogenesis or during the preimplantation period ( 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Published data from case reports, case series, and a small interventional study in pregnant women with acromegaly have demonstrated that acromegaly may improve or stabilize without treatment during pregnancy, particularly if acromegaly is treated before pregnancy. In rare cases, acromegaly may worsen during pregnancy. Since IGF-1 levels may change physiologically during pregnancy and interpreting IGF-1 and growth hormone levels in pregnant women with acromegaly may be unreliable, clinical monitoring is recommended. Data Animal Data The effects of pegvisomant on early embryonic development and embryo-fetal development were evaluated in two separate studies, which were conducted in pregnant rabbits with pegvisomant at subcutaneous doses of 1, 3, and 10 mg/kg/day. There was no evidence of teratogenic effects associated with pegvisomant administration during organogenesis. At the 10 mg/kg/day dose (6 times the maximum human therapeutic dose based on body surface area), a reproducible, slight increase in post-implantation loss was observed in both studies." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of SOMAVERT in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of SOMAVERT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "overdosage": [ "10 OVERDOSAGE In one reported incident of acute overdose with SOMAVERT during pre-marketing clinical studies, a patient self-administered 80 mg/day (2.7 times the maximum recommended maintenance dosage) for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities. In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-1 levels return to within or above the normal range." ], "description": [ "11 DESCRIPTION Pegvisomant is an analog of human growth hormone (GH) of recombinant DNA origin that acts as a GH receptor antagonist. It contains 191 amino acid residues. The molecular weight of pegvisomant is 22 kDa. The molecular weight of the PEG portion of pegvisomant is approximately 5 kDa. The predominant molecular weights of pegvisomant are thus approximately 42, 47, and 52 kDa. The schematic shows the amino acid sequence of the pegvisomant protein (PEG polymers are shown attached to the 5 most probable attachment sites). Pegvisomant is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist. Stippled residues indicate PEG attachment sites (Phe 1 , Lys 38 , Lys 41 , Lys 70 , Lys 115 , Lys 120 , Lys 140 , Lys 145 , Lys 158 ) Shown below are the amino acid substitutions in pegvisomant, relative to human GH. hGH Pegvisomant His 18 Asp 18 Ala 21 Asn 21 Gly 120 Lys 120 Arg 167 Asn 167 Lys 168 Ala 168 Asp 171 Ser 171 Lys 172 Arg 172 Glu 174 Ser 174 Ile 179 Thr 179 SOMAVERT (pegvisomant) for injection is a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution. SOMAVERT is supplied in packages that include a separate glass vial containing Sterile Water for Injection, USP, that is a sterile, nonpyrogenic preparation of water for injection that contains no bacteriostat, antimicrobial agent, or added buffer, to be used as a diluent. SOMAVERT is available in single-dose sterile vials containing 10 mg, 15 mg, 20 mg, 25 mg or 30 mg of pegvisomant. SOMAVERT 10 mg, 15 mg, and 20 mg vials also contain glycine (1.36 mg), mannitol (36 mg), sodium dihydrogen phosphate monohydrate (0.36 mg), and sodium phosphate dibasic anhydrous (1.04 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 10 mg/mL, 15 mg/mL and 20 mg/mL, respectively, with a pH of 7.1 – 7.7. SOMAVERT 25 mg vials also contain glycine (1.7 mg), mannitol (45 mg), sodium dihydrogen phosphate monohydrate (0.45 mg), and sodium phosphate dibasic anhydrous (1.3 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 25 mg/mL with a pH of 7.1 – 7.7. SOMAVERT 30 mg vials also contain glycine (2.04 mg), mannitol (54 mg), sodium dihydrogen phosphate monohydrate (0.54 mg), and sodium phosphate dibasic anhydrous (1.56 mg). After reconstitution with 1 mL of Water for Injection, USP, the resulting concentration is 30 mg/mL with a pH of 7.1 – 7.7. Chemical Structure" ], "description_table": [ "
hGHPegvisomant
His18 Asp18
Ala21 Asn21
Gly120 Lys120
Arg167 Asn167
Lys168 Ala168
Asp171 Ser171
Lys172 Arg172
Glu174 Ser174
Ile179Thr179
" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. Inhibition of GH action results in decreased serum concentrations of IGF-1, as well as other GH-responsive serum proteins such as free IGF-1, the acid-labile subunit of IGF-1 (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3). 12.2 Pharmacodynamics Pegvisomant binds selectively to the GH receptor, and does not cross-react with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to decreased serum concentrations of IGF-1, free IGF-1, ALS, and IGFBP-3 [see Clinical Studies (14, Figure 1) ] . 12.3 Pharmacokinetics Absorption: Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose. Distribution: The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (C max , AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively. The relative bioavailability of 1 × 30 mg pegvisomant was compared to 2 × 15 mg pegvisomant in a single dose study. The AUCinf and C max of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths. Metabolism and Elimination: The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life estimates ranging from 60 to 138 hours following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans. Drug Interaction Studies In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-1 suppression compared with patients not receiving opioids. The mechanism of this interaction is not known [see Drug Interactions (7.2) ] . Specific Populations No pharmacokinetic studies have been conducted in patients with renal impairment, patients with hepatic impairment, geriatric patients, or pediatric patients and the effects of race on the pharmacokinetics of pegvisomant has not been studied. No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of SOMAVERT or other growth hormone analogs. In pre-marketing clinical studies, approximately 17% of the SOMAVERT-treated patients developed low titer, non‑neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of SOMAVERT, the long term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving SOMAVERT. The data above reflect the percentage of patients whose test results were considered positive for antibodies to SOMAVERT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOMAVERT with the incidence of antibodies to other products may be misleading." ], "mechanism_of_action": [ "12.1 Mechanism of Action Pegvisomant selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. Inhibition of GH action results in decreased serum concentrations of IGF-1, as well as other GH-responsive serum proteins such as free IGF-1, the acid-labile subunit of IGF-1 (ALS), and insulin-like growth factor binding protein-3 (IGFBP-3)." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Pegvisomant binds selectively to the GH receptor, and does not cross-react with 19 other cytokine receptors tested, including prolactin. Pegvisomant leads to decreased serum concentrations of IGF-1, free IGF-1, ALS, and IGFBP-3 [see Clinical Studies (14, Figure 1) ] ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption: Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration. The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose. Distribution: The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. After a single subcutaneous administration, exposure (C max , AUC) to pegvisomant increases disproportionately with increasing dose. Mean ± SEM serum pegvisomant concentrations after 12 weeks of therapy with daily doses of 10, 15, and 20 mg were 6600 ± 1330; 16,000 ± 2200; and 27,000 ± 3100 ng/mL, respectively. The relative bioavailability of 1 × 30 mg pegvisomant was compared to 2 × 15 mg pegvisomant in a single dose study. The AUCinf and C max of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths. Metabolism and Elimination: The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. Clearance of pegvisomant following multiple doses is lower than seen following a single dose. