Sildenafil 20mg Tablets

The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range.

• Sildenafil interacts with nitrate medications, causing dangerous drops in blood pressure.
• Store sildenafil in a cool, dry place away from children.
• 20mg is often recommended as a starting dose for ED treatment.
• Food, especially high-fat meals, can delay its onset of action.
• Regular use can improve erectile response over time if prescribed.

It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.

Before Using

This is consistent with ritonavir's marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics 150mg sildenafil for sale [see Dosage and Administration (2.4) and Drug Interactions (7.4)]. 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, 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 Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.

Revatio Tablets

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. 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. 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: VIAGRA is rapidly absorbed. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. 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: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. 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 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. 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 seen in healthy younger volunteers (18–45 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=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered.

• 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.

In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment [see Dosage and Administration (2.5), and Use in Specific Populations (8.6)].

• The societal impact of sildenafil has been profound since its introduction.
• It helped destigmatize the discussion and treatment of erectile dysfunction.
• It spawned a multi-billion dollar market for sexual health pharmaceuticals.
• The "Viagra" brand name became one of the most recognized in the world.
• It led to increased research and development in urology and sexual medicine.
• It also raised important questions about medicalization and lifestyle drugs.
• Direct-to-consumer advertising for ED treatments became widespread.
• It prompted debates about insurance coverage for quality-of-life medications.
• The success of sildenafil accelerated research into other PDE5 inhibitors.
• It highlighted the importance of serendipity in drug discovery.
• Its impact extends beyond medicine into cultural and social spheres.

In addition, N-desmethyl metabolite AUC and Cmax values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with blue sildenafil 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 Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

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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)]. 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)]. Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route).

Population Group	Considerations	Recommendations
Elderly	Altered pharmacokinetics	Start with lower dose
Patients with Renal Impairment	Slower clearance, risk of accumulation	Dose reduction or careful use
Patients with Liver Disease	Reduced metabolism, higher plasma levels	Dose adjustment or caution
Women	Not FDA-approved for female ED	Usually not prescribed

Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers. When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and 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 Viagra (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC.

12. Sildenafil Tablets - Clinical Pharmacology

Viagra had no effect on saquinavir pharmacokinetics.

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A starting oral dose of 25 mg should be considered in those patients [see Dosage and Administration (2.5)]. Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers. When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and 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 Viagra (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC.

How Sildenafil Works to Treat ED

Viagra had no effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. 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 VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. 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)].

What’s the difference between Sildenafil and Tadalafil?

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 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. 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 seen in healthy younger volunteers (18–45 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=50–80 mL/min) and moderate (CLcr=30–49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered.

8.1 Pregnancy: Teratogenic effects

In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared 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 Cmax values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with blue sildenafil 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 Cmax (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)]. Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. 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 VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC.

2.1 Recommended Dosage in Adults

The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. The effectiveness of VIAGRA 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.

8.2 Lactation

At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates.

Condition	Risk Factors	Recommendations
Use with Nitrates	Risk of severe hypotension	Avoid concurrent use
Severe Heart Disease	Increased cardiac stress	Consult cardiologist before use
Severe Liver or Kidney Impairment	Altered drug metabolism	Dose adjustment or avoid use
Hypotension	Blood pressure too low	Use caution, monitor blood pressure
Retinitis Pigmentosa	Risk of vision changes	Consult eye specialist

VIAGRA had no effect on ritonavir pharmacokinetics 150mg sildenafil for sale [see Dosage and Administration (2.4) and Drug Interactions (7.4)]. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

• The medication should be stored at room temperature between 15-30°C (59-86°F).
• Keep the tablets in their original container, tightly closed.
• Protect from light and moisture; avoid storing in bathrooms or near sinks.
• Do not use the medication if the packaging is torn or shows signs of tampering.
• Check the expiration date printed on the bottle or blister pack before use.
• Properly discard any medication that is outdated or no longer needed.
• Do not flush medications down the toilet or pour them into a drain.
• Consult a pharmacist or local waste disposal company for proper disposal methods.
• Many communities have drug take-back programs for safe disposal.
• Keeping old medication increases the risk of accidental ingestion or misuse.
• Safe storage and disposal protect children, pets, and the environment.

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 Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. 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. Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. 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. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused sildenafil 100mg lowest price 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 Cmax of bosentan (125 mg b.i.d.). 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 18–21 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.

Renal Dose Adjustments

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: VIAGRA is rapidly absorbed.

8.6 Renal Impairment

When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. 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: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In clinical studies, VIAGRA 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. VIAGRA 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). VIAGRA 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. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies.

What Are Side Effects Associated with Using Sildenafil?

Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. 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. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused sildenafil 100mg lowest price 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 Cmax of bosentan (125 mg b.i.d.). 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.

Viagra Tablets

Sildenafil was not carcinogenic when administered to mice for 18–21 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. In clinical studies, VIAGRA 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. VIAGRA 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). VIAGRA 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. VIAGRA 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. The effectiveness of VIAGRA 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.

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