{ "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": 249 } }, "results": [ { "spl_product_data_elements": [ "Sildenafil Sildenafil CELLULOSE, MICROCRYSTALLINE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSES TITANIUM DIOXIDE TRIACETIN CALCIUM PHOSPHATE, DIBASIC, DIHYDRATE SILDENAFIL CITRATE SILDENAFIL round C89" ], "recent_major_changes": [ "Warnings and Precautions, Visual Loss ( 5.5 ) 07/2017" ], "indications_and_usage": [ "1 INDICATIONS & USAGE Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [ see Clinical Studies (14) ]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [ see Clinical Studies ( 14 ) ]. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). ( 1 ) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1 , 14 )" ], "dosage_and_administration": [ "2 DOSAGE & ADMINISTRATION Tablet: 20 mg three times a day, 4-6 hours apart ( 2.1 ) 2.1 Sildenafil Tablets The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablets doses 4-6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS & STRENGTHS Sildenafil Tablets, USP Sildenafil tablets, USP are supplied as white to white-off, film-coated, round tablets debossed with \"C 89\" on one side and plain on the other side containing sildenafil citrate equivalent to 20 mg of sildenafil. Tablets: 20 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil tablets are contraindicated in patients with: • Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [ see Warnings and Precautions (5.2) ]. • Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. • Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. • Use with organic nitrates or riociguat ( 4 ) • History of hypersensitivity reaction to sildenafil or any component of the tablet ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. ( 5.1 ) • Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.2 ) • Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. ( 5.3 ) • Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.5 , 5.6 ) • Pulmonary hypertension secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. ( 5.9 ) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children [ see Use in Specific Populations (8.4) ]. 5.2 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil. 5.3 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. these studies. [ ]. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil with caution in these patients. When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [ see Adverse Reactions ( 6.2 ]. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.7 Combination with other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PAH secondary to sickle cell anemia has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: • Mortality with pediatric use[ see Warnings and Precautions (5.1 ) and Use in Specific Populations (8.4) ] • Hypotension [ see Warnings and Precautions (5.2) ] • Vision loss [ see Warnings and Precautions (5.5) ] • Hearing loss [ see Warnings and Precautions (5.6) ] • Priapism [ see Warnings and Precautions (5.8) ] • Vaso-occlusive crisis [ see Warnings and Precautions (5.9) ] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 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. Safety data of sildenafil in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I [see Clinical Studies (14)] . The overall frequency of discontinuation in sildenafil-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil-treated patients (20 mg three times a day) and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients) Placebo, % (n = 70) Sildenafil tablets 20 mg three times a day, % (n = 69) Placebo-Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14) ]. Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol)minus Epoprostenol % Headache 57 34 23 Edema includes peripheral edema 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous system Seizure, seizure recurrence Ophthalmologic NAION [ see Warnings and Precautions ( 5.5 ) and Patient Counseling Information ( 17 ) ]." ], "adverse_reactions_table": [ "
Placebo, % (n = 70) Sildenafil tablets 20 mg three times a day, % (n = 69) Placebo-Subtracted, %
Epistaxis198
Headache39467
Dyspepsia7136
Flushing4106
Insomnia176
Erythema165
Dyspnea exacerbated374
Rhinitis044
Diarrhea693
Myalgia473
Pyrexia363
Gastritis033
Sinusitis033
Paresthesia033
", "
Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol)minus Epoprostenol %
Headache573423
Edema includes peripheral edema251314
Dyspepsia16214
Pain in extremity17611
Diarrhea25187
Nausea25187
Nasal congestion927
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [ see Contraindications (4) ]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended [ see Clinical Pharmacology (12.3) ]. Other drugs that reduce blood pressure Alpha blockers . In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine . When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil [ see Warnings and Precautions (5.2) ]. • Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7) • Use with ritonavir and other potent CYP3A inhibitors: Not recommended. (7, 12.3) • Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. (5.7)" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension ( see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively ( See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. 8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose. During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig-6 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) ]. 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology 12.3) ]. 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [ see Clinical Pharmacology (12.3) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension ( see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively ( See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "pediatric_use": [ "8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose. During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig-6" ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) ]." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION Sildenafil citrate, USP phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula : Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, USP each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide and triacetin. str" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [ see Clinical Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn.s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn.s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [ Study 3 in Clinical Studies ( 14 ) ], there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4) ]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20-50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8: Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administration with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. figure-7 fig-8" ], "clinical_pharmacology_table": [ "
Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn.s/cm 5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn.s/cm 5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [ see Clinical Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn.s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn.s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [ Study 3 in Clinical Studies ( 14 ) ], there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4) ]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry." ], "pharmacodynamics_table": [ "
Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn.s/cm 5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn.s/cm 5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20-50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8: Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administration with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. figure-7 fig-8" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6 minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 10. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. figure-9 figure-10 Table 4. Clinical Worsening Events in Study 2 Placebo (N = 131) Sildenafil Tablets (N = 134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10) Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2 Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6- minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil added to bosentan therapy – lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone . figure-11 fig-12" ], "clinical_studies_table": [ "
Placebo (N = 131) Sildenafil Tablets (N = 134)
Number of subjects with clinical worsening first event 23 8
First Event All Events First Event All Events
Death, n 3 4 0 0
Lung Transplantation, n 1 1 0 0
Hospitalization due to PAH, n 9 11 8 8
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n 9 16 0 2
Initiation of Bosentan, n 1 1 0 0
Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil tablets, USP are supplied as white to off-white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Sildenafil Tablets Package Configuration Strength NDC Debossing on Tablet Bottle of 30 Tablets 20 mg 76420-061-30 repackaged from NDC 33342-121-10 “C 89” Bottle of 60 Tablets 20 mg 76420-061-60 repackaged from NDC 33342-121-10 “C 89” Bottle of 90 Tablets 20 mg 76420-061-90 relabeled from NDC 33342-121-10 “C 89” Recommended Storage for Sildenafil Tablets, USP: Store at controlled room temperature 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature]. Dispense in tight containers (USP)." ], "how_supplied_table": [ "
Sildenafil Tablets
Package ConfigurationStrengthNDCDebossing on Tablet
Bottle of 30 Tablets 20 mg 76420-061-30 repackaged from NDC 33342-121-10 “C 89”
Bottle of 60 Tablets20 mg 76420-061-60 repackaged from NDC 33342-121-10“C 89”
Bottle of 90 Tablets20 mg76420-061-90 relabeled from NDC 33342-121-10“C 89”
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Inform patients of contraindication of sildenafil tablets 20 mg with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets 20 mg not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets 20 mg. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets 20 mg. These events may be accompanied by tinnitus and dizziness. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 PATIENT INFORMATION Sildenafil (sil-DEN-a-fil) Tablets Read this Patient Information before you start taking sildenafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil tablets, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called “poppers” (amyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What are sildenafil tablets? Sildenafil tablets are a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil tablets improve the ability to exercise and can slow down worsening changes in your physical condition. • Sildenafil tablets are not for use in children • Adding sildenafil tablets to another medication used to treat PAH, bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil tablets 20 mg contain the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets 20 mg with VIAGRA or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: • take nitrate medicines. See “ What is the most important information I should know about sildenafil tablets?” • take guanylate cyclase stimulator medicines. See “What is the most important information I should know about sildenafil tablets?” • are allergic to sildenafil or any other ingredient in sildenafil tablets. See “ What are the ingredients in sildenafil tablets? ” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? Tell your doctor about all of your medical conditions, including if you • have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack • have a disease called pulmonary veno-occlusive disease (PVOD) • have high or low blood pressure or blood circulation problems • have an eye problem called retinitis pigmentosa • have or had loss of sight in one or both eyes • have any problem with the shape of your penis or Peyronie’s disease • have any blood cell problems such sickle cell anemia • have a stomach ulcer or any bleeding problems • are pregnant or planning to become pregnant. It is not known if sildenafil tablets could harm your unborn baby. • are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil tablets and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil tablets. Especially tell your doctor if you take • Nitrate medicines. See “ What is the most important information I should know about sildenafil tablets? ” • Riociguat (Adempas). See “What is the most important information I should know about sildenafil tablets?” • Ritonavir (Norvir®) or other medicines used to treat HIV infection • Ketoconazole (Nizoral®) • Itraconazole (Sporanox) • High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil tablets? • Take sildenafil tablets exactly as your doctor tells you. Sildenafil may be prescribed to you as • Sildenafil tablets • Take sildenafil tablet 3 times a day about 4 to 6 hours apart. • Take sildenafil tablets at the same times every day. • If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. • Do not take more than one dose of sildenafil tablets at a time. • Do not change your dose or stop taking sildenafil tablets on your own. Talk to your doctor first. • If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? • low blood pressure . Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. • more shortness of breath than usual . Tell your doctor if you get more short of breath after you start sildenafil tablets. More shortness of breath than usual may be due to your underlying medical condition. • decreased eyesight or loss of sight in one or both eyes (NAION) . If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. • sudden decrease or loss of hearing . If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil tablets, or to other diseases or medicines, to other factors, or to a combination of factors. • heart attack, stroke, irregular heartbeats, and death . Most of these happened in men who already had heart problems. • erections that last several hours . If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil tablets include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn’t go away. These are not all the possible side effects of sildenafil tablets. 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. How should I store sildenafil tablets? • Store sildenafil tablets at controlled room temperature, between 20° to 25°C (68° to 77°F). • Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. For more information call 1-888-943-3210. What are the ingredients in sildenafil tablets? Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, triacetin This Patient Information has been approved by the U.S. Food and Drug Administration. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501", "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Inform patients of contraindication of sildenafil tablets 20 mg with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets 20 mg not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets 20 mg. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets 20 mg. These events may be accompanied by tinnitus and dizziness. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 PATIENT INFORMATION Sildenafil (sil-DEN-a-fil) Tablets Read this Patient Information before you start taking sildenafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil tablets, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called “poppers” (amyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What are sildenafil tablets? Sildenafil tablets are a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil tablets improve the ability to exercise and can slow down worsening changes in your physical condition. • Sildenafil tablets are not for use in children • Adding sildenafil tablets to another medication used to treat PAH, bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil tablets 20 mg contain the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets 20 mg with VIAGRA or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: • take nitrate medicines. See “ What is the most important information I should know about sildenafil tablets?” • take guanylate cyclase stimulator medicines. See “What is the most important information I should know about sildenafil tablets?” • are allergic to sildenafil or any other ingredient in sildenafil tablets. See “ What are the ingredients in sildenafil tablets? ” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? Tell your doctor about all of your medical conditions, including if you • have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack • have a disease called pulmonary veno-occlusive disease (PVOD) • have high or low blood pressure or blood circulation problems • have an eye problem called retinitis pigmentosa • have or had loss of sight in one or both eyes • have any problem with the shape of your penis or Peyronie’s disease • have any blood cell problems such sickle cell anemia • have a stomach ulcer or any bleeding problems • are pregnant or planning to become pregnant. It is not known if sildenafil tablets could harm your unborn baby. • are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil tablets and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil tablets. Especially tell your doctor if you take • Nitrate medicines. See “ What is the most important information I should know about sildenafil tablets? ” • Riociguat (Adempas). See “What is the most important information I should know about sildenafil tablets?” • Ritonavir (Norvir®) or other medicines used to treat HIV infection • Ketoconazole (Nizoral®) • Itraconazole (Sporanox) • High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil tablets? • Take sildenafil tablets exactly as your doctor tells you. Sildenafil may be prescribed to you as • Sildenafil tablets • Take sildenafil tablet 3 times a day about 4 to 6 hours apart. • Take sildenafil tablets at the same times every day. • If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. • Do not take more than one dose of sildenafil tablets at a time. • Do not change your dose or stop taking sildenafil tablets on your own. Talk to your doctor first. • If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? • low blood pressure . Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. • more shortness of breath than usual . Tell your doctor if you get more short of breath after you start sildenafil tablets. More shortness of breath than usual may be due to your underlying medical condition. • decreased eyesight or loss of sight in one or both eyes (NAION) . If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. • sudden decrease or loss of hearing . If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil tablets, or to other diseases or medicines, to other factors, or to a combination of factors. • heart attack, stroke, irregular heartbeats, and death . Most of these happened in men who already had heart problems. • erections that last several hours . If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil tablets include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn’t go away. These are not all the possible side effects of sildenafil tablets. 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. How should I store sildenafil tablets? • Store sildenafil tablets at controlled room temperature, between 20° to 25°C (68° to 77°F). • Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. For more information call 1-888-943-3210. What are the ingredients in sildenafil tablets? Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, triacetin This Patient Information has been approved by the U.S. Food and Drug Administration. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501", "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Inform patients of contraindication of sildenafil tablets 20 mg with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets 20 mg not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets 20 mg. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets 20 mg. These events may be accompanied by tinnitus and dizziness. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 PATIENT INFORMATION Sildenafil (sil-DEN-a-fil) Tablets Read this Patient Information before you start taking sildenafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil tablets, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called “poppers” (amyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What are sildenafil tablets? Sildenafil tablets are a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil tablets improve the ability to exercise and can slow down worsening changes in your physical condition. • Sildenafil tablets are not for use in children • Adding sildenafil tablets to another medication used to treat PAH, bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil tablets 20 mg contain the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets 20 mg with VIAGRA or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: • take nitrate medicines. See “ What is the most important information I should know about sildenafil tablets?” • take guanylate cyclase stimulator medicines. See “What is the most important information I should know about sildenafil tablets?” • are allergic to sildenafil or any other ingredient in sildenafil tablets. See “ What are the ingredients in sildenafil tablets? ” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? Tell your doctor about all of your medical conditions, including if you • have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack • have a disease called pulmonary veno-occlusive disease (PVOD) • have high or low blood pressure or blood circulation problems • have an eye problem called retinitis pigmentosa • have or had loss of sight in one or both eyes • have any problem with the shape of your penis or Peyronie’s disease • have any blood cell problems such sickle cell anemia • have a stomach ulcer or any bleeding problems • are pregnant or planning to become pregnant. It is not known if sildenafil tablets could harm your unborn baby. • are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil tablets and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil tablets. Especially tell your doctor if you take • Nitrate medicines. See “ What is the most important information I should know about sildenafil tablets? ” • Riociguat (Adempas). See “What is the most important information I should know about sildenafil tablets?” • Ritonavir (Norvir®) or other medicines used to treat HIV infection • Ketoconazole (Nizoral®) • Itraconazole (Sporanox) • High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil tablets? • Take sildenafil tablets exactly as your doctor tells you. Sildenafil may be prescribed to you as • Sildenafil tablets • Take sildenafil tablet 3 times a day about 4 to 6 hours apart. • Take sildenafil tablets at the same times every day. • If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. • Do not take more than one dose of sildenafil tablets at a time. • Do not change your dose or stop taking sildenafil tablets on your own. Talk to your doctor first. • If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? • low blood pressure . Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. • more shortness of breath than usual . Tell your doctor if you get more short of breath after you start sildenafil tablets. More shortness of breath than usual may be due to your underlying medical condition. • decreased eyesight or loss of sight in one or both eyes (NAION) . If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. • sudden decrease or loss of hearing . If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil tablets, or to other diseases or medicines, to other factors, or to a combination of factors. • heart attack, stroke, irregular heartbeats, and death . Most of these happened in men who already had heart problems. • erections that last several hours . If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil tablets include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn’t go away. These are not all the possible side effects of sildenafil tablets. 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. How should I store sildenafil tablets? • Store sildenafil tablets at controlled room temperature, between 20° to 25°C (68° to 77°F). • Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. For more information call 1-888-943-3210. What are the ingredients in sildenafil tablets? Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, triacetin This Patient Information has been approved by the U.S. Food and Drug Administration. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Repackaged and Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL label" ], "set_id": "06571775-b651-4e23-a35b-88392aae7e13", "id": "e785ec65-b5e8-693c-e053-2995a90aa9e7", "effective_time": "20220831", "version": "2", "openfda": { "application_number": [ "ANDA203814" ], "brand_name": [ "Sildenafil" ], "generic_name": [ "SILDENAFIL" ], "manufacturer_name": [ "Asclemed USA, Inc." ], "product_ndc": [ "76420-061" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "SILDENAFIL CITRATE" ], "rxcui": [ "577033" ], "spl_id": [ "e785ec65-b5e8-693c-e053-2995a90aa9e7" ], "spl_set_id": [ "06571775-b651-4e23-a35b-88392aae7e13" ], "package_ndc": [ "76420-061-30", "76420-061-60", "76420-061-90" ], "original_packager_product_ndc": [ "33342-121" ], "unii": [ "BW9B0ZE037" ] } }, { "spl_product_data_elements": [ "Sildenafil Sildenafil citrate SILDENAFIL CITRATE SILDENAFIL ANHYDROUS CITRIC ACID SODIUM BENZOATE TRISODIUM CITRATE DIHYDRATE SUCRALOSE TITANIUM DIOXIDE SORBITOL XANTHAN GUM SILICON DIOXIDE (OFF-WHITE) ART-GRAPE" ], "recent_major_changes": [ "Indications and Usage (1) 1/2023 Dosage and Administration (2.1, 2.2, 2.3) 1/2023" ], "indications_and_usage": [ "1 INDICATIONS & USAGE Adults Sildenafil for oral suspension is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies (14)] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information Adults Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening. (1)" ], "dosage_and_administration": [ "2 DOSAGE & ADMINISTRATION Adults: 20 mg three times a day. (2.1) 2.1 Recommended Dosage in Adults Oral Dosage The recommended dosage of sildenafil for oral suspension is 20 mg three times a day. [see Clinical Studies (14)] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Reconstitution of the Powder for Oral Suspension Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL) . Refer to the detailed instructions below. Tap the bottle to loosen the powder. Add 60 mL of water to the bottle. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. Add another 30 mL of water to the bottle. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle. Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution). Incompatibilities Do not mix with any other medication or additional flavoring agent." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS & STRENGTHS Sildenafil for Oral Suspension White to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2-mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. For oral suspension: 10 mg/mL (when reconstituted) (3)" ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.1)] . Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates or riociguat. (4) History of hypersensitivity reaction to sildenafil or any component of the oral suspension. (4)" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. (5.1) Use in pulmonary veno-occlusive disease (PVOD) may cause pulmonary edema and is not recommended. (5.2) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. (5.4, 5.5) Pulmonary hypertension (PH) secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. (5.8) 5.1 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil. 5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.3 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.4 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported post marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”). Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil in patients with retinitis pigmentosa is not recommended. 5.5 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.6 Combination with Other PDE-5 Inhibitors Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. 5.7 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PH secondary to sickle cell disease has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1)] Vision Loss [see Warnings and Precautions (5.4)] Hearing Loss [see Warnings and Precautions (5.5)] Priapism [see Warnings and Precautions (5.7)] Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8)] Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and diarrhea. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Novitium Pharma LLC at 1- 855-204-1431 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, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil-treated adults with PAH (WHO Group I) [see Clinical Studies (14)] the adverse reactions that were reported by at least 10% of sildenafil-treated patients in any dosing group, and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients) Sildenafil 20 mg (n = 69) Sildenafil 40 mg (n = 67) Sildenafil 80 mg (n = 71) Placebo (n = 70) Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6% In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous System Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)] ." ], "adverse_reactions_table": [ "
Sildenafil 20 mg (n = 69) Sildenafil 40 mg (n = 67) Sildenafil 80 mg (n = 71) Placebo (n = 70)
Headache 46% 42% 49% 39%
Flushing 10% 9% 16% 4%
Pain in Limb 7% 15% 9% 6%
Myalgia 7% 6% 14% 4%
Back Pain 13% 13% 9% 11%
Dyspepsia 13% 8% 13% 7%
Diarrhea 9% 12% 10% 6%
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4)] . Strong CYP3A Inhibitors Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)] . Moderate-to-Strong CYP3A Inducers Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)] . Use with strong CYP3A inhibitors: Not recommended. (7, 12.3) Concomitant PDE-5 inhibitors: Avoid use with Viagra® or other PDE-5 inhibitors. (5.6)" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation 8.4 Pediatric Use The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)] . 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)] . 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3)] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)] ." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION Sildenafil, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE- 5). Sildenafil is also marketed as VIAGRA® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H - pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil for Oral Suspension is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the total volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided. structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti- aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn⋅s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn⋅s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. ∗The number of patients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half- lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N- desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age- matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child- Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Figure7 Figure8" ], "clinical_pharmacology_table": [ "
Placebo (n = 65)* Sildenafil 20 mg (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn⋅s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn⋅s/cm5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti- aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn⋅s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn⋅s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. ∗The number of patients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4)] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "pharmacodynamics_table": [ "
Placebo (n = 65)* Sildenafil 20 mg (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn⋅s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn⋅s/cm5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half- lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N- desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age- matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child- Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Figure7 Figure8" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6- minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12. Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6- Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval) Key : PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88%, and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) - Sildenafil Co-administered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil- treated patients experienced a significant delay in time to clinical worsening versus placebo- treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5. Table 4. Clinical Worsening Events in PACES-1 Placebo (N = 131) Sildenafil (N = 134) Number of patients with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10) Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) - Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. figure-3 figure-4 figure-5" ], "clinical_studies_table": [ "
Placebo (N = 131) Sildenafil (N = 134)
Number of patients with clinical worsening first event 23 8
First Event All Events First Event All Events
Death, n 3 4 0 0
Lung transplantation, n 1 1 0 0
Hospitalization due to PAH, n 9 11 8 8
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n 9 16 0 2
Initiation of Bosentan, n 1 1 0 0
Proportion worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil powder for oral suspension is supplied in amber glass bottles. Each bottle contains white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil). Following reconstitution, the total volume of the oral suspension is 112 mL (10 mg sildenafil/mL). A 2 mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. Sildenafil for Oral Suspension, 10 mg/mL Package Configuration Strength NDC Powder for oral suspension - 125 mL Amber Glass Bottle 10 mg/mL (when reconstituted) 70954-168-10 Recommended storage for sildenafil for oral suspension: Store below 30°C (86°F) in the original package in order to protect from moisture. Recommended storage for reconstituted oral suspension: Store below 30°C (86°F) or in refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. The shelf-life of the reconstituted oral suspension is 60 days. Any remaining oral suspension should be discarded 60 days after reconstitution." ], "how_supplied_table": [ "
Sildenafil for Oral Suspension, 10 mg/mL
Package Configuration Strength NDC
Powder for oral suspension - 125 mL Amber Glass Bottle 10 mg/mL (when reconstituted) 70954-168-10
" ], "information_for_patients": [ "17 PATIENT COUNSELLING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Inform patients of contraindication of sildenafil with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil. These events may be accompanied by tinnitus and dizziness. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Novitium Pharma LLC. Manufactured by: Novitium Pharma LLC, 70 Lake Drive, East Windsor New Jersey 08520 LB4137-03 Revised: 01/2024" ], "spl_patient_package_insert": [ "PATIENT INFORMATION Sildenafil (sil den’ a fil) for oral suspension What is the most important information I should know about sildenafil for oral suspension? Never take sildenafil for oral suspension with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrates include: Medicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Isosorbide mononitrate or dinitrate Street drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. See “What are the possible side effects of sildenafil for oral suspension?” for more information about side effects. What is sildenafil for oral suspension? Sildenafil for oral suspension is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. Sildenafil for oral suspension may be used in: adults to improve your ability to exercise and help slow down the worsening of your physical condition. It is not known if sildenafil for oral suspension is safe and effective in children younger than 1 year of age. Do not take sildenafil for oral suspension if you: take medicines called nitrates. take riociguat, a guanylate cyclase stimulator medicine. are allergic to sildenafil or any of the ingredients in sildenafil for oral suspension. See the end of this leaflet for a complete list of ingredients in sildenafil for oral suspension. Before taking sildenafil for oral suspension, tell your healthcare provider about all of your medical conditions, including if you: have low blood pressure have heart problems have pulmonary veno-occlusive disease (PVOD) have bleeding problems or a stomach (peptic) ulcer. It is not known if sildenafil for oral suspension is safe in people with bleeding problems or who have a stomach ulcer. have an eye problem called retinitis pigmentosa have ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing have a deformed penis shape or Peyronie’s disease have any blood cell problems such as sickle cell anemia are pregnant or plan to become pregnant. It is not known if sildenafil for oral suspension will harm your unborn baby. are breastfeeding or plan to breastfeed. Sildenafil for oral suspension passes into your breast milk. It is not known if it can harm your baby. Talk with your healthcare provider about the best way to feed your baby during treatment with sildenafil for oral suspension. Tell your healthcare provider about all of the medicines you take , including prescription and over- the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take: nitrates or guanylate cyclase stimulators. See “What is the most important information I should know about sildenafil for oral suspension?” medicines to treat high blood pressure medicines for erectile dysfunction (impotence). Sildenafil for oral suspension contains sildenafil, which is the same medicine found in another medicine called VIAGRA®. VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with sildenafil for oral suspension. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take sildenafil for oral suspension? Take or give sildenafil for oral suspension exactly as your healthcare provider tells you. Your healthcare provider may change your dose of sildenafil for oral suspension as needed. Do not change your dose or stop taking sildenafil for oral suspension without talking to your healthcare provider. Sildenafil may be prescribed to you as sildenafil for oral suspension. Take your prescribed dose of sildenafil for oral suspension 3 times a day. See the detailed Instructions for Use that comes with sildenafil for oral suspension for information on how to take or give sildenafil for oral suspension. Sildenafil for oral suspension will be mixed for you by your pharmacist. Do not mix Sildenafil for oral suspension with other medicine or flavoring. If you take too much sildenafil for oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of sildenafil for oral suspension? Sildenafil for oral suspension may cause serious side effects, including: See “What is the most important information I should know about sildenafil for oral suspension?” Decreased blood pressure . Sildenafil for oral suspension may cause low blood pressure that last for a short time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with sildenafil for oral suspension. Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with sildenafil for oral suspension, contact your healthcare provider right away. Sudden decrease or loss of hearing , sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing during treatment with sildenafil for oral suspension, contact your healthcare provider right away. In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections. The most common side effects of sildenafil for oral suspension in adults include: nosebleeds headache upset stomach getting red or hot in the face (flushing) arm or leg pain muscle aches and pain back pain diarrhea These are not all the possible side effects of sildenafil for oral suspension. 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 sildenafil for oral suspension? Store mixed (reconstituted) sildenafil oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze mixed sildenafil oral suspension. Throw away (discard) any remaining sildenafil oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label. Keep sildenafil for oral suspension and all medicines out of the reach of children. General information about the safe and effective use of sildenafil for oral suspension. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil for oral suspension for a condition for which it was not prescribed. Do not give sildenafil for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about sildenafil for oral suspension that is written for health professionals. What are the ingredients in sildenafil for oral suspension? Active ingredients : sildenafil citrate Inactive ingredients : Sildenafil for oral suspension : sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Novitium Pharma LLC. Manufactured by: Novitium Pharma LLC, 70 Lake Drive, East Windsor New Jersey 08520 This Patient Information has been approved by the U.S. Food and Drug Administration. LB4137-03 Revised: 01/2024 Instructions for Use Sildenafil (sil den’ a fil) for oral suspension Read this Instructions for Use before you start taking sildenafil oral suspension and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information: Ask your healthcare provider or pharmacist to show you how to measure and take your prescribed dose of sildenafil oral suspension. Your pharmacist will mix (reconstitute) sildenafil oral suspension before it is given to you. Do not take or give sildenafil oral suspension and contact your pharmacist if the medicine in the bottle is still a powder. Always use the oral dosing syringe that comes with sildenafil oral suspension. If your carton does not come with an oral dosing syringe, contact your pharmacist. Do not take or give sildenafil oral suspension if the bottle adaptor is not in the bottle. If the bottle adaptor is not in the bottle, contact your pharmacist. Sildenafil oral suspension should not be mixed with any other medicine or flavoring. Supplies you will need to take or give a dose of sildenafil oral suspension (See Figure A): 1 bottle of sildenafil oral suspension with pre-inserted bottle adaptor 1 oral dosing syringe (provided in the carton) Step 1. Shake the bottle of sildenafil oral suspension for 10 seconds before each use. (See Figure B) Step 2. Remove the cap. Open the bottle by pushing down on the cap and twisting it in the direction of the arrow (counter-clockwise). (See Figure C) Step 3. Fully push down (depress) the plunger of the oral dosing syringe. Then insert the tip of the oral dosing syringe into the bottle adaptor while holding the bottle upright, on a flat surface. (See Figure D) Step 4. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back the plunger of the oral dosing syringe until the bottom of the plunger is even with the mL marking on the syringe for your prescribed dose. (See Figure E) If your dose of sildenafil oral suspension is 1 mL (10 mg), measure 0.5 mL two times for a total of 1 mL of sildenafil oral suspension. If your dose of sildenafil oral suspension is more than 2 mL (20 mg), you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to prepare the divided dose. If you see air bubbles in the oral dosing syringe, slowly push the plunger all the way up so that sildenafil oral suspension flows back into the bottle and repeat Step 4. Step 5. Turn the bottle back upright with the oral dosing syringe still in place. Place the bottle on a flat surface. Remove the oral dosing syringe from the bottle adaptor by pulling straight up on the barrel of the oral dosing syringe. (See Figure F) Do not press on the plunger of the oral dosing syringe at this time. Step 6. Put the tip of the oral dosing syringe into your mouth and point it towards the inside of the cheek. Slowly push the plunger of the oral dosing syringe all the way down to give the entire dose. Do not squirt the medicine out quickly. (See Figure G) If you are giving sildenafil oral suspension, make sure they are in an upright position before giving the medicine. Step 7. Replace the cap on the bottle, leaving the bottle adaptor in place. Turn the cap in the direction of the arrow (clockwise) to close the bottle. (See Figure H) Step 8. Wash the oral dosing syringe after each use. Pull the plunger out of the barrel and rinse both parts with water. (See Figure I) Step 9. Dry all parts with a clean paper towel. Push the plunger back into the barrel. Store the oral dosing syringe with the sildenafil oral suspension bottle. How should I store sildenafil oral suspension? Store mixed (reconstituted) sildenafil oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze mixed sildenafil oral suspension. Throw away (discard) any remaining sildenafil oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label. Keep sildenafil for oral suspension and all medicines out of the reach of children. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Novitium Pharma LLC. Manufactured by: Novitium Pharma LLC, 70 Lake Drive, East Windsor New Jersey 08520 This Instruction for Use has been approved by the U.S. Food and Drug Administration. LB4137-03 Revised: 01/2024 ifu-1 ifu-2 ifu-3 ifu-4 ifu-5 ifu-6 ifu-7 ifu-8 ifu-9" ], "spl_patient_package_insert_table": [ "
Sildenafil (sil den’ a fil) for oral suspension
What is the most important information I should know about sildenafil for oral suspension? Never take sildenafil for oral suspension with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrates include: Medicines that treat chest pain (angina)Nitroglycerin in any form including tablets, patches, sprays, and ointmentsIsosorbide mononitrate or dinitrateStreet drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. See “What are the possible side effects of sildenafil for oral suspension?” for more information about side effects.
