Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.Studies in vitro have shown that sildenafil is selective for PDE-5.
| Ingredient | Quantity per Tablet | Function | Note |
|---|---|---|---|
| Sildenafil Citrate | 50 mg | Active pharmaceutical ingredient | Main active component |
| Croscarmellose Sodium | 20 mg | Disintegrant | Ensures tablet breaks down |
| Lactose Monohydrate | 150 mg | Filler | Used as excipient |
| Magnesium Stearate | 5 mg | Lubricant | Facilitates manufacturing |
| Microcrystalline Cellulose | 100 mg | Binder | Holds tablet together |
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 PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility.
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Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.
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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)].In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects of Sildenafil Citrate on Hemodynamic MeasuresPatients 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 [Study 1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 3.
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The relationship between these effects and improvements in 6-minute walk distance is unknown.Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil Citrate 20 mg Three Times a Day and Placebo GroupEffects of Sildenafil Citrate on Blood PressureSingle oral doses of sildenafil 50 mg sildenafil price 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg).
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Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.Studies in vitro have shown that sildenafil is selective for PDE-5. 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 PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.
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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)].In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects of Sildenafil Citrate on Hemodynamic MeasuresPatients 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 [Study 1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.Table 3. Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil Citrate 20 mg Three Times a Day and Placebo GroupEffects of Sildenafil Citrate on Blood PressureSingle oral doses of sildenafil 50 mg sildenafil price 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours.
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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)].Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.
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The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. 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)].Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).Effects of Sildenafil Citrate on VisionAt single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) 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 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.Pediatric use information is approved for Viatris Specialty LLC’s, REVATIO (sildenafil) tablets.
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However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information.12.3 PharmacokineticsAbsorption and DistributionSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%). When sildenafil citrate 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 C max of 29%. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Protein binding is independent of total drug concentrations.Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).Metabolism and ExcretionSildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized. After chronic dosing of 80 mg three times a day to patients with PAH, no clinically relevant effects on ECG were reported.After chronic dosing of 80 mg three times a day sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively.After chronic dosing of 80 mg three times a day sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.After chronic dosing of 80 mg three times a day sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).Effects of Sildenafil Citrate on VisionAt single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) 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 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.Pediatric use information is approved for Viatris Specialty LLC’s, REVATIO (sildenafil) tablets.
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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. In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.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).Population PharmacokineticsAge, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function.
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None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.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 C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Geriatric PatientsHealthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, sildenafil citrate tables respectively, compared to those 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.Renal ImpairmentIn 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 (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information.12.3 PharmacokineticsAbsorption and DistributionSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%). When sildenafil citrate 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 C max of 29%. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Protein binding is independent of total drug concentrations.Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).Metabolism and ExcretionSildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized.
- Sildenafil 50 mg may cause dizziness; avoid driving if affected.
- Combining sildenafil with certain drugs can be dangerous; discuss with your doctor.
- Do not use if you have severe liver or kidney disease.
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.
- Sildenafil 50 mg is a generic medication; brand names may vary.
- Overuse can lead to priapism, a painful prolonged erection.
- Communicate openly with your healthcare provider about your health status.
In patients with PAH, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.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).Population PharmacokineticsAge, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a significant impact on sildenafil pharmacokinetics in patients with PAH.In patients with PAH, the average steady-state concentrations were 20% to 50% higher when compared to those of healthy volunteers.
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In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic ImpairmentIn volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.Drug Interaction StudiesIn vitro studiesSildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.In vivo studiesThe effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively.CYP3A Inhibitors and Beta BlockersPopulation pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day.
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This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).CYP3A4 InducersConcomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.EpoprostenolThe mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady-state concentrations. There was also a doubling of C min levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Geriatric PatientsHealthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations of sildenafil and its active N-desmethyl metabolite, sildenafil citrate tables respectively, compared to those seen in healthy younger volunteers (18 to 45 years).
| Parameter | Value | Description |
|---|---|---|
| Absorption Rate | Rapid | Usually within 30-120 minutes |
| Bioavailability | Approximately 40% | Percentage of dose reaching circulation |
| Peak Plasma Concentration | About 1 hour after intake | When the highest level in blood is observed |
| Metabolism | Liver (via CYP3A4 enzyme) | Breakdown mainly in the liver |
| Elimination Half-life | 3-5 hours | Time taken for plasma concentration to reduce by half |
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.Renal ImpairmentIn 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 (50 mg) was not altered. In volunteers with severe (CLcr less than 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C max values were significantly increased 200% and 79%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic ImpairmentIn volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.Drug Interaction StudiesIn vitro studiesSildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 (minor route) cytochrome P450 isoforms.
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Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 greater than 150 μM). Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.In vivo studiesThe effects of other drugs on sildenafil pharmacokinetics and the effects of sildenafil on the exposure to other drugs are shown in Figure 7 and Figure 8, respectively.CYP3A Inhibitors and Beta BlockersPopulation pharmacokinetic analysis of data from patients in clinical trials indicated an approximately 30% reduction in sildenafil clearance when it was co-administered with mild/moderate CYP3A inhibitors and an approximately 34% reductions in sildenafil clearance when co-administered with beta-blockers. Sildenafil exposure at a dose of 80 mg three times a day without concomitant medication is shown to be 5-fold the exposure at a dose of 20 mg three times a day.
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This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir).CYP3A4 InducersConcomitant administration of potent CYP3A inducers is expected to cause substantial decreases in plasma levels of sildenafil.Population pharmacokinetic analysis of data from patients in clinical trials indicated approximately 3-fold the sildenafil clearance when it was co-administered with mild CYP3A inducers.EpoprostenolThe mean reduction of sildenafil (80 mg three times a day) bioavailability when co-administered with epoprostenol was 28%, resulting in about 22% lower mean average steady-state concentrations.
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