Sildenafil 50 mg: Onset of Action and Peak Effect

In patients receiving protease inhibitors alone or in combination with ritonavir or the HIV integrase strand transfer inhibitor (INSTI) elvitegravir in combination with cobicistat (CYP3A4 inhibitor), experts recommended that sildenafil dosage not exceed 25 mg every 48 hours for the treatment of ED. The nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, and etravirine may decrease sildenafil exposure via CY3A4 (and 2C19 for etravirine) induction, and experts state that sildenafil dose titration based upon clinical effect may be required.

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[1][250] Population pharmacokinetic analysis of data from clinical trials indicates that sildenafil clearance is reduced when the drug is administered concomitantly with CYP3A4 inhibitors such as ketoconazole.

• Sildenafil 50 mg tablets are used to treat erectile dysfunction.
• The medicine improves blood flow to the penis.
• Take sildenafil 50 mg 30-60 minutes before activity.
• Do not exceed one tablet per 24 hours.
• Common side effects include headache and flushing.
• Avoid consuming high-fat meals before taking it.
• Alcohol may reduce the effectiveness of the medication.
• Consult a doctor if you experience prolonged erections.

Because of the possibility of increased systemic exposure and adverse effects, it is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as ketoconazole or itraconazole. Bosentan, a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19, can increase sildenafil clearance and decrease plasma sildenafil concentrations. [1][212][241] In one study in healthy men, concomitant use of bosentan (125 mg twice daily) and sildenafil at a dose not approved for the treatment of erectile dysfunction (80 mg 3 times daily) resulted in a 63% decrease in AUC and a 55% decrease in peak plasma concentrations of sildenafil at steady state; AUC and peak plasma concentrations of bosentan were increased by 50 and 42%, respectively. [1][241] The clinical importance of this pharmacokinetic interaction is unclear. Concomitant administration of sildenafil and heparin in rabbits had an additive effect on bleeding time. [1] Although the possibility of a similar interaction in humans has not been studied specifically to date, there currently is no evidence that would preclude the use of heparin in sildenafil-treated patients if indicated. Pretreatment with erythromycin (500 mg twice daily for 5 days), a specific CYP3A4 inhibitor, increased the AUC of a single 100-mg dose of sildenafil by 182%. [1][69][239] It is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as erythromycin. No pharmacokinetic interaction has been observed to date between azithromycin (500 mg daily for 3 days) and sildenafil. [1][138][239] Therefore, no dosage adjustments are required in patients receiving these drugs concomitantly.

In a clinical trial combining a single dose of sildenafil (50 mg) and aspirin (150 mg), sildenafil did not potentiate the aspirin-induced increase in bleeding time. In an in vitro human platelet study, sildenafil potentiated the antiaggregatory effect of sodium nitroprusside. The possibility that concomitant administration of rifampin, a potent CYP3A4 inducer, could decrease plasma concentrations of sildenafil should be considered. Additive hypotensive effects can occur if riociguat is used concomitantly with PDE type 5 inhibitors. [1][247] In a study in patients with pulmonary arterial hypertension (PAH) who were receiving stable dosages of sildenafil (20 mg 3 times daily), administration of single doses of riociguat resulted in additive hemodynamic effects. [247] A high rate of drug discontinuance generally has been observed among patients receiving combination therapy with sildenafil and riociguat; at least one death, possibly related to the combined use of these drugs, has been reported. Because of the risk of hypotension, concomitant use of sildenafil and riociguat is contraindicated. The safety and efficacy of sildenafil in combination with other treatments for ED have not been established, and therefore such combined therapy currently is not recommended by the manufacturer. [67] No pharmacokinetic interaction has been observed between warfarin, a CYP2C9 substrate, and sildenafil. Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with blue sildenafil the greatest selectivity for PDE type 5, the principal isoenzyme of PDE involved in the metabolism of cyclic guanosine monophosphate (cGMP) to GMP in the corpora cavernosa of the penis. [1][2][4][5][7][8][10][24][27][33][41][42][54][56][57][67][87][88][91][131] Sildenafil has no direct relaxant effect on isolated human corpora cavernosa of the penis, but enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP.

