Label: SILDENAFIL tablet
Severe impairment has not been studied [seeClinical Pharmacology (12.3)]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [seeClinical Pharmacology (12.3)].
| Interacting Drug / Substance | Effect | Clinical Advice |
|---|---|---|
| Nitrates | Severe hypotension | Do not combine |
| Alpha-blockers | Possible hypotension | Use with caution |
| CYP3A4 inhibitors (e.g., ketoconazole) | Increased sildenafil levels | Adjust dosage accordingly |
10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.In cases of overdose, standard supportive measures should be adopted as required.
Sildenafil may not be suitable for you if you:
Sildenafil tablets, USP are formulated as white to off-white, round shaped film-coated tablets for oral administration. 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 vitrohave shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 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.
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 [seeClinical Pharmacology (12.2)].In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 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 MeasuresAdultsPatients 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 citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown.Table 2: 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 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.
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In cases of overdose, standard supportive measures should be adopted as required. Sildenafil is also marketed as VIAGRA ®for erectile dysfunction.Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil tablets, USP are formulated as white to off-white, round shaped film-coated tablets for oral administration. Each tablet contains sildenafil citrate, USP equivalent to 20 mg of sildenafil. Sildenafil is also marketed as VIAGRA ®for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil tablets, USP are formulated as white to off-white, round shaped film-coated tablets for oral administration. 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 vitrohave shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 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).
| Contraindication | Explanation | Notes |
|---|---|---|
| Use with Nitrates | Can cause severe hypotension | Avoid concurrent use |
| Severe Cardiovascular Disease | Increased risk of adverse events | Consult a doctor before use |
| Hypotension (<90/60 mmHg) | Risk of dangerously low blood pressure | Avoid use in hypotensive patients |
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 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 [seeClinical Pharmacology (12.2)].In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 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 MeasuresAdultsPatients 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 citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown.Table 2: 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 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 women sildenafil 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.
- Patients should avoid grapefruit or grapefruit juice while taking sildenafil tablets.
- Consult your doctor if you experience persistent pain or vision changes.
- Sildenafil tablets can be part of a broader treatment plan including lifestyle changes.
Larger effects were recorded among patients receiving concomitant nitrates [seeContraindications (4)].Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (ECG).
| Brand Name | Manufacturer | Available Dosages | Price Range (USD) |
|---|---|---|---|
| Viagra | Pfizer | 25mg, 50mg, 100mg | $10 - $50 per pill |
| Revatio | Pfizer | 20mg | Used for pulmonary hypertension |
| Sildenafil Generic | Various manufacturers | 25mg, 50mg, 100mg | $1 - $5 per pill |
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 9.0 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. 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. 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%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is 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%.
What other information should I know?
Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Pediatric PatientsPediatric use information is approved for Viatris Specialty LLC’s, REVATIO (sildenafil) tablets. However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information.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, 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. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues.
How should I take sildenafil?
Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. 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. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitropotency 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.
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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 oral 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. There was also a doubling of C minlevels compared to healthy volunteers. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins.
8.7 Patients with Renal Impairment
The decrease women sildenafil 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 [seeContraindications (4)].Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on electrocardiogram (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 9.0 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina.
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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. 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%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is 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%. 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. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitropotency for PDE-5 approximately 50% of the parent drug.
- Use caution when driving or operating machinery after taking sildenafil tablets.
- Avoid excessive alcohol consumption when using sildenafil tablets, as it can increase side effects.
- Consult your doctor before taking sildenafil if you have heart issues or low blood pressure.
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 oral 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. There was also a doubling of C minlevels compared to healthy volunteers.
5.1 Hypotension
Severe impairment has not been studied [seeClinical Pharmacology (12.3)]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [seeClinical Pharmacology (12.3)]. 10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased.
Allergy warning
In cases of overdose, standard supportive measures should be adopted as required. Sildenafil is also marketed as VIAGRA ®for erectile dysfunction.Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil tablets, USP are formulated as white to off-white, round shaped film-coated tablets for oral administration. Each tablet contains sildenafil citrate, USP equivalent to 20 mg of sildenafil. Sildenafil is also marketed as VIAGRA ®for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with PAH compared to healthy volunteers.Pediatric PatientsPediatric use information is approved for Viatris Specialty LLC’s, REVATIO (sildenafil) tablets. However, due to Viatris Specialty LLC’s marketing exclusivity rights, this drug product is not labeled with that information.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, 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.