What is sildenafil for oral suspension? Sildenafil for oral suspension is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. Sildenafil for oral suspension may be used in: adults to improve your ability to exercise and help slow down the worsening of your physical condition.It is not known if sildenafil for oral suspension is safe and effective in children younger than 1 year of age.
Do not take sildenafil for oral suspension if you: take medicines called nitrates.take riociguat, a guanylate cyclase stimulator medicine.are allergic to sildenafil or any of the ingredients in sildenafil for oral suspension. See the end of this leaflet for a complete list of ingredients in sildenafil for oral suspension.
Before taking sildenafil for oral suspension, tell your healthcare provider about all of your medical conditions, including if you: have low blood pressurehave heart problemshave pulmonary veno-occlusive disease (PVOD)have bleeding problems or a stomach (peptic) ulcer. It is not known if sildenafil for oral suspension is safe in people with bleeding problems or who have a stomach ulcer.have an eye problem called retinitis pigmentosahave ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION)have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearinghave a deformed penis shape or Peyronie’s diseasehave any blood cell problems such as sickle cell anemiaare pregnant or plan to become pregnant. It is not known if sildenafil for oral suspension will harm your unborn baby.are breastfeeding or plan to breastfeed. Sildenafil for oral suspension passes into your breast milk. It is not known if it can harm your baby. Talk with your healthcare provider about the best way to feed your baby during treatment with sildenafil for oral suspension. Tell your healthcare provider about all of the medicines you take, including prescription and over- the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take: nitrates or guanylate cyclase stimulators. See “What is the most important information I should know about sildenafil for oral suspension?”medicines to treat high blood pressuremedicines for erectile dysfunction (impotence). Sildenafil for oral suspension contains sildenafil, which is the same medicine found in another medicine called VIAGRA®. VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with sildenafil for oral suspension.Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take sildenafil for oral suspension? Take or give sildenafil for oral suspension exactly as your healthcare provider tells you.Your healthcare provider may change your dose of sildenafil for oral suspension as needed. Do not change your dose or stop taking sildenafil for oral suspension without talking to your healthcare provider.Sildenafil may be prescribed to you as sildenafil for oral suspension.Take your prescribed dose of sildenafil for oral suspension 3 times a day.See the detailed Instructions for Use that comes with sildenafil for oral suspension for information on how to take or give sildenafil for oral suspension. Sildenafil for oral suspension will be mixed for you by your pharmacist. Do not mix Sildenafil for oral suspension with other medicine or flavoring.If you take too much sildenafil for oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away.
What are the possible side effects of sildenafil for oral suspension? Sildenafil for oral suspension may cause serious side effects, including: See “What is the most important information I should know about sildenafil for oral suspension?”Decreased blood pressure. Sildenafil for oral suspension may cause low blood pressure that last for a short time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with sildenafil for oral suspension.Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with sildenafil for oral suspension, contact your healthcare provider right away.Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing during treatment with sildenafil for oral suspension, contact your healthcare provider right away.In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections.The most common side effects of sildenafil for oral suspension in adults include: nosebleeds headacheupset stomachgetting red or hot in the face (flushing)arm or leg painmuscle aches and painback paindiarrheaThese are not all the possible side effects of sildenafil for oral suspension. 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 sildenafil for oral suspension? Store mixed (reconstituted) sildenafil oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C).Do not freeze mixed sildenafil oral suspension.Throw away (discard) any remaining sildenafil oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label.Keep sildenafil for oral suspension and all medicines out of the reach of children.
General information about the safe and effective use of sildenafil for oral suspension. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil for oral suspension for a condition for which it was not prescribed. Do not give sildenafil for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about sildenafil for oral suspension that is written for health professionals.
What are the ingredients in sildenafil for oral suspension? Active ingredients: sildenafil citrate Inactive ingredients: Sildenafil for oral suspension: sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for Oral Suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Novitium Pharma LLC. Manufactured by: Novitium Pharma LLC, 70 Lake Drive, East Windsor New Jersey 08520
" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Carton Container Label newcarton newcontainer" ], "set_id": "083da718-e934-4941-b083-a19b4ebe3935", "id": "7e36fae8-7fbe-44fe-a951-66f18f1b3fe1", "effective_time": "20240122", "version": "4", "openfda": { "application_number": [ "ANDA212260" ], "brand_name": [ "Sildenafil" ], "generic_name": [ "SILDENAFIL CITRATE" ], "manufacturer_name": [ "ANI Pharmaceuticals, Inc." ], "product_ndc": [ "70954-168" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "SILDENAFIL CITRATE" ], "rxcui": [ "1307427" ], "spl_id": [ "7e36fae8-7fbe-44fe-a951-66f18f1b3fe1" ], "spl_set_id": [ "083da718-e934-4941-b083-a19b4ebe3935" ], "package_ndc": [ "70954-168-10" ], "is_original_packager": [ true ], "upc": [ "0370954168102" ], "unii": [ "BW9B0ZE037" ] } }, { "spl_product_data_elements": [ "Sildenafil Sildenafil SILDENAFIL CITRATE SILDENAFIL MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE TRIACETIN DIBASIC CALCIUM PHOSPHATE DIHYDRATE round C89" ], "recent_major_changes": [ "Warnings and Precautions, Visual Loss ( 5.5 ) 07/2017" ], "indications_and_usage": [ "1 INDICATIONS & USAGE Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [ see Clinical Studies (14) ]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [ see Clinical Studies ( 14 ) ]. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). ( 1 ) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1 , 14 )" ], "dosage_and_administration": [ "2 DOSAGE & ADMINISTRATION Tablet: 20 mg three times a day, 4-6 hours apart ( 2.1 ) 2.1 Sildenafil Tablets The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablets doses 4-6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS & STRENGTHS Sildenafil Tablets, USP Sildenafil tablets, USP are supplied as white to white-off, film-coated, round tablets debossed with \"C 89\" on one side and plain on the other side containing sildenafil citrate equivalent to 20 mg of sildenafil. Tablets: 20 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil tablets are contraindicated in patients with: • Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [ see Warnings and Precautions (5.2) ]. • Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. • Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. • Use with organic nitrates or riociguat ( 4 ) • History of hypersensitivity reaction to sildenafil or any component of the tablet ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. ( 5.1 ) • Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.2 ) • Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. ( 5.3 ) • Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.5 , 5.6 ) • Pulmonary hypertension secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. ( 5.9 ) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children [ see Use in Specific Populations (8.4) ]. 5.2 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil. 5.3 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [ see Adverse Reactions ( 6.2 ]. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.7 Combination with other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PAH secondary to sickle cell anemia has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: • Mortality with pediatric use[ see Warnings and Precautions (5.1 ) and Use in Specific Populations (8.4) ] • Hypotension [ see Warnings and Precautions (5.2) ] • Vision loss [ see Warnings and Precautions (5.5) ] • Hearing loss [ see Warnings and Precautions (5.6) ] • Priapism [ see Warnings and Precautions (5.8) ] • Vaso-occlusive crisis [ see Warnings and Precautions (5.9) ] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 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. Safety data of sildenafil in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I [see Clinical Studies (14)] . The overall frequency of discontinuation in sildenafil-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil-treated patients (20 mg three times a day) and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients) Placebo, % (n = 70) Sildenafil tablets 20 mg three times a day, % (n = 69) Placebo-Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14) ]. Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol)minus Epoprostenol % Headache 57 34 23 Edema includes peripheral edema 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous system Seizure, seizure recurrence Ophthalmologic NAION [ see Warnings and Precautions ( 5.5 ) and Patient Counseling Information ( 17 ) ]." ], "adverse_reactions_table": [ "
Placebo, % (n = 70)Sildenafil tablets 20 mg three times a day, % (n = 69)Placebo-Subtracted, %
Epistaxis198
Headache39467
Dyspepsia7136
Flushing4106
Insomnia176
Erythema165
Dyspnea exacerbated374
Rhinitis044
Diarrhea693
Myalgia473
Pyrexia363
Gastritis033
Sinusitis033
Paresthesia033
", "
Sildenafil + Epoprostenol (n = 134)Epoprostenol (n = 131)(Sildenafil + Epoprostenol)minus Epoprostenol %
Headache573423
Edemaincludes peripheral edema251314
Dyspepsia16214
Pain in extremity17611
Diarrhea25187
Nausea25187
Nasal congestion927
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [ see Contraindications (4) ]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended [ see Clinical Pharmacology (12.3) ]. Other drugs that reduce blood pressure Alpha blockers . In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine . When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil [ see Warnings and Precautions (5.2) ]. • Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7) • Use with ritonavir and other potent CYP3A inhibitors: Not recommended. (7, 12.3) • Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. (5.7)" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension ( see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively ( See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. 8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose. During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig-6 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) ]. 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology 12.3) ]. 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [ see Clinical Pharmacology (12.3) ]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension ( see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively ( See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre-and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "pediatric_use": [ "8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose. During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig-6" ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [ see Clinical Pharmacology (12.3) ]." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION Sildenafil citrate, USP phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula : Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil Tablets USP, 20 mg: Sildenafil tablets are formulated as white, film-coated round tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, USP each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide and triacetin. str" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [ see Clinical Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn.s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn.s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [ Study 3 in Clinical Studies ( 14 ) ], there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4) ]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20-50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8: Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administration with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. figure-7 fig-8" ], "clinical_pharmacology_table": [ "
Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn.s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn.s/cm5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [ see Clinical Pharmacology (12.2) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)* mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn.s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn.s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate * The number of patients per treatment group varied slightly for each parameter due to missing assessments. In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [ Study 3 in Clinical Studies ( 14 ) ], there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4) ]. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry." ], "pharmacodynamics_table": [ "
Placebo (n = 65)* Sildenafil 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0)
PVR (dyn.s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn.s/cm5) -78 (-197, 41) -167 (-307, -26)
RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20-50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8: Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administration with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. figure-7 fig-8" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6 minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 10. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. Table 4. Clinical Worsening Events in Study 2 Placebo (N = 131) Sildenafil Tablets (N = 134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10) Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2 Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6- minute walk distance. Similar increases in walk distance (mean increase of 38-41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT Population Sildenafil Protocol A1481244 Study 4 (Sildenafil added to bosentan therapy – lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone . figure-11 fig-12 figure-9 figure-10" ], "clinical_studies_table": [ "
Placebo (N = 131) Sildenafil Tablets (N = 134)
Number of subjects with clinical worsening first event 23 8
First Event All Events First Event All Events
Death, n 3 4 0 0
Lung Transplantation, n 1 1 0 0
Hospitalization due to PAH, n 9 11 8 8
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n 9 16 0 2
Initiation of Bosentan, n 1 1 0 0
Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50436-9121 NDC: 50436-9121-1 36 TABLET, FILM COATED in a BOTTLE NDC: 50436-9121-2 108 TABLET, FILM COATED in a BOTTLE NDC: 50436-9121-3 54 TABLET, FILM COATED in a BOTTLE NDC: 50436-9121-4 81 TABLET, FILM COATED in a BOTTLE" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Inform patients of contraindication of sildenafil tablets 20 mg with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil tablets 20 mg not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets 20 mg. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets 20 mg. These events may be accompanied by tinnitus and dizziness. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Revised: February 2018 PM01596108 PATIENT INFORMATION Sildenafil (sil-DEN-a-fil) Tablets Read this Patient Information before you start taking sildenafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil tablets, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called “poppers” (amyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What are sildenafil tablets? Sildenafil tablets are a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil tablets improve the ability to exercise and can slow down worsening changes in your physical condition. • Sildenafil tablets are not for use in children • Adding sildenafil tablets to another medication used to treat PAH, bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil tablets 20 mg contain the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets 20 mg with VIAGRA or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: • take nitrate medicines. See “ What is the most important information I should know about sildenafil tablets?” • take guanylate cyclase stimulator medicines. See “What is the most important information I should know about sildenafil tablets?” • are allergic to sildenafil or any other ingredient in sildenafil tablets. See “ What are the ingredients in sildenafil tablets? ” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? Tell your doctor about all of your medical conditions, including if you • have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack • have a disease called pulmonary veno-occlusive disease (PVOD) • have high or low blood pressure or blood circulation problems • have an eye problem called retinitis pigmentosa • have or had loss of sight in one or both eyes • have any problem with the shape of your penis or Peyronie’s disease • have any blood cell problems such sickle cell anemia • have a stomach ulcer or any bleeding problems • are pregnant or planning to become pregnant. It is not known if sildenafil tablets could harm your unborn baby. • are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil tablets and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil tablets. Especially tell your doctor if you take • Nitrate medicines. See “ What is the most important information I should know about sildenafil tablets? ” • Riociguat (Adempas). See “What is the most important information I should know about sildenafil tablets?” • Ritonavir (Norvir®) or other medicines used to treat HIV infection • Ketoconazole (Nizoral®) • Itraconazole (Sporanox) • High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil tablets? • Take sildenafil tablets exactly as your doctor tells you. Sildenafil may be prescribed to you as • Sildenafil tablets • Take sildenafil tablet 3 times a day about 4 to 6 hours apart. • Take sildenafil tablets at the same times every day. • If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. • Do not take more than one dose of sildenafil tablets at a time. • Do not change your dose or stop taking sildenafil tablets on your own. Talk to your doctor first. • If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? • low blood pressure . Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. • more shortness of breath than usual . Tell your doctor if you get more short of breath after you start sildenafil tablets. More shortness of breath than usual may be due to your underlying medical condition. • decreased eyesight or loss of sight in one or both eyes (NAION) . If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. • sudden decrease or loss of hearing . If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil tablets, or to other diseases or medicines, to other factors, or to a combination of factors. • heart attack, stroke, irregular heartbeats, and death . Most of these happened in men who already had heart problems. • erections that last several hours . If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil tablets include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn’t go away. These are not all the possible side effects of sildenafil tablets. 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. How should I store sildenafil tablets? • Store sildenafil tablets at controlled room temperature, between 20° to 25°C (68° to 77°F). • Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. For more information call 1-888-943-3210. What are the ingredients in sildenafil tablets? Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate dihydrate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, triacetin This Patient Information has been approved by the U.S. Food and Drug Administration. VIAGRA® is registered trademark of Pfizer Inc. All other trademarks herein are the property of their respective owners. Manufactured for: Macleods Pharma USA, Inc. Plainsboro, NJ 08536 Manufactured by: Macleods Pharmaceutical Ltd. Baddi, Himachal Pradesh, India Revised: February 2018" ], "package_label_principal_display_panel": [ "SILDENAFIL TABLET, FILM COATED Label Image" ], "set_id": "0a9ec226-572a-47f1-aea1-514615b2b6ed", "id": "a29f2c12-6cec-44ec-898e-cf79dafabb55", "effective_time": "20220921", "version": "4", "openfda": {} }, { "spl_product_data_elements": [ "Tadalafil Tadalafil SILICON DIOXIDE COPOVIDONE K25-31 CROSCARMELLOSE SODIUM HYPROMELLOSE 2910 (6 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE 102 POLYOXYL 40 HYDROGENATED CASTOR OIL TALC TITANIUM DIOXIDE TRIACETIN FERRIC OXIDE YELLOW TADALAFIL TADALAFIL 58;L" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%). (1.1) 1.1 Pulmonary Arterial Hypertension Tadalafil tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%)." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION 40 mg once daily, with or without food. (2.1) Dividing the dose (40 mg) over the course of the day is not recommended. (2.1) Use with ritonavir requires dosage adjustments. (2.4) 2.1 Pulmonary Arterial Hypertension The recommended dose of tadalafil tablets is 40 mg (two 20 mg tablets) taken once daily with or without food. Dividing the dose (40 mg) over the course of the day is not recommended. 2.2 Dose Adjustment in Renal Impairment Mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min): Start dosing at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Severe (creatinine clearance <30 mL/min and on hemodialysis): Avoid use of tadalafil tablets because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Use in Specific Populations (8.6) ] . 2.3 Dose Adjustment in Hepatic Impairment Mild or moderate (Child Pugh Class A or B): Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once per day. Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of tadalafil tablets [see Use in Specific Populations (8.7) ] . 2.4 Dose Adjustments for Use with Ritonavir Co-administration of Tadalafil Tablets in Patients on Ritonavir In patients receiving ritonavir for at least one week, start tadalafil tablets at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3) ] . Co-administration of Ritonavir in Patients on Tadalafil Tablets Avoid use of tadalafil tablets during the initiation of ritonavir. Stop tadalafil tablets at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume tadalafil tablets at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Drug Interactions (7.5) and Clinical Pharmacology (12.3) ] ." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 20 mg tablets are yellow colored, oval shaped, film-coated tablets debossed with ‘58’ on one side and ‘L’ on the other side. Tablets (not scored): 20 mg (3)" ], "contraindications": [ "4 CONTRAINDICATIONS Concomitant organic nitrates (4.1) Concomitant Guanylate Cyclase (GC) Stimulators (4.2) History of known serious hypersensitivity reaction to tadalafil tablets or CIALIS (4.3) 4.1 Concomitant Organic Nitrates Tadalafil tablets are contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently. Do not use nitrates within 48 hours of the last dose of tadalafil tablets. Tadalafil tablets potentiate the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and tadalafil tablets on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2) ] . 4.2 Concomitant Guanylate Cyclase (GC) Stimulators Coadministration of GC stimulators such as riociguat with tadalafil tablets are contraindicated. Tadalafil tablets may potentiate the hypotensive effects of GC stimulators. 4.3 Hypersensitivity Reactions Tadalafil tablets are contraindicated in patients with a known serious hypersensitivity to tadalafil tablets or CIALIS. Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions (6.2) ] ." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Hypotension: Carefully consider whether patients with certain underlying cardiovascular disease could be adversely affected by vasodilatory effects of tadalafil. Not recommended in patients with pulmonary veno-occlusive disease. ( 5.1 , 5.2 ) Effects on the eye: Sudden loss of vision could be a sign of non-arteritic ischemic optic neuropathy (NAION) and may be permanent. ( 5.3 ) Hearing impairment: Cases of sudden decrease or loss of hearing have been reported with CIALIS. ( 5.4 ) Concomitant PDE5 inhibitors: Avoid use with CIALIS or other PDE5 inhibitors. ( 5.5 ) Prolonged erection: Advise patients to seek emergency treatment if an erection lasts >4 hours. ( 5.6 ) 5.1 Hypotension Tadalafil has vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing tadalafil, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with preexisting hypotension, with autonomic dysfunction, with left ventricular outflow obstruction, may be particularly sensitive to the actions of vasodilators. 5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. Should signs of pulmonary edema occur when tadalafil is administered, the possibility of associated PVOD should be considered. 5.3 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 in males aged ≥50 in the general population. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, typical of erectile dysfunction treatment, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended. 5.4 Hearing Impairment Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in patients taking tadalafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.2) ]. 5.5 Combination with Other PDE5 Inhibitors Tadalafil is also marketed for erectile dysfunction. The safety and efficacy of taking tadalafil together with another PDE5 inhibitor has not been studied. Inform patients taking tadalafil not to take other PDE5 inhibitors. 5.6 Prolonged Erection There have been reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Patients with conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) are at an increased risk. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions (5.1) ] Visual Loss [see Warnings and Precautions (5.3) and Patient Counseling Information (17) ] Hearing loss [see Warnings and Precautions (5.4) ] Priapism [see Warnings and Precautions (5.6) ] The most common adverse reaction is headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical 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. Tadalafil was administered to 398 patients with PAH during clinical trials worldwide. In trials of tadalafil, a total of 311 and 251 subjects have been treated for at least 182 days and 360 days, respectively. The overall rates of discontinuation because of an adverse event (AE) in the placebo-controlled trial were 9% for tadalafil 40 mg and 15% for placebo. The rates of discontinuation because of AEs, other than those related to worsening of PAH, in patients treated with tadalafil 40 mg was 4% compared to 5% in placebo-treated patients. In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity. Table 1 presents treatment-emergent adverse events reported by ≥9% of patients in the tadalafil 40 mg group and occurring more frequently than with placebo. Table 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in Tadalafil and More Frequent than Placebo by 2% EVENT Placebo (%) (N=82) Tadalafil 20 mg (%) (N=82) Tadalafil 40 mg (%) (N=79) Headache 15 32 42 Myalgia 4 9 14 Nasopharyngitis 7 2 13 Flushing 2 6 13 Respiratory Tract Infection (Upper and Lower) 6 7 13 Pain in Extremity 2 5 11 Nausea 6 10 11 Back Pain 6 12 10 Dyspepsia 2 13 10 Nasal Congestion (Including sinus congestion) 1 0 9 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tadalafil. These events have been chosen for inclusion either because of their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. Cardiovascular and cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil [see Contraindications (4.1) ] . Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors. Body as a whole — Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis Nervous — Migraine, seizure and seizure recurrence, and transient global amnesia Ophthalmologic — Visual field defect, retinal vein occlusion, retinal artery occlusion, and NAION [see Warnings and Precautions (5.3) and Patient Counseling Information (17) ]. Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.4) and Patient Counseling Information (17) ] . Urogenital — Priapism [see Warnings and Precautions (5.6) ] ." ], "adverse_reactions_table": [ "
Table 1: Treatment-Emergent Adverse Events Reported by ≥9% of Patients in Tadalafil and More Frequent than Placebo by 2%
EVENT Placebo (%) (N=82) Tadalafil 20 mg (%) (N=82) Tadalafil 40 mg (%) (N=79)
Headache 15 32 42
Myalgia 4 9 14
Nasopharyngitis 7 2 13
Flushing 2 6 13
Respiratory Tract Infection (Upper and Lower) 6 7 13
Pain in Extremity 2 5 11
Nausea 6 10 11
Back Pain 6 12 10
Dyspepsia 2 13 10
Nasal Congestion (Including sinus congestion) 1 0 9
" ], "drug_interactions": [ "7 DRUG INTERACTIONS 7.1 Nitrates Administration of nitrates within 48 hours after the last dose of tadalafil is contraindicated [see Contraindications (4.1) ] . 7.2 Alpha-Blockers PDE5 inhibitors, including tadalafil, and alpha–adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin [see Clinical Pharmacology (12.2) ] . 7.3 Antihypertensives PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo [see Clinical Pharmacology (12.2) ] . 7.4 Alcohol Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations [See Clinical Pharmacology (12.2) ] . 7.5 CYP3A Inhibitors/Inducers Ritonavir Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Potent Inhibitors of CYP3A Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of tadalafil [see Clinical Pharmacology (12.3) ] . Potent Inducers of CYP3A For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of tadalafil [see Clinical Pharmacology (12.3) ] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Renal Impairment (2.2, 8.6, 12.3) Mild or moderate: Start with 20 mg once daily. (2.2, 8.6) Severe: Avoid use of tadalafil. (2.2, 8.6) Hepatic Impairment (2.2, 8.7, 12.3) Mild or moderate: Consider starting dose of 20 mg once daily. (2.3, 8.7) Severe: Avoid use of tadalafil. (2.3, 8.7) 8.1 Pregnancy Risk Summary Limited data from case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day based on AUC (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed-effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance. 8.2 Lactation Risk Summary There are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Males Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology (12.2) ] . 8.4 Pediatric Use Safety and effectiveness of tadalafil in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered [See Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment For patients with mild or moderate renal impairment, start tadalafil at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] . In patients with severe renal impairment, avoid use of tadalafil because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of tadalafil 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of tadalafil in such patients [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited data from case series with tadalafil use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day based on AUC (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the exposure at the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis based on AUC. In one of two perinatal/postnatal developmental studies in rats, a reduction of postnatal pup survival was observed at dose levels of 60, 200 and 1000 mg/kg. The no-observed-effect-level (NOEL) for developmental toxicity was 30 mg/kg, which provided maternal exposure to unbound tadalafil concentrations approximately 5 times the exposure at the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 200 mg/kg/day, which produced AUCs greater than 8 times the exposure at the MRHD. Surviving offspring had normal development and reproductive performance." ], "labor_and_delivery": [ "8.2 Lactation Risk Summary There are no data on the presence of tadalafil and/or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2.4-times that found in the plasma. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tadalafil and any potential adverse effects on the breastfed child from tadalafil or from the underlying maternal condition." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Infertility Males Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men or women [see Clinical Pharmacology (12.2) ] ." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of tadalafil in pediatric patients have not been established." ], "geriatric_use": [ "8.5 Geriatric Use Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered [See Clinical Pharmacology (12.3) ] ." ], "overdosage": [ "10 OVERDOSAGE Single doses up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to tadalafil elimination." ], "description": [ "11 DESCRIPTION Tadalafil, an oral treatment for pulmonary arterial hypertension, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Tadalafil has the molecular formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41. The structural formula is: The chemical designation is pyrazino[1′,2′:1,6]pyrido[3,4–b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a white or almost white powder that is practically insoluble in water and very slightly soluble in ethanol. Tadalafil Tablets USP are available as yellow colored, oval shaped, film-coated tablets for oral administration. Each tablet contains 20 mg of tadalafil USP and the following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyoxyl 40 hydrogenated castor oil, talc, titanium dioxide, triacetin, and yellow iron oxide. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas. In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro , tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined. 12.2 Pharmacodynamics Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use tadalafil in patients taking any form of nitrates [see Contraindications (4.1) ] . A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood–pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable [See Contraindications (4.1) ] . Effects on Blood Pressure . The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1. a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope. Figure 1: Effects of Tadalafil on Blood Pressure Effects on Cardiac Electrophysiology The effect of a single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double–blinded, placebo, and active–controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QT c (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QT c (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with a 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. Effects on Exercise Stress Testing The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post–exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood–pressure–lowering effects of nitrates. Effects on Vision Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients). Effects on Sperm Characteristics Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo. Dose-Response Relationship Dose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm -5 and -209 dynes*sec*cm -5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively. Figure 1 12.3 Pharmacokinetics Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 1.3-fold higher than after a single dose. Absorption — After single oral-dose administration, the maximum observed plasma concentration (C max ) of tadalafil is achieved between 2 and 8 hours (median time of 4 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil may be taken with or without food. Distribution — The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Metabolism — Tadalafil is predominantly metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. Elimination — Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). Population pharmacokinetics — In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers. Geriatric patients In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on C max was observed relative to that in healthy subjects 19 to 45 years of age. Renal impairment In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in C max and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination [see Dosage and Administration (2.2) ] . Hepatic impairment In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3) ] . Patients with diabetes mellitus In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted. Race Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted. Gender In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and C max ) were observed. No dose adjustment is warranted. Drug interaction studies Tadalafil is a substrate of and predominantly metabolized by CYP3A. Cytochrome P450 3A4 inhibitors Ketoconazole increased tadalafil exposure relative to the values for tadalafil alone (Figure 2). Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. Ritonavir Ritonavir increased tadalafil 20–mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in a time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.4) and Drug Interactions (7.5) ] . Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure. Cytochrome P450 3A4 inducers Rifampin (600 mg daily), a CYP3A inducer, reduced tadalafil 10 mg single–dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.5) ] . Bosentan, a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose co-administration (Figure 2). Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. Exposure changes of tadalafil following co-administration with other drugs are shown in Figure 2. a Ritonavir is also a CYP2C9/CYP2C19/CYP2D6 Inhibitor and CYP3A inducer. b [see Dosage and Administration (2.4) ] . c Bosentan is also a CYP2C9/CYP2C19 inducer. Figure 2: Impact of Other Drugs on the Pharmacokinetics of Tadalafil Cytochrome P450 substrates Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Exposure changes of drugs following co-administration with tadalafil are shown in Figure 3. a A small augmentation (increase of 3 beats per minute) in heart rate was observed with theophylline. b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and C max ) of bosentan metabolites. c 95% CI Figure 3: Impact of Tadalafil on the Pharmacokinetics of Other Drugs Figure 2 Figure 3" ], "mechanism_of_action": [ "12.1 Mechanism of Action Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas. In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro , tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Do not use tadalafil in patients taking any form of nitrates [see Contraindications (4.1) ] . A double–blind, placebo–controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre–specified timepoints following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). A significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood–pressure lowering effects at this timepoint. After 48 hours, the interaction was not detectable [See Contraindications (4.1) ] . Effects on Blood Pressure . The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1. a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination. Some patients had symptoms associated with the decrease in blood pressure including syncope. Figure 1: Effects of Tadalafil on Blood Pressure Effects on Cardiac Electrophysiology The effect of a single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double–blinded, placebo, and active–controlled (intravenous ibutilide) crossover study in 90 healthy males aged 18 to 53 years. The mean change in QT c (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QT c (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). In this study, the mean increase in heart rate associated with a 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute. Effects on Exercise Stress Testing The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was similar to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post–exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood–pressure–lowering effects of nitrates. Effects on Vision Single oral doses of PDE inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (<0.1% of patients). Effects on Sperm Characteristics Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo. Dose-Response Relationship Dose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm -5 and -209 dynes*sec*cm -5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively. Figure 1" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 1.3-fold higher than after a single dose. Absorption — After single oral-dose administration, the maximum observed plasma concentration (C max ) of tadalafil is achieved between 2 and 8 hours (median time of 4 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined. The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil may be taken with or without food. Distribution — The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Metabolism — Tadalafil is predominantly metabolized by CYP3A to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. Elimination — Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). Population pharmacokinetics — In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers. Geriatric patients In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on C max was observed relative to that in healthy subjects 19 to 45 years of age. Renal impairment In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in C max and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil, respectively. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination [see Dosage and Administration (2.2) ] . Hepatic impairment In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3) ] . Patients with diabetes mellitus In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted. Race Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted. Gender In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and C max ) were observed. No dose adjustment is warranted. Drug interaction studies Tadalafil is a substrate of and predominantly metabolized by CYP3A. Cytochrome P450 3A4 inhibitors Ketoconazole increased tadalafil exposure relative to the values for tadalafil alone (Figure 2). Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. Ritonavir Ritonavir increased tadalafil 20–mg single-dose exposure relative to the values for tadalafil alone. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in a time-dependent manner. The initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.4) and Drug Interactions (7.5) ] . Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure. Cytochrome P450 3A4 inducers Rifampin (600 mg daily), a CYP3A inducer, reduced tadalafil 10 mg single–dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone [see Drug Interactions (7.5) ] . Bosentan, a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil systemic exposure following multiple-dose co-administration (Figure 2). Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. Exposure changes of tadalafil following co-administration with other drugs are shown in Figure 2. a Ritonavir is also a CYP2C9/CYP2C19/CYP2D6 Inhibitor and CYP3A inducer. b [see Dosage and Administration (2.4) ] . c Bosentan is also a CYP2C9/CYP2C19 inducer. Figure 2: Impact of Other Drugs on the Pharmacokinetics of Tadalafil Cytochrome P450 substrates Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Exposure changes of drugs following co-administration with tadalafil are shown in Figure 3. a A small augmentation (increase of 3 beats per minute) in heart rate was observed with theophylline. b Tadalafil (40 mg qd) had no clinically significant effect on exposure (AUC and C max ) of bosentan metabolites. c 95% CI Figure 3: Impact of Tadalafil on the Pharmacokinetics of Other Drugs Figure 2 Figure 3" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20 to 100% of the dogs that resulted in a decrease in spermatogenesis in 40 to 75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years. 13.2 Animal Toxicology and/or Pharmacology Animal studies showed vascular inflammation in tadalafil–treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1– to 17–fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1– and 6-month studies at unbound tadalafil exposure of 0.5– to 38–fold the human exposure (AUC) at the MRHD of 40 mg. In a 12–month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4– to 10–fold the human exposure at the MRHD of 40 mg. The abnormal blood–cell findings were reversible within 2 weeks upon removal of the drug." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20 to 100% of the dogs that resulted in a decrease in spermatogenesis in 40 to 75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years." ], "animal_pharmacology_and_or_toxicology": [ "13.2 Animal Toxicology and/or Pharmacology Animal studies showed vascular inflammation in tadalafil–treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1– to 17–fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1– and 6-month studies at unbound tadalafil exposure of 0.5– to 38–fold the human exposure (AUC) at the MRHD of 40 mg. In a 12–month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4– to 10–fold the human exposure at the MRHD of 40 mg. The abnormal blood–cell findings were reversible within 2 weeks upon removal of the drug." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Tadalafil for Pulmonary Arterial Hypertension A randomized, double-blind, 16 week placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension, defined as a resting mean pulmonary artery pressure (mPAP) ≥25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg, and pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. Allowed background therapy included bosentan (maintenance dosing up to 125 mg twice daily) and chronic anticoagulation. The use of prostacyclin or analogue, L-arginine, phosphodiesterase inhibitor, or other chronic PAH medications were not permitted. Subjects were randomly assigned to 1 of 5 treatment groups (tadalafil 2.5, 10, 20, 40 mg, or placebo) in a 1:1:1:1:1 ratio. Subjects had to be at least 12 years of age and had a diagnosis of PAH that was idiopathic, heritable, related to connective tissue disease, anorexigen use, human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of a congenital systemic-to-pulmonary shunt of least 1 year in duration (for example, ventricular septal defect, patent ductus arteriosus). Patients with a history of left-sided heart disease, severe renal insufficiency, or pulmonary hypertension related to conditions other than specified in the inclusion criteria were not eligible for enrollment. The mean age of all subjects was 54 years (range 14 to 90 years) with the majority of subjects being Caucasian (81%) and female (78%). PAH etiologies were predominantly idiopathic or heritable PAH (61%) and related to connective tissue disease (23%). More than half (53%) of the subjects in the study were receiving concomitant bosentan therapy. The majority of subjects had a World Health Organization (WHO) Functional Class III (65%) or II (32%). The mean baseline 6-minute walk distance (6-MWD) was 343 meters. Of the 405 subjects, 341 completed the study. The primary efficacy endpoint was the change from baseline at week 16 in 6-MWD ( see Figure 4). In the tadalafil 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD was 33 meters (95% C.I. 15 to 50 meters; p=0.0004). The improvement in 6-MWD was apparent at 8 weeks of treatment and then maintained at week 12 and week 16. Figure 4: 6-Minute Walk Distance (meters) Mean Change from Baseline, with 95% Confidence Intervals Placebo-adjusted changes in 6-MWD at 16 weeks were evaluated in subgroups ( see Figure 5). In patients taking only tadalafil 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean change in 6-MWD was 44 meters. In patients taking tadalafil 40 mg and concomitant bosentan therapy, the placebo adjusted mean change in 6-MWD was 23 meters. Figure 5: Placebo-adjusted Mean Change in 6-Minute Walk Distance (meters) of Tadalafil 40 mg, with 95% Confidence Intervals There was less clinical worsening (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE5 inhibitor], or worsening WHO functional class) in the tadalafil 40 mg group compared to the placebo group and the groups that used lower doses of tadalafil. Table 2: Number (percent) with Clinical Worsening a a Subjects may be counted in more than one category Tadalafil Placebo N=82 2.5 mg N=82 10 mg N=80 20 mg N=82 40 mg N=79 Total with clinical worsening 13 (16) 10 (12) 7 (9) 8 (10) 4 (5) Death 1 0 1 0 0 Hospitalization for worsening PAH 2 2 3 0 1 New PAH therapy 0 1 0 2 1 Worsening WHO class 11 10 6 6 3 The Kaplan-Meier plot of times to clinical worsening is shown below in Figure 6. Figure 6: Kaplan-Meier Plot of Time to Clinical Worsening Figure 4 Figure 5 Figure 6 14.2 Long-Term Treatment of Pulmonary Arterial Hypertension Patients (N=357) from the placebo-controlled study entered a long-term extension study. Of these, 311 patients have been treated with tadalafil for at least 6 months and 182 for 1 year (median exposure 356 days; range 2 days to 415 days). The survival rate in the extension study was 96.5 per 100 patient years. Without a control group, these data must be interpreted cautiously." ], "clinical_studies_table": [ "
Table 2: Number (percent) with Clinical Worsening a
aSubjects may be counted in more than one category
Tadalafil
Placebo N=82 2.5 mg N=82 10 mg N=80 20 mg N=82 40 mg N=79
Total with clinical worsening 13 (16) 10 (12) 7 (9) 8 (10) 4 (5)
Death 1 0 1 0 0
Hospitalization for worsening PAH 2 2 3 0 1
New PAH therapy 0 1 0 2 1
Worsening WHO class 11 10 6 6 3
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tadalafil Tablets USP 20 mg are yellow colored, oval shaped, film-coated tablets debossed with ‘58’ on one side and ‘L’ on the other side. Bottles of 6 NDC 82868-028-06 Bottles of 15 NDC 82868-028-15 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep out of reach of children." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) Inform patients of contraindication of tadalafil with any use of organic nitrates or GC stimulators. Inform patients that tadalafil is also marketed as CIALIS for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking tadalafil not to take CIALIS or other PDE5 inhibitors. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking tadalafil. Such an event may be a sign of NAION. Also discuss with patients that there is an increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking tadalafil. These events may be accompanied by tinnitus and dizziness." ], "spl_patient_package_insert": [ "PATIENT INFORMATION Tadalafil Tablets USP (ta da' la fil) Read this patient information before you start taking tadalafil tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is the most important information I should know about tadalafil tablets? Never take tadalafil tablets with any nitrate or guanylate cyclase stimulator medicines: Your blood pressure could drop quickly to an unsafe level You could get dizzy, faint and even have a heart attack or stroke. Nitrates include: Medicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Other nitrate medicines (isosorbide mononitrate or dinitrate) Street drugs that are inhaled, called “poppers” (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat (Adempas ® ) a medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension Ask your healthcare provider or pharmacist if you are not sure if you take a nitrate or guanylate cyclase stimulator medicine. What are tadalafil tablets? Tadalafil tablets are a prescription medicine used to treat pulmonary arterial hypertension (PAH, high blood pressure in your lungs) to improve your ability to exercise. It is not known if tadalafil tablets are safe or effective in children. Who should not take tadalafil tablets? Do not take tadalafil tablets if you take any medicines called nitrates. use recreational drugs called “poppers” like amyl nitrate, butyl nitrate or nitrite. take any medicines called guanylate cyclase stimulators are allergic to tadalafil or any other ingredient in tadalafil tablets. See “ What are the ingredients in tadalafil tablets? ” at the end of this leaflet. See “What is the most important information I should know about tadalafil tablets? ” What should I tell my healthcare provider before taking tadalafil tablets? Before taking tadalafil tablets, tell your healthcare provider about all of your medical conditions, including if you: are allergic to tadalafil tablets or Cialis or any of its ingredients. See the end of this leaflet for a complete list of ingredients in tadalafil tablets. have pulmonary veno-occlusive disease (PVOD) have heart problems have low blood pressure have liver problems have kidney problems or get dialysis have retinitis pigmentosa, a rare genetic eye disease have ever had any sudden vision loss, including any damage to your optic nerve or NAION. have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing have a deformed penis shape or Peyronie’s disease have had an erection that lasted more than 4 hours have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia are pregnant or planning to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breast feed. If you breastfeed while taking tadalafil tablets, it is likely that tadalafil will pass into your breast milk. You and your healthcare provider should decide if you will take tadalafil tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tadalafil tablets and other medicines may affect each other. Especially tell your healthcare provider if you take any of these medicines * : nitrates or guanylate cyclase stimulators (see “ What is the most important information I should know about tadalafil tablets? ”) alpha blockers, used to treat prostate disease and high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint. protease inhibitors, used to treat HIV infection, such as ritonavir (Norvir ® , Kaletra ® ) ketoconazole (Extina ® , Xolegel ® , Ketozole ® , Nizoral A-D ® , Nizoral ® ) itraconazole (Sporanox ® ) erythromycin (several brand names exist. Please consult your healthcare provider to determine if you are taking this medicine) rifampin (Rifadin ® , Rifamate ® , Rifater ® , Rimactane ® ) bosentan (Tracleer ® ) phenobarbital, phenytoin (Dilantin ® ), carbamazepine (Tegretol ® ) CIALIS ® or other medicines or treatments for erectile dysfunction (impotence). Tadalafil tablets are also marketed as CIALIS for the treatment of male erectile dysfunction (ED, impotence) and for the signs and symptoms of benign prostatic hyperplasia (BPH, enlarged prostate). Do not take both tadalafil tablets and CIALIS. Do not take tadalafil tablets and other medicines or treatments for erectile dysfunction. Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take tadalafil tablets? Take tadalafil tablets exactly as your healthcare provider tells you. Take tadalafil tablets at the same time every day. You should take both tablets at the same time, one after the other, every day. Do not split your dose. Tadalafil tablets can be taken with or without food. Do not change your dose or stop taking tadalafil tablets without speaking to your healthcare provider. If you take too much tadalafil, call your healthcare provider or go to an emergency department right away. What should I avoid while taking tadalafil tablets? Do not have more than 4 alcohol-containing drinks in a short period of time while you take tadalafil tablets. Drinking too much alcohol can lower your blood pressure. You could get dizzy or faint. What are the possible side effects of tadalafil tablets? The following side effects were reported rarely in patients taking tadalafil: Decreased eyesight or loss of vision in one or both eyes (NAION). If you notice a sudden decrease or loss of vision in one or both eyes, contact a healthcare provider right away. Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing, contact a healthcare provider right away. In men, an erection that lasts more than 4 hours (with or without pain). Talk to your healthcare provider or go to the emergency department right away. An erection that lasts more than 4 hours must be treated as soon as possible or you can have lasting damage to your penis, including the inability to have erections. See “What is the most important information I should know about tadalafil tablets?” The most common side effects with tadalafil tablets include: headache muscle pain getting red or hot in the face (flushing) nausea pain in the arms, legs, or back upset stomach stuffy or congested nose Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of tadalafil tablets. For more information, ask your healthcare provider or pharmacist. 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 Tadalafil Tablets? Store tadalafil tablets at room temperature between 20° to 25°C (68° to 77°F). Keep tadalafil tablets and all medicines out of the reach of children. General Information about the safe and effective use of tadalafil tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use tadalafil tablets for a condition for which it was not prescribed. Do not give tadalafil tablets to other people, even if they have the same symptoms you have. They may harm them. This patient information leaflet summarizes the most important information about tadalafil tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about tadalafil tablets that is written for healthcare professionals. For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. What Are The Ingredients In Tadalafil Tablets? Active Ingredient: tadalafil Inactive Ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyoxyl 40 hydrogenated castor oil, talc, titanium dioxide, triacetin, and yellow iron oxide. Rx only This Patient Information has been approved by the U.S. Food and Drug Administration. *The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. The makers of these brands are not affiliated with and do not endorse Aurobindo Pharma Limited or its products. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 05/2021" ], "package_label_principal_display_panel": [ "Principal Display Panel NDC: 82868-028-15 Label" ], "set_id": "0afd0728-256a-293b-e063-6394a90a3c5f", "id": "46dca45a-dcd4-7994-e063-6294a90a573a", "effective_time": "20251226", "version": "2", "openfda": { "application_number": [ "ANDA206286" ], "brand_name": [ "Tadalafil" ], "generic_name": [ "TADALAFIL" ], "manufacturer_name": [ "Northwind Health Company, LLC" ], "product_ndc": [ "82868-028" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "TADALAFIL" ], "rxcui": [ "402019" ], "spl_id": [ "46dca45a-dcd4-7994-e063-6294a90a573a" ], "spl_set_id": [ "0afd0728-256a-293b-e063-6394a90a3c5f" ], "package_ndc": [ "82868-028-06", "82868-028-15" ], "original_packager_product_ndc": [ "65862-880" ], "nui": [ "N0000175599", "N0000020026" ], "pharm_class_epc": [ "Phosphodiesterase 5 Inhibitor [EPC]" ], "pharm_class_moa": [ "Phosphodiesterase 5 Inhibitors [MoA]" ], "unii": [ "742SXX0ICT" ] } }, { "effective_time": "20160706", "recent_major_changes": [ "CONTRAINDICATIONS 04/2015" ], "drug_interactions": [ "7 DRUG INTERACTIONS Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors. ( 5.7 ) Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications ( 4 )] . Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology ( 12.3 ) ] ]. Other drugs that reduce blood pressure Alpha-blockers In drug-drug interaction studies, Viagra ® and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil [see Warnings and Precautions ( 5.2 ) ]." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 ) ]." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14) ]. Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg T hree Times a Day and Placebo Group Placebo (n = 65) * Sildenafil Tablets 20 mg three times a day (n = 65) * mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0) PVR (dyn ⋅ s/cm5) 49 (-54, 153) -122 (-217, -27) SVR (dyn ⋅ s/cm5) -78 (-197, 41) -167 (-307, -26) R A P (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate ∗The number ofpatients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with Viagra ® , therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry." ], "spl_patient_package_insert": [ "PATIENT INFORMATION Sildenafil Tablets Read this Patient Information before you start taking sildenafil and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil, ask your doctor or pharmacist. What is the most important information I should know about sildenafil tablets? Never take sildenafil tablets with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include M edicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Isosorbide mononitrate or dinitrate Street drugs called “poppers” (amyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What is sildenafil? Sildenafil is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil improves the ability to exercise and can slow down worsening changes in your physical condition. Sildenafil is not for use in children Adding sildenafil to another medication used to treat PAH does not result in improvement in your ability to exercise. Sildenafil 20 mg tablets contains the same medicine as Viagra ® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil tablets 20 mg with sildenafil Viagra ® or other PDE-5 inhibitors. Who should not take sildenafil tablets? Do not take sildenafil if you : take nitrate medicines.See “ What is the most important information I should know about sildenafil tablets?” take guanylate cyclase stimulator medicines. See “ What is the most important information I should know about sildenafil tablets? ” are allergic to sildenafilor anyother ingredient in sildenafil. See “ What are the ingredients in sildenafil tablets?” at the end of this leaflet. What should I tell my doctor before taking sildenafil tablets? Tell your doctor about all of your medical conditions, including if you have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack have a disease called pulmonary veno-occlusive disease (PVOD) have high or low blood pressure or blood circulation problems have an eye problem called retinitis pigmentosa have or had loss of sight in one or both eyes have anyproblem with the shapeof your penis or Peyronie’s disease have any blood cell problems such sickle cell anemia have a stomach ulcer or any bleeding problems are pregnant or planning to become pregnant. It is not known if sildenafil could harm your unborn baby. are breastfeeding. It is not known if sildenafil passes into your breast milk or if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil. Especially tell your doctor if you take Nitrate medicines. See “ What is the most important information I should know a b o ut sildenafil tablets? ” Riociguat (Adempas). See “ What is the most important information I should know about sildenafil tablets? ” Ritonavir (Norvir®) or other medicines used to treat HIV infection Ketoconazole (Nizoral®) Itraconazole (Sporanox) High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil tablets? Take sildenafil tablets exactly as your doctor tells you. Sildenafil may be prescribed to you as Sildenafil tablets Take sildenafil tablet 3 times a day about 4 to 6 hours apart. Take sildenafil tablets at the same times every day. If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. Do not take more than one dose of sildenafil at a time. Do not change your dose or stop taking sildenafil on your own. Talk to your doctor first. If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil tablets? low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. m o re shortness of breath than usual. Tell your doctor if you get more short of breath after you start sildenafil. More shortness of breath than usual may be due to your underlying medical condition. decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil, or to other diseases or medicines, to other factors, or to a combination of factors. heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already had heart problems. erections that last several hours. If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil tablets include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn’t go away. These are not all the possible side effects of sildenafil. 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. How should I store sildenafil tablets? Store sildenafil tablets at controlled room temperature, between 20°C to 25°C (68°F to 77°F). Keep sildenafil tablets and all medicines away from children. General information about sildenafil tablets Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil tablets for a condition for which it was not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil tablets. If you would like more information about sildenafil tablets talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil tablets that is written for health professionals. For more information call 1-888-375-3784. What are the ingredients in sildenafil tablets? A ctive ingredients: sildenafil citrate Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and opadry II 33K505001 blue containing hypromellose, titanium dioxide, lactose monohydrate, triacetin, FD&C blue #2/indigo carmine aluminum lake. This Patient Information has been approved by the U.S. Food and Drug Administration. Rx Only Manufactured by: Dr. Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Revised: 0615" ], "description": [ "11 DESCRIPTION Sildenafil phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as Viagra ® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white powder. Freely soluble in dimethyl formamide and a molecular weight of 666.7. Sildenafil tablets are formulated as blue colored, round, film-coated tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate dehydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and opadry II 33K505001 blue containing hypromellose, titanium dioxide, lactose monohydrate, triacetin, FD&C blue #2/indigo carmine aluminum lake. structure" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "labor_and_delivery": [ "8.2 Labor and Delivery The safety and efficacy of sildenafil during labor and delivery have not been studied." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Sildenafil Tablets Sildenafil tablets are supplied as blue, round, film-coated tablets with “R” debossed on one side and “372” debossed on other side containing sildenafil citrate equivalent to 20 mg of sildenafil. Tablets 20 mg ( 3)" ], "clinical_pharmacology_table": [ "
Placebo (n = 65)* Sildenafil Tablets 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0)
PVR (dyn⋅ s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn⋅ s/cm5) -78 (-197, 41) -167 (-307, -26)
R A P (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology ( 12.2 ) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 mcM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. fig7 fig8" ], "clinical_studies_table": [ "
Placebo (N=131) Sildenafil Tablets (N=134)
Number of subjects with clinical worsening first event 23 8
First Event All Events First Event All Events
Death, n 3 4 0 0
Lung Transplantation, n 1 1 0 0
Hospitalization due to PAH, n 9 11 8 8
Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n 9 1 16 1 0 0 2 0
Proportion Worsened95% Confidence Intervals 0.187(0.12 – 0.26) 0.062(0.02 – 0.10)
" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy [see Clinical Studies ( 14 )]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connected tissue disease (CTD) (25%). Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening.. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). (1)" ], "set_id": "0cd30ad7-1c4a-4c1e-aad3-a121119291c6", "id": "36f97c68-613f-3617-e054-00144ff8d46c", "pediatric_use": [ "8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6. Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig6" ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil tablets are contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2) ]. Concomitant use of riociguat, a guanylate cyclase stimulator. PDE5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates or riociguat. (4) History of hypersensitivity reaction to sildenafil or any component of the tablet. (4)" ], "pharmacodynamics_table": [ "
Placebo (n = 65)* Sildenafil Tablets 20 mg three times a day (n = 65)*
mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0)
PVR (dyn⋅ s/cm5) 49 (-54, 153) -122 (-217, -27)
SVR (dyn⋅ s/cm5) -78 (-197, 41) -167 (-307, -26)
R A P (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3)
CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7)
HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4)
" ], "pregnancy": [ "8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "nursing_mothers": [ "8.3 Nursing Mothers It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when sildenafil is administered to a nursing woman." ], "spl_product_data_elements": [ "sildenafil sildenafil CROSCARMELLOSE SODIUM DIBASIC CALCIUM PHOSPHATE DIHYDRATE HYDROXYPROPYL CELLULOSE (TYPE H) MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE TITANIUM DIOXIDE LACTOSE MONOHYDRATE TRIACETIN FD&C BLUE NO. 2 HYPROMELLOSE 2910 (6 MPA.S) SILDENAFIL CITRATE SILDENAFIL R;372" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. (5.1) Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. (5.2) Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. (5.3) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.5 , 5.6 ) Pulmonary hypertension secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. ( 5.9 ) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. [see Use in Specific Populations ( 8.4) ]. 5.2 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil. 5.3 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5 to11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.7 Combination with other PDE-5 Inhibitors Sildenafil is also marketed as Viagra ® . The safety and efficacy of combinations of sildenafil tablets 20 mg with Viagra ® or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil tablets 20 mg not to Viagra ® or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PAH secondary to sickle cell anemia has not been established." ], "adverse_reactions_table": [ "
ADVERSE EVENT Placebo, % (n = 70) Sildenafil Tablets 20 mg three times a day , % (n = 69) Placebo- Subtracted, %
Epistaxis 1 9 8
Headache 39 46 7
Dyspepsia 7 13 6
Flushing 4 10 6
Insomnia 1 7 6
Erythema 1 6 5
Dyspnea exacerbated 3 7 4
Rhinitis 0 4 4
Diarrhea 6 9 3
Myalgia 4 7 3
Pyrexia 3 6 3
Gastritis 0 3 3
Sinusitis 0 3 3
Paresthesia 0 3 3
", "
Sildenafil Tablets+ Epoprostenol (n=134) Epoprostenol (n=131) (Sildenafil Tablets + Epoprostenol) minus Epoprostenol
Headache 57 34 23
Edema^ 25 13 14
Dyspepsia 16 2 14
Pain in extremity 17 6 11
Diarrhea 25 18 7
Nausea 25 18 7
Nasal congestion 9 2 7
" ], "openfda": {}, "version": "3", "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Tablet: 20 mg three times a day, 4 to 6 hours apart (2.1) 2.1 Sildenafil Tablets The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil doses 4 to 6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )] Hypotension [see Warnings and Precautions ( 5.2 ) ] Vision loss [see Warnings and Precautions ( 5.5 ) ] Hearing loss [see Warnings and Precautions ( 5.6 ) ] Priapism [see Warnings and Precautions ( 5.8 ) ] Vaso-occlusive crisis [see Warnings and Precautions (5.9) ] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis ( 6.1 , 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.go v/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. Safety data of sildenafil in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I [see Clinical Studies ( 14) ]. The overall frequency of discontinuation in sildenafil-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil-treated patients (20 mg three times a day ) and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients) ADVERSE EVENT Placebo, % (n = 70) Sildenafil Tablets 20 mg three times a day , % (n = 69) Placebo- Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately colortinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies ( 14) ] . Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil Tablets+ Epoprostenol (n=134) Epoprostenol (n=131) (Sildenafil Tablets + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edema^ 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 ^includes peripheral edema 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous system: Seizure, seizure recurrence" ], "spl_unclassified_section": [ "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient information) Inform patients of contraindication of sildenafil tablets 20 mg with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as Viagra ® for erectile dysfunction. Advise patients taking sildenafil tablets 20 mg not to take Viagra ® or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil tablets 20 mg. Such an event may be a sign of NAION Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil tablets 20 mg. These events may be accompanied by tinnitus and dizziness. Trademarks are the property of their respective owners. R X Only Manufactured by: Dr. Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Revised: 0615" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Labor and Delivery The safety and efficacy of sildenafil during labor and delivery have not been studied. 8.3 Nursing Mothers It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when sildenafil is administered to a nursing woman. 8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6. Figure 6: Kaplan-Meier Plot of Mortality by Sildenafil Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. fig6 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 ) ]. 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology ( 12.3 ) ]. 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology ( 12.3 )] ." ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil tablets 20 mg are blue colored, round, film-coated tablets with “R” debossed on one side and “372” debossed on other side and are supplied in bottles of 14, 30, 90, 100, 500 and unit dose packages of 8 (2 x4’s). Bottles of 14 NDC 55111-372-52 Bottles of 30 NDC 55111-372-30 Bottles of 90 NDC 55111-372-90 Bottles of 100 NDC 55111-372-01 Bottles of 500 NDC 55111-372-05 Unit dose packages of 8 (2x4) NDC 55111-372-08 Recommended storage for sildenafil tablets : Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature]." ], "clinical_studies": [ "14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II to III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (Figure 9), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4,8 and 12 in Study1:Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 10. Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval Key : PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. Table 4. Clinical Worsening Events in Study 2 Placebo (N=131) Sildenafil Tablets (N=134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n 9 1 16 1 0 0 2 0 Proportion Worsened95% Confidence Intervals 0.187(0.12 – 0.26) 0.062(0.02 – 0.10) Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2 Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. fig9 fig10 fig11" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL DRUG: sildenafil GENERIC: sildenafil DOSAGE: TABLET, FILM COATED ADMINSTRATION: ORAL NDC: 52125-710-60 COLOR: blue SHAPE: ROUND SCORE: No score SIZE: 7 mm IMPRINT: R;372 PACKAGING: 60 in 1 VIAL OUTER PACKAGING: 2 in 1 CARTON ACTIVE INGREDIENT(S): SILDENAFIL CITRATE 20mg in 1 INACTIVE INGREDIENT(S): CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE TITANIUM DIOXIDE FD&C BLUE NO. 2 TRIACETIN CROSCARMELLOSE SODIUM DIBASIC CALCIUM PHOSPHATE DIHYDRATE HYPROMELLOSE 2910 (6 MPA.S) Hydroxypropyl Cellulose (Type H) MAGNESIUM STEARATE Remedy_Label" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology ( 12.2 ) ]. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14) ]. Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg T hree Times a Day and Placebo Group Placebo (n = 65) * Sildenafil Tablets 20 mg three times a day (n = 65) * mPAP (mmHg) 0.6 (-0.8, 2) -2.1 (-4.3, 0) PVR (dyn ⋅ s/cm5) 49 (-54, 153) -122 (-217, -27) SVR (dyn ⋅ s/cm5) -78 (-197, 41) -167 (-307, -26) R A P (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate ∗The number ofpatients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with Viagra ® , therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than150 mcM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. fig7 fig8" ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ] }, { "spl_product_data_elements": [ "Bosentan Bosentan BOSENTAN BOSENTAN ANHYDROUS CETYL ALCOHOL CROSCARMELLOSE SODIUM ETHYLCELLULOSES FERRIC OXIDE RED FERRIC OXIDE YELLOW GLYCERYL DIBEHENATE HYPROMELLOSES MAGNESIUM STEARATE POVIDONE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO STARCH, CORN TALC TITANIUM DIOXIDE TRIACETIN ORANGE WHITE 125;NAT Bosentan Bosentan BOSENTAN BOSENTAN ANHYDROUS CETYL ALCOHOL CROSCARMELLOSE SODIUM ETHYLCELLULOSES FERRIC OXIDE RED FERRIC OXIDE YELLOW GLYCERYL DIBEHENATE HYPROMELLOSES MAGNESIUM STEARATE POVIDONE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO STARCH, CORN TALC TITANIUM DIOXIDE TRIACETIN ORANGE WHITE N" ], "boxed_warning": [ "WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY Because of the risks of hepatotoxicity and birth defects, bosentan tablets are available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.3 )]. Hepatotoxicity In clinical studies, bosentan tablets caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4 ), Warnings and Precautions (5.1 )]. In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with bosentan tablets in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan tablets in these cases could not be excluded. In at least one case, the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of bosentan tablets. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping bosentan tablets with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)] . Elevations in aminotransferases require close attention [see Dosage and Administration (2.4 )]. Bosentan tablets should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN, treatment with bosentan tablets should be stopped. There is no experience with the reintroduction of bosentan tablets in these circumstances. Embryo-Fetal Toxicity Bosentan tablets are likely to cause major birth defects if used by pregnant females based on animal data [see W arnings and Precautions (5.2 ), Use in Specific Populations (8.1 )]. Therefore, pregnancy must be excluded before the start of treatment with bosentan tablets. Throughout treatment and for one month after stopping bosentan tablets, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan tablets [see Drug Interactions (7.2 )]. Obtain monthly pregnancy tests. WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Bosentan tablets are available only through a restricted distribution program called the Bosentan REMS Program because of these risks ( 5.3 ): Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with bosentan tablets ( 5.1 ). Measure liver aminotransferases prior to initiation of treatment and then monthly ( 2.1 , 5.1 ). Discontinue bosentan tablets if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 x ULN (2.4 , 5.1 ). Based on animal data, bosentan tablets are likely to cause major birth defects if used during pregnancy ( 4.1 , 5.2 , 8.1 ). Must exclude pregnancy before and during treatment ( 2.1 , 4.1 , 8.1 ). To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan tablets ( 4.1 , 5.2 , 8.1 )." ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Bosentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1 )]. in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to results in an improvement in exercise ability. Bosentan tablets are endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) ( 1 ). in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to results in an improvement in exercise ability. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after 4 weeks ( 2.2 ). Patients 12 years of age and younger: dosage is based on weight, see Table 1 ( 2.2 ). Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3 X Upper Limit of Normal (ULN) ( 2.1 ). 2.1 Required Monitoring Healthcare professionals who prescribe bosentan tablets must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with bosentan tablets [see Warnings and Precautions (5.3)]. Obtain a pregnancy test in females of reproductive potential prior to bosentan tablets treatment, monthly during treatment and one month after stopping bosentan tablets. Initiate treatment with bosentan tablets in females of reproductive potential only after a negative pregnancy test [see Boxed Warning , Contraindications (4.1 ), Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3 )]. Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Warnings and Precautions (5.1 )]. 2.2 Recommended Dosage Administer bosentan tablets orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity. Table 1: Dosing Recommendations Initial 4 weeks Maintenance (after 4 weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients ≤12 years of age ≥ 4-8 kg >8-16 kg >16-24 kg >24-40 kg 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 2.3 Administration Bosentan film-coated tablets should be administered orally twice daily. 2.4 Dosage Adjustments for Aminotransferase Elevations If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2. Discontinue bosentan tablets if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or bilirubin ≥ 2 x Upper Limit of Normal (ULN). There is no experience with the reintroduction of bosentan tablets in these circumstances. Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations > 3 x ULN ALT/AST levels Treatment and monitoring recommendations > 3 and ≤ 5 x ULN Confirm by another aminotransferase test; if confirmed, - in adults and pediatric patients >12 years and >40 kg , reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days. > 5 and ≤ 8 x ULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, - in adults and pediatric patients >12 years, and >40kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients , consider reintroduction at the dose used prior to treatment interuption, with reassessment of aminotransferase levels with in 3 days. > 8 x ULN Stop treatment permanently. There is no experience with reintroduction of bosentan in these circumstances. 2.5 Use with Ritonavir Co-administration of Bosentan Tablets in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start bosentan tablets at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1 )]. Co-administration of Ritonavir in Patients on Bosentan Tablets Discontinue use of bosentan tablets at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan tablets at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1 )]. 2.6 Use in Patients with Pre-existing Hepatic Impairment Avoid initiation of bosentan tablets in patients with aminotransferases >3 x ULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions (5.3 ), Use in Specific Populations (8.6 ), Clinical Pharmacology (12.3 )]." ], "dosage_and_administration_table": [ "
