Sildenafil tablets, USP are formulated as blue, film-coated oval biconvex tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionThe 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. 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's patent expiration has increased availability of generics.
• Dapoxetine is relatively newer, approved in the early 2000s.
• Lifestyle factors like smoking can impact medication effectiveness.
• Both medications have different mechanisms of action.
• Dapoxetine's efficacy is confirmed through multiple clinical trials.
• Sildenafil may cause temporary visual disturbances.
• Proper dosage timing enhances effectiveness and safety.
• Always discard expired medications safely to avoid misuse.

Sildenafil at recommended doses has no effect in the absence of sexual stimulation.Binding CharacteristicsStudies in vitrohave shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700- fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ 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, an inhibition of platelet thrombus formation in vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects ofsildenafil tablets on Erectile Response:In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil tablets administration compared with placebo. Most studies assessed the efficacy of sildenafil tablets approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.Effects ofsildenafil tabletson Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours.

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Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of sildenafil tablets, 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 (4.1)].Effects ofsildenafil tablets on Blood Pressure When Nitroglycerin is subsequently administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours vardenafil with dapoxetine tablets post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)].Effects ofSildenafil tablets on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of sildenafil tablets with doxazosin, an alpha-adrenergic blocking agent.Study 1: sildenafil tablets with DoxazosinIn the first study, a single oral dose of sildenafil tablets100 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 tablets100 mg or matching placebo was administered simultaneously with doxazosin.

• Sildenafil can cause a drop in blood pressure in some users.
• Dapoxetine's adverse effects are usually mild and transient.
• Patients on medication for heart disease should consult a doctor first.
• Sexual activity itself can pose risks for some health conditions.
• Combining sildenafil with other ED medications is not recommended.
• Dapoxetine may interact with other serotonergic drugs.
• Use caution when operating machinery after taking these drugs.
• Always inform your doctor about other medications being used.

Following a review of the data from these first 4 subjects (details provided below), the sildenafil tablets dose was reduced to 25 mg.

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Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of sildenafil tablets, 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 (4.1)].Effects ofsildenafil tablets on Blood Pressure When Nitroglycerin is subsequently administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours vardenafil with dapoxetine tablets post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)].Effects ofSildenafil tablets on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of sildenafil tablets with doxazosin, an alpha-adrenergic blocking agent.Study 1: sildenafil tablets with DoxazosinIn the first study, a single oral dose of sildenafil tablets100 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 tablets100 mg or matching placebo was administered simultaneously with doxazosin.

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Following a review of the data from these first 4 subjects (details provided below), the sildenafil tablets dose was reduced to 25 mg. Thereafter, 17 subjects were treated with sildenafil tablets 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5 years.For the 17 subjects who received sildenafil tablets25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil tablets or matching placebo are shown in Figure 2.Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil tablets or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more time points. There were no subjects treated with sildenafil tablets 25 mg who had a standing SBP < 85mmHg.

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There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil tablets 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 tablets and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.Of the four subjects who received sildenafil tablets100 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 tablets 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 < 85mmHg. Thereafter, 17 subjects were treated with sildenafil tablets 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8 mg (2 subjects).

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Sildenafil tablets, USP are formulated as blue, film-coated oval biconvex tablets equivalent to 25 mg, 50 mg and 100 mg of sildenafil for oral administration. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionThe 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. 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 CharacteristicsStudies in vitrohave shown that sildenafil is selective for PDE5.

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Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700- fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ 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.

Interactions that increase your risk for side effects

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, an inhibition of platelet thrombus formation in vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects ofsildenafil tablets on Erectile Response:In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil tablets administration compared with placebo. Most studies assessed the efficacy of sildenafil tablets approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.Effects ofsildenafil tabletson Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1–2 hours after dosing, and was not different than placebo at 8 hours. The mean subject age was 66.5 years.For the 17 subjects who received sildenafil tablets25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil tablets or matching placebo are shown in Figure 2.Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil tablets or matching placebo.

4.1 Nitrates

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 tablets with DoxazosinIn the second study, a single oral dose of sildenafil tablets 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 tablets 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 63.9 years.Twenty subjects received sildenafil tablets 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 tablets 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.For the 19 subjects who received both sildenafil tablets and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil tablets or matching placebo are shown in Figure 3.Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the first doxazosin study.

Drugs you should not use with sildenafil

There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil tablets 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30 mmHg following sildenafil tablets 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets 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 tablets with DoxazosinIn the third study, a single oral dose of sildenafil tablets 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.

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Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more time points. There were no subjects treated with sildenafil tablets 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following sildenafil tablets 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 tablets and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.Of the four subjects who received sildenafil tablets100 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 tablets 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 < 85mmHg. 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 tablets with DoxazosinIn the second study, a single oral dose of sildenafil tablets 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 tablets 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 63.9 years.Twenty subjects received sildenafil tablets 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 tablets 50 mg.

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This patient had been taking minoxidil, a potent vasodilator, during the study.For the 19 subjects who received both sildenafil tablets and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil tablets or matching placebo are shown in Figure 3.Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of sildenafil tablets 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30 mmHg following sildenafil tablets 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets 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 tablets with DoxazosinIn the third study, a single oral dose of sildenafil tablets 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH.