Olvion Drug Interactions

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.
In Vivo Studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-administered with CYP3A4 inhibitors (eg, 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 specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure area under the curve (AUC). In addition, co-administration of the HIV protease inhibitor saquinavir, also a CYP34A inhibitor, at steady state (1200 mg 3 times daily) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil peak plasma concentration (C_max) and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics (see Dosage & Administration). Stronger CYP3A4 inhibitors eg, ketoconazole and itraconazole would be expected to have greater effects.
Co-administration of 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 C_max and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hrs, the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was administered 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).
Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism may give rise to modest increase in plasma levels of sildenafil.
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.
Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (eg, tolbutamide, warfarin), CYP2D6 inhibitors (eg, selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, angiotensin converting enzyme inhibitors and calcium channel blockers.
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, T_max, 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 micrometer).
Given sildenafil C_max of approximately 1 micrometer 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 3 specific drug-drug interaction studies, the α-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 lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking α-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals (see Dosage & Administration and Precautions).
No significant interactions were shown when sildenafil (50mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised 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 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 effects 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 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.
Incompatibilities: Not applicable.