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to range between 36 to 28 mL/h for subcutaneous doses ranging from 10 to 20 mg/day, respectively. Clearance of pegvisomant was found to increase with body weight. Pegvisomant is eliminated from serum with a mean half-life estimates ranging from 60 to 138 hours following either single or multiple doses. Less than 1% of administered drug is recovered in the urine over 96 hours. The elimination route of pegvisomant has not been studied in humans. Drug Interaction Studies In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-1 suppression compared with patients not receiving opioids. The mechanism of this interaction is not known [see Drug Interactions (7.2) ] . Specific Populations No pharmacokinetic studies have been conducted in patients with renal impairment, patients with hepatic impairment, geriatric patients, or pediatric patients and the effects of race on the pharmacokinetics of pegvisomant has not been studied. No gender effect on the pharmacokinetics of pegvisomant was found in a population pharmacokinetic analysis." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8, and 20 mg/kg (about 2, 9, and 22-fold a single 30 mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections. Mutagenesis Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration). Impairment of Fertility Fertility studies have not been conducted with pegvisomant." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Pegvisomant was administered subcutaneously to rats daily for 2 years at doses of 2, 8, and 20 mg/kg (about 2, 9, and 22-fold a single 30 mg dose in humans on an AUC basis). Long term treatment with pegvisomant at 8 and 20 mg/kg caused an increase in malignant fibrous histiocytoma at injection sites in males. Injection site tumors were not seen in female rats at the same doses. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections. Mutagenesis Pegvisomant did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration). Impairment of Fertility Fertility studies have not been conducted with pegvisomant." ], "clinical_studies": [ "14 CLINICAL STUDIES A total of one hundred twelve patients (63 men and 49 women) with acromegaly participated in a 12-week, randomized, double-blind, multi-center study comparing placebo and SOMAVERT. The mean ±SD age was 48±14 years, and the mean duration of acromegaly was 8±8 years. Ninety three had undergone previous pituitary surgery, of which 57 had also been treated with conventional radiation therapy. Six patients had undergone irradiation without surgery, nine had received only drug therapy, and four had received no previous therapy. At study start, the mean ± SD time since the subjects' last surgery and/or irradiation therapy, respectively, was 6.8 ± 0.93 years (n=63) and 5.6 ± 0.57 years (n=93). Subjects were qualified for enrollment if their serum IGF-1, drawn after the required drug washout period, was ≥1.3 times the upper limit of the age-adjusted normal range. They were randomly assigned at the baseline visit to one of four treatment groups: placebo (n=32), 10 mg/day (n=26), 15 mg/day (n= 26), or 20 mg/day (n=28) of SOMAVERT subcutaneously IGF-1. The primary efficacy endpoint was IGF-1 percent change in IGF-1 concentrations from baseline to week 12. The three groups that received SOMAVERT showed statistically significant (p<0.01) reductions in serum levels of IGF-1 compared with the placebo group (Table 4). Table 4. Mean Percent Change from Baseline in IGF-1 at Week 12 for Intent-to-Treat Population Placebo n=31 SOMAVERT 10 mg/day n=26 15 mg/day n=26 20 mg/day n=28 Mean baseline IGF-1 (ng/mL) (SD) 670 (288) 627 (251) 649 (293) 732 (205) Mean percent change from baseline in IGF-1 (SD) -4.0 (17) -27 (28) -48 (26) -63 (21) SOMAVERT minus Placebo (95% CI for treatment difference) -23 P<0.01; n=number of patients; SD = standard deviation (-35, -11) -44 (-56, -33) -59 (-68, -49) There were also reductions in serum levels of free IGF-1, IGFBP-3, and ALS compared with placebo at all post-baseline visits (Figure 1). Figure 1. Effects of SOMAVERT on Serum Markers (Mean ± Standard Error) After 12 weeks of treatment, the following percentages of patients had normalized IGF-1 (Figure 2): Figure 2. Percent of Patients Whose IGF-1 Levels Normalized at Week 12 Table 5 shows the effect of treatment with SOMAVERT on ring size (standard jeweler's sizes converted to a numeric score ranging from 1 to 63), and on signs and symptoms of acromegaly. Each individual score for a sign or symptom of acromegaly (for soft-tissue swelling, arthralgia, headache, perspiration and fatigue) was based on a nine-point ordinal rating scale (0 = absent and 8 = severe and incapacitating), and the total score for signs or symptoms of acromegaly was derived from the sum of the individual scores. Mean baseline scores were as follows: ring size = 47.1; total signs and symptoms = 15.2; soft tissue swelling = 2.5; arthralgia = 3.2; headache = 2.4; perspiration = 3.3; and fatigue = 3.7. Table 5. Mean Change from Baseline (SD) at Week 12 for Ring Size and Signs and Symptoms of Acromegaly Placebo n=30 SOMAVERT 10 mg/day n=26 15 mg/day n=24–25 20 mg/day n=26–27 Ring size -0.1 (2.3) -0.8 (1.6) -1.9 (2.0) -2.5 (3.3) Total score for signs and symptoms of acromegaly 1.3 (6.0) -2.5 (4.3) -4.4 (5.9) -4.7 (4.7) Soft-tissue swelling 0.3 (2.3) -0.7 (1.6) -1.2 (2.3) -1.3 (1.3) Arthralgia 0.1 (1.8) -0.3 (1.8) -0.5 (2.5) -0.4 (2.1) Headache 0.1 (1.7) -0.4 (1.6) -0.3 (1.4) -0.3 (2.0) Perspiration 0.1 (1.7) -0.6 (1.6) -1.1 (1.3) -1.7 (1.6) Fatigue 0.7 (1.5) -0.5 (1.4) -1.3 (1.7) -1.0 (1.6) Serum growth hormone (GH) concentrations, as measured by research assays using antibodies that do not cross-react with pegvisomant, rose within two weeks of beginning treatment with SOMAVERT. The largest increase in GH concentration was seen in patients treated with doses of SOMAVERT 20 mg/day. This effect is presumably the result of diminished inhibition of GH secretion as IGF-1 levels fall. As shown in Figure 3, when patients with acromegaly were given a loading dose of SOMAVERT followed by a fixed daily dose, the rise in GH was inversely proportional to the fall in IGF-1 and generally stabilized by week 2. Serum GH concentrations remained stable in patients treated with SOMAVERT for the average of 43 weeks (range, 0–82 weeks). Figure 3. Percent Change in Serum GH and IGF-1 Concentrations In the open-label extension to the clinical study, 109 subjects (including 6 new patients) with mean treatment exposure of 42.6 weeks (range 1 day – 82 weeks), 93 (85.3%) subjects had an adverse event, 16 (14.7%) had an SAE, and 4 (3.7%) discontinued due to an AE (headaches, elevated liver function tests, pancreatic cancer, and weight gain). A total of 100 (92.6%) of the 108 subjects with available IGF-1 data had a normal IGF-1 concentration at any visit during the study. Figure 1 Figure 2 Figure 3" ], "clinical_studies_table": [ "
Table 4. Mean Percent Change from Baseline in IGF-1 at Week 12 for Intent-to-Treat Population
Placebo n=31SOMAVERT
10 mg/day n=2615 mg/day n=2620 mg/day n=28
Mean baseline IGF-1 (ng/mL) (SD)670 (288)627 (251)649 (293)732 (205)