Initial 4 weeks Maintenance (after 4 weeks)
Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily
Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily
Patients ≤12 years of age ≥ 4-8 kg >8-16 kg >16-24 kg >24-40 kg 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily
", "
ALT/AST levels Treatment and monitoring recommendations
> 3 and ≤ 5 x ULN Confirm by another aminotransferase test; if confirmed, - in adults and pediatric patients >12 years and >40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 3 days.
> 5 and ≤ 8 x ULN Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, - in adults and pediatric patients >12 years, and >40kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients, consider reintroduction at the dose used prior to treatment interuption, with reassessment of aminotransferase levels with in 3 days.
> 8 x ULN Stop treatment permanently. There is no experience with reintroduction of bosentan in these circumstances.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 62.5 mg tablets: Orange-white coloured, round, biconvex, film-coated tablets with plain surface on one side and ‘N’ on other side. 125 mg tablets: Orange-white coloured, oval, biconvex film-coated tablets debossed with '125' on one side 'NAT' on other side. • Film-coated tablet: 62.5 mg and 125 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS • Pregnancy ( 4.1 ) • Use with Cyclosporine A ( 4.2 ) • Use with Glyburide ( 4.3 ) • Hypersensitivity ( 4.4 ) 4.1 Pregnancy Use of bosentan tablets is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan tablets. [see Boxed Warning , Warnings and Precautions (5.2 ) Drug Interactions (7.2 ), Use in Specific Populations (8.1 )]. 4.2 Use with Cyclosporine A Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan tablets and cyclosporine A is contraindicated [see Cytochrome P450 Drug Interactions (7.1 )]. 4.3 Use with Glyburide An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and bosentan tablets is contraindicated [see Cytochrome P450 Drug Interactions (7.1 )]. 4.4 Hypersensitivity Bosentan tablets are contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema [see Ad verse Reactions (6.2), Description (11 )]." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Fluid retention: May require intervention ( 5.4 ). Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing bosentan tablets ( 5.5 ). Decreased sperm counts ( 5.6 ). Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter ( 5.7 ). 5.1 Hepatotoxicity ALT or AST > 3 x ULN were observed in 11% of bosentan tablets-­treated patients (n = 658) compared to 2% of placebo-treated patients (n = 280). Three­-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥ 3 x ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan tablets. In a pooled analysis of four pediatric studies in PAH (n-100), elevations in liver aminotransferases ≥3 x ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 2 x ULN) is a marker for potential serious hepatotoxicity. Elevations of AST or ALT associated with bosentan tablets are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with bosentan tablets. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration (2.1, 2.4 )]. Discontinue bosentan tablets if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN. Avoid initiation of bosentan tablets in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, Dosage and Administration (2.6 ), Use in Specific Populations (8.6)]. In WHO Functional Class II patients, consider whether the benefits of bosentan tablets are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. 5.2 Embryo-fetal Toxicity Based on data from animal reproduction studies, bosentan tablets may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to bosentan tablets treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with bosentan tablets and for at least one month after the last dose [see Dosage and Administration (2 ), Use in Specific Populations (8.1 , 8.3 )]. Bosentan tablets are only available for females through a restricted program under REMS [see Warnings and Precautions (5.3)]. 5.3 Prescribing and Distribution Program for Bosentan Tablets Because of the risks of hepatotoxicity and birth defects, bosentan is available only through a restricted program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program. [see Boxed Warning , Warnings and Precautions (5.1 , 5.2), Contraindications (4.1 ) ]. Required components of the Bosentan REMS are: Healthcare professionals who prescribe bosentan tablets must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements. Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly. To receive bosentan tablets, all patients must understand the risks and benefits, and complete a patient enrollment form. Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS Program requirements. Further information about bosentan tablets and the Bosentan REMS Program is available at www. BosentanREMSProgram.com or 1-866-359-2612. 5.4 Fluid Retention Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of bosentan tablets and other endothelin receptor antagonists. In PAH clinical trials with bosentan tablets, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients. In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting bosentan tablets. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as bosentan tablets or underlying heart failure, and the possible need for treatment or discontinuation of bosentan tablets. [see Adverse Reactions (6.1 ) and Clinical Studies (14.2 )]. 5.5 Pulmonary Veno-Occlusive Disease If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether bosentan tablets should be discontinued. 5.6 Decreased Sperm Counts Decreased sperm counts have been observed in patients receiving bosentan tablets. Preclinical data also suggest that bosentan tablets, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1 ), Nonclinical Toxicology (13.1 )]. 5.7 Decreases in Hemoglobin and Hematocrit Treatment with bosentan tablets can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see Adverse Reactions 6.1 ]." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning , Warnings and Precautions (5.1 )] Embryo-fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.2 )] Fluid Retention [see Warnings and Precautions (5.4 )] Common adverse reactions (≥3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical 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. Safety data on bosentan tablets were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan tablets in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years and n=39 for more than 2 years). Exposure of PAH patients (n=328) to bosentan tablets ranged from 1 day to 1.7 years (n= 174 more than 6 months and n=28 more than 12 months). Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on bosentan tablets (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on bosentan tablets was abnormal liver function. The adverse drug events that occurred in ≥3% of the bosentan tablets-treated patients and were more common on bosentan tablets in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse events* occurring in ≥3% of patients treated with bosentan tablets 125 to 250 mg twice daily and more common on bosentan tablets in placebo-controlled studies in pulmonary arterial hypertension *Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. ** Respiratory Tract Infection combines the terms \"Nasopharyngitis\", \"Upper Respiratory Tract Infection\" and \"Respiratory Tract Infection\". Combined data from Study 351, BREATHE-1 and EARLY Adverse Event Bosentan tablets n = 258 Placebo n=172 No. % No. % Respiratory Tract Infection** 56 22% 30 17% Headache 39 15% 25 14% Edema 28 11% 16 9% Chest Pain 13 5% 8 5% Syncope 12 5% 7 4% Flushing 10 4% 5 3% Hypotension 10 4% 3 2% Sinusitis 9 4% 4 2% Arthralgia 9 4% 3 2% Serum Aminotransferases, abnormal 9 4% 3 2% Palpitations 9 4% 3 2% Anemia 8 3% - - Bosentan tablets were evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Decreased Sperm Counts An open-label, single arm, multicenter, safety study evaluated the effect on testicular function of bosentan tablets 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan tablets. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan tablets were discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as bosentan tablets have an adverse effect on spermatogenesis. Decreases in Hemoglobin and Hematocrit Treatment with bosentan tablets can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. The overall mean decrease in hemoglobin concentration for adult bosentan tablets-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan tablets treatment and hemoglobin levels stabilized by 4 to 12 weeks of bosentan tablets treatment. In placebo-controlled studies of all uses of bosentan tablets, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan tablets-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients . A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan tablets-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan tablets treatment. During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of bosentan tablets-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. In a pooled analysis of pediatric patients (N=100) with PAH treated with bosentan tablets, a decrease in hemoglobin levels to < 10 g/dL from baseline was reported in 11% of patients. There was no decrease to < 8 g/dL. 6.2 Postmarketing Experience There have been several postmarketing reports of angioedema associated with the use of bosentan tablets. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing bosentan tablets. The following additional adverse reactions have been reported during the postapproval use of bosentan tablets. Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to bosentan tablets exposure: Unexplained hepatic cirrhosis [see Boxed Warning ] Liver failure [see Boxed Warning ] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4 )] Thrombocytopenia Rash Jaundice Anemia requiring transfusion Neutropenia and leukopenia Nasal congestion" ], "adverse_reactions_table": [ "
*Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. ** Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection". Combined data from Study 351, BREATHE-1 and EARLY
Adverse Event Bosentan tablets n = 258 Placebo n=172
No. % No. %
Respiratory Tract Infection** 56 22% 30 17%
Headache 39 15% 25 14%
Edema 28 11% 16 9%
Chest Pain 13 5% 8 5%
Syncope 12 5% 7 4%
Flushing 10 4% 5 3%
Hypotension 10 4% 3 2%
Sinusitis 9 4% 4 2%
Arthralgia 9 4% 3 2%
Serum Aminotransferases, abnormal 9 4% 3 2%
Palpitations 9 4% 3 2%
Anemia 8 3% - -
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Cytochrome P450: Coadministration of bosentan tablets with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan tablets and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ) Hormonal contraceptives: Bosentan tablets use decreases contraceptive exposure and reduces effectiveness ( 7.2 ). 7.1 Cytochrome P450 Drug Interactions Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see pharmacokinetics (12.3) ]. Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan tablets will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan tablets is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan tablets are co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYPlA2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, bosentan tablets are not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Figure 1: CYP3A induction-mediated effect of bosentan on other drugs Figure 2: Effect of other drugs on bosentan bosentan fig1 bosentan fig2 7.2 Hormonal Contraceptives Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan tablets are co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan tablets [see Use in Specific Populations (8.3)]. An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS • Nursing mothers: Choose breastfeeding or bosentan tablets (8.2 ). 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, bosentan tablets may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and are contraindicated during pregnancy [see Contraindications (4.1 )]. There are limited data on bosentan tablets use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m 2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population 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 Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m 2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m 2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs. 8.2 Lactation Risk Summary There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan tablets, advise women not to breastfeed during treatment with bosentan tablets. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating bosentan tablets, monthly during treatment and one month after stopping treatment with bosentan tablets. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. Contraception Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using bosentan tablets and should not be used as a patient’s only contraceptive method [see Drug Interactions (7.2 )]. Females of reproductive potential using bosentan tablets must use two acceptable methods of contraception during treatment and for 1 month after treatment with bosentan tablets. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning ]. Infertility Males Decreased sperm counts have been observed in patients receiving bosentan tablets. Based on these findings and findings in animals, bosentan tablets may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warning s and Precautions (5.6 ), Adverse Reactions (6.1), Nonclinical Toxicology (13.1 )]. 8.4 Pediatric Use The efficacy of bosentan tablets in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with bosentan tablets. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with bosentan tablets [see Pulmonary Arterial Hypertension ( 14.1 )] . Safety in pediatric patients is supported by data from 100 pediatric patients treated with bosentan tablets for a median of 17 months [see Clinical Studies Experience ( 6.1 ), Pulmonary Arterial Hypertension ( 14.1 )]. Juvenile Animal Toxicity Data In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was 4 times (at Day 4 postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure, respectively. No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH. 8.5 Geriatric Use Clinical studies of bosentan tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6 Hepatic Impairment Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (C max and AUC) of bosentan. The pharmacokinetics of bosentan tablets have not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Bosentan tablets should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1 ), Pharmacokinetics (12.3 )]. 8.7 Renal Impairment The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [ see Pharmacokinetics (12.3 )]." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, bosentan tablets may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and are contraindicated during pregnancy [see Contraindications (4.1 )]. There are limited data on bosentan tablets use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m 2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population 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 Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m 2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m 2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs." ], "labor_and_delivery": [ "8.2 Lactation Risk Summary There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan tablets, advise women not to breastfeed during treatment with bosentan tablets." ], "nursing_mothers": [ "8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating bosentan tablets, monthly during treatment and one month after stopping treatment with bosentan tablets. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus. Contraception Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using bosentan tablets and should not be used as a patient’s only contraceptive method [see Drug Interactions (7.2 )]. Females of reproductive potential using bosentan tablets must use two acceptable methods of contraception during treatment and for 1 month after treatment with bosentan tablets. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning ]. Infertility Males Decreased sperm counts have been observed in patients receiving bosentan tablets. Based on these findings and findings in animals, bosentan tablets may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warning s and Precautions (5.6 ), Adverse Reactions (6.1), Nonclinical Toxicology (13.1 )]." ], "pediatric_use": [ "8.4 Pediatric Use The efficacy of bosentan tablets in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with bosentan tablets. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with bosentan tablets [see Pulmonary Arterial Hypertension ( 14.1 )] . Safety in pediatric patients is supported by data from 100 pediatric patients treated with bosentan tablets for a median of 17 months [see Clinical Studies Experience ( 6.1 ), Pulmonary Arterial Hypertension ( 14.1 )]. Juvenile Animal Toxicity Data In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was 4 times (at Day 4 postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure, respectively. No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of bosentan tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects." ], "overdosage": [ "10 OVERDOSAGE Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg twice daily of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan tablets taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support. Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding." ], "description": [ "11 DESCRIPTION Bosentan tablets, an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl- N -[ 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-­[2,2’]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.63 and a molecular formula of C 27 H 29 N 5 O 6 S.H 2 O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.l and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Bosentan tablets are available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: cetyl alcohol, corn starch, croscarmellose sodium, ethyl cellulose, glyceryl behenate, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulphate, sodium starch glycolate, talc, titanium dioxide and triacetin. Each 62.5 mg of bosentan tablet contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each 125 mg of bosentan tablet contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan. bosentan chemical structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B . Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown. Endothelin-l (ET-l) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. ET-l concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-l in this disease. 12.3 Pharmacokinetics General After oral administration, maximum plasma concentrations of bosentan are attained within 3 to 5 hours and the terminal elimination half-life is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in in healthy adult subjects. In a relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet. Absorption The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L. Elimination Metabolism Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10% to 20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50 to 65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3 to 5 days. Excretion Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after a single intravenous dose is about 4 L/h in patients with PAH. Specific Populations Pediatric The average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged 3 to 15 years treated with 31.25, 62.5 or 125 mg (approximately 2 mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. Following administration of 4 mg/kg twice daily doses of dispersible tablet in patients with PAH aged 2 to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with 2 mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily. The exposure to bosentan at 2 mg/kg three times daily dosing of dispersible tablet is similar to that of 2 mg/kg twice daily dosing in patients with PAH aged 3 months to 12 years. Based on these findings, exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients. Hepatic Impairment In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment. In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in 3 patients with normal liver function and PAH of other etiologies. The pharmacokinetics of bosentan tablets have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [See Dosage and Administration (2.2 ), Warnings and Precautions (5.1 ), Use in Specific Populations (8.6 )]. Renal Impairment In patients with severe renal impairment (creatinine clearance 15 to 30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important. Drug Interactions Ketoconazole Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of bosentan tablets is necessary, but increased effects of bosentan tablets should be considered. Warfarin Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan tablets and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan tablets- and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction. Tadalafil Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and C max by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and C max ) of bosentan or its metabolites. Figure 3: CYP Induction-mediated effect of bosentan on other drugs Figure 4: Effects of other drugs on bosentan bosentan fig3 bosentan fig4" ], "mechanism_of_action": [ "12.1 Mechanism of Action Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B . Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown. Endothelin-l (ET-l) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. ET-l concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-l in this disease." ], "pharmacokinetics": [ "12.3 Pharmacokinetics General After oral administration, maximum plasma concentrations of bosentan are attained within 3 to 5 hours and the terminal elimination half-life is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in in healthy adult subjects. In a relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet. Absorption The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L. Elimination Metabolism Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10% to 20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50 to 65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3 to 5 days. Excretion Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after a single intravenous dose is about 4 L/h in patients with PAH. Specific Populations Pediatric The average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged 3 to 15 years treated with 31.25, 62.5 or 125 mg (approximately 2 mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. Following administration of 4 mg/kg twice daily doses of dispersible tablet in patients with PAH aged 2 to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with 2 mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily. The exposure to bosentan at 2 mg/kg three times daily dosing of dispersible tablet is similar to that of 2 mg/kg twice daily dosing in patients with PAH aged 3 months to 12 years. Based on these findings, exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients. Hepatic Impairment In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment. In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in 3 patients with normal liver function and PAH of other etiologies. The pharmacokinetics of bosentan tablets have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [See Dosage and Administration (2.2 ), Warnings and Precautions (5.1 ), Use in Specific Populations (8.6 )]. Renal Impairment In patients with severe renal impairment (creatinine clearance 15 to 30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important. Drug Interactions Ketoconazole Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of bosentan tablets is necessary, but increased effects of bosentan tablets should be considered. Warfarin Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan tablets and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan tablets- and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction. Tadalafil Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and C max by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and C max ) of bosentan or its metabolites. Figure 3: CYP Induction-mediated effect of bosentan on other drugs Figure 4: Effects of other drugs on bosentan bosentan fig3 bosentan fig4" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis and Mutagenesis Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m 2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan. Impairment of Fertility/Testicular Function The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents. Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m 2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4 to ­6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis and Mutagenesis Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m 2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan. Impairment of Fertility/Testicular Function The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents. Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m 2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4 to ­6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD)." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension WHO Functional Class III-IV Two randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared 2 doses (125 mg twice daily and 250 mg twice daily) of bosentan tablets with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III-IV) PAH: idiopathic or heritable PAH (72%) or PAH associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with PAH associated with other conditions such as HIV disease or recurrent pulmonary emboli. In both studies, bosentan tablets or placebo was added to patients’ current therapy, which could have included a combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. Bosentan tablets was given at a dose of 62.5 mg twice daily for 4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or 8 (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351. The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for a mean of 2.4 years. Submaximal Exercise Ability Results of the 6-minute walk distance at 3 months (Study 351) or 4 months (BREATHE-1) are shown in Table 4. Table 4: Effects of bosentan tablets on 6-minute walk distance Distance in meters: mean ± standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for study 351. (a) p=0.01; by Wilcoxon; (b) p=0.0001; by Wilcoxon; (c) p=0.02; by Student’s t-test. BREATHE-l Study 351 Bosentan tablets 125 mg twice daily (n=74) Bosentan tablets 250 mg twice daily (n=70) Placebo (n=69) Bosentan tablets 125 mg twice daily (n=21) Placebo (n=11) Baseline 326 ± 73 333 ± 75 344 ± 76 360 ± 86 355 ± 82 End point 353 ± 115 379 ± 101 336 ± 129 431 ± 66 350 ± 147 Change from baseline 27 ± 75 46 ± 62 -8 ± 96 70 ± 56 -6 ± 121 Placebo- subtracted 35 (a) 54 (b) 76 (c) In both trials, treatment with bosentan tablets resulted in a significant increase in exercise ability. The improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (Figure 5). It was maintained for up to 7 months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended [see Dosage and Administration (2.1 )]. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences. Figure 5: Mean Change in 6-min Walk Distance (BREATHE-1) Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined bosentan tablets (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean ± standard error of the mean. Hemodynamic Changes Invasive hemodynamic parameters were assessed in Study 351. Treatment with bosentan tablets led to a significant increase in cardiac index (CI) associated with a significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 5). The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown. fig5 Table 5: Change from Baseline to Week 12: Hemodynamic Parameters Values shown are means ± SD (a) p≤0.001; (b) p<0.02 Bosentan tablets 125 mg twice daily Placebo CI (L/min/m 2 ) n=20 n=10 Baseline 2.35±0.73 2.48±1.03 Absolute Change 0.50±0.46 -0.52±0.48 Treatment Effect 1.02 (a) Mean PAP (mmHg) n=20 n=10 Baseline 53.7±13.4 55.7±10.5 Absolute Change -1.6±5.1 5.1±8.8 Treatment Effect -6.7 (b) PVR (dyn•sec•cm -5 ) n=19 n=10 Baseline 896±425 942±430 Absolute Change -223±245 191±235 Treatment Effect -415 (a) Mean RAP (mmHg) n=19 n=10 Baseline 9.7±5.6 9.9±4.1 Absolute Change -1.3±4.1 4.9±4.6 Treatment Effect -6.2 (a) Symptoms and Functional Status Symptoms of PAH were assessed by Borg dyspnea score, WHO functional class, and rate of “clinical worsening.” Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was a significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in bosentan tablets-treated patients. There was a significant reduction in the rate of clinical worsening (Table 6 and Figure 6). Figure 6 shows the log-rank test reflecting clinical worsening over 28 weeks. Table 6: Incidence of Clinical Worsening, Intent To Treat Population Note: Patients may have had more than one reason for clinical worsening. (a) p=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups. (b) p=0.033 vs. placebo by Fisher’s exact test. (c) Receipt of epoprostenol was always a consequence of clinical worsening. BREATHE-l Study 351 Bosentan tablets 125/250 mg twice daily (n = 144) Placebo (n = 69) Bosentan tablets 125 mg twice daily (n=21) Placebo (n = 11) Patients with clinical worsening [n (%)] 9 (6%) (a) 14 (20%) 0 (0%) (b) 3 (27%) Death 1 (1%) 2 (3%) 0 (0%) 0 (0%) Hospitalization for PAH 6 (4%) 9 (13%) 0 (0%) 3 (27%) Discontinuation due to worsening of PAH 5 (3%) 6 (9%) 0 (0%) 3 (27%) Receipt of epoprostenol (c) 4 (3%) 3 (4%) 0 (0%) 3 (27%) Figure 6: Time to Clinical Worsening (BREATHE-1) Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=144 in the bosentan tablets group and n=69 in the placebo group) participated in the first 16 weeks of the study. A subset of this population (n=35 in the bosentan tablets group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks. WHO Functional Class II In a randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received bosentan tablets 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. Enrolled patients were treatment-naïve (n = 156) or on a stable dose of sildenafil (n = 29). The coprimary endpoints were change from baseline to month 6 in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints. Compared with placebo, bosentan tablets treatment was associated with a reduced incidence of worsening of at least one functional class (3% bosentan tablets vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; p < 0.05). The + 19 m mean (+14 m median) increase in 6-minute walk distance with bosentan tablets vs. placebo was not significant (p = 0.08). There was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with bosentan tablets compared with placebo (hazard ratio 0.2, p = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline. Long-term Treatment of PAH Long-term follow-up of patients with Class III and IV PAH who were treated with bosentan tablets in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment. These uncontrolled observations do not allow comparison with a group not given bosentan tablets and cannot be used to determine the long-term effect of bosentan tablets on mortality. Pediatric Studies The efficacy of bosentan was evaluated in an open-label, uncontrolled study in 19 pediatric patients with PAH aged 3 to 15 years. Patients had primary pulmonary hypertension (n = 10) or PAH related to congenital heart diseases (9 patients) and were WHO functional class II (n = 15, 79%) or class III (n = 4; 21%) at baseline. Patients were dosed with bosentan at approximately 2 mg/kg twice daily (body weight adjusted dose, corresponding to the recommended adult dose) [see Dosage and Administration ( 2.1 )] for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study. Hemodynamics were measured in 17 patients (Table 7). The mean decrease in PVR was 389 dyn·sec·cm -5 , which was similar to the effect seen in adults. Hemodynamic improvements from baseline were similar with or without co-administration of epoprostenol. Table 7: Change from Baseline to Week 12: Hemodynamic Parameters Bosentan tablets 2 mg/kg twice daily CI (L/min/m 2 ) n=17 Baseline 4.0±1.5 Absolute change 0.5±1.4 Mean PAP (mm Hg) n=18 Baseline 60±18 Absolute change -8±9 PVR(dyn.sec.cm -5 ) n=17 Baseline 1195±755 Absolute change -389±616 Mean RAP (mm Hg) n=18 Baseline 6.1±2.7 Absolute change -0.5±2.3 Values shown are means ± SD Pulmonary Arterial Hypertension in Adults related to Congenital Heart Disease with Left-to-Right Shunts A small study (N=54) and its open-label extension (N=37) of up to 40 weeks in adult patients with Eisenmenger physiology demonstrated effects of bosentan tablets on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1). fig6 14.2 Lack of Benefit in Congestive Heart Failure Bosentan tablets are not effective in the treatment of congestive heart failure with left ventricular dysfunction. In a pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or bosentan tablets (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of bosentan tablets was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first 4 to 8 weeks after bosentan tablets were initiated. In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4 to 8 weeks of treatment with bosentan tablets. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure." ], "clinical_studies_table": [ "
Distance in meters: mean ± standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for study 351. (a)p=0.01; by Wilcoxon; (b)p=0.0001; by Wilcoxon; (c)p=0.02; by Student’s t-test.