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[1][116][131] Sildenafil is eliminated mainly in the feces as metabolites following oral administration. [1][67][91][116][131] In healthy adults and those with ED, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine. Importance of instructing patients to read the manufacturer's patient information before starting sildenafil therapy and each time their prescription is refilled. [1]Instruct patients to avoid contraindicated medications such as regular and/or intermittent use of organic nitrates, organic nitrites (e.g., ''poppers''), and riociguat. [1]Inform patients that sildenafil is marketed for erectile dysfunction (Viagra) and pulmonary arterial hypertension (Revatio®).

What should I do if I accidentally use too much sildenafil?

[1] Advise patients taking Viagra® not to take Revatio® or other PDE type 5 inhibitors. [1]Advise patients of the potential for sildenafil to augment the blood pressure lowering effect of α-adrenergic blocking agents (e.g., doxazosin) and anti-hypertensive medications (e.g., amlodipine) and concomitant administration may lead to symptomatic hypotension in some patients. [1]Inform patients taking sildenafil for erectile dysfunction and with potential for cardiac risk of sexual activity (e.g., patients with preexisting cardiovascular risk factors) to refrain from further activity and seek medical attention immediately if they experience symptoms (e.g., chest pain, dizziness, nausea) upon initiation of sexual activity.

Key takeaways

[1][2][4][5][7][8][10][33][41][42][127][131] During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpora cavernosa. [1][2][4][56][67][91][131] By selectively inhibiting PDE type 5, sildenafil causes accumulation of cGMP in various tissues. [1][2][4][5][31][33][34][41][42][56][57][67][91][131] Because sildenafil potentiates the accumulation of cGMP rather than stimulating its production, the drug is effective only when cGMP production in the penis is increased by sexual arousal. [34][91][131] Sildenafil at recommended doses has no effect on erectile function in the absence of sexual stimulation.

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In patients receiving protease inhibitors alone or in combination with ritonavir or the HIV integrase strand transfer inhibitor (INSTI) elvitegravir in combination with cobicistat (CYP3A4 inhibitor), experts recommended that sildenafil dosage not exceed 25 mg every 48 hours for the treatment of ED. The nonnucleoside reverse transcriptase inhibitors efavirenz, nevirapine, and etravirine may decrease sildenafil exposure via CY3A4 (and 2C19 for etravirine) induction, and experts state that sildenafil dose titration based upon clinical effect may be required. [1][250] Population pharmacokinetic analysis of data from clinical trials indicates that sildenafil clearance is reduced when the drug is administered concomitantly with CYP3A4 inhibitors such as ketoconazole. Because of the possibility of increased systemic exposure and adverse effects, it is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as ketoconazole or itraconazole. Bosentan, a moderate inducer of CYP3A4, CYP2C9, and possibly CYP2C19, can increase sildenafil clearance and decrease plasma sildenafil concentrations.

How should I store sildenafil?

[1][212][241] In one study in healthy men, concomitant use of bosentan (125 mg twice daily) and sildenafil at a dose not approved for the treatment of erectile dysfunction (80 mg 3 times daily) resulted in a 63% decrease in AUC and a 55% decrease in peak plasma concentrations of sildenafil at steady state; AUC and peak plasma concentrations of bosentan were increased by 50 and 42%, respectively. [1][241] The clinical importance of this pharmacokinetic interaction is unclear. Concomitant administration of sildenafil and heparin in rabbits had an additive effect on bleeding time. [1] Although the possibility of a similar interaction in humans has not been studied specifically to date, there currently is no evidence that would preclude the use of heparin in sildenafil-treated patients if indicated. Pretreatment with erythromycin (500 mg twice daily for 5 days), a specific CYP3A4 inhibitor, increased the AUC of a single 100-mg dose of sildenafil by 182%.

Vitamin K Antagonists

[1][69][239] It is recommended that a lower initial sildenafil dose (25 mg) be considered in patients with ED receiving potent CYP3A4 inhibitors such as erythromycin. No pharmacokinetic interaction has been observed to date between azithromycin (500 mg daily for 3 days) and sildenafil. [1][138][239] Therefore, no dosage adjustments are required in patients receiving these drugs concomitantly. In a clinical trial combining a single dose of sildenafil (50 mg) and aspirin (150 mg), sildenafil did not potentiate the aspirin-induced increase in bleeding time. In an in vitro human platelet study, sildenafil potentiated the antiaggregatory effect of sodium nitroprusside. [1][4][33][34][91][127][130][131][132] Sildenafil also exhibits some activity against other PDE isoenzymes.