Mean percent change from baseline in IGF-1 (SD)-4.0 (17) -27 (28) -48 (26) -63 (21)
SOMAVERT minus Placebo (95% CI for treatment difference)-23P<0.01; n=number of patients; SD = standard deviation (-35, -11)-44 (-56, -33)-59 (-68, -49)
", "
Figure 1. Effects of SOMAVERT on Serum Markers (Mean ± Standard Error)
", "
Figure 2. Percent of Patients Whose IGF-1 Levels Normalized at Week 12
", "
Table 5. Mean Change from Baseline (SD) at Week 12 for Ring Size and Signs and Symptoms of Acromegaly
Placebo n=30SOMAVERT
10 mg/day n=2615 mg/day n=24–2520 mg/day n=26–27
Ring size-0.1 (2.3)-0.8 (1.6)-1.9 (2.0)-2.5 (3.3)
Total score for signs and symptoms of acromegaly1.3 (6.0)-2.5 (4.3)-4.4 (5.9)-4.7 (4.7)
Soft-tissue swelling0.3 (2.3)-0.7 (1.6)-1.2 (2.3)-1.3 (1.3)
Arthralgia0.1 (1.8)-0.3 (1.8)-0.5 (2.5)-0.4 (2.1)
Headache0.1 (1.7)-0.4 (1.6)-0.3 (1.4)-0.3 (2.0)
Perspiration0.1 (1.7)-0.6 (1.6)-1.1 (1.3)-1.7 (1.6)
Fatigue0.7 (1.5)-0.5 (1.4)-1.3 (1.7)-1.0 (1.6)
", "
Figure 3. Percent Change in Serum GH and IGF-1 Concentrations
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING SOMAVERT (pegvisomant) for injection is a white lyophilized powder supplied in the following strengths and package configurations: SOMAVERT (pegvisomant) for injection Package Configuration NDC 10 mg dose vial NDC 0009-5176-02 15 mg dose vial NDC 0009-5178-02 20 mg dose vial NDC 0009-5180-02 25 mg dose vial NDC 0009-5199-01 30 mg dose vial NDC 0009-5200-01 Each package of SOMAVERT also includes a single-dose vial containing 5 mL of Sterile Water for Injection, USP. Storage Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze." ], "how_supplied_table": [ "
Package ConfigurationNDC
10 mg dose vialNDC 0009-5176-02
15 mg dose vialNDC 0009-5178-02
20 mg dose vialNDC 0009-5180-02
25 mg dose vialNDC 0009-5199-01
30 mg dose vialNDC 0009-5200-01
" ], "storage_and_handling": [ "Storage Prior to reconstitution, SOMAVERT should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Inform patients (and/or their caregivers) of the following information to aid in the safe and effective use of SOMAVERT: • Not to use SOMAVERT if they are allergic to SOMAVERT or anything in it. • They will need blood testing to check IGF-1 levels and liver tests before and during treatment with SOMAVERT and that the dose of SOMAVERT may be changed based on the results of these tests. • SOMAVERT has not been studied in pregnant women and instruct them to notify their healthcare provider as soon as they are aware that they are pregnant. • It is not known whether SOMAVERT is excreted in human milk and instruct them to notify their healthcare provider if they plan to do so. • Pregnancy: Inform female patients that treatment with SOMAVERT may result in unintended pregnancy [see Females and Males of Reproductive Potential (8.3) ]. Advise patients (and/or their caregivers) of the following adverse reactions: • The most common reported adverse reactions are injection site reaction, elevations of liver tests, pain, nausea, and diarrhea. • If they have liver test elevations they may need to have more frequent liver tests and/or discontinue SOMAVERT. Instruct patients to immediately discontinue therapy and contact their physician if they become jaundiced. • GH-secreting tumors may enlarge in people with acromegaly and that these tumors need to be watched carefully and monitored by MRI imaging. • Thickening under the skin may occur at the injection site that could lead to lumps and that switching sites may prevent or lessen this. • If they have diabetes mellitus, they may require careful monitoring and dose reductions of insulin and/or oral hypoglycemic agents while on SOMAVERT. • If they take opioids, they may need higher SOMAVERT doses to achieve appropriate IGF-1 suppression. Advise patients that SOMAVERT is supplied as lyophilized powder in different strengths of 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg in a sterile glass vial within a package also containing a single-dose flip top vial of sterile water (diluent) for injection. Advise patients that the stoppers on both vials are not made with natural rubber latex. Advise patients to follow the directions for reconstitution provided with each package including shaking may cause denaturation (destruction) of the active ingredient (therefore do not shake ). Advise patients that the package of SOMAVERT should be stored in a refrigerator 2°C to 8°C (36°F to 46°F) prior to use. It should NOT BE FROZEN." ], "spl_unclassified_section": [ "U.S. License No. 1216 This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com . LAB-0196-23.0 Logo" ], "spl_patient_package_insert": [ "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 7/2023 PATIENT INFORMATION SOMAVERT (SOM-ah-vert) (pegvisomant) for injection, for subcutaneous use What is SOMAVERT? SOMAVERT is a prescription medicine used to treat people who have too much growth hormone (acromegaly). SOMAVERT is used to treat people who are not able to be treated or have not already been helped by surgery or radiation. It is not known if SOMAVERT is safe and effective in children. Before you use SOMAVERT, tell your healthcare provider about all of your medical conditions, including if you: • are allergic to pegvisomant or any of the ingredients in SOMAVERT. Do not take SOMAVERT if you are allergic to pegvisomant or any of the ingredients in SOMAVERT . See the end of this Patient Information leaflet for a complete list of ingredients in SOMAVERT. • have diabetes. • have or have had liver problems. • are pregnant or plan to become pregnant. It is not known if SOMAVERT will harm your unborn baby. Tell your healthcare provider if you become pregnant while using SOMAVERT. • are breastfeeding or plan to breastfeed. It is not known if SOMAVERT passes into your breast milk. You and your healthcare provider should decide how you will feed your baby if you take SOMAVERT. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. SOMAVERT may affect the way other medicines work, and other medicines may affect how SOMAVERT works. Especially tell your healthcare provider if you take: • insulin or other medicines used to treat diabetes. • narcotics (opioid medicines). Your healthcare provider may change your dose of SOMAVERT if you take opioids. If you are not sure, ask your healthcare provider or pharmacist whether you take these medicines. How should I use SOMAVERT? • Read the Instructions for Use at the end of this Patient Information for information about the right way to use SOMAVERT. • Your healthcare provider should do blood tests to check your liver and insulin-like growth factor-1 (IGF-1) levels before you start and while you use SOMAVERT. Your healthcare provider may need to change your dose of SOMAVERT. • SOMAVERT is given 1 time each day as an injection under your skin (subcutaneous). Some people may need to give 2 injections for their dose each day. Your healthcare provider will tell you if you need to give 2 injections for your dose. • Your first injection of SOMAVERT should be given by your healthcare provider. • Your healthcare provider will teach you or your caregiver how to use SOMAVERT. • If you use too much SOMAVERT, call your healthcare provider right away. • If you miss a dose of SOMAVERT, just take the next dose at the regular time. Do not take 2 doses at the same time. If you are not sure about your dosing, ask your healthcare provider. What are the possible side effects of SOMAVERT? SOMAVERT may cause serious side effects, including: • changes in your blood sugar leve l. Your healthcare provider may change your dose of diabetes medicine while you take SOMAVERT. • liver problems . Stop injecting SOMAVERT right away and call your healthcare provider if you have any of the following symptoms of liver problems: o yellowing of your eyes (jaundice) o dark, amber-colored urine o feeling very tired (fatigue or exhaustion) o nausea and vomiting o pain in your stomach (abdomen) o generalized swelling o bruising easily • skin thickening at your injection site that could lead to lumps (lipohypertrophy ) • allergic reactions . Call your healthcare provider right away if you have any of the following symptoms of a serious allergic reaction: o swelling of your face, tongue, lips, or throat o wheezing or trouble breathing o skin rash, redness, or swelling o severe itching o dizziness or fainting The most common side effects of SOMAVERT include: • pain • infection • nausea • flu syndrome • injection site reaction • diarrhea • abnormal liver tests. If your liver test results are too high, you may have to have more frequent liver tests These are not all of the possible side effects of SOMAVERT. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 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 SOMAVERT? • Before you mix the SOMAVERT powder and the liquid: o Store SOMAVERT in a refrigerator between 36°F to 46°F (2°C to 8°C). o Do not freeze SOMAVERT. • After you mix the SOMAVERT powder and liquid: o Keep the mixed SOMAVERT at room temperature between 59°F to 77°F (15°C to 25°C). o Keep SOMAVERT inside the vial or the syringe until you are ready to inject it. o You must use the mixed SOMAVERT within 6 hours after you mix it . o If you have not used the mixed SOMAVERT within 6 hours, throw the SOMAVERT away. Keep SOMAVERT and all medicines out of the reach of children. General information about the safe and effective use of SOMAVERT. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SOMAVERT for a condition for which it was not prescribed. Do not give SOMAVERT to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information summarizes the most important information about SOMAVERT. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SOMAVERT that is written for health professionals. What are the ingredients in SOMAVERT? Active ingredient: pegvisomant, including polyethylene glycol Inactive ingredients: glycine, mannitol, sodium dihydrogen phosphate monohydrate, and sodium phosphate dibasic anhydrous. U.S. License No. 1216 LAB-0197-12.0 For more information, go to www.SOMAVERT.com or call 1-800-645-1280. Logo" ], "spl_patient_package_insert_table": [ "are allergic to pegvisomant or any of the ingredients in SOMAVERT. Do not take SOMAVERT if you are allergic to pegvisomant or any of the ingredients in SOMAVERT. See the end of this Patient Information leaflet for a complete list of ingredients in SOMAVERT.have diabetes.have or have had liver problems.are pregnant or plan to become pregnant. It is not known if SOMAVERT will harm your unborn baby. Tell your healthcare provider if you become pregnant while using SOMAVERT.are breastfeeding or plan to breastfeed. It is not known if SOMAVERT passes into your breast milk. You and your healthcare provider should decide how you will feed your baby if you take SOMAVERT.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. SOMAVERT may affect the way other medicines work, and other medicines may affect how SOMAVERT works. Especially tell your healthcare provider if you take:insulin or other medicines used to treat diabetes.narcotics (opioid medicines). Your healthcare provider may change your dose of SOMAVERT if you take opioids.If you are not sure, ask your healthcare provider or pharmacist whether you take these medicines.Read the Instructions for Use at the end of this Patient Information for information about the right way to use SOMAVERT.Your healthcare provider should do blood tests to check your liver and insulin-like growth factor-1 (IGF-1) levels before you start and while you use SOMAVERT. Your healthcare provider may need to change your dose of SOMAVERT.SOMAVERT is given 1 time each day as an injection under your skin (subcutaneous). Some people may need to give 2 injections for their dose each day. Your healthcare provider will tell you if you need to give 2 injections for your dose.Your first injection of SOMAVERT should be given by your healthcare provider.Your healthcare provider will teach you or your caregiver how to use SOMAVERT.If you use too much SOMAVERT, call your healthcare provider right away.If you miss a dose of SOMAVERT, just take the next dose at the regular time. Do not take 2 doses at the same time. If you are not sure about your dosing, ask your healthcare provider.changes in your blood sugar level. Your healthcare provider may change your dose of diabetes medicine while you take SOMAVERT.liver problems. Stop injecting SOMAVERT right away and call your healthcare provider if you have any of the following symptoms of liver problems:yellowing of your eyes (jaundice)dark, amber-colored urinefeeling very tired (fatigue or exhaustion)nausea and vomitingpain in your stomach (abdomen)generalized swellingbruising easilyskin thickening at your injection site that could lead to lumps (lipohypertrophy)allergic reactions. Call your healthcare provider right away if you have any of the following symptoms of a serious allergic reaction:swelling of your face, tongue, lips, or throatwheezing or trouble breathingskin rash, redness, or swellingsevere itchingdizziness or faintingpaininfectionnauseaflu syndromeinjection site reactiondiarrheaabnormal liver tests. If your liver test results are too high, you may have to have more frequent liver testsBefore you mix the SOMAVERT powder and the liquid:Store SOMAVERT in a refrigerator between 36°F to 46°F (2°C to 8°C).Do not freeze SOMAVERT.After you mix the SOMAVERT powder and liquid:Keep the mixed SOMAVERT at room temperature between 59°F to 77°F (15°C to 25°C).Keep SOMAVERT inside the vial or the syringe until you are ready to inject it.You must use the mixed SOMAVERT within 6 hours after you mix it.If you have not used the mixed SOMAVERT within 6 hours, throw the SOMAVERT away.Keep SOMAVERT and all medicines out of the reach of children.
This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 7/2023
PATIENT INFORMATION SOMAVERT (SOM-ah-vert) (pegvisomant) for injection, for subcutaneous use
What is SOMAVERT? SOMAVERT is a prescription medicine used to treat people who have too much growth hormone (acromegaly). SOMAVERT is used to treat people who are not able to be treated or have not already been helped by surgery or radiation. It is not known if SOMAVERT is safe and effective in children.
Before you use SOMAVERT, tell your healthcare provider about all of your medical conditions, including if you:
•••••••
How should I use SOMAVERT?
•••••••
What are the possible side effects of SOMAVERT? SOMAVERT may cause serious side effects, including:
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The most common side effects of SOMAVERT include:
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These are not all of the possible side effects of SOMAVERT. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 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 SOMAVERT?
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General information about the safe and effective use of SOMAVERT. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SOMAVERT for a condition for which it was not prescribed. Do not give SOMAVERT to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information summarizes the most important information about SOMAVERT. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SOMAVERT that is written for health professionals.
