Drugs Affecting Hepatic Microsomal Enzymes: Since sildenafil is metabolized via the hepatic cytochrome P450 (CYP450) enzymes 3A4 and 2C9, taking sildenafil with the following drugs which inhibit CYP may reduce sildenafil clearance and increase its plasma levels: CYP 3A4 and CYP2C9 inhibitors e.g., ritonavir (co-administration is not advised); Nonspecific CYP inhibitors, e.g., cimetidine; Specific CYP3A4 inhibitors, e.g., erythromycin and saquinavir; Stronger CYP3A4 inhibitors, e.g., ketoconazole or itraconazole; Weak inhibitors of CYP3A4, e.g., grapefruit juice.
On the other hand, CYP3A4 inducers such as rifampicin may decrease plasma sildenafil levels.
Co-administration of sildenafil 80 mg thrice a day (at steady state) and bosentan (moderate inducer of CYP3A4, CYP2C9, and possibly of cytochrome P450 2C19) 125 mg twice a day (at steady state) reduces the area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax) of sildenafil and increases the AUC and Cmax of bosentan.
A starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors.
Sildenafil has been shown to have no effect on the pharmacokinetics of tolbutamide and warfarin (CYP2C9 inhibitors) and the selective serotonin reuptake inhibitors and tricyclic antidepressants (CYP2D6 inhibitors).
Alpha-adrenergic Blockers: Concomitant administration of PDE5 inhibitors, including sildenafil, and alpha-adrenergic blockers (e.g., doxazosin, alfuzosin, prazosin, tamsulosin) can significantly lower blood pressure and lead to symptomatic hypotension (see Precautions).
Antihypertensive Agents: The risk of hypotension may be increased in patients taking sildenafil together with antihypertensive therapy and a CYP3A4 inhibitor.
Sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor) in vitro.
N-desmethyl sildenafil's AUC was increased by loop and potassium-sparing diuretics (62%) and non-specific beta blockers (102%). These effects on the metabolite are not expected to be of clinical significance.
Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component, it has the potential to have some serious interaction with sildenafil.
No effect on sildenafil pharmacokinetics have been observed when sildenafil is used with thiazide and related diuretics, angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers.
Alcohol: Use of sildenafil 50 mg did not potentiate the hypotensive effect of alcohol in healthy individuals.
Anti-Thrombotic Agents: Sildenafil is not expected to potentiate aspirin-induced increase in bleeding time.
Antacids: Administration with single doses of aluminum and magnesium hydroxide-containing antacids is not expected to affect the oral bioavailability of sildenafil.
Azithromycin: No effects on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite were observed when used concomitantly with azithromycin.
Other Therapies for Erectile Dysfunction: Combined use of sildenafil with other agents for erectile dysfunction is not recommended (see Precautions).
Concomitant use of sildenafil and heparin has been shown to have an additive effect on bleeding time in anesthesized rabbits; however, this interaction has not been studied in humans.