12 CLINICAL PHARMACOLOGY

Additive hypotensive effects may be anticipated when PDE type 5 inhibitors are administered concurrently with α-adrenergic blocking agents (e.g., terazosin, doxazosin, tamsulosin). [1] Stepwise increases in the dosage of the α-adrenergic blocking agent may further lower blood pressure when a PDE type 5 inhibitor is administered concurrently.

• 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.

[1] In several placebo-controlled crossover studies in patients with benign prostatic hyperplasia receiving doxazosin (4 or 8 mg daily) under steady-state conditions, administration of a single dose of sildenafil (50 or 100 mg) resulted in symptomatic hypotension (e.g., dizziness, lightheadedness, nausea, headache, fatigue) in some patients, occurring within approximately 0.5-4 hours of sildenafil administration. [1] Although symptomatic hypotension occurred in a few patients who received sildenafil 50 or 100 mg, syncope was not reported during these drug interaction studies.

Drug Label Information

[1] Caution is advised when PDE type 5 inhibitors are used concomitantly with an α-adrenergic blocking agent. [1] Patients should be hemodynamically stable on α-adrenergic blocking therapy prior to initiating therapy with a PDE type 5 inhibitor.

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[1] Patients who demonstrate hemodynamic instability on α-adrenergic blocking therapy are at increased risk of symptomatic hypotension with concomitant use of PDE type 5 inhibitors.

What Can Go Wrong with Sex time?

Additive hypotensive effects may be anticipated when PDE type 5 inhibitors are administered concurrently with α-adrenergic blocking agents (e.g., terazosin, doxazosin, tamsulosin). [1] Stepwise increases in the dosage of the α-adrenergic blocking agent may further lower blood pressure when a PDE type 5 inhibitor is administered concurrently. [1] In several placebo-controlled crossover studies in patients with benign prostatic hyperplasia receiving doxazosin (4 or 8 mg daily) under steady-state conditions, administration of a single dose of sildenafil (50 or 100 mg) resulted in symptomatic hypotension (e.g., dizziness, lightheadedness, nausea, headache, fatigue) in some patients, occurring within approximately 0.5-4 hours of sildenafil administration. [1] Although symptomatic hypotension occurred in a few patients who received sildenafil 50 or 100 mg, syncope was not reported during these drug interaction studies. [1] Caution is advised when PDE type 5 inhibitors are used concomitantly with an α-adrenergic blocking agent.

Sildenafil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

[1] Patients should be hemodynamically stable on α-adrenergic blocking therapy prior to initiating therapy with a PDE type 5 inhibitor. [1] Patients who demonstrate hemodynamic instability on α-adrenergic blocking therapy are at increased risk of symptomatic hypotension with concomitant use of PDE type 5 inhibitors. [1] In patients who are hemodynamically stable on α-adrenergic blocking therapy, PDE type 5 inhibitors should be initiated at the lowest recommended dose. [1] Conversely, in patients taking an optimized dose of a PDE type 5 inhibitor, therapy with an α-adrenergic blocking agent should be initiated at the lowest recommended dosage. [1] Incremental increases in the dosage of the α-adrenergic blocking agent during such concomitant therapy may be associated with a further lowering of blood pressure.

Allergy warning

[1] Safety of combination therapy with an α-adrenergic blocking agent may be affected by other variables, including intravascular volume depletion and concomitant use of other antihypertensive agents. Following administration of a single 100-mg sildenafil dose in hypertensive patients whose blood pressure was controlled with amlodipine 5 or 10 mg daily, mean supine blood pressure was reduced (systolic by 8 mm Hg, diastolic by 7 mm Hg). [1][29][154] The greatest decreases in supine systolic and diastolic blood pressures following sildenafil administration were in patients with the highest baseline blood pressures, suggesting that the likelihood of a hypotensive episode during combined use with amlodipine is low. While reported experience with use of sildenafil in HIV-infected patients receiving antiretroviral therapy is limited, clinically important pharmacokinetic interactions have been demonstrated when the drug was used concomitantly with ritonavir and saquinavir. [1][240] Pretreatment with saquinavir (1200-mg liquid-filled capsules [no longer commercially available in the US] 3 times daily) or ritonavir (500 mg twice daily) followed by a single dose of sildenafil (100 mg) increased sildenafil AUC by 210 or 1000%, respectively, and sildenafil peak plasma concentrations by 140 or 300%, respectively. [1] In patients who are hemodynamically stable on α-adrenergic blocking therapy, PDE type 5 inhibitors should be initiated at the lowest recommended dose. [1] Conversely, in patients taking an optimized dose of a PDE type 5 inhibitor, therapy with an α-adrenergic blocking agent should be initiated at the lowest recommended dosage. [1] Incremental increases in the dosage of the α-adrenergic blocking agent during such concomitant therapy may be associated with a further lowering of blood pressure.

