Sildenafil metabolism is principally mediated by the cytochrome-450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce Sildenafil clearance. Pharmacokinetic analysis of clinical trial data indicated a reduction in Sildenafil clearance when co-administered with CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific CYP inhibitor, when co-administered with Sildenafil (50 mg) caused a 56% increase in plasma Sildenafil concentrations in healthy volunteers. When a single 100-mg dose of Sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at a steady state (500 mg twice daily for 5 days), there was a 182% increase in Sildenafil systemic exposure (AUC). In addition, co-administration with the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a steady state (1200 mg thrice daily) resulted in a 140% increase in Sildenafil Cmax and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P-450 inhibitor at a steady slate (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. Sildenafil had no effect on ritonavir pharmacokinetics. Stronger CYP3A4 inhibitors (e.g. ketoconazole and itraconazole) would be expected to have greater effects. 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/aluminum hydroxide) did not affect the bioavailability of Sildenafil.
Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (e.g. tolbutamide, warfarin), CYP2D6 inhibitors (e.g. selective serotonin re-uptake inhibitors, tricyclic anti-depressants), thiazide and related diuretics, angiotensin-converting enzyme (ACE inhibitors and calcium-channels blockers).
In normal 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.
Other Drugs: In vitro studies, Sildenafil is a weak inhibitor of the cytochrome P-450 isoforms 1A2, 2G9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 micromole). Given Sildenafil peek plasma concentrations of approximately 1 micromole 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 effects 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 highly contraindicated.
In three specific drug-drug interaction studies, the α-blocker doxazosin (4 and 8 mg) and Sildenafil (25, 50 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 mm Hg, 9/5 mm Hg and 8/4 mm Hg, respectively, were observed. When Sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazoxin 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 a-blocker therapy may lead to symptomatic hypotension in sensitive individuals.
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/negative effect profile in patients taking Sildenafil with and without antihypertensive medication.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with maximum blood alcohol levels of 0.08% (80 mg/dL).