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VIAGRA (SILDENAFIL CITRATE): DRUG INTERACTIONS

Effects of Other Drugs on Viagra (Sildenafil Citrate)

In vitro studies

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies

Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with Viagra (Sildenafil Citrate) tablets 50 mg to healthy volunteers.

When a single 100 mg dose of Sildenafil (Viagra) was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Sildenafil (Viagra) tablets 100 mg single dose resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil Citrate (Viagra) had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine).

In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with Sildenafil Citrate (Viagra) tablets 100 mg single dose resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Viagra had no effect on ritonavir pharmacokinetics.

Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

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 cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of Viagra (Sildenafil).

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of Viagra (Sildenafil) Tablets on Other Drugs

In vitro studies

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 mM). Given sildenafil peak plasma concentrations of approximately 1 mM after recommended doses, it is unlikely that Viagra (Sildenafil Citrate) will alter the clearance of substrates of these isoenzymes.

In vivo studies

Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Viagra (Sildenafil Citrate) tablets with doxazosin, an alpha-adrenergic blocking agent.

In the first study, a single oral dose of Sildenafil (Viagra) 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, Sildenafil (Viagra) tablets 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the dose of this drug was reduced to 25 mg. Thereafter, 17 subjects were treated with Sildenafil Citrate (Viagra) tablets 25 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8mg (2 subjects). The mean subject age was 66.5 years.

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after Viagra or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of < 85 mmHg or a decrease from baseline in standing systolic blood pressure of > 30 mmHg at one or more timepoints. There were no subjects treated with Viagra tablets 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP > 30mmHg following Viagra (Sildenafil) 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both Viagra (Sildenafil) tablets and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received Viagra (Sildenafil Citrate) 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with Viagra (Sildenafil Citrate) tablets with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.

In the second study, a single oral dose of Sildenafil (Viagra) 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, Sildenafil (Viagra) tablets 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received Sildenafil Citrate (Viagra) 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with Sildenafil Citrate (Viagra) tablets 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

Blood pressure was measured after administration of Viagra tablets at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of Viagra (Sildenafil) 50 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP > 30mmHg following Viagra (Sildenafil) tablets 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both Viagra (Sildenafil Citrate) 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.

In the third study, a single oral dose of Viagra (Sildenafil Citrate) tablets 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of Sildenafil (Viagra) 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using Viagra 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, Sildenafil (Viagra) 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. The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened. 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 Citrate (Viagra) 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 Viagra 50 mg).

Blood pressure was measured after administration of Sildenafil Citrate (Viagra) tablets at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking Viagra 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 > 30mmHg following Viagra (Sildenafil) 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 Viagra (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 Viagra (Sildenafil Citrate) 50 mg and 100 mg. There were no episodes of syncope reported in this study.

When Viagra (Sildenafil Citrate) 100 mg oral tablets was coadministered 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.

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

Sildenafil (Viagra) 50 mg did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil (Viagra) tablets 50 mg did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

Sildenafil at steady state (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan (125 mg b.i.d.).

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