BREATHE-l Study 351
Bosentan tablets 125 mg twice daily (n=74) Bosentan tablets 250 mg twice daily (n=70) Placebo (n=69) Bosentan tablets 125 mg twice daily (n=21) Placebo (n=11)
Baseline 326 ± 73 333 ± 75 344 ± 76360 ± 86 355 ± 82
End point 353 ± 115 379 ± 101 336 ± 129 431 ± 66 350 ± 147
Change from baseline 27 ± 75 46 ± 62 -8 ± 96 70 ± 56 -6 ± 121
Placebo- subtracted 35 (a) 54 (b) 76 (c)
", "
Values shown are means ± SD (a)p≤0.001; (b)p<0.02
Bosentan tablets 125 mg twice daily Placebo
CI (L/min/m2) n=20 n=10
Baseline 2.35±0.73 2.48±1.03
Absolute Change 0.50±0.46 -0.52±0.48
Treatment Effect 1.02(a)
Mean PAP (mmHg) n=20 n=10
Baseline 53.7±13.4 55.7±10.5
Absolute Change -1.6±5.1 5.1±8.8
Treatment Effect -6.7(b)
PVR (dyn•sec•cm-5) n=19 n=10
Baseline 896±425 942±430
Absolute Change -223±245 191±235
Treatment Effect -415(a)
Mean RAP (mmHg) n=19 n=10
Baseline 9.7±5.6 9.9±4.1
Absolute Change -1.3±4.1 4.9±4.6
Treatment Effect -6.2(a)
", "
Note: Patients may have had more than one reason for clinical worsening. (a)p=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups. (b)p=0.033 vs. placebo by Fisher’s exact test. (c)Receipt of epoprostenol was always a consequence of clinical worsening.
BREATHE-l Study 351
Bosentan tablets 125/250 mg twice daily (n = 144) Placebo (n = 69) Bosentan tablets 125 mg twice daily (n=21) Placebo (n = 11)
Patients with clinical worsening [n (%)] 9 (6%)(a) 14 (20%) 0 (0%)(b) 3 (27%)
Death 1 (1%) 2 (3%) 0 (0%) 0 (0%)
Hospitalization for PAH 6 (4%) 9 (13%) 0 (0%) 3 (27%)
Discontinuation due to worsening of PAH 5 (3%) 6 (9%) 0 (0%) 3 (27%)
Receipt of epoprostenol(c) 4 (3%) 3 (4%) 0 (0%) 3 (27%)
", "
Bosentan tablets 2 mg/kg twice daily
CI (L/min/m2) n=17
Baseline 4.0±1.5
Absolute change 0.5±1.4
Mean PAP (mm Hg) n=18
Baseline 60±18
Absolute change -8±9
PVR(dyn.sec.cm-5) n=17
Baseline 1195±755
Absolute change -389±616
Mean RAP (mm Hg) n=18
Baseline 6.1±2.7
Absolute change -0.5±2.3
Values shown are means ± SD
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 62.5 mg: Orange-white coloured, round, biconvex, film-coated tablets with plain surface on one side and 'N' on other side packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing. NDC 68180-387-07: Bottle containing 60 tablets. NDC 68180-387-11: Blister of 14 tablets. NDC 68180-387-13: Carton of 56 (4x14 tablets) unit dose tablets. 125 mg: Orange -white coloured, oval, biconvex, film-coated tablets debossed with '125' on one side 'NAT' on other side packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing. NDC 68180-386-07: Bottle containing 60 tablets. NDC 68180-386-11: Blister of 14 tablets. NDC 68180-386-13: Carton of 56 (4x14 tablets) unit dose tablets. Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature]." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Restricted access Advise the patient that bosentan tablets are only available through a restricted access program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers must review the contents of the bosentan tablets Medication Guide with the patient before initiating bosentan tablets. Instruct patients that the risks associated with bosentan tablets include: Hepatotoxicity Discuss with the patient the requirement to measure serum aminotransferases monthly. Embryo-fetal toxicity Educate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with bosentan tablets and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking bosentan tablets and for one month after discontinuing bosentan tablets [see Use in Specific Populations (8.1 )]. Females who have intrauterine devices (IUD) or tubal sterilization can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed. Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected. Advise the patient that bosentan tablets are available only from specialty pharmacies that are enrolled in Bosentan REMS Program. Patients must sign the Bosentan Patient Enrollment and Consent Form to confirm that they understand the risks of bosentan. Lactation Advise women not to breastfeed during treatment with bosentan tablets [see Use in Specific Populations (8.2 )]. Infertility Advise males of reproductive potential that bosentan tablets may impair fertility [see Warnings and Precautions (5.6 ), Adverse Reactions (6.1 ), Use in Specific Populations (8.3 ) and Nonclinical Toxicology (13.1 )]. Other Risks Associated with Bosentan Tablets Instruct patients that the risks associated with bosentan tablets also include the following: Decreases in hemoglobin and hematocrit - advise patients of the importance of hemoglobin testing Decreases in sperm count Fluid retention Manufactured by: Natco Pharma Limited Kothur- 509 228, Telangana, India Distributed by: Lupin Pharmaceuticals, Inc . Baltimore, Maryland 21202 United States" ], "spl_medguide": [ "Medication Guide Bosentan ( bow-SEN-tan ) Tablets Read the Medication Guide that comes with bosentan tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about bosentan tablets? Bosentan tablets are only available through Bosentan REMS Program. Before you begin taking bosentan tablets, you must read and agree to all of the instructions in the Bosentan REMS Program. Bosentan tablets can cause serious side effects including: Liver damage. Liver damage may not cause symptoms at first. Only a blood test can show if you have early liver damage. You must have your blood tested to check your liver function before you start bosentan tablets and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage. Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking bosentan tablets: nausea vomiting fever unusual tiredness stomach area (abdominal) pain yellowing of the skin or the whites of your eyes (jaundice) Serious birth defects. Bosentan tablets can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking bosentan tablets or during bosentan tablets treatment. Serious birth defects from bosentan tablets can happen early in pregnancy. Females who are able to get pregnant must have a negative pregnancy test before starting treatment with bosentan tablets, each month during treatment with bosentan tablets, and 1 month after stopping treatment with bosentan tablets. Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do a pregnancy test and will order a pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with bosentan tablets, and for one month after stopping bosentan tablets because the medicine may still be in the body. If you have had a tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with bosentan tablets. If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. See the chart below for Acceptable Birth Control Options during treatment with bosentan tablets. Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control. Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant. If you are the parent or caregiver of a female child who started taking bosentan tablets before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. Acceptable birth control options. Option 1 Option 2 Option 3 Option 4 One method from this list: or One method from this list: or One method from this list: or One method from this list: Standard intrauterine device (Copper T 380A IUD) Intrauterine system (LNg 20 IUS: progesterone IUS) Tubal sterilization Estrogen and progesterone oral contraceptives (“the pill”) Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant Diaphragm with spermicide Cervical cap with spermicide Partner’s vasectomy PLUS One method from this list : PLUS One method from this list : Male condom Diaphragm with spermicide Cervical cap with spermicide Estrogen and progesterone oral contraceptives (“the pill”) Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant PLUS One method from this list : Male condom Male condom Diaphragm with spermicide Cervical cap with spermicide See “What are the possible side effects of bosentan tablets?” for more information about side effects. What are bosentan tablets? Bosentan tablets are prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs. Bosentan tablets can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Bosentan tablets lowers high blood pressure in your lungs and lets your heart pump blood more efficiently. Bosentan tablets are only: Prescribed by healthcare providers who are enrolled in the Bosentan REMS Program. Available to people who understand and agree to enroll in Bosentan REMS Program. Who should not take bosentan tablets? Do not take bosentan tablets if you: are pregnant, plan to become pregnant, or become pregnant during bosentan tablets treatment. Bosentan tablets can cause serious birth defects. All females should read the birth defects section of “What is the most important information I should know about bosentan tablets?” take any of these medicines: cyclosporine A used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplants glyburide used to treat diabetes are allergic to bosentan or any of the ingredients in bosentan tablets. See the end of this Medication Guide for a complete list of the ingredients in bosentan tablets. If you have a rash, hives or your lips swell after taking bosentan tablets, it may be a sign of allergy. You should stop taking your bosentan tablets and talk to your healthcare provider. What should I tell my healthcare provider before taking bosentan tablets? Bosentan tablets may not be right for you. Tell your healthcare provider about all your medical conditions, including if you: have liver problems. are breast-feeding or plan to breast feed. It is not known if bosentan passes into your milk. You and your healthcare provider should decide if you will take bosentan tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bosentan tablets and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take: hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with bosentan tablets. simvastatin or other “-statin” medicines used to lower cholesterol rifampin used for tuberculosis ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections warfarin sodium used to prevent blood clots ritonavir used to treat HIV There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider or pharmacist when you get a new medicine. How should I take bosentan tablets? Your healthcare provider will give you detailed information about the Bosentan REMS Program. Bosentan tablets are available only through certified pharmacies. You will only receive a 30- day supply of bosentan tablets at one time. Take bosentan tablets exactly as prescribed. Your healthcare provider will tell you how much bosentan tablets to take and when to take it. In most cases, you will take 1 tablet in the morning and 1 in the evening. You can take bosentan tablets orally with or without food. If you take more than the prescribed dose of bosentan tablets, call your healthcare provider right away. If you miss a dose of bosentan tablets, take your tablet as soon as you remember. Do not take 2 doses at the same time. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not stop taking bosentan tablets unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking bosentan tablets, speak with your healthcare provider about the right way to stop. What are the possible side effects of bosentan tablets? Bosentan tablets can cause serious side effects, including: See \"What is the most important information I should know about bosentan tablets?\" Fluid retention and swelling of your ankles and legs. Bosentan tablets can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this. Lower Sperm Count. Some men who take bosentan tablets may have lower sperm counts. This may affect your ability to father a child. Tell your healthcare provider if fertility is a concern for you. Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with bosentan tablets. The most common side effects of bosentan tablets include: respiratory tract infection headache fainting flushing low blood pressure inflamed nose passages (sinusitis) joint pain irregular heart beats 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 bosentan tablets. 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. You may also report side effect to Lupin Pharmaceuticals, Inc. at 1-800-399-2561. How should I store bosentan tablets? Store bosentan tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep bosentan tablets and all medicines out of the reach of children. General information about bosentan tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bosentan tablets for a condition for which it was not prescribed. Do not give bosentan tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about bosentan tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about bosentan tablets that is written for health professionals. For more information, go to www.lupinpharmaceuticals.com. What are the ingredients in bosentan tablets? Active ingredient: bosentan Inactive ingredients: cetyl alcohol, corn starch, croscarmellose sodium, ethyl cellulose, glyceryl behenate, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and triacetin. Manufactured by: Natco Pharma Limited Kothur- 509 228, Telangana, India Distributed by: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: January 2023" ], "spl_medguide_table": [ "
Medication Guide Bosentan (bow-SEN-tan) Tablets
Read the Medication Guide that comes with bosentan tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about bosentan tablets? Bosentan tablets are only available through Bosentan REMS Program. Before you begin taking bosentan tablets, you must read and agree to all of the instructions in the Bosentan REMS Program. Bosentan tablets can cause serious side effects including: Liver damage. Liver damage may not cause symptoms at first. Only a blood test can show if you have early liver damage. You must have your blood tested to check your liver function before you start bosentan tablets and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage. Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking bosentan tablets: nauseavomitingfever unusual tirednessstomach area (abdominal) pain yellowing of the skin or the whites of your eyes (jaundice) Serious birth defects. Bosentan tablets can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking bosentan tablets or during bosentan tablets treatment. Serious birth defects from bosentan tablets can happen early in pregnancy. Females who are able to get pregnant must have a negative pregnancy test before starting treatment with bosentan tablets, each month during treatment with bosentan tablets, and 1 month after stopping treatment with bosentan tablets.Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do a pregnancy test and will order a pregnancy test for you depending on your menstrual cycle.Females who are able to get pregnant are females who:have entered puberty, even if they have not started their menstrual period, andhave a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, orhave gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with bosentan tablets, and for one month after stopping bosentan tablets because the medicine may still be in the body. If you have had a tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with bosentan tablets. If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. See the chart below for Acceptable Birth Control Options during treatment with bosentan tablets. Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control. Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant. If you are the parent or caregiver of a female child who started taking bosentan tablets before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. Acceptable birth control options.
Option 1 Option 2 Option 3 Option 4
One method from this list: or One method from this list: or One method from this list: or One method from this list:
Standard intrauterine device (Copper T 380A IUD) Intrauterine system (LNg 20 IUS: progesterone IUS) Tubal sterilization Estrogen and progesterone oral contraceptives (“the pill”) Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant Diaphragm with spermicide Cervical cap with spermicide Partner’s vasectomy
PLUS One method from this list:
PLUS One method from this list: Male condom Diaphragm with spermicide Cervical cap with spermicide Estrogen and progesterone oral contraceptives (“the pill”) Estrogen and progesterone transdermal patch Vaginal ring Progesterone injection Progesterone implant
PLUS One method from this list: Male condom
Male condom Diaphragm with spermicide Cervical cap with spermicide
See “What are the possible side effects of bosentan tablets?” for more information about side effects.
What are bosentan tablets? Bosentan tablets are prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs. Bosentan tablets can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Bosentan tablets lowers high blood pressure in your lungs and lets your heart pump blood more efficiently. Bosentan tablets are only: Prescribed by healthcare providers who are enrolled in the Bosentan REMS Program. Available to people who understand and agree to enroll in Bosentan REMS Program.
Who should not take bosentan tablets? Do not take bosentan tablets if you:are pregnant, plan to become pregnant, or become pregnant during bosentan tablets treatment. Bosentan tablets can cause serious birth defects. All females should read the birth defects section of “What is the most important information I should know about bosentan tablets?”take any of these medicines: cyclosporine A used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplants glyburide used to treat diabetes are allergic to bosentan or any of the ingredients in bosentan tablets. See the end of this Medication Guide for a complete list of the ingredients in bosentan tablets. If you have a rash, hives or your lips swell after taking bosentan tablets, it may be a sign of allergy. You should stop taking your bosentan tablets and talk to your healthcare provider.
What should I tell my healthcare provider before taking bosentan tablets? Bosentan tablets may not be right for you. Tell your healthcare provider about all your medical conditions, including if you:have liver problems. are breast-feeding or plan to breast feed. It is not known if bosentan passes into your milk. You and your healthcare provider should decide if you will take bosentan tablets or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Bosentan tablets and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take: hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with bosentan tablets. simvastatin or other “-statin” medicines used to lower cholesterolrifampin used for tuberculosis ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections warfarin sodium used to prevent blood clotsritonavir used to treat HIV There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep a list of them and show it to your healthcare provider or pharmacist when you get a new medicine.
How should I take bosentan tablets? Your healthcare provider will give you detailed information about the Bosentan REMS Program. Bosentan tablets are available only through certified pharmacies. You will only receive a 30- day supply of bosentan tablets at one time. Take bosentan tablets exactly as prescribed. Your healthcare provider will tell you how much bosentan tablets to take and when to take it. In most cases, you will take 1 tablet in the morning and 1 in the evening.You can take bosentan tablets orally with or without food. If you take more than the prescribed dose of bosentan tablets, call your healthcare provider right away.If you miss a dose of bosentan tablets, take your tablet as soon as you remember. Do not take 2 doses at the same time. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not stop taking bosentan tablets unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking bosentan tablets, speak with your healthcare provider about the right way to stop.
What are the possible side effects of bosentan tablets? Bosentan tablets can cause serious side effects, including: See "What is the most important information I should know about bosentan tablets?"Fluid retention and swelling of your ankles and legs. Bosentan tablets can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this. Lower Sperm Count. Some men who take bosentan tablets may have lower sperm counts. This may affect your ability to father a child. Tell your healthcare provider if fertility is a concern for you. Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with bosentan tablets. The most common side effects of bosentan tablets include: respiratory tract infection headache fainting flushing low blood pressure inflamed nose passages (sinusitis) joint pain irregular heart beats 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 bosentan tablets. 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. You may also report side effect to Lupin Pharmaceuticals, Inc. at 1-800-399-2561.
How should I store bosentan tablets? Store bosentan tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep bosentan tablets and all medicines out of the reach of children.
General information about bosentan tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bosentan tablets for a condition for which it was not prescribed. Do not give bosentan tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about bosentan tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about bosentan tablets that is written for health professionals. For more information, go to www.lupinpharmaceuticals.com.