• Sildenafil 50 mg is available by prescription only.
• Store tablets in a cool, dry place away from sunlight.
• Do not use with nitrate medications to prevent risk.
• Seek medical advice if you have heart problems.
• It may interact with other medications like antihypertensives.
• Not recommended for women or children.
• The tablet should be swallowed whole with water.
• Do not crush or chew the tablet.

[1][4][5][31][44][57][67][87][88] In vitro, sildenafil is about 10 times more active against PDE type 5 than against PDE type 6, greater than 70-80 times more active against PDE type 5 than against PDE type 1, greater than 1000 times more active against PDE type 5 than against PDE types 2 and 4, and 4000 times more active against PDE type 5 than against PDE type 3. [1][4][27][31][45][52][55][57][67][87][88] The duration of erectile responsiveness (i.e., the time period in which adequate sexual stimulation can produce an erection) with oral sildenafil has been reported to be approximately 2 hours, with some penile responsiveness persisting for up to 4 hours after oral administration. [1] In the largest clinical study published to date, the onset and duration of action of oral sildenafil were not reported. [33][34] In most other placebo-controlled studies in which improvement in erection was determined by penile plethysmography, the erectile effect was determined at a fixed time of 60 minutes after an oral dose of the drug. Sildenafil is rapidly absorbed following oral administration; sildenafil 100g the mean absolute bioavailability is 41% (range, 25-63%).

[1][4][56][67][91][116][249] Although studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged. [1][4][56][67][91][116][131][249] Pharmacokinetics of the drug (as determined by peak plasma concentrations or AUC) are dose proportional over the single-dose range of 1.25-200 mg.[1][4][56][91][116][131] Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults. [1][4][91][127][130][249] Administration with a high-fat meal delays GI absorption, with a reduction in peak plasma concentrations of about 29% and a delay in time to peak plasma concentrations of about 60 minutes; the extent of absorption is not affected. Sildenafil appears to be widely distributed in the body. [1][4][67][116][131] Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration.

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The possibility that concomitant administration of rifampin, a potent CYP3A4 inducer, could decrease plasma concentrations of sildenafil should be considered. Additive hypotensive effects can occur if riociguat is used concomitantly with PDE type 5 inhibitors. [1][247] In a study in patients with pulmonary arterial hypertension (PAH) who were receiving stable dosages of sildenafil (20 mg 3 times daily), administration of single doses of riociguat resulted in additive hemodynamic effects. [247] A high rate of drug discontinuance generally has been observed among patients receiving combination therapy with sildenafil and riociguat; at least one death, possibly related to the combined use of these drugs, has been reported. Because of the risk of hypotension, concomitant use of sildenafil and riociguat is contraindicated.

Drug Interactions

The safety and efficacy of sildenafil in combination with other treatments for ED have not been established, and therefore such combined therapy currently is not recommended by the manufacturer. [67] No pharmacokinetic interaction has been observed between warfarin, a CYP2C9 substrate, and sildenafil. Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with blue sildenafil the greatest selectivity for PDE type 5, the principal isoenzyme of PDE involved in the metabolism of cyclic guanosine monophosphate (cGMP) to GMP in the corpora cavernosa of the penis. [1][2][4][5][7][8][10][24][27][33][41][42][54][56][57][67][87][88][91][131] Sildenafil has no direct relaxant effect on isolated human corpora cavernosa of the penis, but enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP. [1][2][4][5][7][8][10][33][41][42][127][131] During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpora cavernosa.

