Sildenafil

1 INDICATIONS & USAGE Sildenafil tablets are indicated for the treatment of erectile dysfunction. Sildenafil tablet is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) (1)

2 DOSAGE & ADMINISTRATION •For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity (2.1) •Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg (2.1) •Maximum recommended dosing frequency is once per day (2.1) 2.1 Dosage Information For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food Sildenafil tablets may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations Sildenafil tablets were shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [see Contraindications (4.1), Drug Interactions (7.1), and Clinical Pharmacology (12.2)]. When sildenafil tablets are co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil tablets treatment and sildenafil tablets should be initiated at 25 mg [see Warnings and Precautions (5.5), Drug Interactions (7.2), and Clinical Pharmacology (12.2)]. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [see Warnings and Precautions (5.6), Drug Interactions (7.4), and Clinical Pharmacology (12.3)]. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [see Drug Interactions (7.4) and Clinical Pharmacology (12.3)]. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of sildenafil tablets in these patients resulted in higher plasma levels of sildenafil [see Use in Specific Populations ( 8.5, 8.6, 8.7) and Clinical Pharmacology ( 12.3)].

5 WARNINGS AND PRECAUTIONS •Patients should not use sildenafil tablets if sexual activity is inadvisable due to cardiovascular status (5.1) •Patients should seek emergency treatment if an erection lasts >4 hours. Use sildenafil tablets with caution in patients predisposed to priapism (5.2) •Patients should stop sildenafil tablets and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION). Sildenafil tablets should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a”crowded” optic disc may also be at an increased risk of NAION. (5.3) •Patients should stop sildenafil tablets and seek prompt medical attention in the event of sudden decrease or loss of hearing (5.4) •Caution is advised when sildenafil tablets are co-administered with alpha-blockers or anti-hypertensives. Concomitant use may lead to hypotension (5.5) •Decreased blood pressure, syncope, and prolonged erection may occur at higher sildenafil exposures. In patients taking strong CYP inhibitors, such as ritonavir, sildenafil exposure is increased. Decrease in sildenafil tablets dosage is recommended (2.4, 5.6) 5.1 Cardiovascular There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including sildenafil tablets, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment. Sildenafil tablets have systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), [see Clinical Pharmacology (12.2)]. While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity. Use with caution in patients with the following underlying conditions which can be particularly sensitive to the actions of vasodilators including sildenafil tablets – those with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure. There are no controlled clinical data on the safety or efficacy of sildenafil tablets in the following groups; if prescribed, this should be done with caution. •Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months; •Patients with resting hypotension (BP <90/50 mmHg) or hypertension (BP >170/110 mmHg); •Patients with cardiac failure or coronary artery disease causing unstable angina. 5.2 Prolonged Erection and Priapism Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil tablets. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result. Sildenafil tablets should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). However, there are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with sickle …

4 CONTRAINDICATIONS •Administration of sildenafil tablets to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. Sildenafil tablets were shown to potentiate the hypotensive effect of nitrates ( 4.1 , 7.1 , 12.2 ) •Known hypersensitivity to sildenafil or any component of tablet (4.2) •Administration with guanylate cyclase (GC) stimulators, such as riociguat (4.3) 4.1 Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway [see Clinical Pharmacology ( 12.1 , 12.2)] , sildenafil tablets were shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken sildenafil tablets, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see Dosage and Administration (2.3), Drug Interactions (7.1), and Clinical Pharmacology (12.2)]. 4.2 Hypersensitivity Reactions Sildenafil tablets are contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil tablets and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [see Adverse Reactions (6.1)]. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use sildenafil tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including sildenafil tablets, may potentiate the hypotensive effects of GC stimulators.

7 DRUG INTERACTIONS •Sildenafil tablets can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) •With concomitant use of alpha blockers, initiate sildenafil tablets at 25 mg dose (2.3) •CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil tablets exposure (2.4 , 7.4, 12.3 ) •Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6) •Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg (2.4, 7.4) 7.1 Nitrates Administration of sildenafil tablets with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil tablets were shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration (2.3), Contraindications (4.1), Clinical Pharmacology (12.2)]. 7.2 Alpha-blockers Use caution when co-administering alpha-blockers with sildenafil tablets because of potential additive blood pressure-lowering effects. When sildenafil tablets are co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil tablets treatment and sildenafil tablets should be initiated at the lowest dose [see Dosage and Administration (2.3), Warnings and Precautions (5.5), Clinical Pharmacology (12.2)]. 7.3 Amlodipine When sildenafil tablets 100 mg were co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see Warnings and Precautions (5.5), Clinical Pharmacology (12.2)]. 7.4 Ritonavir and Other CYP3A4 Inhibitors Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of sildenafil tablets in a 48 hour period [see Dosage and Administration ( 2.4), Warnings and Precautions (5.6), Clinical Pharmacology ( 12.3)]. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of sildenafil tablets should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itracanozole) [see Dosage and Administration (2.4), Clinical Pharmacology ( 12.3)]. 7.5 Alcohol In a drug-drug interaction study sildenafil 50 mg given with alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [ see Clinical Pharmacology ( 12.2) ].

8.1 Pregnancy: Teratogenic effects Risk Summary Sildenafil tablets is not indicated for use in females. There are no data with the use of sildenafil tablets in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2 basis (see Data). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2 basis in a 50 kg subject.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: •Cardiovascular [see Warnings and Precautions (5.1)] •Prolonged Erection and Priapism [see Warnings and Precautions (5.2)] •Effects on the Eye [see Warnings and Precautions (5.3)] •Hearing Loss [ see Warnings and Precautions (5.4)] •Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions (5.5)] •Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions (5.6)] •Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions (5.7)] •Effects on Bleeding [see Warnings and Precautions (5.8)] •Counseling Patients About Sexually Transmitted Diseases [see Warnings and Precautions (5.9)] The most common adverse reactions reported in clinical trials (≥ 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Evaric Pharmaceuticals, Inc. at 1-866-495-1995 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 clinical practice. Sildenafil tablets were administered to over 3700 patients (aged 19 to 87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil tablets (2.5%) was not significantly different from placebo (2.3%). In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently. Table 1: Adverse Reactions Reported by ≥2% of Patients with Sildenafil Tablets and More Frequently than Placebo in Fixed-Dose Phase II/III Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision † 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% † Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil tablets were taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil tablets at least once weekly, and the following adverse reactions were reported: Table 2. Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction SILDENAFIL TABLETS PLACEBO N=734 N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision † 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% † Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil tablets is uncertain. Reported events include those with a plausible relation to drug use; omit…