What are the ingredients in bosentan tablets? Active ingredient: bosentan Inactive ingredients: cetyl alcohol, corn starch, croscarmellose sodium, ethyl cellulose, glyceryl behenate, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, povidone (K-90), pregelatinized starch, sodium lauryl sulfate, sodium starch glycolate, talc, titanium dioxide and triacetin. Manufactured by: Natco Pharma Limited Kothur- 509 228, Telangana, India Distributed by: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States
" ], "package_label_principal_display_panel": [ "Bosentan tablets 62.5 mg Bottle of 60 Tablets Rx Only 60 Tablets NDC 68180-387-07 Each tablet contains 62.5 mg of anhydrous bosentan. Attention: Dispense with enclosed Medication Guide. 62-5mg bottle carton 62-5mg bottle label", "Bosentan tablets 125 mg Bottle of 60 Tablets Rx Only 60 Tablets NDC 68180-386-07 Each tablet contains 125 mg of anhydrous bosentan. Attention: Dispense with enclosed Medication Guide. 125mg bottle carton 125mg bottle label" ], "set_id": "0d825e26-af37-43b7-98b5-a6cfd5a425c7", "id": "3b5e6b7a-d7f4-4b96-b879-d0745957134a", "effective_time": "20230919", "version": "10", "openfda": {} }, { "spl_product_data_elements": [ "Ambrisentan Ambrisentan AMBRISENTAN AMBRISENTAN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE FD&C RED NO. 40 LECITHIN, SOYBEAN POLYETHYLENE GLYCOL 4000 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE Pale C;386 Ambrisentan Ambrisentan AMBRISENTAN AMBRISENTAN CROSCARMELLOSE SODIUM LACTOSE MONOHYDRATE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE FD&C RED NO. 40 LECITHIN, SOYBEAN POLYETHYLENE GLYCOL 4000 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE Deep C;387" ], "boxed_warning": [ "WARNING: EMBRYO-FETAL TOXICITY Ambrisentan tablets are contraindicated for use during pregnancy because it may cause major birth defects if used by pregnant patients, based on studies in animals [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )] . Therefore, for females of reproductive potential, exclude pregnancy before the initiation of treatment with ambrisentan tablets. Advise use of effective contraception before initiation, during treatment, and for one month after treatment with ambrisentan tablets [see Dosage and Administration ( 2.2 ) Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )] . When pregnancy is detected, discontinue ambrisentan tablets as soon as possible ( 5.1 ). WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Based on animal data ambrisentan tablets may cause fetal harm if used during pregnancy ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: Exclude pregnancy before the start of treatment. Use effective contraception prior to initiation of treatment, during treatment, and for one month after treatment with ambrisentan tablets ( 2.2 , 4.1 , 5.1 , 8.1 , 8.3 ). When pregnancy is detected, discontinue ambrisentan tablets as soon as possible ( 5.1 )." ], "recent_major_changes": [ "RECENT MAJOR CHANGES SECTION Box Warning 4/2025 Indications and Usage ( 1 ) 4/2025 Dosage and Administration, Pregnancy Testing in Females of Reproductive Potential ( 2.2 ) 4/2025 Warnings and Precautions for Use Embryo-fetal Toxicity ( 5.1 ) 4/2025 Ambrisentan Risk Evaluation and Mitigation Strategy (REMS) (5.2) (removed) 4/2025" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adult patients: To improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%). Ambrisentan tablet is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in adult patients: To improve exercise ability and delay clinical worsening. Studies establishing effectiveness included trials predominantly in patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%) ( 1 )." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Initiate treatment at 5 mg once daily ( 2.1 ). Titrate at 4-week intervals as needed and tolerated ( 2.1 ). Do not split, crush, or chew tablets ( 2.1 ). 2.1 Adult Dosage Initiate treatment at 5 mg once daily. At 4-week intervals, the dose of ambrisentan can be increased, as needed and tolerated, to ambrisentan10 mg. Do not split, crush, or chew tablets. 2.2 Pregnancy Testing in Females of Reproductive Potential Exclude pregnancy before initiating treatment with ambrisentan tablets in females of reproductive potential [ see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 , 8.3 ) ]." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 5 mg and 10 mg film-coated tablets for oral administration Each 5 mg tablet is pale pink square shaped biconvex film coated tablets debossed with 'C' on one side and '386' on other side. Each 10 mg tablet is deep pink oval shaped biconvex film coated tablets debossed with 'C' on one side and '387' on other side. Tablet: 5 mg and 10 mg ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Idiopathic Pulmonary Fibrosis ( 4.2 ) 4.1 Pregnancy Ambrisentan tablets may cause fetal harm when administered to a pregnant female. Ambrisentan tablets are contraindicated in females who are pregnant. Ambrisentan tablets were consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )] . 4.2 Idiopathic Pulmonary Fibrosis Ambrisentan tablets are contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies ( 14.4 )] ." ], "pregnancy": [ "4.1 Pregnancy Ambrisentan tablets may cause fetal harm when administered to a pregnant female. Ambrisentan tablets are contraindicated in females who are pregnant. Ambrisentan tablets were consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )] .", "8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets use in pregnant women. Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as ambrisentan tablets have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 )] . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Data Animal Data Ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥7 mg/kg/day (24.7 h•μg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•μg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 x (on a mg/m 2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 x the human dose based on mg/m 2 ." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Fluid retention may require intervention ( 5.2 ). If patients develop acute pulmonary edema during initiation of therapy with ambrisentan tablets, consider underlying pulmonary venoocclusive disease and discontinue treatment if necessary ( 5.3 ). Decreases in sperm count have been observed in patients taking endothelin receptor antagonists ( 5.4 ). Decreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at 1 month, and periodically thereafter ( 5.5 ). 5.1 Embryo-fetal Toxicity Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm when administered during pregnancy and is contraindicated during pregnancy. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of ambrisentan tablets. Advise patients who can become pregnant of the potential risk to a fetus. Obtain a pregnancy test prior to initiation of treatment with ambrisentan tablets. Advise patients who can become pregnant to use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with ambrisentan tablets. When pregnancy is detected, discontinue use as soon as possible [see Dosage and Administration ( 2.2 ), and Use in Specific Populations ( 8.1 , 8.3 )] . 5.2 Fluid Retention Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg ambrisentan tablets compared to placebo [see Adverse Reactions ( 6.1 )] . Most edema was mild to moderate in severity. In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting ambrisentan tablets. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy. 5.3 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD) If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of PVOD should be considered, and if confirmed ambrisentan tablets should be discontinued. 5.4 Decreased Sperm Counts Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Ambrisentan tablets may have an adverse effect on spermatogenesis [see Use in Specific Populations ( 8.6 ) and Nonclinical Toxicology ( 13.1 )] . 5.5 Hematological Changes Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with ambrisentan. These decreases were observed within the first few weeks of treatment with ambrisentan, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving ambrisentan in the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis. In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. Measure hemoglobin prior to initiation of ambrisentan tablets, at one month, and periodically thereafter. Initiation of ambrisentan therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan tablets." ], "adverse_reactions": [ "6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 )] Fluid Retention [see Warnings and Precautions ( 5.2 )] Pulmonary Edema with PVOD [see Warnings and Precautions ( 5.3 )] Decreased Sperm Count [see Warnings and Precautions ( 5.4 )] Hematologic Changes [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (>3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. 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. Safety data for ambrisentan are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH). The exposure to ambrisentan in these studies ranged from 6 days to 100 days. In ARIES-1 and ARIES-2, a total of 261 patients received ambrisentan at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in >3% more patients receiving ambrisentan than receiving placebo are shown in Table 1. Table 1 Adverse Reactions with Placebo-Adjusted Rates >3% in ARIES-1 and ARIES-2 Placebo (N=132) Ambrisentan (N=261) Adverse Reaction n (%) n (%) Placebo-adjusted (%) Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4 Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3 Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent. Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (<65 years) receiving ambrisentan (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving ambrisentan (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously. The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for ambrisentan (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for ambrisentan (5%; 13/261 patients). During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 x upper limit of normal (ULN) were 0% on ambrisentan and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause. Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities In an uncontrolled, open - label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations >3 x ULN were treated with ambrisentan. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 x ULN, but 9 patients had elevations >8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on ambrisentan tablets 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of ambrisentan tablets to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re - administration of previously used ERAs or show that ambrisentan led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that ambrisentan may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal. 6.2 Postmarketing Experience The following adverse reactions were identified during post-approval use of ambrisentan. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia requiring transfusion [see Warnings and Precautions ( 5.5 )] heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash). Elevations of liver aminotransferases (ALT, AST) have been reported with ambrisentan use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Adverse Reactions ( 6.1 )] ." ], "adverse_reactions_table": [ "
Table 1 Adverse Reactions with Placebo-Adjusted Rates >3% in ARIES-1 and ARIES-2
Placebo (N=132)Ambrisentan (N=261)
Adverse Reactionn (%)n (%)Placebo-adjusted (%)
Peripheral edema14 (11)45 (17)6
Nasal congestion2 (2)15 (6)4
Sinusitis0 (0)8 (3)3
Flushing1 (1)10 (4)3
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine [see Clinical Pharmacology ( 12.3 )] . Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily ( 7 )." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS Breastfeeding: Choose ambrisentan tablets or breastfeeding ( 8.2 ). Not recommended in patients with moderate or severe hepatic impairment ( 8.7 ). 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets use in pregnant women. Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as ambrisentan tablets have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 )] . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Data Animal Data Ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥7 mg/kg/day (24.7 h•μg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•μg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 x (on a mg/m 2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 x the human dose based on mg/m 2 . 8.2 Lactation Risk Summary It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan tablets, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan tablets, taking into account the importance of the drug to the mother. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on data from animal reproductive toxicity studies, ambrisentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications ( 4.1 ), Use in Specific Populations ( 8.1 )] . Verify that patients who can become pregnant are not pregnant prior to initiating ambrisentan. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient should discuss the risks to the pregnancy and the fetus. Contraception Patients who can become pregnant who are using ambrisentan should use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with ambrisentan to prevent pregnancy [see Warnings and Precautions ( 5.1 )] . Infertility Males In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data [see Nonclinical Toxicology ( 13.1 )] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan tablets have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see Warnings and Precautions ( 5.5 )] . 8.4 Pediatric Use Safety and effectiveness of ambrisentan in pediatric patients have not been established. Juvenile Animal Data In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (-3% to -8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC. 8.5 Geriatric Use In the two placebo-controlled clinical studies of ambrisentan tablets, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan tablets than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients. 8.6 Renal Impairment The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see Clinical Pharmacology ( 12.3 )] . Dose adjustment of ambrisentan tablets in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment. The impact of hemodialysis on the disposition of ambrisentan has not been investigated. 8.7 Hepatic Impairment Pre-existing Hepatic Impairment The influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology ( 12.3 )] . Ambrisentan tablets are not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan tablets in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients. Elevation of Liver Transaminases Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions ( 6.1 , 6.2 )]. In patients who develop hepatic impairment after ambrisentan tablet initiation, the cause of liver injury should be fully investigated. Discontinue ambrisentan tablets if elevations of liver aminotransferases are >5 x ULN or if elevations are accompanied by bilirubin >2 x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded." ], "nursing_mothers": [ "8.2 Lactation Risk Summary It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan tablets, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan tablets, taking into account the importance of the drug to the mother." ], "pediatric_use": [ "8.4 Pediatric Use Safety and effectiveness of ambrisentan in pediatric patients have not been established. Juvenile Animal Data In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (-3% to -8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC." ], "geriatric_use": [ "8.5 Geriatric Use In the two placebo-controlled clinical studies of ambrisentan tablets, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan tablets than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients." ], "overdosage": [ "10 OVERDOSAGE There is no experience with overdosage of ambrisentan tablets. The highest single dose of ambrisentan tablets administered to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention." ], "description": [ "11 DESCRIPTION Ambrisentan is an endothelin receptor antagonist. The chemical name of ambrisentan is (+)-(2 S )-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C 22 H 22 N 2 O 4 and a molecular weight of 378.42 and has the following structural formula: Figure 1 Ambrisentan Structural Formula Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive. Ambrisentan is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each square, pale pink ambrisentan tablet contains 5 mg of ambrisentan. Each oval, deep pink ambrisentan tablet contains 10 mg of ambrisentan. Ambrisentan tablets are unscored. structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ET A and ET B , mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ET A are vasoconstriction and cell proliferation, while the predominant actions of ET B are vasodilation, antiproliferation, and ET-1 clearance. In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH. Ambrisentan is a high-affinity (K i = 0.011 nM) ET A receptor antagonist with a high selectivity for the ET A versus ET B receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known. 12.2 Pharmacodynamics Cardiac Electrophysiology In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either ambrisentan tablet 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Ambrisentan tablet 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of ambrisentan tablets increased mean QTc at t max by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving ambrisentan tablet 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected. 12.3 Pharmacokinetics The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours. Drug Interactions In Vitro Studies Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine [see Drug Interactions ( 7 )] . In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC 50 of 47 μM, 45 μM, and approximately 100 μM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations. In Vivo Studies The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively. Figure 2 Effects of Other Drugs on Ambrisentan Pharmacokinetics * Omeprazole: based on population pharmacokinetic analysis in PAH patients ** Rifampin: AUC and C max were measured at steady-state. On Day 3 of coadministration a transient 2-fold increase in AUC was noted that was no longer evident by Day 7. Day 7 results are presented. Figure 3 Effects of Ambrisentan on Other Drugs * Active metabolite of mycophenolate mofetil ** GMR (95% CI) for INR figure-2 figure-3" ], "mechanism_of_action": [ "12.1 Mechanism of Action Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ET A and ET B , mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ET A are vasoconstriction and cell proliferation, while the predominant actions of ET B are vasodilation, antiproliferation, and ET-1 clearance. In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH. Ambrisentan is a high-affinity (K i = 0.011 nM) ET A receptor antagonist with a high selectivity for the ET A versus ET B receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Cardiac Electrophysiology In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either ambrisentan tablet 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Ambrisentan tablet 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of ambrisentan tablets increased mean QTc at t max by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving ambrisentan tablet 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected." ], "pharmacokinetics": [ "12.3 Pharmacokinetics The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours. Drug Interactions In Vitro Studies Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine [see Drug Interactions ( 7 )] . In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC 50 of 47 μM, 45 μM, and approximately 100 μM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations. In Vivo Studies The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively. Figure 2 Effects of Other Drugs on Ambrisentan Pharmacokinetics * Omeprazole: based on population pharmacokinetic analysis in PAH patients ** Rifampin: AUC and C max were measured at steady-state. On Day 3 of coadministration a transient 2-fold increase in AUC was noted that was no longer evident by Day 7. Day 7 results are presented. Figure 3 Effects of Ambrisentan on Other Drugs * Active metabolite of mycophenolate mofetil ** GMR (95% CI) for INR figure-2 figure-3" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group. Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay). The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a mg/m 2 basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high- and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group. Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay). The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension (PAH) Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of ambrisentan tablets and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg ambrisentan tablets to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg ambrisentan to placebo. In both studies, ambrisentan tablets or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36 ® Health Survey were assessed. Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease. Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian. Submaximal Exercise Ability Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 3 and Figure 4. Table 3 Changes from Baseline in 6-Minute Walk Distance (meters) (ARIES-1 and ARIES-2) ARIES-1 ARIES-2 Placebo (N=67) 5 mg (N=67) 10 mg (N=67) Placebo (N=65) 2.5 mg (N=64) 5 mg (N=63) Baseline 342 ± 73 340 ± 77 342 ± 78 343 ± 86 347 ± 84 355 ± 84 Mean change from baseline -8 ± 79 23 ± 83 44 ± 63 -10 ± 94 22 ± 83 49 ± 75 Placebo-adjusted mean change from baseline – 31 51 – 32 59 Placebo-adjusted median change from baseline – 27 39 – 30 45 p-value a – 0.008 <0.001 – 0.022 <0.001 Mean ± standard deviation a p-values are Wilcoxon rank sum test comparisons of ambrisentan tablets to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients Figure 4 Mean Change in 6-Minute Walk Distance (ARIES-1 and ARIES-2) Mean change from baseline in 6-minute walk distance in the placebo and ambrisentan tablet groups. Values are expressed as mean ± standard error of the mean. In both studies, treatment with ambrisentan tablets resulted in a significant improvement in 6-minute walk distance for each dose of ambrisentan tablets and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with ambrisentan tablets, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with ambrisentan tablets were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously. Clinical Worsening Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the ambrisentan tablet clinical trials are shown in Table 4 and Figure 5. Table 4 Time to Clinical Worsening (ARIES-1 and ARIES-2) ARIES-1 ARIES-2 Placebo (N=67) Ambrisentan tablets (N=134) Placebo (N=65) Ambrisentan tablets (N=127) Clinical worsening, no. (%) 7 (10%) 4 (3%) 13 (22%) 8 (6%) Hazard ratio – 0.28 – 0.30 p-value, Log-rank test – 0.030 – 0.005 Intention-to-treat population. Note: Patients may have had more than one reason for clinical worsening. Nominal p-values There was a significant delay in the time to clinical worsening for patients receiving ambrisentan tablets compared to placebo. Results in subgroups such as the elderly were also favorable. Figure 5 Time to Clinical Worsening (ARIES-1 and ARIES-2) Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of patients without events in ARIES-1 and ARIES-2. p-values shown are the log-rank comparisons of ambrisentan tablets to placebo stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients. figure-4 figure-5 14.3 Long-term Treatment of PAH In long - term follow - up of patients who were treated with ambrisentan (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open - label extension (N=383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on ambrisentan tablets for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given ambrisentan tablets and cannot be used to determine the long-term effect of ambrisentan tablets on mortality. 14.4 Adverse Effects in Idiopathic Pulmonary Fibrosis (IPF) A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared ambrisentan tablets (N=329) to placebo (N=163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on ambrisentan tablets. More patients taking ambrisentan tablets died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) [see Contraindications ( 4.2 )] ." ], "clinical_studies_table": [ "
Table 3 Changes from Baseline in 6-Minute Walk Distance (meters) (ARIES-1 and ARIES-2)
ARIES-1ARIES-2
Placebo (N=67)5 mg (N=67)10 mg (N=67)Placebo (N=65)2.5 mg (N=64)5 mg (N=63)
Baseline342 ± 73340 ± 77342 ± 78343 ± 86347 ± 84355 ± 84
Mean change from baseline-8 ± 7923 ± 8344 ± 63-10 ± 9422 ± 8349 ± 75
Placebo-adjusted mean change from baseline–3151–3259
Placebo-adjusted median change from baseline–2739–3045
p-valuea–0.008<0.001–0.022<0.001
", "
Table 4 Time to Clinical Worsening (ARIES-1 and ARIES-2)
ARIES-1ARIES-2
Placebo (N=67)Ambrisentan tablets (N=134)Placebo (N=65)Ambrisentan tablets (N=127)
Clinical worsening, no. (%)7 (10%)4 (3%)13 (22%)8 (6%)
Hazard ratio–0.28–0.30
p-value, Log-rank test–0.030–0.005
Intention-to-treat population.
Note: Patients may have had more than one reason for clinical worsening.
Nominal p-values
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Ambrisentan film - coated tablets are supplied as follows: Tablet Strength Package Configuration NDC No. Description of Tablet; Debossed on Tablet 5 mg 30 count bottle 69097-386-02 Square biconvex; pale pink; “C” on one side and “386” on other side 10 count blister 69097-386-19 10 mg 30 count bottle 69097-387-02 Oval biconvex; deep pink; “C” on one side and “387” on other side 10 count blister 69097-387-19 Store at 25° C (77° F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature] . Store ambrisentan tablets in its original packaging." ], "how_supplied_table": [ "
Tablet StrengthPackage ConfigurationNDC No.Description of Tablet; Debossed on Tablet
5 mg30 count bottle69097-386-02Square biconvex; pale pink; “C” on one side and “386” on other side
10 count blister69097-386-19
10 mg30 count bottle69097-387-02Oval biconvex; deep pink; “C” on one side and “387” on other side
10 count blister69097-387-19
" ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Medication Guide). Embryo-fetal Toxicity Instruct patients on the risk of fetal harm when ambrisentan tablets are used in pregnancy [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant. Educate and counsel patients who can become pregnant about the need to use effective contraception prior to treatment with ambrisentan tablets, during treatment, and for one month after treatment discontinuation [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 , 8.3 )] . Patients who can become pregnant should have a negative pregnancy test prior to treatment with ambrisentan tablets [see Dosage and Administration ( 2.2 ), Contraindications ( 4.1 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.1 , 8.3 )] . Counsel patients who can become pregnant about pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning ] . Hepatic Effects Advise patients of the symptoms of potential liver injury and instruct them to report any of these symptoms to their physician. Hematological Change Advise patients of the importance of hemoglobin testing. Other Risks Associated with Ambrisentan tablets Instruct patients that the risks associated with ambrisentan tablets also include the following: Decreases in sperm count Fluid overload Administration Advise patients not to split, crush, or chew tablets. Disclaimer: Other brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited. Manufactured by: Cipla Ltd. Patalganga-410220, Maharashtra, India Manufactured for: Cipla USA, Inc., 10 Independence Boulevard, Suite 300, Warren New Jersey - 07059 Revised: 04/2025" ], "spl_medguide": [ "Medication Guide Ambrisentan (AM bri SEN tan) Tablets Read this Medication Guide before you start taking ambrisentan tablets and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about ambrisentan tablets? Serious birth defects. Ambrisentan tablets can cause serious birth defects if taken during pregnancy. Females should not be pregnant when they start taking ambrisentan tablets or become pregnant during treatment with ambrisentan tablets. Females who are able to get pregnant should have a negative pregnancy test before beginning treatment with ambrisentan tablets. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do a pregnancy test, and will order a pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, or who are infertile for any other medical reason and this infertility is permanent and cannot be reversed Females who are able to get pregnant should use effective contraception before beginning ambrisentan tablets, during treatment with ambrisentan tablets, and for one month after stopping ambrisentan tablets because the medicine may still be in the body. Talk with your doctor or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable forms of birth control that you may use to prevent pregnancy during treatment with ambrisentan tablets. If you decide that you want to change the form of birth control that you use, talk with your doctor or gynecologist to be sure that you choose another acceptable form of birth control. Do not have unprotected sex. Talk to your doctor or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your doctor may tell you to use emergency birth control. Tell your doctor right away if you miss a menstrual period or think you may be pregnant for any reason. If you are the parent or caregiver of a female child who started taking ambrisentan tablets before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your doctor right away if you notice that she is developing breast buds or pubic hair. Your doctor should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. What is ambrisentan tablet? Ambrisentan tablet is a prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. Ambrisentan tablets can improve your ability to exercise and it can help slow down the worsening of your physical condition and symptoms. It is not known if ambrisentan tablet is safe and effective in children. Who should not take ambrisentan tablets? Do not take ambrisentan tablets if: you are pregnant, plan to become pregnant, or become pregnant during treatment with ambrisentan tablets. Ambrisentan tablets can cause serious birth defects. (See “What is the most important information I should know about ambrisentan tablets?” ) you have a condition called Idiopathic Pulmonary Fibrosis (IPF) What should I tell my doctor before taking ambrisentan tablets? Before you take ambrisentan tablets, tell your doctor if you: have been told that you have a low red blood cell level (anemia) have liver problems have any other medical conditions Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Ambrisentan tablets and other medicines may affect each other, causing side effects. Do not start any new medicines until you check with your doctor. Especially tell your doctor if you take the medicine cyclosporine (Gengraf, Neoral, Sandimmune). Your doctor may need to change your dose of ambrisentan tablets. How should I take ambrisentan tablets? Take ambrisentan tablets exactly as your doctor tells you to take it. Do not stop taking ambrisentan tablets unless your doctor tells you to stop. You can take ambrisentan tablets with or without food. Do not split, crush or chew ambrisentan tablets. It will be easier to remember to take ambrisentan tablets if you take it at the same time each day. If you take more than your regular dose of ambrisentan tablets, call your doctor right away. If you miss a dose, take it as soon as you remember that day. Take your next dose at the regular time. Do not take two doses at the same time to make up for a missed dose. What should I avoid while taking ambrisentan tablets? Do not get pregnant while taking ambrisentan tablets. (See the serious birth defects section of the Medication Guide above called “What is the most important information I should know about ambrisentan tablets?” ) If you miss a menstrual period, or think you might be pregnant, call your doctor right away. It is not known if ambrisentan passes into your breast milk. You should not breastfeed if you are taking ambrisentan tablets. Talk to your doctor about the best way to feed your baby if you take ambrisentan tablets. What are the possible side effects of ambrisentan tablets? Ambrisentan tablets can cause serious side effects including: See “ What is the most important information I should know about ambrisentan tablets? ” Swelling all over the body (fluid retention) can happen within weeks after starting ambrisentan tablets. Tell your doctor right away if you have any unusual weight gain, tiredness, or trouble breathing while taking ambrisentan tablets. These may be symptoms of a serious health problem. You may need to be treated with medicine or need to go to the hospital. Decreased sperm count. Decreased sperm counts have happened in some men taking a medicine that is like ambrisentan tablets. A decreased sperm count may affect the ability to father a child. Tell your doctor if being able to have children is important to you. Low red blood cell levels (anemia) can happen during the first weeks after starting ambrisentan tablets. If this happens, you may need a blood transfusion. Your doctor will do blood tests to check your red blood cells before starting ambrisentan tablets. Your doctor may also do these tests during treatment with ambrisentan tablets. The most common side effects of ambrisentan tablets include: swelling of hands, legs, ankles and feet (peripheral edema) stuffy nose (nasal congestion) inflamed nasal passages (sinusitis) hot flashes or getting red in the face (flushing) Some medicines that are like ambrisentan tablets can cause liver problems. Tell your doctor if you get any of these symptoms of a liver problem while taking ambrisentan tablets: loss of appetite nausea or vomiting fever achiness generally do not feel well pain in the upper right stomach (abdominal) area yellowing of your skin or the whites of your eyes dark urine itching Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of ambrisentan tablets. 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. How should I store ambrisentan tablets? Store ambrisentan tablets at room temperature between 68°F to 77°F (20°C to 25°C), in the package it comes in. Keep ambrisentan tablets and all medicines out of the reach of children. General information about the safe and effective use of ambrisentan tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ambrisentan tablets for a condition for which it was not prescribed. Do not give ambrisentan tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about ambrisentan tablets. If you would like more information, ask your doctor. You can ask your doctor or pharmacist for information about ambrisentan tablets that is written for health professionals. What are the ingredients in ambrisentan tablets? Active ingredient: ambrisentan Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Disclaimer: Other brands listed are the registered trademarks of their respective owners and are not trademarks of Cipla Limited. Manufactured by: Cipla Ltd. Patalganga-410220, Maharashtra, India Manufactured for : Cipla USA, Inc., 10 Independence Boulevard, Suite 300, Warren New Jersey - 07059 For more information call 1-866-604-3268. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2025" ], "package_label_principal_display_panel": [ "PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 69097-386-02 Rx Only Ambrisentan Tablets 5 mg DISPENSER: Each time Ambrisentan Tablets is dispensed give the patient the attached Medication Guide. 30 Tablets Cipla NDC 69097-386-19 Rx Only Ambrisentan Tablets 5 mg Each tablet contains 5 mg of ambrisentan. 10 Tablets Note to Authorized Dispenser: Provide a copy of the Ambrisentan Tablets Medication Guide included in this carton to each patient. Cipla NDC 69097-387-02 Rx Only Ambrisentan Tablets 10 mg DISPENSER: Each time Ambrisentan Tablets is dispensed give the patient the attached Medication Guide. 30 Tablets Cipla NDC 69097-387-19 Rx Only Ambrisentan Tablets 10 mg Each tablet contains 10 mg of ambrisentan. 10 Tablets Note to Authorized Dispenser: Provide a copy of the Ambrisentan Tablets Medication Guide included in this carton to each patient. Cipla ambrisentan-tabs-5mg-30s ambrisentan-tabs-5mg-10s ambrisentan-tabs-10mg-30s ambrisentan-tabs-10mg-10s" ], "set_id": "0e418384-cae1-47ae-ac5e-afc845d694f6", "id": "7921a3aa-6e99-4f28-a5d3-a3047b1ec3cc", "effective_time": "20250422", "version": "8", "openfda": { "application_number": [ "ANDA210715" ], "brand_name": [ "Ambrisentan" ], "generic_name": [ "AMBRISENTAN" ], "manufacturer_name": [ "Cipla USA Inc." ], "product_ndc": [ "69097-386", "69097-387" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "AMBRISENTAN" ], "rxcui": [ "722116", "722122" ], "spl_id": [ "7921a3aa-6e99-4f28-a5d3-a3047b1ec3cc" ], "spl_set_id": [ "0e418384-cae1-47ae-ac5e-afc845d694f6" ], "package_ndc": [ "69097-386-19", "69097-386-02", "69097-387-02", "69097-387-19" ], "is_original_packager": [ true ], "upc": [ "0369097387020", "0369097386023" ], "nui": [ "N0000175581", "N0000175364" ], "pharm_class_epc": [ "Endothelin Receptor Antagonist [EPC]" ], "pharm_class_moa": [ "Endothelin Receptor Antagonists [MoA]" ], "unii": [ "HW6NV07QEC" ] } }, { "spl_product_data_elements": [ "Sildenafil Sildenafil SILDENAFIL CITRATE SILDENAFIL ANHYDROUS CITRIC ACID SILICON DIOXIDE SODIUM BENZOATE SODIUM CITRATE, UNSPECIFIED FORM SORBITOL SUCRALOSE TITANIUM DIOXIDE XANTHAN GUM" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Adults Sildenafil for oral suspension is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies ( 14 )] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Adults Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Adults: 20 mg three times a day. ( 2.1 ) 2.1 Recommended Dosage in Adults Oral Dosage The recommended dosage of sildenafil for oral suspension is 20 mg three times a day [see Clinical Studies ( 14 )] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Reconstitution of the Powder for Oral Suspension Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL) . Refer to the detailed instructions below. 1. Tap the bottle to loosen the powder. 2. Add 60 mL of water to the bottle. 3. Replace cap and shake the bottle vigorously for a minimum of 30 seconds. 4. Add another 30 mL of water to the bottle. 5. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 6. Remove the cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle. 7. Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution). Incompatibilities Do not mix with any other medication or additional flavoring agent." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Sildenafil for Oral Suspension White to off-white crystalline powder containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle intended for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2 mL oral syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. For oral suspension: 10 mg/mL (when reconstituted) ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions ( 5.1 )] . Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet, injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates or riociguat. ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.1 ) Use in pulmonary veno-occlusive disease (PVOD) may cause pulmonary edema and is not recommended. ( 5.2 ) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.4 , 5.5 ) Pulmonary hypertension (PH) secondary to sickle cell disease: Sildenafil may cause serious vaso-occlusive crises. ( 5.8 ) 5.1 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when coadministering blood pressure lowering drugs with sildenafil. 5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.3 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.4 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”). Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking sildenafil. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of sildenafil in patients with retinitis pigmentosa is not recommended. 5.5 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.6 Combination with Other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA ® . The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. 5.7 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PH secondary to sickle cell disease has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Hypotension [see Warnings and Precautions ( 5.1 )] Vision Loss [see Warnings and Precautions ( 5.4 )] Hearing Loss [see Warnings and Precautions ( 5.5 )] Priapism [see Warnings and Precautions ( 5.7 )] Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions ( 5.8 )] Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and diarrhea. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil-treated adults with PAH (WHO Group I) [see Clinical Studies (14)] the adverse reactions that were reported by at least 10% of sildenafil-treated patients in any dosing group, and were more frequent in sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients) Sildenafil 20 mg (n = 69) Sildenafil 40 mg (n = 67) Sildenafil 80 mg (n = 71) Placebo (n = 70) Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6% In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies ( 14 )] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous System Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions ( 5.4 ), Patient Counseling Information ( 17 )] ." ], "adverse_reactions_table": [ "
Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients)
Sildenafil20 mg(n = 69)Sildenafil40 mg(n = 67)Sildenafil80 mg(n = 71)Placebo(n = 70)
Headache46%42%49%39%
Flushing10%9%16%4%
Pain in Limb7%15%9%6%
Myalgia7%6%14%4%
Back Pain13%13%9%11%
Dyspepsia13%8%13%7%
Diarrhea9%12%10%6%
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications ( 4 )] . Strong CYP3A Inhibitors Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology ( 12.3 )] . Moderate-to-Strong CYP3A Inducers Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14 )] . Use with strong CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors. ( 5.6 ) Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations) . Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. 8.4 Pediatric Use The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] . 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology ( 12.3 )] . 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CL cr <30 mL/min) [see Clinical Pharmacology ( 12.3 )] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations) . Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "labor_and_delivery": [ "8.4 Pediatric Use The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] ." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION Sildenafil for oral suspension, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® (sildenafil tablets USP) for erectile dysfunction. Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water. Sildenafil for oral suspension is supplied as white to off-white powder containing 1.57 g of sildenafil citrate, USP (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the total volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include anhydrous citric acid, colloidal silicon dioxide, grape flavor, sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan gum. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided. formula" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology ( 12.2 )] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) * Sildenafil 20 mg (n = 65) * mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications ( 4 )] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was coadministered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when coadministered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was coadministered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when coadministered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Figure 1 Figure 2" ], "clinical_pharmacology_table": [ "
Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
Placebo(n = 65)*Sildenafil 20 mg (n = 65)*
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn∙s/cm5)49 (-54, 153)-122 (-217, -27)
SVR (dyn∙s/cm5)-78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate.