Long-term use

[1][2][4][56][67][91][131] By selectively inhibiting PDE type 5, sildenafil causes accumulation of cGMP in various tissues. [1][2][4][5][31][33][34][41][42][56][57][67][91][131] Because sildenafil potentiates the accumulation of cGMP rather than stimulating its production, the drug is effective only when cGMP production in the penis is increased by sexual arousal. [34][91][131] Sildenafil at recommended doses has no effect on erectile function in the absence of sexual stimulation. [1][4][33][34][91][127][130][131][132] Sildenafil also exhibits some activity against other PDE isoenzymes. [1][4][5][31][44][57][67][87][88] In vitro, sildenafil is about 10 times more active against PDE type 5 than against PDE type 6, greater than 70-80 times more active against PDE type 5 than against PDE type 1, greater than 1000 times more active against PDE type 5 than against PDE types 2 and 4, and 4000 times more active against PDE type 5 than against PDE type 3. [1][67][91][116][131] Sildenafil is distributed to a limited extent in semen following oral administration, with less than 0.001% of a single dose appearing in semen 90 minutes after dosing in healthy individuals. [1][67] Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen. [67] Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours (range: 3-5 hours). [1][4][67][91][116][127][130][131] Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route).

See also:

[1][26][67][91][131] Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those observed with sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil's pharmacologic activity. [1][67][131] The N-demethylated metabolite, the major circulating metabolite, has a phosphodiesterase selectivity profile similar to that of sildenafil and an in vitro potency for PDE type 5 of approximately 50% of the parent drug. [1][116][131] Sildenafil is eliminated mainly in the feces as metabolites following oral administration. [1][67][91][116][131] In healthy adults and those with ED, approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine. Importance of instructing patients to read the manufacturer's patient information before starting sildenafil therapy and each time their prescription is refilled. [1]Instruct patients to avoid contraindicated medications such as regular and/or intermittent use of organic nitrates, organic nitrites (e.g., ''poppers''), and riociguat. [1]Inform patients that sildenafil is marketed for erectile dysfunction (Viagra) and pulmonary arterial hypertension (Revatio®). [1] Advise patients taking Viagra® not to take Revatio® or other PDE type 5 inhibitors.

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[1][4][27][31][45][52][55][57][67][87][88] The duration of erectile responsiveness (i.e., the time period in which adequate sexual stimulation can produce an erection) with oral sildenafil has been reported to be approximately 2 hours, with some penile responsiveness persisting for up to 4 hours after oral administration. [1] In the largest clinical study published to date, the onset and duration of action of oral sildenafil were not reported. [33][34] In most other placebo-controlled studies in which improvement in erection was determined by penile plethysmography, the erectile effect was determined at a fixed time of 60 minutes after an oral dose of the drug. Sildenafil is rapidly absorbed following oral administration; sildenafil 100g the mean absolute bioavailability is 41% (range, 25-63%). [1][4][56][67][91][116][249] Although studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged.

Before taking sildenafil,

[1][4][56][67][91][116][131][249] Pharmacokinetics of the drug (as determined by peak plasma concentrations or AUC) are dose proportional over the single-dose range of 1.25-200 mg.[1][4][56][91][116][131] Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults. [1][4][91][127][130][249] Administration with a high-fat meal delays GI absorption, with a reduction in peak plasma concentrations of about 29% and a delay in time to peak plasma concentrations of about 60 minutes; the extent of absorption is not affected. Sildenafil appears to be widely distributed in the body. [1][4][67][116][131] Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins; protein binding reportedly is independent of plasma concentration. [1][67][91][116][131] Sildenafil is distributed to a limited extent in semen following oral administration, with less than 0.001% of a single dose appearing in semen 90 minutes after dosing in healthy individuals.

Organic Nitrates, Nitrites, and Nitric Oxide Donors

[1][67] Such concentrations are unlikely to cause any effects in sexual partners exposed to the semen. [67] Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours (range: 3-5 hours). [1][4][67][91][116][127][130][131] Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route). [1][26][67][91][131] Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those observed with sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil's pharmacologic activity. [1][67][131] The N-demethylated metabolite, the major circulating metabolite, has a phosphodiesterase selectivity profile similar to that of sildenafil and an in vitro potency for PDE type 5 of approximately 50% of the parent drug. [1]Advise patients of the potential for sildenafil to augment the blood pressure lowering effect of α-adrenergic blocking agents (e.g., doxazosin) and anti-hypertensive medications (e.g., amlodipine) and concomitant administration may lead to symptomatic hypotension in some patients. [1]Inform patients taking sildenafil for erectile dysfunction and with potential for cardiac risk of sexual activity (e.g., patients with preexisting cardiovascular risk factors) to refrain from further activity and seek medical attention immediately if they experience symptoms (e.g., chest pain, dizziness, nausea) upon initiation of sexual activity.