What are the ingredients in SOMAVERT? Active ingredient: pegvisomant, including polyethylene glycol Inactive ingredients: glycine, mannitol, sodium dihydrogen phosphate monohydrate, and sodium phosphate dibasic anhydrous.U.S. License No. 1216 LAB-0197-12.0 For more information, go to www.SOMAVERT.com or call 1-800-645-1280.
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE SOMAVERT (SOM-ah-vert) (pegvisomant) for injection, for subcutaneous use Read this Instructions for Use before you start using SOMAVERT and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment. Your healthcare provider should show you or a caregiver how to inject SOMAVERT the right way before you inject it for the first time. Important Information: • SOMAVERT is for use under the skin only (subcutaneous). • Do not share your SOMAVERT syringes or needles with anyone else. You may give an infection to them or get an infection from them. • Do not use SOMAVERT after the expiration date (EXP) on the label. • Inject SOMAVERT within 6 hours of mixing it. If you wait more than 6 hours, you must throw away the medicine without injecting it. Supplies you need to give each injection of SOMAVERT. See Figure A . • 1 package of SOMAVERT that contains: o 1 vial of powdered SOMAVERT medicine (powder vial) o 1 vial of liquid (diluent) labeled \"Sterile Water for Injection, USP\" to mix the powdered medicine The vials in the package of SOMAVERT have stoppers that are not made with natural rubber latex. The SOMAVERT package does not come with syringes and needles. • a 1 mL syringe with a 21 gauge to 27 gauge needle that is at least 1 inch long. This is the syringe and needle needed to mix the medicine (diluent syringe). • a 1 mL insulin syringe with attached needle. This is the syringe needed for your injection. • 2 alcohol swabs • 1 small clean, dry cotton pad • 1 sharps disposal container for throwing away used needles and syringes. See \" Disposing of used needles and syringes \" at the end of these instructions. • a clean, flat surface to work on, like a table Figure A Preparing and mixing your SOMAVERT medicine The SOMAVERT medicine comes as a dry powder. Before you use SOMAVERT, you must mix the dry powder with the vial of diluent that comes in the SOMAVERT package. Do not use any other liquid to mix the medicine. Note: If you need to give 2 injections for your SOMAVERT dose, you need 2 packages of SOMAVERT to prepare 2 separate vials of medicine. Step 1. Remove 1 package of SOMAVERT from the refrigerator about 10 minutes before you plan to give your SOMAVERT injection. Let the SOMAVERT stand at room temperature to warm up the medicine. Step 2. Wash your hands with soap and warm water. Dry your hands well. Step 3. Remove the plastic caps from the tops of the powder vial and the diluent vial. See Figure B . Do not touch the rubber vial stoppers. The stoppers are clean. If the stoppers are touched by anything, you must clean them with an alcohol swab before use. Figure B Step 4. Carefully remove the cap from the diluent syringe with the larger needle and set the cap aside on the table. See Figure C . Figure C Step 5. Pull the plunger of the diluent syringe out to the 1 mL mark. With 1 hand, firmly hold the vial of diluent. With the other hand, push the needle of the diluent syringe straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the vial. See Figure D . Figure D Step 6. Firmly hold the diluent vial and syringe together, with the needle still in the vial. Then turn the diluent vial with the diluent syringe upside down. Hold them at eye level. See Figure E . Figure E Step 7. Slide 1 hand carefully down the diluent vial so you can firmly hold the neck of the vial with your thumb and forefinger. Hold the upper part of the syringe with your other fingers. With the other hand, slowly pull the plunger out to the 1 mL mark on the diluent syringe. See Figure F . Figure F Step 8. Check the diluent syringe for air bubbles. If you see bubbles, tap the diluent syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. See Figure G . If you push too much of the liquid back into the vial, pull the plunger out again to the 1 mL mark. Figure G Step 9. Make sure that 1 mL of diluent remains in the diluent syringe. Pull the needle out of the vial. The vial should still have diluent in it. Do not use the leftover diluent in the vial. Step 10 . Push the needle of the diluent syringe straight through the stopper of the vial of powdered SOMAVERT. Then, tilt the diluent syringe to the side and gently push the plunger to inject the diluent down the inner side of the SOMAVERT powder vial. Be sure the diluent does not fall directly on the powder, but flows down the inside wall of the vial. See Figure H . Figure H Step 11. When the diluent syringe is empty, pull the needle out of the powder vial. Throw away the diluent vial with the leftover liquid in it. Throw away the diluent syringe and needle in the sharps container. See \" Disposing of used needles and syringes \" at the end of these instructions. Step 12. Hold the medicine vial of SOMAVERT upright between your hands and gently roll it to dissolve the powder into a solution. See Figure I . Figure I • Do not shake the medicine vial. Shaking may destroy the medicine. • The liquid medicine should be clear after the powder is dissolved. Do not use the vial if: o the liquid medicine looks cloudy, hazy, or slightly colored or o you see solid particles in the liquid medicine or o you see foam in the vial Tell your pharmacist and ask for another vial. Do not throw the vial away because the pharmacist may ask that you return it. • Inject SOMAVERT within 6 hours of mixing it. If you wait more than 6 hours, you must throw away the medicine without injecting it. • Each mixed medicine vial contains 1 dose of SOMAVERT. Do not split the liquid medicine into multiple doses. Preparing your SOMAVERT injection syringe: Step 13. Clean the rubber stopper of the vial of SOMAVERT with an alcohol swab. • Carefully remove the cap from the insulin syringe and set the cap on the table. • Pull the insulin syringe plunger out to the 1 mL mark. With 1 hand, firmly hold the vial. With the other hand, push the needle straight through the center of the rubber stopper and deep into the vial. Gently push the plunger in until the air is injected into the medicine vial. See Figure J . Figure J Step 14. Firmly hold the medicine solution vial and insulin syringe together, with the needle still deeply inserted into the vial. Carefully turn the vial and syringe together upside down. Hold them at eye level. See Figure K . Figure K Step 15. Slide 1 hand carefully down the medicine solution vial so you can firmly hold the neck of the vial with your thumb and forefinger. Hold the upper part of the syringe with your other fingers. With the other hand, slowly pull the plunger out to the 1 mL mark on the insulin syringe. See Figure L . Figure L Step 16. Check the insulin syringe for air bubbles. If you see bubbles, tap the insulin syringe barrel until the bubbles rise to the top of the syringe. Carefully push the plunger in to push only the air bubbles back into the vial. See Figure M . Figure M Step 17. Withdraw the entire 1 mL of medicine solution from the vial. If your dose of SOMAVERT is less than 1 mL, your healthcare provider will tell you how much medicine solution to withdraw. Slowly withdraw the needle to keep the tip in the liquid until you get all the medicine solution you need out of the vial. See Figure N . Note: • If your dose of SOMAVERT is less than 1 mL, your healthcare provider will tell you how much medicine solution to withdraw. • If your dose of SOMAVERT is more than 1 mL, your healthcare provider will tell you how much more medicine solution to withdraw from a second vial into another syringe, and where to give your second injection. Set the syringe and needle on the table without anything touching the needle. Figure N Selecting your SOMAVERT injection site: Step 18. SOMAVERT is injected under the skin (subcutaneous). Injection sites may include your upper arm, upper thigh, stomach area (abdomen) and buttocks. See Figure O . Figure O • Choose your injection site from 1 of the areas your healthcare provider told you to use. Only a caregiver can inject in your upper arm. • Choose a different injection site each day so lumps do not develop in your skin. Keep a record of each day's injection site as you inject your daily dose of SOMAVERT. • Do not use an area of your body that has: o a rash o broken skin o bruising o lumps in your skin • If you need to give 2 injections for your dose of SOMAVERT, choose a different site for your second injection. Giving your SOMAVERT injection: Step 19. Clean your injection site with an alcohol