DRUG INTERACTIONS

In dose period 1, subjects were administered open-label doxazosin and a single dose of sildenafil tablets 50 mg simultaneously, after at least 14 consecutive days of doxazosin. Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil tablets 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1.

• Common adverse reactions (≥2%) include headache, flushing, and dyspepsia.
• Nasal congestion, back pain, and myalgia are also frequently reported.
• Diarrhea, dizziness, and rash occur in a smaller percentage of users.
• Visual disturbances (color tinge, blurred vision) are dose-related.
• These effects are usually mild to moderate and transient in nature.
• Serious cardiovascular events are rare but possible, especially in at-risk patients.
• Priapism is a urological emergency that requires immediate treatment.
• Sudden hearing loss, often accompanied by tinnitus and dizziness, is rare.
• Allergic reactions, including skin rash and itching, can occur.
• There have been reports of seizures and anxiety in post-marketing experience.
• Most side effects diminish with continued use or dose adjustment.

Thereafter, sildenafil tablets 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil tablets 50 mg.

• 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.

Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil tablets 50 mg). For the 20 subjects who received sildenafil tablets 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil tablets or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. All three were taking sildenafil tablets 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil tablets 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil tablets 50 mg and 100 mg. Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil tablets 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Alcohol: Sildenafil tablets (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions(7.5)].

What special precautions should I follow?

In dose period 1, subjects were administered open-label doxazosin and a single dose of sildenafil tablets 50 mg simultaneously, after at least 14 consecutive days of doxazosin. Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil tablets 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Thereafter, sildenafil tablets 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil tablets 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil tablets 50 mg).

How does sildenafil work (mechanism of action)?

For the 20 subjects who received sildenafil tablets 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil tablets or matching placebo are shown in Figure 4. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the previous doxazosin studies. All three were taking sildenafil tablets 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil tablets 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil tablets 50 mg and 100 mg.

What is sildenafil used for?

Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil tablets 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Alcohol: Sildenafil tablets (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [see Drug Interactions(7.5)]. Effects of Sildenafil Tablets on Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of sildenafil tablets on cardiac output. Effects of Sildenafil Tablets on Cardiac Parameters:Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of sildenafil tablets on cardiac output. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil tablets on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil Tablets on Vision:At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination 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 twice the maximum recommended dose revealed no effects of sildenafil tablets on sildenafil syrup visual acuity, intraocular pressure, or pupillometry. Effects of Sildenafil Tablets on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil tablets in healthy volunteers.

Sildenafil tablets are rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). Absorption and Distribution: Sildenafil tablets are rapidly absorbed. When sildenafil tablets are 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%.

See also:

Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil tablets on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil Tablets on Vision:At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination 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 twice the maximum recommended dose revealed no effects of sildenafil tablets on sildenafil syrup visual acuity, intraocular pressure, or pupillometry. Effects of Sildenafil Tablets on Sperm:There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil tablets in healthy volunteers.

Why it’s used

Sildenafil tablets are rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). Absorption and Distribution: Sildenafil tablets are rapidly absorbed. When sildenafil tablets are 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%. Metabolism and Excretion:Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. Pharmacokinetics in Special Populations 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 to 45 years).

Pregnancy Categories

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 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil tablets (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared 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 C maxvalues significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with 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 C max(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)]. Metabolism and Excretion:Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. Pharmacokinetics in Special Populations 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 to 45 years).

• The future of sildenafil includes research into new therapeutic areas.
• Investigations are ongoing for its use in heart failure with preserved ejection fraction.
• Studies examine its potential benefits in Alzheimer's disease and vascular dementia.
• Its application in jet lag and sleep cycle disorders is being explored.
• Research continues for its use in various forms of female sexual dysfunction.
• Novel delivery systems, like microneedle patches, are in preclinical development.
• Combination therapies with other agents for enhanced effect are being tested.
• The search for more selective PDE5 inhibitors with fewer side effects continues.
• Genetic factors influencing drug response are an area of pharmacogenomic research.
• Sildenafil remains a valuable tool for basic research in vascular biology.
• Its story is a continuing one of scientific discovery and application.

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 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil tablets (50 mg) were not altered.

In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared 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 C maxvalues significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with 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 C max(47%) compared to age-matched volunteers with no hepatic impairment.

How to take liquid

Drug Interaction Studies Effects of Other blue sildenafil Drugs on Sildenafil Tablets Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil tablets (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil tablets were administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand 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 sildenafil tablets (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. 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)].

13.1 Carcinogenesis & Mutagenesis & Impairment of Fertility

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 sildenafil tablets (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC. Sildenafil tablets had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4)and Drug Interactions (7.4)]. 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 C max. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil tablets. Effects of Sildenafil Tablets on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM).

8.1 Pregnancy: Teratogenic effects

Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil tablets will alter the clearance of substrates of these isoenzymes. In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil tablets (50 mg) did not potentiate the increase in bleeding time caused 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 C maxof bosentan (125 mg b.i.d.). Carcinogenesis 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. 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)]. Drug Interaction Studies Effects of Other blue sildenafil Drugs on Sildenafil Tablets Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil tablets (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil tablets were administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand 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 sildenafil tablets (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. 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 sildenafil tablets (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC.

• Numerous clinical guidelines mention the use of sildenafil for ED and PAH.
• The American Urological Association (AUA) guidelines include sildenafil as first-line therapy.
• The European Association of Urology (EAU) guidelines provide similar recommendations.
• For PAH, guidelines from the ACCP and ESC/ERS recommend PDE5 inhibitors.
• Sildenafil is often recommended as monotherapy or in combination for PAH.
• Guidelines emphasize the importance of patient assessment and counseling.
• They recommend starting with the lowest effective dose and titrating as needed.
• Guidelines caution against use in patients with cardiovascular instability.
• Regular follow-up is recommended to assess efficacy and adverse effects.
• Treatment should be part of a comprehensive management plan for the condition.
• Guidelines are regularly updated as new evidence emerges from clinical trials.

Sildenafil tablets had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4)and Drug Interactions (7.4)].

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 C max. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil tablets. Effects of Sildenafil Tablets on Other Drugs In vitro studies: Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM).

1. Indications and Usage for Sildenafil Tablets

Sildenafil was not carcinogenic when administered to mice for 18 to 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.

Less common

Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that sildenafil tablets will alter the clearance of substrates of these isoenzymes. In vivo studies: No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Sildenafil tablets (50 mg) did not potentiate the increase in bleeding time caused 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 C maxof bosentan (125 mg b.i.d.). Carcinogenesis 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 to 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.