*The number of patients per treatment group varied slightly for each parameter due to missing assessments.
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology ( 12.2 )] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) * Sildenafil 20 mg (n = 65) * mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications ( 4 )] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "pharmacodynamics_table": [ "
Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
Placebo(n = 65)*Sildenafil 20 mg (n = 65)*
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn∙s/cm5)49 (-54, 153)-122 (-217, -27)
SVR (dyn∙s/cm5)-78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate.
*The number of patients per treatment group varied slightly for each parameter due to missing assessments.
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (V ss ) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was coadministered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when coadministered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was coadministered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when coadministered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%. Figure 1 Figure 2" ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES SUPER-1 (NCT00644605) - Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12. Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by S tudy Subpopulation in SUPER-1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88%, and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) – Sildenafil Coadministered with Epoprostenol A randomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5. Table 4. Clinical Worsening Events in PACES-1 Placebo (N = 131) Sildenafil (N = 134) Number of patients with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion worsened 95% Confidence Interval 0.187 (0.12 to 0.26) 0.062 (0.02 to 0.10) Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) –Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Figure 3 Figure 4 Figure 5" ], "clinical_studies_table": [ "
Table 4. Clinical Worsening Events in PACES-1
Placebo(N = 131)Sildenafil(N = 134)
Number of patients with clinical worsening first event238
First EventAll EventsFirst EventAll Events
Death, n3400
Lung transplantation, n1100
Hospitalization due to PAH, n91188
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n91602
Initiation of Bosentan, n1100
Proportion worsened95% Confidence Interval0.187(0.12 to 0.26)0.062(0.02 to 0.10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil for oral suspension is supplied in amber glass bottles. Each bottle contains white to off-white powder containing 1.57 g of sildenafil citrate, USP (equivalent to 1.12 g sildenafil). Following reconstitution, the total volume of the oral suspension is 112 mL (10 mg sildenafil/mL). A 2 mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided. Sildenafil for Oral Suspension Package Configuration Strength NDC Powder for oral suspension – bottle 10 mg/mL (when reconstituted) 0591-4050-94 Recommended storage for sildenafil for oral suspension: Store below 30°C (86°F) in the original package in order to protect from moisture. Recommended storage for reconstituted oral suspension: Store below 30°C (86°F) or in refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze. The shelf-life of the reconstituted oral suspension is 60 days. Any remaining oral suspension should be discarded 60 days after reconstitution." ], "how_supplied_table": [ "
Sildenafil for Oral Suspension
Package ConfigurationStrengthNDC
Powder for oral suspension – bottle10 mg/mL (when reconstituted)0591-4050-94
" ], "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 of contraindication of sildenafil with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil. These events may be accompanied by tinnitus and dizziness. Brands listed are the trademarks of their respective owners. Manufactured In Croatia By: Pliva Hrvatska d.o.o. Zagreb, Croatia Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. A 6/2024" ], "spl_patient_package_insert": [ "PATIENT INFORMATION Sildenafil (sil den ' a fil) for Oral Suspension What is the most important information I should know about sildenafil for oral suspension? Never take sildenafil for oral suspension with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrates include: Medicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Isosorbide mononitrate or dinitrate Street drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. See “What are the possible side effects of sildenafil for oral suspension?” for more information about side effects. What is sildenafil for oral suspension? Sildenafil for oral suspension is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. Sildenafil for oral suspension may be used in: adults to improve your ability to exercise and help slow down the worsening of your physical condition. It is not known if sildenafil for oral suspension is safe and effective in children younger than 1 year of age. Do not take sildenafil for oral suspension if you: take medicines called nitrates. take riociguat, a guanylate cyclase stimulator medicine. are allergic to sildenafil or any of the ingredients in sildenafil for oral suspension. See the end of this leaflet for a complete list of ingredients in sildenafil for oral suspension. Before taking sildenafil for oral suspension, tell your healthcare provider about all of your medical conditions, including if you: have low blood pressure have heart problems have pulmonary veno-occlusive disease (PVOD) have bleeding problems or a stomach (peptic) ulcer. It is not known if sildenafil for oral suspension is safe in people with bleeding problems or who have a stomach ulcer. have an eye problem called retinitis pigmentosa have ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing have a deformed penis shape or Peyronie’s disease have any blood cell problems such as sickle cell anemia are pregnant or plan to become pregnant. It is not known if sildenafil for oral suspension will harm your unborn baby. are breastfeeding or plan to breastfeed. Sildenafil citrate passes into your breast milk. It is not known if it can harm your baby. Talk with your healthcare provider about the best way to feed your baby during treatment with sildenafil for oral suspension. Tell your healthcare provider about all of the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take: nitrates or guanylate cyclase stimulators. See “ What is the most important information I should know about sildenafil for oral suspension? ” medicines to treat high blood pressure medicines for erectile dysfunction (impotence). Sildenafil for oral suspension contains sildenafil, which is the same medicine found in another medicine called VIAGRA ® . VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with sildenafil for oral suspension. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take sildenafil for oral suspension? Take or give sildenafil for oral suspension exactly as your healthcare provider tells you. Your healthcare provider may change your dose of sildenafil for oral suspension as needed. Do not change your dose or stop taking sildenafil for oral suspension without talking to your healthcare provider. Take your prescribed dose of sildenafil for oral suspension 3 times a day. See the detailed Instructions for Use that comes with sildenafil for oral suspension for information on how to take or give sildenafil for oral suspension. Sildenafil for oral suspension will be mixed for you by your pharmacist. Do not mix sildenafil for oral suspension with other medicine or flavoring. If you take too much sildenafil for oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of sildenafil for oral suspension? Sildenafil for oral suspension may cause serious side effects, including: See “What is the most important information I should know about sildenafil for oral suspension?” Decreased blood pressure. Sildenafil for oral suspension may cause low blood pressure that last for a short time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with sildenafil for oral suspension. Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with sildenafil for oral suspension, contact your healthcare provider right away. Sudden decrease or loss of hearing , sometimes with ringing in the ears and dizziness . If you notice a sudden decrease or loss of hearing during treatment with sildenafil for oral suspension, contact your healthcare provider right away. In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections. The most common side effects of sildenafil for oral suspension in adults include: nosebleeds headache upset stomach getting red or hot in the face (flushing) arm or leg pain muscle aches and pain back pain diarrhea These are not all the possible side effects of sildenafil for oral suspension. 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 sildenafil for oral suspension? Store mixed (reconstituted) sildenafil for oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze mixed sildenafil for oral suspension. Throw away (discard) any remaining sildenafil for oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label. Keep sildenafil for oral suspension and all medicines out of the reach of children. General information about the safe and effective use of sildenafil for oral suspension Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil for oral suspension for a condition for which it was not prescribed. Do not give sildenafil for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about sildenafil for oral suspension that is written for health professionals. What are the ingredients in sildenafil for oral suspension? Active ingredient: sildenafil citrate Inactive ingredients: anhydrous citric acid, colloidal silicon dioxide, grape flavor, sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan gum Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Brands listed are the trademarks of their respective owners. Manufactured In Croatia By: Pliva Hrvatska d.o.o. , Zagreb, Croatia Manufactured For: Teva Pharmaceuticals , Parsippany, NJ 07054 For more information, call Teva at 1-888-838-2872. This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. A 6/2024" ], "spl_patient_package_insert_table": [ "
PATIENT INFORMATIONSildenafil (sil den' a fil) for Oral Suspension
What is the most important information I should know about sildenafil for oral suspension?Never take sildenafil for oral suspension with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level.Nitrates include:Medicines that treat chest pain (angina)Nitroglycerin in any form including tablets, patches, sprays, and ointmentsIsosorbide mononitrate or dinitrateStreet drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite)Guanylate cyclase stimulators include:Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine.See “What are the possible side effects of sildenafil for oral suspension?” for more information about side effects.
What is sildenafil for oral suspension?Sildenafil for oral suspension is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. Sildenafil for oral suspension may be used in:adults to improve your ability to exercise and help slow down the worsening of your physical condition.It is not known if sildenafil for oral suspension is safe and effective in children younger than 1 year of age.
Do not take sildenafil for oral suspension if you:take medicines called nitrates. take riociguat, a guanylate cyclase stimulator medicine. are allergic to sildenafil or any of the ingredients in sildenafil for oral suspension. See the end of this leaflet for a complete list of ingredients in sildenafil for oral suspension.
Before taking sildenafil for oral suspension, tell your healthcare provider about all of your medical conditions, including if you:have low blood pressurehave heart problemshave pulmonary veno-occlusive disease (PVOD)have bleeding problems or a stomach (peptic) ulcer. It is not known if sildenafil for oral suspension is safe in people with bleeding problems or who have a stomach ulcer.have an eye problem called retinitis pigmentosahave ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION)have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearinghave a deformed penis shape or Peyronie’s diseasehave any blood cell problems such as sickle cell anemiaare pregnant or plan to become pregnant. It is not known if sildenafil for oral suspension will harm your unborn baby.are breastfeeding or plan to breastfeed. Sildenafil citrate passes into your breast milk. It is not known if it can harm your baby. Talk with your healthcare provider about the best way to feed your baby during treatment with sildenafil for oral suspension.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Sildenafil for oral suspension and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take:nitrates or guanylate cyclase stimulators. See “What is the most important information I should know about sildenafil for oral suspension?”medicines to treat high blood pressure medicines for erectile dysfunction (impotence). Sildenafil for oral suspension contains sildenafil, which is the same medicine found in another medicine called VIAGRA®. VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with sildenafil for oral suspension.Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take sildenafil for oral suspension?Take or give sildenafil for oral suspension exactly as your healthcare provider tells you.Your healthcare provider may change your dose of sildenafil for oral suspension as needed. Do not change your dose or stop taking sildenafil for oral suspension without talking to your healthcare provider.Take your prescribed dose of sildenafil for oral suspension 3 times a day.See the detailed Instructions for Use that comes with sildenafil for oral suspension for information on how to take or give sildenafil for oral suspension. Sildenafil for oral suspension will be mixed for you by your pharmacist. Do not mix sildenafil for oral suspension with other medicine or flavoring.If you take too much sildenafil for oral suspension, call your healthcare provider or go to the nearest hospital emergency room right away.
What are the possible side effects of sildenafil for oral suspension?Sildenafil for oral suspension may cause serious side effects, including: See “What is the most important information I should know about sildenafil for oral suspension?” Decreased blood pressure. Sildenafil for oral suspension may cause low blood pressure that last for a short time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with sildenafil for oral suspension. Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with sildenafil for oral suspension, contact your healthcare provider right away. Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing during treatment with sildenafil for oral suspension, contact your healthcare provider right away. In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections. The most common side effects of sildenafil for oral suspension in adults include:
nosebleedsheadacheupset stomachgetting red or hot in the face (flushing)arm or leg painmuscle aches and painback paindiarrhea
These are not all the possible side effects of sildenafil for oral suspension.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 sildenafil for oral suspension?Store mixed (reconstituted) sildenafil for oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C).Do not freeze mixed sildenafil for oral suspension.Throw away (discard) any remaining sildenafil for oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label.Keep sildenafil for oral suspension and all medicines out of the reach of children.
General information about the safe and effective use of sildenafil for oral suspensionMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil for oral suspension for a condition for which it was not prescribed. Do not give sildenafil for oral suspension to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about sildenafil for oral suspension that is written for health professionals.
What are the ingredients in sildenafil for oral suspension?Active ingredient: sildenafil citrateInactive ingredients: anhydrous citric acid, colloidal silicon dioxide, grape flavor, sodium benzoate, sodium citrate dihydrate, sorbitol, sucralose, titanium dioxide, and xanthan gumPediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information.Brands listed are the trademarks of their respective owners.Manufactured In Croatia By: Pliva Hrvatska d.o.o., Zagreb, Croatia Manufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 For more information, call Teva at 1-888-838-2872.
This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. A 6/2024
" ], "instructions_for_use": [ "INSTRUCTIONS FOR USE Sildenafil (sil den ' a fil) for Oral Suspension Read this Instructions for Use before you start taking sildenafil for oral suspension and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information: Ask your healthcare provider or pharmacist to show you how to measure and take your prescribed dose of sildenafil for oral suspension. Your pharmacist will mix (reconstitute) sildenafil for oral suspension before it is given to you. Do not take or give sildenafil for oral suspension and contact your pharmacist if the medicine in the bottle is still a powder. Always use the oral dosing syringe that comes with sildenafil for oral suspension. If your carton does not come with an oral dosing syringe, contact your pharmacist. Do not take or give sildenafil for oral suspension if the bottle adaptor is not in the bottle. If the bottle adaptor is not in the bottle, contact your pharmacist. Sildenafil for oral suspension should not be mixed with any other medicine or flavoring. Supplies you will need to take or give a dose of sildenafil for oral suspension (See Figure A): 1 bottle of sildenafil for oral suspension with pre-inserted bottle adaptor 1 oral dosing syringe (provided in the carton) Figure A Step 1. Shake the bottle of sildenafil for oral suspension for 10 seconds before each use. (See Figure B) Figure B Step 2. Remove the cap. Open the bottle by pushing down on the cap and twisting it in the direction of the arrow (counter-clockwise). (See Figure C) Figure C Step 3. Fully push down (depress) the plunger of the oral dosing syringe. Then insert the tip of the oral dosing syringe into the bottle adaptor while holding the bottle upright, on a flat surface. (See Figure D) Figure D Step 4. Turn the bottle upside down while holding the oral dosing syringe in place. Slowly pull back the plunger of the oral dosing syringe until the bottom of the plunger is even with the mL marking on the syringe for your prescribed dose. (See Figure E) If your dose of sildenafil for oral suspension is 1 mL (10 mg), measure 0.5 mL two times for a total of 1 mL of sildenafil for oral suspension. If your dose of sildenafil for oral suspension is more than 2 mL (20 mg), you will need to divide the dose. Follow the instructions given to you by your healthcare provider or pharmacist about how to prepare the divided dose. If you see air bubbles in the oral dosing syringe, slowly push the plunger all the way up so that sildenafil for oral suspension flows back into the bottle and repeat Step 4. Figure E Step 5. Turn the bottle back upright with the oral dosing syringe still in place. Place the bottle on a flat surface. Remove the oral dosing syringe from the bottle adaptor by pulling straight up on the barrel of the oral dosing syringe. (See Figure F) Do not press on the plunger of the oral dosing syringe at this time. Figure F Step 6. Put the tip of the oral dosing syringe into your mouth and point it towards the inside of the cheek. Slowly push the plunger of the oral dosing syringe all the way down to give the entire dose. Do not squirt the medicine out quickly. (See Figure G) If you are giving sildenafil for oral suspension, make sure they are in an upright position before giving the medicine. Adult Figure G Step 7. Replace the cap on the bottle, leaving the bottle adaptor in place. Turn the cap in the direction of the arrow (clockwise) to close the bottle. (See Figure H) Figure H Step 8. Wash the oral dosing syringe after each use. Pull the plunger out of the barrel and rinse both parts with water. (See Figure I) Figure I Step 9. Dry all parts with a clean paper towel. Push the plunger back into the barrel. Store the oral dosing syringe with the sildenafil for oral suspension bottle. How should I store sildenafil for oral suspension? Store mixed (reconstituted) sildenafil oral suspension below 86°F (30°C) or in a refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze mixed sildenafil for oral suspension. Throw away (discard) any remaining sildenafil for oral suspension 60 days after mixed by the pharmacist. See the “Discard after” date written on the bottle label. Keep sildenafil for oral suspension and all medicines out of the reach of children. Pediatric use information is approved for Viatris Specialty LLC’s, REVATIO (sildenafil) for oral suspension. However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information. Manufactured In Croatia By: Pliva Hrvatska d.o.o. , Zagreb, Croatia Manufactured For: Teva Pharmaceuticals , Parsippany, NJ 07054 This Instruction for Use has been approved by the U.S. Food and Drug Administration. Rev. A 6/2024 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL NDC 0591-4050-94 Sildenafil for Oral Suspension 10 mg/mL For Oral Use Only Shake Well Before Each Use Grape Flavored Rx only 112 mL following Reconstitution carton" ], "set_id": "0e6428c0-e0e9-4fc0-8615-6a9678d2286c", "id": "4c7d4ea0-d3b7-4a20-b5d6-09207153aaad", "effective_time": "20240630", "version": "6", "openfda": { "application_number": [ "ANDA211534" ], "brand_name": [ "Sildenafil" ], "generic_name": [ "SILDENAFIL" ], "manufacturer_name": [ "Actavis Pharma, Inc." ], "product_ndc": [ "0591-4050" ], "product_type": [ "HUMAN PRESCRIPTION DRUG" ], "route": [ "ORAL" ], "substance_name": [ "SILDENAFIL CITRATE" ], "rxcui": [ "1307427" ], "spl_id": [ "4c7d4ea0-d3b7-4a20-b5d6-09207153aaad" ], "spl_set_id": [ "0e6428c0-e0e9-4fc0-8615-6a9678d2286c" ], "package_ndc": [ "0591-4050-94" ], "is_original_packager": [ true ], "unii": [ "BW9B0ZE037" ] } }, { "spl_product_data_elements": [ "Sildenafil sildenafil citrate MICROCRYSTALLINE CELLULOSE ANHYDROUS DIBASIC CALCIUM PHOSPHATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE, UNSPECIFIED TITANIUM DIOXIDE LACTOSE MONOHYDRATE TRIACETIN SILDENAFIL CITRATE SILDENAFIL SDF20" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Sildenafil is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil was added to background epoprostenol therapy [see Clinical Studies (14) ] . Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II–III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II–III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). ( 1 ) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1 , 14 ) Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14) ] ." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION Tablets and oral suspension: 5 mg or 20 mg three times a day, 4–6 hours apart; see full prescribing information for reconstitution instructions for the Powder for Oral Suspension ( 2.1 , 2.2 ) 2.1 Sildenafil Tablets and Oral Suspension The recommended dose of sildenafil is 5 mg or 20 mg three times a day. Administer sildenafil doses 4–6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended." ], "contraindications": [ "4 CONTRAINDICATIONS Sildenafil is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2) ] . Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates or riociguat. ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet or oral suspension. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. ( 5.1 ) Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.2 ) Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. ( 5.3 ) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.5 , 5.6 ) Pulmonary hypertension secondary to sickle cell disease: sildenafil may cause serious vaso-occlusive crises. ( 5.9 ) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children [see Use in Specific Populations (8.4) ]. 5.2 Hypotension Sildenafil has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil. 5.3 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil to patients with veno-occlusive disease, administration of sildenafil to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (\"crowded disc\"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of \"crowded\" optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [see Adverse Reactions (6.2 ] . Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil. 5.7 Combination with other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA ® . The safety and efficacy of combinations of sildenafil with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil than by those randomized to placebo. The effectiveness and safety of sildenafil in the treatment of PAH secondary to sickle cell anemia has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] Hypotension [see Warnings and Precautions (5.2) ] Vision loss [see Warnings and Precautions (5.5) ] Hearing loss [see Warnings and Precautions (5.6) ] Priapism [see Warnings and Precautions (5.8) ] Vaso-occlusive crisis [see Warnings and Precautions (5.9) ] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC 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. Safety data of sildenafil in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I [see Clinical Studies (14) ] . The overall frequency of discontinuation in sildenafil-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil-treated patients (20 mg three times a day) and were more frequent in sildenafil-treated patients than in placebo-treated patients, are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients) Placebo, % (n = 70) Sildenafil 20 mg three times a day, % (n = 69) Placebo-Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14) ] . Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edema includes peripheral edema 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors. Nervous system Seizure, seizure recurrence. Ophthalmologic NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17) ] ." ], "adverse_reactions_table": [ "
Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients)
Placebo, % (n = 70) Sildenafil 20 mg three times a day, % (n = 69) Placebo-Subtracted, %
Epistaxis198
Headache39467
Dyspepsia7136
Flushing4106
Insomnia176
Erythema165
Dyspnea exacerbated374
Rhinitis044
Diarrhea693
Myalgia473
Pyrexia363
Gastritis033
Sinusitis033
Paresthesia033
", "
Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil + Epoprostenol group at least 6% greater than Epoprostenol group)
Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol) minus Epoprostenol
Headache573423
Edema includes peripheral edema251314
Dyspepsia16214
Pain in extremity17611
Diarrhea25187
Nausea25187
Nasal congestion927
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. ( 7 ) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. ( 5.7 ) Nitrates Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4) ] . Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ] . Other drugs that reduce blood pressure Alpha blockers . In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine . When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil [see Warnings and Precautions (5.2) ] ." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively [See Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. 8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6. Kaplan-Meier Plot of Mortality by Sildenafil Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. Figure 6 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] . 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3) ] . 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively [See Data ]. The estimated background risk of major birth defects and miscarriage for the indicated population 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "pediatric_use": [ "8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of sildenafil on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil remained on his/her dose of sildenafil or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6. Kaplan-Meier Plot of Mortality by Sildenafil Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of sildenafil, particularly chronic use, is not recommended in children. Figure 6" ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] ." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION Sildenafil, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil Tablets: Sildenafil is formulated as white, film-coated round tablets for oral administration. Each tablet contains sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin. Sildenafil for Oral Suspension: Sildenafil is supplied as white to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g sildenafil) in an amber glass bottle intended for reconstitution. Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. The inactive ingredients include sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous and grape flavor. In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 0.5 mL and 2 mL dose markings) are provided. Chemical Structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo. 12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg three times a day (n = 65) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)] , there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20–50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8. Effects of Sildenafil on Other Drugs Figure 7 Figure 8 CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%." ], "clinical_pharmacology_table": [ "
Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments.Sildenafil 20 mg three times a day (n = 65)
mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn∙s/cm 5) 49 (-54, 153)-122 (-217, -27)
SVR (dyn∙s/cm 5) -78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of Sildenafil on Hemodynamic Measures Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg three times a day (n = 65) mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn∙s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn∙s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg [Study 3 in Clinical Studies (14)] , there were no significant differences in the effects on hemodynamic variables between doses. Effects of Sildenafil on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1–2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of Sildenafil on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry." ], "pharmacodynamics_table": [ "
Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments.Sildenafil 20 mg three times a day (n = 65)
mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn∙s/cm 5) 49 (-54, 153)-122 (-217, -27)
SVR (dyn∙s/cm 5) -78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25–63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate). Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20–50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50–80 mL/min) and moderate (CLcr = 30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively. Figure 7. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 8. Effects of Sildenafil on Other Drugs Figure 7 Figure 8 CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 inducers including bosentan Concomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38- times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38- times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) functional classes II–III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45–50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 9 ), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 10. Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously. Figure 9 Figure 10 Study 2 (Sildenafil co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. Table 4. Clinical Worsening Events in Study 2 Placebo (N = 131) Sildenafil (N = 134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10) Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2 Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Figure 11 Study 3 (Sildenafil monotherapy (1 mg, 5 mg, and 20 mg three times a day)) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38–41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT Population Sildenafil Protocol A1481244 Figure 12 Study 4 (Sildenafil added to bosentan therapy – lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5–125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone." ], "clinical_studies_table": [ "
Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
", "
Table 4. Clinical Worsening Events in Study 2
Placebo (N = 131) Sildenafil (N = 134)
Number of subjects with clinical worsening first event238
First EventAll EventsFirst EventAll Events
Death, n3400
Lung Transplantation, n1100
Hospitalization due to PAH, n91188
Clinical deterioration resulting in:
Change of Epoprostenol Dose, n 9 16 0 2
Initiation of Bosentan, n1100
Proportion Worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10)
", "
Sildenafil Protocol A1481244
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING Sildenafil tablets are supplied as white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows: Sildenafil Tablets Package Configuration Strength NDC Engraving on Tablet Bottle of 10 Tablets 20 mg 43063-550-10 SDF20 Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20°C – 25°C (68°F – 77°F); excursions permitted to 15°C – 30°C (59°F – 86°F) [see USP Controlled Room Temperature]." ], "how_supplied_table": [ "
Sildenafil Tablets
Package Configuration StrengthNDCEngraving on Tablet
Bottle of 10 Tablets20 mg43063-550-10SDF20