swab. See Figure P . Let your skin dry before you inject your medicine. Figure P Step 20. With 1 hand, gently pinch up your skin at your injection site. See Figure Q . Figure Q Step 21. Carefully pick up the insulin syringe with your other hand and hold it like a pen. In a single, smooth motion, push the needle straight down and completely into your skin (at a 90-degree angle). • Keep the needle pushed all the way into your skin while you slowly push the syringe plunger in with the index finger of your other hand. See Figure R . • Keep the needle all the way into your skin until all of the medicine is injected under your skin and the insulin syringe is empty. Figure R Step 22. Release your pinched skin and pull the needle straight out. See Figure S . Figure S Step 23. Do not rub your injection area. A small amount of bleeding may happen. If you have a small amount of bleeding, press a small clean, dry cotton pad over the area and press gently for 1 or 2 minutes, or until the bleeding has stopped. See Figure T . Figure T Disposing of used needles and syringes: • Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. See Figure U . Do not throw away (dispose of) loose needles and syringes in your household trash. Figure U • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: o made of a heavy-duty plastic, o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, o upright and stable during use, o leak-resistant, and o properly labeled to warn of hazardous waste inside the container. • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpdisposal . • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. This Instructions for Use has been approved by the U.S. Food and Drug Administration. U.S. License No. 1216 LAB-1362-3.0 Revised: July 2023 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P Figure Q Figure R Figure S Figure T Figure U Logo" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 10 mg Vial Label Pfizer Somavert ® pegvisomant for injection 10 mg (as protein) For Subcutaneous Use Only single dose vial 1 Vial Rx only Principal Display Panel - 10 mg Vial Label", "PRINCIPAL DISPLAY PANEL - 10 mg Kit Carton NDC 0009-5176-01 Pfizer Somavert ® pegvisomant for injection 10 mg (as protein) For Subcutaneous Injection Only single dose vial Package also contains Sterile Water for Injection, USP Rx only Principal Display Panel - 10 mg Kit Carton", "PRINCIPAL DISPLAY PANEL - 15 mg Vial Label Pfizer Somavert ® pegvisomant for injection 15 mg (as protein) For Subcutaneous Use Only single dose vial 1 Vial Rx only Principal Display Panel - 15 mg Vial Label", "PRINCIPAL DISPLAY PANEL - 15 mg Kit Carton NDC 0009-5178-01 Pfizer Somavert ® pegvisomant for injection 15 mg (as protein) For Subcutaneous Injection Only single dose vial Package also contains Sterile Water for Injection, USP Rx only Principal Display Panel - 15 mg Kit Carton", "PRINCIPAL DISPLAY PANEL - 20 mg Vial Label Pfizer Somavert ® pegvisomant for injection 20 mg (as protein) For Subcutaneous Use Only single dose vial 1 Vial Rx only Principal Display Panel - 20 mg Vial Label", "PRINCIPAL DISPLAY PANEL - 20 mg Kit Carton NDC 0009-5180-01 Pfizer Somavert ® pegvisomant for injection 20 mg (as protein) For Subcutaneous Injection Only single dose vial Package also contains Sterile Water for Injection, USP Rx only Principal Display Panel - 20 mg Kit Carton", "PRINCIPAL DISPLAY PANEL - 25 mg Vial Label Pfizer Somavert ® pegvisomant for injection 25 mg (as protein) For Subcutaneous Use Only single dose vial 1 Vial Rx only Principal Display Panel - 25 mg Vial Label", "PRINCIPAL DISPLAY PANEL - 25 mg Kit Carton NDC 0009-5199-01 Pfizer Somavert ® pegvisomant for injection 25 mg (as protein) For Subcutaneous Injection Only single dose vial Package also contains Sterile Water for Injection, USP Rx only Principal Display Panel - 25 mg Kit Carton", "PRINCIPAL DISPLAY PANEL - 30 mg Vial Label Pfizer Somavert ® pegvisomant for injection 30 mg (as protein) For Subcutaneous Use Only single dose vial 1 Vial Rx only Principal Display Panel - 30 mg Vial Label", "PRINCIPAL DISPLAY PANEL - 30 mg Kit Carton NDC 0009-5200-01 Pfizer Somavert ® pegvisomant for injection 30 mg (as protein) For Subcutaneous Injection Only single dose vial Package also contains Sterile Water for Injection, USP Rx only Principal Display Panel - 30 mg Kit Carton" ], "set_id": "222a28ca-70c3-474c-850e-fae39eaaf40f", "id": "c02fdcd0-cfee-4c93-8e49-e6cef8f6ed1d", "effective_time": "20250107", "version": "35", "openfda": {} }, { "spl_product_data_elements": [ "Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE LACTIC ACID, UNSPECIFIED FORM MANNITOL PHENOL SODIUM BICARBONATE WATER Octreotide Acetate Octreotide Acetate OCTREOTIDE ACETATE OCTREOTIDE LACTIC ACID, UNSPECIFIED FORM MANNITOL PHENOL SODIUM BICARBONATE WATER" ], "recent_major_changes": [ "Warnings and Precautions, Steatorrhea and Malabsorption of Dietary Fats ( 5.5 ) 07/2024" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Octreotide acetate injection is a somatostatin analogue indicated: Acromegaly : To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. ( 1.1 ) Carcinoid Tumors : For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. ( 1.2 ) Vasoactive Intestinal Peptide Tumors (VIPomas) : For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. ( 1.3 ) Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide acetate injection; these trials were not optimally designed to detect such effects. ( 1.4 ) 1.1 Acromegaly Octreotide acetate injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. 1.2 Carcinoid Tumors Octreotide acetate injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors Octreotide acetate injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors. 1.4 Important Limitations of Use Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with octreotide acetate injection; these trials were not optimally designed to detect such effects." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Octreotide acetate injection may be administered subcutaneously or intravenously. ( 2.1 ) Acromegaly : Recommended initial octreotide acetate dosage is 50 mcg three times daily during the initial 2 weeks of therapy. Maintenance dose 100 mcg to 500 mcg three times daily. ( 2.2 ) Carcinoid Tumors : Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy. ( 2.3 ) VIPomas : Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. ( 2.4 ) 2.1 Dosage and Administration Overview Octreotide acetate injection may be administered subcutaneously or intravenously. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Sites should be rotated in a systematic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Octreotide acetate injection is not compatible in Total Parenteral Nutrition solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product. Octreotide acetate injection may be diluted in volumes of 50 mL to 200 mL and infused intravenously over 15 to 30 minutes or administered by intravenous (IV) push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus. Assess total and/or free T4 levels at baseline and periodically during chronic octreotide acetate therapy. 2.2 Recommended Dosage and Monitoring for Acromegaly The recommended initial dosage of octreotide acetate is 50 mcg three times daily to be administered subcutaneously. Increase octreotide acetate dose based upon GH or IGF-1 levels. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 levels within normal range. Monitor GH or IGF-1 every two weeks after initiating octreotide acetate therapy or with dosage change, and to guide titration. The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. Octreotide acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide acetate injection therapy may be resumed. 2.3 Recommended Dosage and Monitoring for Carcinoid Tumors The recommended daily dosage of octreotide acetate injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in two to four divided doses given subcutaneously (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. Measurement of urinary 5-hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy. 2.4 Recommended Dosage and Monitoring for Vasoactive Intestinal Peptide Tumors Daily dosages of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required. Measurement of Plasma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Injection: 200 mcg/mL and 1000 mcg/mL of octreotide (as acetate) as a clear solution in a multi-dose vial. Injection: 200 mcg/mL and 1000 mcg/mL of octreotide (as acetate) in a multi-dose vial. ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Sensitivity to this drug or any of its components. Sensitivity to this drug or any of its components. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Cardiac Function Abnormalities : Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving octreotide acetate injection intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. ( 5.1 ) Cholelithiasis and Complications of Cholelithiasis : Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.2 ) Glucose Metabolism : Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. ( 5.3 ) Thyroid Function : Hypothyroidism may occur. Monitor thyroid levels periodically. ( 5.4 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency. ( 5.5 ) 5.1 Cardiac Function Abnormalities Complete Atrioventricular Block Patients who receive octreotide acetate injection intravenously may be at increased risk for higher degree atrioventricular blocks. In postmarketing reports, complete atrioventricular block was reported in patients receiving IV octreotide acetate injection during surgical procedures. In the majority of patients, octreotide acetate injection was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving octreotide acetate injection for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate injection intravenously. Other Cardiac Conduction Abnormalities Other cardiac conduction abnormalities have occurred during treatment with octreotide acetate injection. In acromegalic patients, bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during octreotide acetate injection therapy [see Adverse Reactions (6) ] . Other electrocardiogram (ECG) changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R-wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of octreotide acetate injection therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge. 5.2 Cholelithiasis and Complications of Cholelithiasis Octreotide acetate injection may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide acetate injection therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate injection for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide acetate injection therapy and died. If complications of cholelithiasis are suspected, discontinue octreotide acetate injection and treat appropriately. 5.3 Hyperglycemia and Hypoglycemia Octreotide acetate injection alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate injection therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate injection in 3% and 16% of acromegalic patients, respectively [see Adverse Reactions (6)]. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate injection therapy was reported in one patient with no history of hyperglycemia. Monitor glucose levels during octreotide acetate injection therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly. 5.4 Thyroid Function Abnormalities Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T4) is recommended during chronic therapy [see Adverse Reactions (6)]. 5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including octreotide acetate. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving octreotide acetate, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly 5.6 Changes in Vitamin B 12 Levels Depressed vitamin B 12 levels and abnormal Schilling’s tests have been observed in some patients receiving octreotide acetate injection therapy, and monitoring of vitamin B 12 levels is recommended during octreotide acetate injection therapy." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Complete Atrioventricular Block [see Warnings and Precautions ( 5.1 )] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions ( 5.2 )] Hyperglycemia and Hypoglycemia [see Warnings and Precautions ( 5.3 )] Thyroid Function Abnormalities [see Warnings and Precautions ( 5.4 )] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions ( 5.5 ) Changes in Vitamin B 12 Levels [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (incidence > 10%) in patients with acromegaly are gallbladder abnormalities, sinus bradycardia, diarrhea, loose stools, nausea, abdominal discomfort, hyperglycemia, and hypothyroidism. In other patients, most common adverse reactions (incidence > 10%) are gallbladder abnormalities. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma Limited at 864-879-9994 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, 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. Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic octreotide acetate injection therapy [see Warnings and Precautions (5.1) ] . In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received octreotide acetate injection for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate injection for 1 month or less developed gallstones. Cardiac In acromegalics, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during octreotide acetate injection therapy [see Warnings and Precautions (5.1) ] . Gastrointestinal Diarrhea, loose stools, nausea, and abdominal discomfort were each seen in 34% to 61% of acromegalic patients in U.S. studies. 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5% to 10% of patients with carcinoid tumors and VIPomas. The frequency of these symptoms was not dose related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness, and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 8% and 4% required initiation of thyroid replacement therapy during octreotide acetate injection therapy [see Warnings and Precautions (5.4) ] . In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6%, and dizziness in 5%. Pancreatitis was also observed [see Warnings and Precautions (5.2) ] . Other Adverse Events 1% to 4% Other events, each observed in 1% to 4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance, and depression. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving octreotide acetate injection. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of octreotide acetate injection. 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. Hepatobiliary : cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy Gastrointestinal : intestinal obstruction, pancreatic exocrine insufficiency Hematologic : thrombocytopenia" ], "drug_interactions": [ "7 DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with octreotide acetate injection : cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. ( 7 ) Lutetium Lu 177 Dotatate Injection : Discontinue octreotide acetate injection at least 24 hours prior to each lutetium Lu 177 dotatate dose. ( 7.6 ) 7.1 Cyclosporine Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide acetate injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when octreotide acetate injection treatment is initiated or when the dose is altered and anti-diabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. 7.6 Lutetium Lu 177 Dotatate Injection Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue octreotide acetate injection at least 24 hours prior to each lutetium Lu 177 dotatate dose." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential : Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) 8.1 Pregnancy Risk Summary The limited data with octreotide acetate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA (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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide acetate injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02 to 1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA. 8.2 Lactation Risk Summary There is no information available on the presence of octreotide acetate injection in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that octreotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for octreotide acetate injection, and any potential adverse effects on the breastfed child from octreotide acetate injection or from the underlying maternal condition. Data Following a subcutaneous dose (1 mg/kg) of octreotide to lactating rats, transfer of octreotide into milk was observed at a low concentration compared to plasma (milk/plasma ratio of 0.009). 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility. 8.4 Pediatric Use Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide acetate injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month. 