SILDENAFIL- sildenafil_tablet, film coated

The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics Studies in vitro see Clinical Pharmacology ( 12. 2 In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro in vivo in vivo Effects of Sildenafil on Erectile Response: registered registered Effects of Sildenafil on Blood Pressure: see Contraindications (4. 1) Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Effects of Sildenafil on Blood Pressure When Nitroglycerin is Subsequently Administered: see Contraindications (4. 1) Effects of Sildenafil on Blood Pressure When Coadministered with Alpha-Blockers: Study 1: Sildenafil with Doxazosin In the first study, a single oral dose of sildenafil 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, sildenafil 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the sildenafil dose was reduced to 25 mg. Thereafter, 17 subjects were treated with sildenafil 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66. For the 17 subjects who received sildenafil 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil 25 mg Supine 7. 7) Standing 6. 8) Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1. 5, 3, 4, 6 and 8 hours after sildenafil or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of 30 mmHg at one or more timepoints. There were no subjects treated with sildenafil 25 mg who had a standing SBP 30mmHg following sildenafil 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Of the four subjects who received sildenafil 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with sildenafil with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14. 8 mmHg and 21. 5 mmHg, respectively. Two of these subjects had a standing SBP < 85 mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension. Study 2: Sildenafil with Doxazosin In the second study, a single oral dose of sildenafil 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, sildenafil 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63. Twenty subjects received sildenafil 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with sildenafil 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study. For the 19 subjects who received both sildenafil and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil 50 mg (95% CI) Supine 9. 68) Standing 11. 90) Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of 30 mmHg following sildenafil 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. Study 3: Sildenafil with Doxazosin In the third study, a single oral dose of sildenafil 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of sildenafil 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, sildenafil 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66. Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil 50 mg). For the 20 subjects who received sildenafil 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil 100 mg Supine 7. 1) Standing 4. 3) Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of 30 mmHg following sildenafil 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil 50 mg and 100 mg. There were no episodes of syncope reported in this study. Effect of Sildenafil on Blood Pressure When Coadministered with Anti-hypertensives: Effect of Sildenafil on Blood Pressure When Coadministered with Alcohol: see Drug Interactions (7. 5) Effects of Sildenafil on Cardiac Parameters: Studies have produced relevant data on the effects of sildenafil on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions. The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Means +/- SD At rest After 4 minutes of exercise N Baseline (B2) n Sildenafil (D1) n Baseline n Sildenafil PAOP (mmHg) 8 8. 3 Mean PAP (mmHg) 8 16. 7 +/- 4 8 12. 2 Mean RAP (mmHg) 7 5. 7 - - - - Systolic SAP (mmHg) 8 150. 0 Diastolic SAP (mmHg) 8 73. 9 +/- 10 8 84. 4 Cardiac output (L/min) 8 5. 5 Heart rate (bpm) 8 67 +/- 11. 9 +/- 12 8 101. 4 Effects of Sildenafil on Vision: Effects of Sildenafil on Sperm: figure1 figure2 figure3 figure4 Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers. Absorption and Distribution: max max ss Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0. 001% of the administered dose may appear in the semen of patients. Metabolism and Excretion: in vitro After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach. Pharmacokinetics in Special Populations Geriatrics: see Dosage and Administration (2. 5), and Use in Specific Populations (8. 5) Renal Impairment: max see Dosage and Administration (2. 6) In addition, N-desmethyl metabolite AUC and C max Hepatic Impairment: max see Dosage and Administration (2. 7) Therefore, age > 65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2. 5) Drug Interaction Studies Effects of Other Drugs on Sildenafil Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e. , saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2. 4) In vivo Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C max max see Dosage and Administration (2. 4) and Drug Interactions (7. 4) In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C max see Dosage and Administration (2. 4) Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels. In a study of healthy male volunteers, coadministration of sildenafil at steady state (80 mg t. ) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b. ) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil. In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite. Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence. Effects of Sildenafil on Other Drugs In vitro Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 muM). Given sildenafil peak plasma concentrations of approximately 1 muM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes. In vivo No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t. ) resulted in a 50% increase in AUC and a 42% increase in C max figure5.

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

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) 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. Sildenafil tablets may be taken with or without food. Sildenafil tablets were shown to potentiate the hypotensive effects of nitrates and their administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [see Contraindications (4. 2) When sildenafil tablets are coadministered 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. 2) 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. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that coadministration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3-fold [see Drug Interactions (7. 4) and Clinical Pharmacology (12. Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e. , 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.

