13 NONCLINICAL TOXICOLOGY

Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. All three were taking sildenafil tablets 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness.

• Sildenafil helps facilitate natural arousal, not cause an instant erection.
• It is important to hydrate well when taking sildenafil.
• The medication can interact with certain herbal supplements.
• Avoid sharing medication with others due to potential health risks.
• Regular check-ups can help monitor the effects of sildenafil on health.

There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil tablets 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 tablets and placebo.

Usual Adult Dose for Pulmonary Hypertension

Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. All three were taking sildenafil tablets 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil tablets 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 tablets 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 tablets 50 mg and 100 mg. Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil tablets 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.

4.1 Nitrates

Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Alcohol: Sildenafil tablets (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions(7.5)]. Effects of Sildenafil Tablets on Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of sildenafil tablets on cardiac output. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing.

5.3 Effects on the Eye

These results demonstrated that the effect of sildenafil tablets on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil Tablets on Vision:At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil tablets on visual acuity, intraocular pressure, or pupillometry. Effects of Sildenafil Tablets on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil tablets in healthy volunteers. Sildenafil tablets are rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil tablets 50 mg and 100 mg.

Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil tablets 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. Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Alcohol: Sildenafil tablets (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions(7.5)]. Effects of Sildenafil Tablets on Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of sildenafil tablets on cardiac output.

• Sildenafil is available in various dosage forms beyond oral tablets.
• Revatio is available as an injectable solution for intravenous use in PAH.
• The IV dose is 10mg administered three times a day as a bolus injection.
• There is also an oral suspension formulation of Revatio for pediatric use.
• A topical gel formulation of sildenafil has been investigated for ED.
• Orally disintegrating tablets and fast-dissolving films are also in development.
• Different formulations aim to improve onset of action or patient convenience.
• The bioavailability and pharmacokinetics differ between formulations.
• Only the oral tablet and IV solution are currently widely approved and available.
• Patients should never switch formulations without consulting their doctor.
• The dose and dosing frequency are specific to each formulation and indication.

Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil tablets on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil Tablets on Vision:At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil tablets on visual acuity, intraocular pressure, or pupillometry. Effects of Sildenafil Tablets on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil tablets in healthy volunteers.

What is sildenafil?

Absorption and Distribution: Sildenafil tablets are rapidly absorbed. When sildenafil tablets are taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T maxof 60 minutes and a mean reduction in C maxof 29%. Metabolism and Excretion:Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. Pharmacokinetics in Special Populations Geriatrics: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 sildenafil tablets lp 100 mg 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 [ see Dosage and Administration (2.5),and Use in Specific Populations (8.5)] 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 tablets (50 mg) were not altered.

Dosage Modifications

In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared to age-matched volunteers with no renal impairment [see Dosage and Administration (2.5),and Use in Specific Populations (8.6)]. In addition, N-desmethyl metabolite AUC and C maxvalues significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment:In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max(47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [see Dosage and Administration (2.5),and Use in Specific Populations (8.7)]. Drug Interaction Studies Effects of Other Drugs on Sildenafil Tablets Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route).

What are the serious side effects of sildenafil?

In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil tablets (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil tablets were administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil tablets (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co- administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see Dosage and Administration (2.4)and Drug Interactions ( 7.4)]. In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil tablets (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC. Sildenafil tablets are rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). Absorption and Distribution: Sildenafil tablets are rapidly absorbed. When sildenafil tablets are taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T maxof 60 minutes and a mean reduction in C maxof 29%. Metabolism and Excretion:Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. Pharmacokinetics in Special Populations Geriatrics: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 sildenafil tablets lp 100 mg 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 [ see Dosage and Administration (2.5),and Use in Specific Populations (8.5)] 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 tablets (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared to age-matched volunteers with no renal impairment [see Dosage and Administration (2.5),and Use in Specific Populations (8.6)]. In addition, N-desmethyl metabolite AUC and C maxvalues significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment:In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max(47%) compared to age-matched volunteers with no hepatic impairment.

What special precautions should I follow?

Sildenafil tablets had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4)and Drug Interactions (7.4)]. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max. Single doses of antacid (magnesium sildenafil softgel capsule hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil tablets. Effects of Sildenafil Tablets on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil tablets will alter the clearance of substrates of these isoenzymes.

Viagra Tablets

In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil tablets (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.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.). 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/m2 basis in a 50 kg subject.

Can I take sildenafil every day?

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. In clinical studies, sildenafil tablets 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 tablets were 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 tablets were 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 tablets demonstrated statistically significant improvement compared to placebo in all 21 studies. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [see Dosage and Administration (2.5),and Use in Specific Populations (8.7)].

Drug Interaction Studies Effects of Other Drugs on Sildenafil Tablets Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil tablets (50 mg) to healthy volunteers.

• Myths and misconceptions about sildenafil are common and should be addressed.
• It is not a "party drug" or aphrodisiac; it requires sexual stimulation to work.
• It does not cause spontaneous erections without sexual arousal.
• More is not always better; higher doses increase side effect risk, not pleasure.
• It is not addictive, but psychological dependence on its use can develop.
• It does not permanently cure erectile dysfunction; effects are temporary.
• It is not safe to use just because it is widely available or discussed.
• Herbal "natural Viagra" products are not regulated and can be dangerous.
• It does not protect against sexually transmitted infections or prevent pregnancy.
• It is not approved or proven to enhance sexual performance in men without ED.
• Accurate information from a healthcare provider is essential.

When a single 100 mg dose of sildenafil tablets were administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil tablets (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC.

Frequently asked questions for Sildenafil

Efficacy Endpoints in Controlled Clinical Studies The effectiveness of sildenafil tablets were 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.

How Sildenafil works

Alcohol interaction warning

Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co- administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see Dosage and Administration (2.4)and Drug Interactions ( 7.4)]. In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil tablets (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC. Sildenafil tablets had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4)and Drug Interactions (7.4)]. In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max. Single doses of antacid (magnesium sildenafil softgel capsule hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil tablets. Effects of Sildenafil Tablets on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil tablets will alter the clearance of substrates of these isoenzymes. In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil tablets (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.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.). 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/m2 basis in a 50 kg subject. 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. In clinical studies, sildenafil tablets 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 tablets were 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 tablets were 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 tablets demonstrated statistically significant improvement compared to placebo in all 21 studies. Efficacy Endpoints in Controlled Clinical Studies The effectiveness of sildenafil tablets were 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.