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VIAGRA (sildenafil citrate) Drug Interactions

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Drug Interactions

Serious Drug Interactions
 

  • Use of organic nitrates in any form is absolutely contraindicated (see Contraindications section)

Overview

In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route) (see ACTION AND CLINICAL PHARMACOLOGY). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50>150 μM). Given sildenafil peak plasma concentrations of approximately 1 μM after recommended doses, it is unlikely that VIAGRA will alter the clearance of the substrates of these isoenzymes.

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

Drug-Drug Interactions

Effects of Other Drugs on VIAGRA
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, angiotensin converting enzyme (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.

In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principle circulating metabolite.

CYP3A4 Inhibitors
The concomitant use of potent cytochrome P-450 3A4 inhibitors (e.g. erythromycin, saquinavir, ritonavir, ketoconazole, itraconazole) as well as the non-specific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY).

When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg b.i.d. for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).

When the dose of sildenafil for subjects receiving potent CYP3A4 inhibitors was administered as recommended, the maximum free plasma sildenafil concentration did not exceed 200 nM for any individual and was consistently well tolerated.

In a study of healthy male volunteers, co-administration of the endothelin antagonist bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Sildenafil increased bosentan AUC and Cmax by 49.8% and 42%, respectively. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma concentrations of sildenafil.

Cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers.

Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). However, there was no increased incidence of adverse events in these patients.

HIV Protease Inhibitor
In addition, coadministration of the HIV protease inhibitor saquinavir, also CYP3A4 inhibitor, at steady state (1200 mg t.i.d) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole, itraconazole would be expected to have still greater effects (see DOSAGE AND ADMINISTRATION).

Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P-450 inhibitor, at steady state (500 mg b.i.d) with sildenafil (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 the marked effects of ritonavir on a broad range of P-450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION).

CYP3A4 Inducers
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.

CYP2C9 Substrate
No significant interactions were shown with tolbutamide (single 250 mg dose) or warfarin (single 40 mg dose), both of which are metabolized by CYP2C9, when co-administered with 50 mg sildenafil.

Antacids
In normal healthy male volunteers, co-administration of single doses of antacid (magnesium hydroxide/aluminium hydroxide) with sildenafil did not affect the AUC, Cmax, elimination rate constant, or subsequent half-life of sildenafil. The Tmax was reduced by 0.42 hours.

Effect of VIAGRA on Other Drugs

Alpha-blockers
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, for 25 mg, 50 mg, or 100 mg respectively, were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals (see WARNINGS AND PRECAUTIONS).

Some alpha-blockers and antidepressants have reported priapism or prolonged/painful erections in their labels.

Bleeding Time
VIAGRA (50 mg) did not potentiate the increase in bleeding time, measured using a standard simplate method, caused by acetylsalicylic acid (150 mg).

Use with Other Concomitant Therapies:

Antihypertensives
When VIAGRA (100 mg) was co-administered with amlodipine, 5 mg or 10 mg, in hypertensive patients, the mean additional reduction of supine blood pressure was 8 mm Hg systolic and 7 mm Hg diastolic (see ACTION AND CLINICAL PHARMACOLOGY).

Patients on multiple antihypertensive medications were included in the pivotal clinical trials for VIAGRA (sildenafil citrate). Analysis of the safety database was carried out after pooling of the following classes of antihypertensive medication: diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive medicinal products (vasodilator and centrally-acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenoceptor blockers. The analysis showed no differences in the adverse effect profile of patients taking VIAGRA with and without antihypertensive medication.

A large controlled study was performed in men with erectile dysfunction and arterial hypertension who were taking combinations of diuretics, beta blockers, ACE inhibitors and calcium channel blockers. The incidence rate of all adverse events, including those possibly related to hypotensive episodes, was consistent with observations in other patient populations. Also, there was no evidence of an increased incidence rate of any adverse event in the subgroups taking 2 antihypertensive agents and 3 or more antihypertensive agents. There was no indication of additional safety risk of sildenafil use in this subject population (see DETAILED PHARMACOLOGY).

Bosentan
Sildenafil at steady state (80 mg three times a day) resulted in a 49.8% increase in bosentan AUC and a 42% increase in bosentan Cmax (125 mg twice a day) (see DRUGS INTERACTIONS).

Drug-Food Interactions

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increases in plasma levels of sildenafil.

VIAGRA (sildenafil citrate) can be taken with or without food. However, when VIAGRA is taken with a high-fat meal, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. AUC is decreased by 11%. The patient may find that it takes longer to work if taken with a high-fat meal (see ACTION AND CLINICAL PHARMACOLOGY).