8.5 Geriatric Use Clinical studies of octreotide acetate injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal Impairment In patients with severe renal failure requiring dialysis, the half-life of octreotide acetate may be increased, necessitating adjustment of the maintenance dosage [See Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment-Cirrhotic Patients In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary The limited data with octreotide acetate injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental-effects were observed with IV administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at IV doses below the MRHD based on BSA (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 In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 300 mcg/day of octreotide acetate injection or 20 mg to 30 mg once a month of octreotide acetate for injectable suspension, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received IV doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at IV doses of 0.02 to 1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of GH inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA." ], "pediatric_use": [ "8.4 Pediatric Use Safety and efficacy of octreotide acetate injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate injection in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate injection use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of octreotide acetate injection using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m 2 in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m 2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of octreotide acetate injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy." ], "overdosage": [ "10 OVERDOSAGE A limited number of accidental overdoses of octreotide acetate injection in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss. If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222." ], "description": [ "11 DESCRIPTION Octreotide acetate injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered lactic acid solution for administration by deep subcutaneous or IV injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-,cyclic (2 → 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. Octreotide acetate injection is available as sterile 5 mL multi-dose vials in 2 strengths, containing 200 mcg or 1000 mcg octreotide (as acetate). Each mL of multi-dose vials also contains lactic acid, USP (3.4 mg), mannitol, USP (45 mg), phenol, USP (5.0 mg), sodium bicarbonate, USP (quantity sufficient to pH 4.2 ± 0.3), water for injection, USP (quantity sufficient to 1 mL). Lactic acid and sodium bicarbonate are added to provide a buffered solution, pH to 4.2 ± 0.3. The molecular weight of octreotide acetate is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: octreotide-spl-structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Octreotide acetate injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea). 12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2) ] . Octreotide suppresses secretion of TSH. 12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, IV and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. In patients with acromegaly, the volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of octreotide acetate injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal impairment (CL CR 40 to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR 10 to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal impairment not requiring dialysis (CL CR < 10 mL/min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. 12.6 Immunogenicity Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate injection were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients." ], "mechanism_of_action": [ "12.1 Mechanism of Action Octreotide acetate injection exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea)." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly. Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2) ] . Octreotide suppresses secretion of TSH." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, IV and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve (AUC) values were dose proportional after IV single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg 3 times a day (1,500 mcg/day). In patients with acromegaly, a mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. Distribution In healthy volunteers, the distribution of octreotide from plasma was rapid (tα½ = 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. In patients with acromegaly, the volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L, and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. Elimination The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of octreotide acetate injection is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the disposition and elimination half-lives were similar to normal subjects. Specific Populations Renal Impairment In patients with mild renal impairment (CL CR 40 to 60 mL/min), octreotide t 1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (CL CR 10 to 39 mL/min) t 1/2 was 3.0 hours and total body clearance 7.3 L/hr. In patients with severe renal impairment not requiring dialysis (CL CR < 10 mL/min), octreotide t 1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Hepatic Impairment Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t 1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t 1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate injection. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Octreotide acetate injection is available in 5 mL multi-dose vials as follows: NDC Package 68083-515-01 200 mcg/mL octreotide (as acetate) - 5 mL fill Box of one 68083-516-01 1000 mcg/mL octreotide (as acetate) - 5 mL fill Box of one Storage and Handling For prolonged storage, octreotide acetate injection multi-dose vials should be stored at refrigerated temperatures 2°C to 8°C (36°F to 46°F) and store in outer carton in order to protect from light. At room temperature (20°C to 30°C or 70°F to 86°F), octreotide acetate injection is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Dispose unused product or waste properly. Octreotide acetate injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours." ], "how_supplied_table": [ "
NDC Package
68083-515-01 200 mcg/mL octreotide (as acetate) - 5 mL fill Box of one
68083-516-01 1000 mcg/mL octreotide (as acetate) - 5 mL fill Box of one
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Sterile Subcutaneous Injection Technique Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer octreotide acetate injection. Cholelithiasis and Complications of Cholelithiasis Advise patients to contact their healthcare provider if they experience signs or symptoms of gallstones (cholelithiasis) or complications of cholelithiasis (e.g., cholecystitis, cholangitis, and pancreatitis) [see Warnings and Precautions (5.2) ]. Steatorrhea and Malabsorption of Dietary Fats Advise patients to contact their healthcare provider if they experience new or worsening of steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss [see Warnings and Precautions (5.5) ]. Pregnancy Inform female patients that treatment with octreotide acetate injection may result in unintended pregnancy [see Use in Specific Populations (8.3) ]. Manufactured by: Gland Pharma Limited Pashamylaram, Hyderabad -502307, India. Revised: 07/2024" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Vial Label - 1,000 mcg/5 mL (200 mcg/mL) NDC 68083-515-01 Rx only Octreotide Acetate Injection 1,000 mcg/5 mL (200 mcg/mL) FOR SUBCUTANEOUS OR INTRAVENOUS INJECTION 5 mL Multiple-Dose Vial Carton Label - 1,000 mcg/5 mL (200 mcg/mL) NDC 68083-515-01 Rx only Octreotide Acetate Injection 1,000 mcg/5 mL (200 mcg/mL) FOR SUBCUTANEOUS OR INTRAVENOUS INJECTION STORE REFRIGERATED AT 2°C to 8°C (36°F to 46°F); PROTECT FROM LIGHT. AFTER INITIAL USE, DISCARD WITHIN 14 DAYS 5 mL Multiple-Dose Vial Vial Label - 5,000 mcg/5 mL (1,000 mcg/mL) NDC 68083-516-01 Rx only Octreotide Acetate Injection 5,000 mcg/5 mL (1000 mcg/mL) FOR SUBCUTANEOUS OR INTRAVENOUS INJECTION 5 mL Multiple-Dose Vial Carton Label - 5,000 mcg/5 mL (1,000 mcg/mL) NDC 68083-516-01 Rx only Octreotide Acetate Injection 5,000 mcg/5 mL (1,000 mcg/mL) FOR SUBCUTANEOUS OR INTRAVENOUS INJECTION STORE REFRIGERATED AT 2°C to 8°C (36°F to 46°F); PROTECT FROM LIGHT. AFTER INITIAL USE, DISCARD WITHIN 14 DAYS 5 mL Multiple-Dose Vial octreotide-spl-1000-mcg-vial octreotide-spl-1000-mcg-carton octreotide-spl-5000-mcg-vial octreotide-spl-5000-mcg-carton" ], "set_id": "2344ae7a-c2f0-433b-9133-1dcb16bb18a0", "id": "5869eaa3-e390-4dff-97df-1adf431ef64f", "effective_time": "20240725", "version": "7", "openfda": { "application_number": [ "ANDA216807" ], "brand_name": [ "Octreotide Acetate" ], "generic_name": [ "OCTREOTIDE ACETATE" ], "manufacturer_name": [ "Gland Pharma Limited" ], "product_ndc": [ "68083-515", "68083-516" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "INTRAVENOUS", "SUBCUTANEOUS" ], "substance_name": [ "OCTREOTIDE ACETATE" ], "rxcui": [ "312071", "314152" ], "spl_id": [ "5869eaa3-e390-4dff-97df-1adf431ef64f" ], "spl_set_id": [ "2344ae7a-c2f0-433b-9133-1dcb16bb18a0" ], "package_ndc": [ "68083-515-01", "68083-516-01" ], "is_original_packager": [ true ], "upc": [ "0368083515010", "0368083516017" ], "unii": [ "75R0U2568I" ] } } ] }