How to Increase Bed-Time with Ayurveda Medicines

[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][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.

What are the most common side effects of sildenafil?

[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.

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[1] Safety of combination therapy with an α-adrenergic blocking agent may be affected by other variables, including intravascular volume depletion and concomitant use of other antihypertensive agents. Following administration of a single 100-mg sildenafil dose in hypertensive patients whose blood pressure was controlled with amlodipine 5 or 10 mg daily, mean supine blood pressure was reduced (systolic by 8 mm Hg, diastolic by 7 mm Hg). [1][29][154] The greatest decreases in supine systolic and diastolic blood pressures following sildenafil administration were in patients with the highest baseline blood pressures, suggesting that the likelihood of a hypotensive episode during combined use with amlodipine is low.

Mechanism of action

While reported experience with use of sildenafil in HIV-infected patients receiving antiretroviral therapy is limited, clinically important pharmacokinetic interactions have been demonstrated when the drug was used concomitantly with ritonavir and saquinavir. [1][240] Pretreatment with saquinavir (1200-mg liquid-filled capsules [no longer commercially available in the US] 3 times daily) or ritonavir (500 mg twice daily) followed by a single dose of sildenafil (100 mg) increased sildenafil AUC by 210 or 1000%, respectively, and sildenafil peak plasma concentrations by 140 or 300%, respectively. [1][85][136][137][139] In these patients receiving ritonavir and sildenafil, plasma concentrations at 24 hours were approximately 200 ng/mL compared with 5 ng/mL when sildenafil was given alone. [1][139] Sildenafil is only a weak inhibitor of CYP3A4 and CYP2D6 isoenzymes and single doses of the drug had no effect on steady-state saquinavir or ritonavir pharmacokinetics in healthy adults. A decrease in sildenafil clearance and a substantial increase in sildenafil concentrations also is expected with protease inhibitors alone or in combination with ritonavir (e.g., amprenavir , atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, tipranavir, darunavir). 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.

Packaging Type	Quantity	Notes
Blister Pack	4, 8, 12 pills	Common for individual doses
Bottle	30, 60, 90 pills	For ongoing treatment
Pediatric Packaging	Not applicable	Sildenafil for children not approved

[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%.

Side Effect	Severity	Frequency	Recommendations
Headache	Mild	Common	Take analgesics
Flushing	Mild	Common	Cool environment
Nasal Congestion	Mild	Sometimes	Use decongestants
Dizziness	Mild	Less common	Avoid sudden movements

[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 sildenafil 60mg single dose of sildenafil (50 mg) and aspirin (150 mg), sildenafil did not potentiate the aspirin-induced increase in bleeding time.

Proper Use

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.

Misconception	Reality	Explanation
Sildenafil cures erectile dysfunction	It does not cure, only treats symptoms	Helps achieve an erection, not a cure
Takes effect immediately	Usually takes 30-60 minutes	Depends on individual and food intake
Only for older men	Used by men of various ages	Suitable for adult men of different ages

[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 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.

5.8 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Disease

[1][85][136][137][139] In these patients receiving ritonavir and sildenafil, plasma concentrations at 24 hours were approximately 200 ng/mL compared with 5 ng/mL when sildenafil was given alone. [1][139] Sildenafil is only a weak inhibitor of CYP3A4 and CYP2D6 isoenzymes and single doses of the drug had no effect on steady-state saquinavir or ritonavir pharmacokinetics in healthy adults. A decrease in sildenafil clearance and a substantial increase in sildenafil concentrations also is expected with protease inhibitors alone or in combination with ritonavir (e.g., amprenavir , atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, tipranavir, darunavir). 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. 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.

Regional issues

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][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][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.

• Sildenafil tablets may interact with medications like alpha-blockers and certain antibiotics.
• Overdose symptoms include severe hypotension, headache, and visual disturbances.
• Always keep sildenafil tablets out of reach of children and pets.

[1] In the largest clinical study published to date, the onset and duration of action of oral sildenafil were not reported.

8.7 Patients with Renal Impairment

[1][138][239] Therefore, no dosage adjustments are required in patients receiving these drugs concomitantly. In a clinical trial combining a sildenafil 60mg 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.

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[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.

How does sildenafil work (mechanism of action)?

Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with 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. [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. [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.