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Effects of other medicinal products on sildenafil: 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: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine).
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 sildenafil (50 mg) to healthy volunteers.
When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady-state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady-state (1200 mg three times daily) 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 (see Dosage & Administration). Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have greater effects.
Co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady-state (500 mg twice daily) 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 ritonavir's marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics see Dosage & Administration.
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.
Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.
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.
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.
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 major circulating metabolite.
Effects of sildenafil on other medicinal products: In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 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 sildenafil will alter the clearance of substrates of these isoenzymes.
In vivo studies: Sildenafil was shown to potentiate the hypotensive effect of acute and chronic nitrates. Therefore, use of nitric oxide donors, organic nitrates, or organic nitrites in any form either regularly or intermittently with sildenafil is contraindicated (see Contraindications).
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, 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 light-headedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals (see Dosage & Administration and Precautions).
No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (100 mg) did not affect the steady-state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates (see previously mentioned, Effects of other medicinal products on sildenafil).
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 previously mentioned, Effects of other medicinal products on sildenafil).
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08% (80 mg/dL).
No interaction was seen when sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients. The mean additional reduction on supine systolic blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
Analysis of the safety database showed no difference in the side effect profile in patients taking sildenafil with and without antihypertensive medication.
