13 NONCLINICAL TOXICOLOGY

Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)].

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.

Chemical synthesis

During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies(14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day. 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)] .

Study 1: Sildenafil citrate with Doxazosin

Severe impairment has not been studied [see Clinical Pharmacology (12.3)] . No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3)] . Sildenafil tablets, 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 Tablets USP: Sildenafil citrate is formulated as white, film-coated round tablets for oral administration. 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. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)]. Concomitant use of sildenafil citrate with nitrates in any form is contraindicated [see Contraindications (4)] .

Strong CYP3A Inhibitors Concomitant use of sildenafil citrate with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Moderate-to-Strong CYP3A Inducers Concomitant use of Sildenafil citrate with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Reduce the dose of sildenafil tablets 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)].

Mechanism of action

Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)]. 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. 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. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)].

Recreational use

Concomitant use of sildenafil citrate with nitrates in any form is contraindicated [see Contraindications (4)] . Strong CYP3A Inhibitors Concomitant use of sildenafil citrate with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Moderate-to-Strong CYP3A Inducers Concomitant use of Sildenafil citrate with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Reduce the dose of sildenafil tablets 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)]. 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. 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.

• Sildenafil is sometimes used off-label for other health issues.
• Its interaction with blood thinners should be monitored.
• Men with retinitis pigmentosa should avoid sildenafil.
• Always inform healthcare providers about all treatments.
• Use sildenafil in conjunction with a healthy lifestyle.
• Avoid unnecessary medication to prevent side effects.
• Be aware of potential drug interactions with sildenafil.
• Proper storage maintains medication efficacy over time.

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). 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/m2 basis, 32-and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day.

Before Using

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. 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). 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. 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/m2 basis).

5.5 Hearing Loss

Each tablet contains sildenafil citrate equivalent to sildenafil citrate 120 mg 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, microcrystalline cellulose, sodium stearyl fumarate, titanium dioxide and triacetin. Studies in vitro have shown that sildenafil is selective for PDE5. 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.

Why it’s used

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)] . Effects of Sildenafil Citrate on Hemodynamic Measures Patients on all sildenafil citrate 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 tablets 20 mg three times a day and placebo dosing regimens is displayed in Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil Tablets 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 * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. The safety and efficacy of Sildenafil citrate have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of sildenafil citrate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil citrate have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies(14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day. 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)] . Severe impairment has not been studied [see Clinical Pharmacology (12.3)] .

Warnings for Viagra

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). 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.

Erectile dysfunction

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/m2 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/m2 basis). Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. The safety and efficacy of Sildenafil citrate have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of sildenafil citrate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil citrate have not been established in pediatric patients younger than 1 year of age. No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3)] . Sildenafil tablets, 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.

• Always use the lowest effective dose of sildenafil.
• Follow your doctor’s instructions carefully.
• Do not alter the dosage without consulting your doctor.
• Keep track of your health conditions and medications.
• Use sildenafil responsibly to prevent dependency.
• Seek prompt medical attention for prolonged erections.
• Consider lifestyle changes to improve ED symptoms.
• Education about sildenafil can improve treatment outcomes.

Sildenafil Tablets USP: Sildenafil citrate is formulated as white, film-coated round tablets for oral administration. Each tablet contains sildenafil citrate equivalent to sildenafil citrate 120 mg 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, microcrystalline cellulose, sodium stearyl fumarate, titanium dioxide and triacetin. Studies in vitro have shown that sildenafil is selective for PDE5. 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.

MeSH terms

Patients on sildenafil tablets medium and high dose groups achieved a dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. Improvements were observed with cardiac index in all three sildenafil tablets dose groups over placebo. Data on other hemodynamic measures for the sildenafil tablets low, medium and high dose groups compared to placebo is displayed in Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively.

12.3 Pharmacokinetics

Effects of Sildenafil Citrate 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). 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)] . Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When sildenafil tablet 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 Cmax of 29%. 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)] . Effects of Sildenafil Citrate on Hemodynamic Measures Patients on all sildenafil citrate 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 tablets 20 mg three times a day and placebo dosing regimens is displayed in Table 2. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil Tablets 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 * The number of patients per treatment group varied slightly for each parameter due to missing assessments. Patients on sildenafil tablets medium and high dose groups achieved a dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. Improvements were observed with cardiac index in all three sildenafil tablets dose groups over placebo. Data on other hemodynamic measures for the sildenafil tablets low, medium and high dose groups compared to placebo is displayed in Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. Note: n = 52, 56, 55, 54, 56, and 56 placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively. Effects of Sildenafil Citrate 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). 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)] . Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25 to 63%). When sildenafil tablet 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 Cmax of 29%. 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. 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). 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.