" ], "storage_and_handling": [ "Recommended Storage for Sildenafil Tablets: Store at controlled room temperature 20°C – 25°C (68°F – 77°F); excursions permitted to 15°C – 30°C (59°F – 86°F) [see USP Controlled Room Temperature]." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients of contraindication of sildenafil with regular and/or intermittent use of organic nitrates. Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking sildenafil not to take VIAGRA or other PDE-5 inhibitors. Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil. Such an event may be a sign of NAION. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil. These events may be accompanied by tinnitus and dizziness." ], "spl_unclassified_section": [ "This product's label may have been updated. For current full prescribing information, please visit www.greenstonellc.com. LAB-0562-8.0" ], "spl_patient_package_insert": [ "PATIENT INFORMATION Sildenafil tablets Sildenafil oral suspension Read this Patient Information before you start taking sildenafil and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about sildenafil, ask your doctor or pharmacist. What is the most important information I should know about sildenafil? Never take sildenafil with any nitrate or guanylate cyclase stimulator medicines. Your blood pressure could drop quickly to an unsafe level. Nitrate medicines include: Medicines that treat chest pain (angina) Nitroglycerin in any form including tablets, patches, sprays, and ointments Isosorbide mononitrate or dinitrate Street drugs called \"poppers\" (amyl nitrate or nitrite) Guanylate cyclase stimulators include: Riociguat (Adempas) Ask your doctor or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. What is sildenafil? Sildenafil is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. Sildenafil improves the ability to exercise and can slow down worsening changes in your physical condition. Sildenafil is not for use in children Adding sildenafil to another medication used to treat PAH bosentan (Tracleer ® ), does not result in improvement in your ability to exercise. Sildenafil contains the same medicine as VIAGRA ® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take sildenafil with VIAGRA or other PDE-5 inhibitors. Who should not take Sildenafil? Do not take sildenafil if you: take nitrate medicines. See \" What is the most important information I should know about sildenafil? \" take guanylate cyclase stimulator medicines. See \" What is the most important information I should know about sildenafil? \" are allergic to sildenafil or any other ingredient in sildenafil tablets or oral suspension. See \" What are the ingredients in sildenafil tablets and oral suspension? \" at the end of this leaflet. What should I tell my doctor before taking sildenafil? Tell your doctor about all of your medical conditions, including if you have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack have a disease called pulmonary veno-occlusive disease (PVOD) have high or low blood pressure or blood circulation problems have an eye problem called retinitis pigmentosa have or had loss of sight in one or both eyes have any problem with the shape of your penis or Peyronie's disease have any blood cell problems such as sickle cell anemia have a stomach ulcer or any bleeding problems are pregnant or planning to become pregnant. It is not known if sildenafil could harm your unborn baby. are breastfeeding. Sildenafil passes into your breast milk, it is not known if it could harm your baby. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. Sildenafil and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take sildenafil. Especially tell your doctor if you take Nitrate medicines. See \" What is the most important information I should know about sildenafil? \" Riociguat (Adempas). See \" What is the most important information I should know about sildenafil? \" Ritonavir (Norvir ® ) or other medicines used to treat HIV infection Ketoconazole (Nizoral ® ) Itraconazole (Sporanox) High blood pressure medicine Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. How should I take sildenafil? Take sildenafil exactly as your doctor tells you. Sildenafil may be prescribed to you as Sildenafil tablets or sildenafil oral suspension Take sildenafil tablet or oral suspension 3 times a day about 4 to 6 hours apart. Take sildenafil tablets or oral suspension at the same times every day. Sildenafil oral suspension will be mixed for you by your pharmacist. Do not mix sildenafil oral suspension with other medicine or flavoring. Shake well for at least 10 seconds before each dose. If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time. Do not take more than one dose of sildenafil at a time. Do not change your dose or stop taking sildenafil on your own. Talk to your doctor first. If you take too much sildenafil, call your doctor or go to the nearest hospital emergency room. What are the possible side effects of sildenafil? low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. more shortness of breath than usual. Tell your doctor if you get more short of breath after you start sildenafil. More shortness of breath than usual may be due to your underlying medical condition. decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil, or to other diseases or medicines, to other factors, or to a combination of factors. heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already had heart problems. erections that last several hours. If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis. The most common side effects with sildenafil include: Nosebleed, headache, upset stomach, getting red or hot in the face (flushing), trouble sleeping, as well as fever, erection increased, respiratory infection, nausea, vomiting, bronchitis, pharyngitis, runny nose, and pneumonia in children. Tell your doctor if you have any side effect that bothers you or doesn't go away. These are not all the possible side effects of sildenafil. 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. How should I store sildenafil? Store sildenafil tablets at controlled room temperature, between 20°C – 25°C (68°F to 77°F). Store sildenafil reconstituted oral suspension below 30°C (86°F) or in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze sildenafil oral suspension. Throw away sildenafil oral suspension after 60 days. Keep sildenafil and all medicines away from children. General information about sildenafil Medicines are sometimes prescribed for purposes that are not in the patient leaflet. Do not use sildenafil for a condition for which it was not prescribed. Do not give sildenafil to other people, even if they have the same symptoms you have. It could harm them. This patient leaflet summarizes the most important information about sildenafil. If you would like more information about sildenafil talk with your doctor. You can ask your doctor or pharmacist for information about sildenafil that is written for health professionals. For more information go to www.greenstonellc.com or call 1-800-438-1985. What are the ingredients in sildenafil tablets and oral suspension? Sildenafil tablets Active ingredients: sildenafil citrate Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin Sildenafil for oral suspension Active ingredients: sildenafil citrate Inactive ingredients: sorbitol, citric acid anhydrous, sucralose, sodium citrate dihydrate, xanthan gum, titanium dioxide, sodium benzoate, colloidal silicon dioxide anhydrous, and grape flavor This product's label may have been updated. For current full prescribing information, please visit www.greenstonellc.com. This Patient Information has been approved by the U.S. Food and Drug Administration. LAB-0563-7.0 Revised: February 2020" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL - 20 mg Tablet Bottle Label sildenafil tablets 20 mg* Rx only 43063550 Label" ], "set_id": "11282baa-580a-43d9-89b9-acbd3bd427be", "id": "e6631ee3-dc7b-c74d-e053-2995a90a2d4c", "effective_time": "20220816", "version": "22", "openfda": {} }, { "spl_product_data_elements": [ "Liqrev sildenafil SILDENAFIL CITRATE SILDENAFIL ACESULFAME POTASSIUM CITRIC ACID MONOHYDRATE GLYCERIN DIMETHICONE SILICON DIOXIDE SODIUM BENZOATE TRISODIUM CITRATE DIHYDRATE XANTHAN GUM WATER" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Adults LIQREV is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies (14) ] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Adults LIQREV is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening. ( 1 )" ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • Adults: 20 mg orally three times a day. ( 2.1 ) 2.1 Recommended Dosage in Adults The recommended dosage of LIQREV is 20 mg orally three times a day [see Clinical Studies (14) . A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. Shake well for at least 10 seconds before use. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS Oral Suspension: 10 mg/mL; white to off-white opaque suspension with a strawberry flavor. Each 1 mL of oral suspension contains 10 mg sildenafil (equivalent to 14 mg sildenafil citrate). • Oral Suspension: 10 mg/mL (3) Each 1 mL of oral suspension contains 10 mg sildenafil (equivalent to 14 mg sildenafil citrate)." ], "contraindications": [ "4 CONTRAINDICATIONS LIQREV is contraindicated in patients with: • Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.1) ] . • Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. • Known hypersensitivity to sildenafil or any component of the oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. • Use with organic nitrates or riociguat. ( 4 ) • History of hypersensitivity reaction to sildenafil or any component of the oral suspension. ( 4 )" ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. ( 5.1 ) • Use in pulmonary veno-occlusive disease (PVOD) may cause pulmonary edema and is not recommended. ( 5.2 ) • Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. ( 5.4 , 5.5 ) • Pulmonary hypertension (PH) secondary to sickle cell disease: LIQREV may cause serious vaso-occlusive crises. ( 5.8 ) 5.1 Hypotension LIQREV has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing LIQREV, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co‑administering blood pressure lowering drugs with LIQREV. 5.2 Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno‑occlusive disease (PVOD). Since there are no clinical data on administration of LIQREV to patients with veno‑occlusive disease, administration of LIQREV to such patients is not recommended. Should signs of pulmonary edema occur when LIQREV is administered, consider the possibility of associated PVOD. 5.3 Epistaxis The incidence of epistaxis was 13% in patients taking LIQREV with PAH secondary to CTD. This effect was not seen in idiopathic PAH (Sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in Sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of LIQREV is unknown in patients with bleeding disorders or active peptic ulceration. 5.4 Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported post marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”). Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking LIQREV. There are no controlled clinical data on the safety or efficacy of LIQREV in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of LIQREV in patients with retinitis pigmentosa is not recommended. 5.5 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including LIQREV. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of LIQREV, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including LIQREV. 5.6 Combination with Other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA ® . The safety and efficacy of combinations of LIQREV with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking LIQREV not to take VIAGRA or other PDE-5 inhibitors. 5.7 Priapism Use LIQREV with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell disease, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result. 5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received Sildenafil than by those randomized to placebo. The effectiveness and safety of LIQREV in the treatment of PH secondary to sickle cell disease has not been established." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: • Hypotension [see Warnings and Precautions (5.1) ] • Vision Loss [see Warnings and Precautions (5.4) ] • Hearing Loss [see Warnings and Precautions (5.5) ] • Priapism [see Warnings and Precautions (5.7) ] • Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease [see Warnings and Precautions (5.8) ] Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain and diarrhea. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma, Inc. at 1-844-321-1443 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, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 Sildenafil-treated adults with PAH (WHO Group I) [see Clinical Studies (14) ] the adverse reactions that were reported by at least 10% of Sildenafil-treated patients in any dosing group, and were more frequent in Sildenafil-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. The overall frequency of discontinuation in Sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients) Sildenafil 20 mg (n = 69) Sildenafil 40 mg (n = 67) Sildenafil 80 mg (n = 71) Placebo (n = 70) Headache 46% 42% 49% 39% Flushing 10% 9% 16% 4% Pain in Limb 7% 15% 9% 6% Myalgia 7% 6% 14% 4% Back Pain 13% 13% 9% 11% Dyspepsia 13% 8% 13% 7% Diarrhea 9% 12% 10% 6% In a placebo-controlled fixed dose titration study (PACES-1) of Sildenafil (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined Sildenafil + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14) ] . Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors. Nervous System Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions (5.4) , Patient Counseling Information (17) ] ." ], "adverse_reactions_table": [ "
Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil-Treated Patients than Placebo-Treated Patients)
Sildenafil20 mg(n = 69)Sildenafil40 mg(n = 67)Sildenafil80 mg(n = 71)Placebo(n = 70)
Headache46%42%49%39%
Flushing10%9%16%4%
Pain in Limb7%15%9%6%
Myalgia7%6%14%4%
Back Pain13%13%9%11%
Dyspepsia13%8%13%7%
Diarrhea9%12%10%6%
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Nitrates Concomitant use of LIQREV with nitrates in any form is contraindicated [see Contraindications (4) ] . Strong CYP3A Inhibitors Concomitant use of LIQREV with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ] . Moderate-to-Strong CYP3A Inducers Concomitant use of LIQREV with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of LIQREV may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of LIQREV to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] . • Use with strong CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) • Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors. ( 5.6 ) Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no‑observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of LIQREV to an infant during lactation. 8.4 Pediatric Use The safety and effectiveness of LIQREV have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] . 8.6 Patients with Hepatic Impairment No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3) ] . 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3) ] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no‑observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis)." ], "risks": [ "Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations ). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively.", "Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of LIQREV to an infant during lactation." ], "pediatric_use": [ "8.4 Pediatric Use The safety and effectiveness of LIQREV have not been established in pediatric patients younger than 1 year of age. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "geriatric_use": [ "8.5 Geriatric Use Clinical studies of sildenafil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] ." ], "overdosage": [ "10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine." ], "description": [ "11 DESCRIPTION LIQREV, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water. It has a chemical formula of C 22 H 3 N 6 O 4 S.C 6 H 8 O 7 and a molecular weight of 666.7 g.mol -1 . LIQREV (sildenafil) Oral Suspension 10 mg/mL is supplied as a white to off-white, opaque, strawberry-flavored suspension. LIQREV is provided in 122 mL in an amber glass bottle with a child resistant tamper-evident cap. Each bottle contains 1.22 g sildenafil (equivalent to 1.71g sildenafil citrate). The inactive ingredients include acesulfame potassium, citric acid monohydrate, glycerin, simethicone emulsion, sodium benzoate, sucralose, strawberry flavor, tri-sodium citrate dihydrate, xanthan gum, and water. Sildenafil Citrate Structural Formula" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo . 12.2 Pharmacodynamics Effects of LIQREV on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14) ] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg (n = 65) mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn×s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn×s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) Effects of LIQREV on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of sildenafil 80 mg three times a day to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of sildenafil 80 mg three times a day to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of sildenafil 80 mg three times a day to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of LIQREV on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. 12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When LIQREV is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in peak plasma concentration (C max ) of 29%, while the extent of absorption (AUC) is increased by 11%. The mean steady state volume of distribution volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically‑designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%." ], "clinical_pharmacology_table": [ "
Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate.
Placebo(n = 65)The number of patients per treatment group varied slightly for each parameter due to missing assessments.Sildenafil 20 mg(n = 65)
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn×s/cm5)49 (-54, 153)-122 (-217, -27)
SVR (dyn×s/cm5)-78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2) ] . In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro , and the mild peripheral arterial-venous dilatation in vivo ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Effects of LIQREV on Hemodynamic Measures Adults Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14) ] . Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown. Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate. Placebo (n = 65) The number of patients per treatment group varied slightly for each parameter due to missing assessments. Sildenafil 20 mg (n = 65) mPAP (mmHg) 0.6 (-0.8, 2.0) -2.1 (-4.3, 0.0) PVR (dyn×s/cm 5 ) 49 (-54, 153) -122 (-217, -27) SVR (dyn×s/cm 5 ) -78 (-197, 41) -167 (-307, -26) RAP (mmHg) 0.3 (-0.9, 1.5) -0.8 (-1.9, 0.3) CO (L/min) -0.1 (-0.4, 0.2) 0.4 (0.1, 0.7) HR (beats/min) -1.3 (-4.1, 1.4) -3.7 (-5.9, -1.4) Effects of LIQREV on Blood Pressure Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg, and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see Contraindications (4) ] . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG). After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported. After chronic dosing of sildenafil 80 mg three times a day to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively. After chronic dosing of sildenafil 80 mg three times a day to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 and 9.1 mmHg, respectively. After chronic dosing of sildenafil 80 mg three times a day to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). Effects of LIQREV on Vision At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil on visual acuity, intraocular pressure, or pupillometry. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information." ], "pharmacodynamics_table": [ "
Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil 20 mg Three Times a Day and Placebo Group
mPAP = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate.
Placebo(n = 65)The number of patients per treatment group varied slightly for each parameter due to missing assessments.Sildenafil 20 mg(n = 65)
mPAP (mmHg)0.6 (-0.8, 2.0)-2.1 (-4.3, 0.0)
PVR (dyn×s/cm5)49 (-54, 153)-122 (-217, -27)
SVR (dyn×s/cm5)-78 (-197, 41)-167 (-307, -26)
RAP (mmHg)0.3 (-0.9, 1.5)-0.8 (-1.9, 0.3)
CO (L/min)-0.1 (-0.4, 0.2)0.4 (0.1, 0.7)
HR (beats/min)-1.3 (-4.1, 1.4)-3.7 (-5.9, -1.4)
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics Absorption and Distribution Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When LIQREV is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in peak plasma concentration (C max ) of 29%, while the extent of absorption (AUC) is increased by 11%. The mean steady state volume of distribution volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Metabolism and Excretion Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. After oral administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Population Pharmacokinetics Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH. In patients with PAH, the average steady-state concentrations were 20 to 50% higher when compared to those of healthy volunteers. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers. Pediatric Patients Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information Geriatric Patients Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18 to 45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively. Renal Impairment In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in patients with severe renal impairment compared to patients with normal renal function. Hepatic Impairment In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied. Drug Interaction Studies In vitro studies Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 µM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations. In vivo studies The effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 1 and Figure 2, respectively. Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs Figure 1. Effects of Other Drugs on Sildenafil Pharmacokinetics Figure 2. Effects of Sildenafil on Other Drugs CYP3A Inhibitors and Beta Blockers Population pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day. This concentration range covers the same increased sildenafil exposure observed in specifically‑designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). CYP3A4 Inducers Including Bosentan Concomitant administration of strong CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil. Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers. Epoprostenol The mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Alcohol Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%." ], "nonclinical_toxicology": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33- and 37-times, for male and female rats, respectively, the human exposure at the RHD of 20 mg three times a day. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m 2 basis. Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity. There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19- and 38-times for males and females, respectively, the human exposure at the RHD of 20 mg three times a day." ], "clinical_studies": [ "14 CLINICAL STUDIES SUPER-1 ( NCT00644605) - Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day] A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6‑minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12. Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily. SUPER-2 (NCT00159887) Long-term Treatment of PAH In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) - LIQREV Co-administered with Epoprostenol A randomized, double-blind, placebo‑controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003). Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 3 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than Sildenafil-treated patients and that Sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5. Table 3. Clinical Worsening Events in PACES-1 Placebo (N = 131) LIQREV (N = 134) Number of patients with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n 9 1 16 1 0 0 2 0 Proportion worsened 95% Confidence Interval 0.187 (0.12 – 0.26) 0.062 (0.02 – 0.10) Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on Sildenafil compared to placebo. More than twice as many Sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) - Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity A randomized, double-blind, placebo‑controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval) Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1" ], "clinical_studies_table": [ "
Table 3. Clinical Worsening Events in PACES-1
Placebo(N = 131)LIQREV(N = 134)
Number of patients with clinical worsening first event238
First EventAll EventsFirst EventAll Events
Death, n3400
Lung transplantation, n1100
Hospitalization due to PAH, n91188
Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n911610020
Proportion worsened95% Confidence Interval0.187(0.12 – 0.26)0.062(0.02 – 0.10)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING LIQREV (sildenafil) Oral Suspension 10 mg/mL is a white to off-white, opaque, strawberry-flavored suspension. It is available in a 122 mL amber glass bottle with a child resistant tamper-evident cap (NDC 46287-055-01). Store from 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP for controlled room temperature]. Shake well before use for at least 10 seconds. Use the bottle within 90 days once it has been opened." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). • Inform patients of contraindication of LIQREV with regular and/or intermittent use of organic nitrates. • Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. • Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking LIQREV not to take VIAGRA or other PDE-5 inhibitors. • Advise patients to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking LIQREV. Such an event may be a sign of NAION. • Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking LIQREV. These events may be accompanied by tinnitus and dizziness. Distributed by: CMP Pharma, Inc. Farmville, NC 27828" ], "spl_patient_package_insert": [ "PATIENT INFORMATION LIQREV ® (LIK-rev) (sildenafil) oral suspension What is the most important information I should know about LIQREV? Never take LIQREV with any nitrate or guanylate cyclase stimulator medicines: • Your blood pressure could drop quickly to an unsafe level. Nitrates include: • Medicines that treat chest pain (angina) • Nitroglycerin in any form including tablets, patches, sprays, and ointments • Isosorbide mononitrate or dinitrate • Street drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite) Guanylate cyclase stimulators include: • Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. See “What are the possible side effects of LIQREV?” for more information about side effects. What is LIQREV? LIQREV is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. LIQREV may be used in: • adults to improve your ability to exercise and help slow down the worsening of your physical condition. It is not known if sildenafil is safe and effective in children younger than 1 year of age. Do not take LIQREV if you: • take medicines called nitrates. • take riociguat, a guanylate cyclase stimulator medicine. • are allergic to sildenafil or any of the ingredients in LIQREV. See the end of this leaflet for a complete list of ingredients in LIQREV. Before taking LIQREV, tell your healthcare provider about all your medical conditions, including if you: • have low blood pressure • have heart problems • have pulmonary veno-occlusive disease (PVOD) • have bleeding problems or a stomach (peptic) ulcer. It is not known if LIQREV is safe in people with bleeding problems or who have a stomach ulcer. • have an eye problem called retinitis pigmentosa • have ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) • have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing • have a deformed penis shape or Peyronie’s disease • have any blood cell problems such as sickle cell anemia • are pregnant or plan to become pregnant. It is not known if LIQREV will harm your unborn baby. • are breastfeeding or plan to breastfeed. LIQREV passes into your breast milk. It is not known if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with LIQREV. Tell your healthcare provider about all of the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. LIQREV and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take: • nitrates or guanylate cyclase stimulators. See “ What is the most important information I should know about LIQREV? ” • medicines to treat high blood pressure • medicines for erectile dysfunction (impotence). LIQREV contains sildenafil, which is the same medicine found in another medicine called VIAGRA ® . VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with LIQREV. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take LIQREV? • Take or give LIQREV exactly as your healthcare provider tells you. • Your healthcare provider may change your dose of LIQREV as needed. Do not change your dose or stop taking LIQREV without talking to your healthcare provider. • Take your prescribed dose of LIQREV by mouth 3 times each day. • Shake LIQREV well for at least 10 seconds before each dose. • Use an oral dosing syringe to correctly measure your dose. Ask your pharmacist for an oral dosing syringe if you do not have one. • If you take too much LIQREV, call your healthcare provider or go to the nearest hospital emergency room. What are the possible side effects of LIQREV? LIQREV may cause serious side effects, including: • See “What is the most important information I should know about LIQREV?” • Decreased blood pressure. LIQREV may cause low blood pressure that last for a short period of time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with LIQREV. • Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with LIQREV, contact your healthcare provider right away. • Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing during treatment with LIQREV, contact your healthcare provider right away. • In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections. The most common side effects with LIQREV in adults include: • headache • getting red or hot in the face (flushing) • arm or leg pain • muscle aches and pain • upset stomach • back pain • diarrhea • nosebleeds These are not all the possible side effects of LIQREV. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information. How should I store LIQREV? • Store LIQREV oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). Use the bottle within 90 days once it has been opened. • Do not freeze LIQREV oral suspension. Keep LIQREV and all medicines out of the reach of children. General information about the safe and effective use of LIQREV. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LIQREV for a condition for which it was not prescribed. Do not give LIQREV to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LIQREV that is written for health professionals. What are the ingredients in LIQREV? Active ingredients: sildenafil citrate Inactive ingredients: The inactive ingredients include acesulfame potassium, citric acid monohydrate, glycerin, simethicone emulsion, sodium benzoate, sucralose, strawberry flavor, tri-sodium citrate dihydrate, xanthan gum, and water. Distributed by: CMP Pharma, Inc. Farmville, NC 27828 For more information, go to www.LIQREV.com. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 04/2023" ], "spl_patient_package_insert_table": [ "Your blood pressure could drop quickly to an unsafe level.Nitrates include:Medicines that treat chest pain (angina)Nitroglycerin in any form including tablets, patches, sprays, and ointmentsIsosorbide mononitrate or dinitrateStreet drugs called “poppers” (amyl nitrate, butyl nitrate or nitrite)Guanylate cyclase stimulators include:Riociguat, a medicine that treats pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Ask your healthcare provider or pharmacist if you are not sure if you are taking a nitrate or a guanylate cyclase stimulator medicine. See “What are the possible side effects of LIQREV?” for more information about side effects.adults to improve your ability to exercise and help slow down the worsening of your physical condition.It is not known if sildenafil is safe and effective in children younger than 1 year of age. take medicines called nitrates. take riociguat, a guanylate cyclase stimulator medicine. are allergic to sildenafil or any of the ingredients in LIQREV. See the end of this leaflet for a complete list of ingredients in LIQREV. have low blood pressure have heart problems have pulmonary veno-occlusive disease (PVOD)have bleeding problems or a stomach (peptic) ulcer. It is not known if LIQREV is safe in people with bleeding problems or who have a stomach ulcer.have an eye problem called retinitis pigmentosahave ever had sudden loss of vision in one or both eyes, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION)have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearinghave a deformed penis shape or Peyronie’s diseasehave any blood cell problems such as sickle cell anemiaare pregnant or plan to become pregnant. It is not known if LIQREV will harm your unborn baby.are breastfeeding or plan to breastfeed. LIQREV passes into your breast milk. It is not known if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with LIQREV. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. LIQREV and certain other medicines may affect each other and can cause side effects. Especially tell your healthcare provider if you take:nitrates or guanylate cyclase stimulators. See “What is the most important information I should know about LIQREV?” medicines to treat high blood pressure medicines for erectile dysfunction (impotence). LIQREV contains sildenafil, which is the same medicine found in another medicine called VIAGRA®. VIAGRA is used for the treatment of erectile dysfunction. Do not take VIAGRA or other PDE-5 inhibitors during treatment with LIQREV.Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.Take or give LIQREV exactly as your healthcare provider tells you. Your healthcare provider may change your dose of LIQREV as needed. Do not change your dose or stop taking LIQREV without talking to your healthcare provider.Take your prescribed dose of LIQREV by mouth 3 times each day.Shake LIQREV well for at least 10 seconds before each dose.Use an oral dosing syringe to correctly measure your dose. Ask your pharmacist for an oral dosing syringe if you do not have one.If you take too much LIQREV, call your healthcare provider or go to the nearest hospital emergency room.See “What is the most important information I should know about LIQREV?”Decreased blood pressure. LIQREV may cause low blood pressure that last for a short period of time. If you take medicines to treat high blood pressure, your healthcare provider should monitor your blood pressure during treatment with LIQREV. Decreased eyesight or permanent loss of vision in one or both eyes can be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Most people who develop NAION have certain risk factors. You can ask your healthcare provider if you have questions about risk factors for NAION. If you notice a sudden decrease or loss of vision in one or both eyes during treatment with LIQREV, contact your healthcare provider right away.Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing during treatment with LIQREV, contact your healthcare provider right away.In men, an erection that lasts for more than 4 hours (priapism). If you have an erection, with or without pain, that lasts more than 4 hours, contact your healthcare provider or get emergency medical help right away. A painful erection that lasts more than 6 hours must be treated right away or you can have lasting damage to your penis, including the inability to have erections.The most common side effects with LIQREV in adults include:headachegetting red or hot in the face (flushing)arm or leg painmuscle aches and painupset stomachback paindiarrheanosebleedsStore LIQREV oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). Use the bottle within 90 days once it has been opened.Do not freeze LIQREV oral suspension.Keep LIQREV and all medicines out of the reach of children.
What is the most important information I should know about LIQREV?Never take LIQREV with any nitrate or guanylate cyclase stimulator medicines:
••••••
What is LIQREV?LIQREV is a prescription medicine used to treat pulmonary arterial hypertension (PAH). PAH is a type of high blood pressure in the arteries of your lungs. LIQREV may be used in:
•
Do not take LIQREV if you:
•••
Before taking LIQREV, tell your healthcare provider about all your medical conditions, including if you:
••••••••••••••
How should I take LIQREV?
••••••
What are the possible side effects of LIQREV?LIQREV may cause serious side effects, including:
•••••
••••
••••
These are not all the possible side effects of LIQREV.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.Pediatric use information is approved for Viatris Specialty LLC's, REVATIO (sildenafil) tablets. However, because of Viatris Specialty LLC's marketing exclusivity rights, this drug product is not labeled with that information.
How should I store LIQREV?
••
General information about the safe and effective use of LIQREV. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LIQREV for a condition for which it was not prescribed. Do not give LIQREV to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LIQREV that is written for health professionals.
What are the ingredients in LIQREV?Active ingredients: sildenafil citrateInactive ingredients: The inactive ingredients include acesulfame potassium, citric acid monohydrate, glycerin, simethicone emulsion, sodium benzoate, sucralose, strawberry flavor, tri-sodium citrate dihydrate, xanthan gum, and water. Distributed by: CMP Pharma, Inc. Farmville, NC 27828For more information, go to www.LIQREV.com.
" ], "package_label_principal_display_panel": [ "PRINCIPAL DISPLAY PANEL – 122 mL 122 mL Rx Only NDC 46287-055-01 Liqrev ® (Sildenafil) Oral Suspension 10 mg/mL FOR ORAL USE ONLY SHAKE WELL BEFORE USE Liqrev Bottle Label" ], "set_id": "13fb930a-fc46-4e0d-8d05-39162c156714", "id": "867a9816-7a7c-4647-9e5f-5c8836de1e62", "effective_time": "20240528", "version": "2", "openfda": {} } ] }