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 Coadministered 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 AvKARE, Inc. at 1-855-361-3993, or FDA at 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 was administered to over 3700 patients (aged 19 to 87 years) during premarketing 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 (2. 5%) was not significantly different from placebo (2. 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 Treated with Sildenafil and More Frequent 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 Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred 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% When sildenafil was 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 at least once weekly, and the following adverse reactions were reported: Table 2. Adverse Reactions Reported by >= 2% of Patients Treated with Sildenafil and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction SILDENAFIL PLACEBO N = 734 N = 725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision 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. 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to sildenafil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole: Cardiovascular: Digestive: Hemic and Lymphatic: Metabolic and Nutritional: Musculoskeletal: Nervous: Respiratory: Skin and Appendages: Special Senses: Urogenital: Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking sildenafil with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. The following adverse reactions have been identified during post approval use of sildenafil. 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. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Cardiovascular and cerebrovascular Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported postmarketing in temporal association with the use of sildenafil. 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 the use of sildenafil and 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, to a combination of these factors, or to other factors [see Warnings and Precautions (5. 1) (17) Hemic and Lymphatic: Nervous: Respiratory: Special senses: Hearing [see Warnings and Precautions (5. 4) (17) Ocular Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) 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 [see Warnings and Precautions (5. 3) (17) Urogenital: [see Warnings and Precautions (5.

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. 2) Known hypersensitivity to sildenafil or any component of tablet (4. 2) Administration with guanylate cyclase (GC) stimulators, such as riociguat (4. 3) Consistent with its known effects on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12. 2)], 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 coadministered at this time point [see Dosage and Administration (2. 3), Drug Interactions (7. 1), and Clinical Pharmacology (12. Sildenafil tablets are contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil tablets and REVATIO registered [see Adverse Reactions (6. 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.

Geriatric use: Consider a starting dose of 25 mg (2. 5) Severe renal impairment: Consider a starting dose of 25 mg (2. 6) Hepatic impairment: Consider a starting dose of 25 mg (2. 7) Risk Summary Sildenafil is not indicated for use in females. There are no data with the use of sildenafil 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 (see Data). Data Animal Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 2 Risk Summary Sildenafil is not indicated for use in females. Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production. Sildenafil is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18 to 45 years) [ see Clinical Pharmacology (12. 3) see Clinical Pharmacology (12. 3) Of the total number of subjects in clinical studies of sildenafil, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (>= 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [ see Dosage and Administration (2. 5) No dose adjustment is required for mild (CLcr = 50 to 80 mL/min) and moderate (CLcr = 30 to 49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr < 30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of C max see Dosage and Administration (2. 3) In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max see Dosage and Administration (2.

Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives (4. 2) With concomitant use of alpha blockers, initiate sildenafil at 25 mg dose (2. 3) CYP3A4 inhibitors (e. , ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil exposure (2. 3) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period (2. 6) Erythromycin or strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg (2. 4) Administration of sildenafil 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 was shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration (2. 2) Use caution when coadministering alpha-blockers with sildenafil because of potential additive blood pressure-lowering effects. When sildenafil is coadministered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil treatment and sildenafil should be initiated at the lowest dose [see Dosage and Administration (2. 2) When sildenafil 100 mg was coadministered 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. 2) Coadministration 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 in a 48 hour period [see Dosage and Administration (2. 3) Coadministration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max max [see Dosage and Administration (2. 3) 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.

OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18 to 21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2 Mutagenesis Sildenafil was negative in in vitro in vitro in vivo Impairment of Fertility There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.
CLINICAL STUDIES
In clinical studies, sildenafil was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. Efficacy Endpoints in Controlled Clinical Studies The effectiveness of sildenafil was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. Efficacy Results from Controlled Clinical Studies The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with sildenafil was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. Figure 6: Effect of Sildenafil and Placebo on Maintenance of Erection by Baseline Score. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of sildenafil, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n = 644) (with most patients eventually receiving 100 mg), results were similar. Figure 7: Percentage of Patients Reporting an Improvement in Erections. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1. 3 on 50 to 100 mg of sildenafil vs 0. 4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that sildenafil improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. Sildenafil improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n = 268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of sildenafil; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on sildenafil compared to placebo. On a global improvement question, 57% of sildenafil patients reported improved erections versus 10% on placebo. Diary data indicated that on sildenafil, 48% of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n = 178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil. On a global improvement question, 83% of patients reported improved erections on sildenafil versus 12% on placebo. Diary data indicated that on sildenafil, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, sildenafil improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n = 179) and two titration studies (total n = 149) showed 84% of sildenafil patients reported improvement in erections compared with 26% of placebo. Diary data in two of the studies (n = 178) showed rates of successful intercourse per attempt of 70% for sildenafil and 29% for placebo. Efficacy Results in Subpopulations in Controlled Clinical Studies A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. Sildenafil was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and anti-hypertensives/diuretics. figure6 figure7.
PATIENT INFORMATION
Sildenafil Tablets USP (sil-DEN-a-fil) What is the most important information I should know about sildenafil tablets? Sildenafil tablets can cause your blood pressure to drop suddenly to an unsafe level if they are taken with certain other medicines. Do not take sildenafil tablets if you take medicines called guanylate cyclase stimulators which include: Riociguat (Adempas registered Tell all your healthcare providers that you take sildenafil tablets. Stop sexual activity and get medical help right away if you get symptoms such as chest pain, dizziness, or nausea during sex. Sexual activity can put an extra strain on your heart, especially if your heart is already weak from a heart attack or heart disease. Ask your doctor if your heart is healthy enough to handle the extra strain of having sex. Sildenafil tablets do not protect you or your partner from getting sexually transmitted diseases, including HIVem dashthe virus that causes AIDS. What are sildenafil tablets? Sildenafil tablets are a prescription medicine used to treat erectile dysfunction (ED). You will not get an erection just by taking this medicine. Sildenafil tablets help a man with erectile dysfunction get and keep an erection only when he is sexually excited (stimulated). Sildenafil tablets are not for use in women or children. It is not known if sildenafil tablets are safe and effective in women or children under 18 years of age. Who should not take sildenafil tablets? Do not take sildenafil tablets if you: take medicines called nitrates (such as nitroglycerin) use street drugs called “poppers” such as amyl nitrate or amyl nitrite, and butyl nitrate take any medicines called guanylate cyclase stimulators such as riociguat (Adempas) are allergic to sildenafil, as contained in sildenafil tablets and REVATIO registered What should I tell my healthcare provider before taking sildenafil tablets? Before you take sildenafil tablets, tell your healthcare provider if you: have or have had heart problems such as a heart attack, irregular heartbeat, angina, chest pain, narrowing of the aortic valve or heart failure have had heart surgery within the last 6 months have pulmonary hypertension have had a stroke have low blood pressure, or high blood pressure that is not controlled have a deformed penis shape have had an erection that lasted for more than 4 hours have problems with your blood cells such as sickle cell anemia, multiple myeloma, or leukemia have retinitis pigmentosa, a rare genetic (runs in families) eye disease have ever had severe vision loss, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION) have bleeding problems have or have had stomach ulcers have liver problems have kidney problems or are having kidney dialysis have any other medical conditions Tell your healthcare provider about all the medicines you take* Sildenafil tablets may affect the way other medicines work, and other medicines may affect the way sildenafil tablets work causing side effects. Especially tell your healthcare provider if you take any of the following: medicines called nitrates (see “ What is the most important information I should know about sildenafil tablets? medicines called guanylate cyclase stimulators, such as riociguat (Adempas) medicines called alpha blockers such as Hytrin registered registered registered registered registered registered registered medicines called HIV protease inhibitors, such as ritonavir (Norvir registered registered registered registered registered some types of oral antifungal medicines, such as ketoconazole (Nizoral registered registered some types of antibiotics, such as clarithromycin (Biaxin registered registered other medicines that treat high blood pressure other medicines or treatments for ED sildenafil tablets contain sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat a rare disease called pulmonary arterial hypertension (PAH). Sildenafil tablets should not be used with REVATIO or with other PAH treatments containing sildenafil or any other PDE5 inhibitors (such as Adcirca registered 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 to show to your healthcare provider and pharmacist when you get a new medicine. How should I take sildenafil tablets? Take sildenafil tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many sildenafil tablets to take and when to take them. Your healthcare provider may change your dose if needed. Take sildenafil tablets about 1 hour before sexual activity. You may take sildenafil tablets between 30 minutes to 4 hours before sexual activity if needed. Sildenafil tablets can be taken with or without food. If you take sildenafil tablets after a high fat meal (such as a cheeseburger and french fries), sildenafil tablets may take a little longer to start working Do not If you accidentally take too many sildenafil tablets, call your doctor or go to the nearest hospital emergency room right away. What are the possible side effects of sildenafil tablets? Sildenafil tablets can cause serious side effects. an erection that will not go away (priapism). sudden vision loss in one or both eyes. sudden hearing decrease or hearing loss. The most common side effects of sildenafil tablets are: headache flushing upset stomach abnormal vision, such as changes in color vision (such as having a blue color tinge) and blurred vision stuffy or runny nose back pain muscle pain nausea dizziness rash In addition, heart attack, stroke, irregular heartbeats and death have happened rarely in men taking sildenafil tablets. Most, but not all, of these men had heart problems before taking sildenafil tablets. It is not known if sildenafil tablets caused these problems. Tell your healthcare provider if you have any side effect that bothers you or does not go away. These are not all the possible side effects of sildenafil 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 sildenafil tablets? Store sildenafil tablets at 68° to 77°F (20° to 25°C). Keep sildenafil tablets and all medicines out of the reach of children. General information about the safe and effective use of sildenafil tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use sildenafil tablets for a condition for which they were not prescribed. Do not give sildenafil tablets to other people, even if they have the same symptoms that you have. They may harm them. This Patient Information leaflet summarizes the most important information about sildenafil tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about sildenafil tablets that is written for health professionals. For more information, call 1-855-361-3993. What are the ingredients in sildenafil tablets USP? Active ingredient: Inactive ingredients: This Patient Information has been approved by the U.S. Food and Drug Administration. This product’s label may have been updated. For more information, call 1-855-361-3993. All brand names listed are the registered trademarks of their respective owners and are not trademarks of AvKARE, Inc. Manufactured for:

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