In vitro studies

Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9. Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)] . 

In vivo studies

Potent CYP3A4 inhibitors

Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil AUC and a 4-fold increase in maximum concentration (C max) when co-administered with vardenafil hydrochloride tablets (5 mg) in healthy volunteers. A 5-mg vardenafil hydrochloride tablet dose should not be exceeded in a 24-hour period when used in combination with 200 mg once daily ketoconazole. Since higher doses of ketoconazole (400 mg daily) may result in higher increases in C max and AUC, a single 2.5 mg dose of vardenafil hydrochloride tablets should not be exceeded in a 24-hour period when used in combination with ketoconazole 400 mg daily. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] 

Indinavir (800 mg t.i.d.) co-administered with vardenafil hydrochloride tablets 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life. It is recommended not to exceed a single 2.5 mg vardenafil hydrochloride tablets dose in a 24-hour period when used in combination with indinavir. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2).] 

Ritonavir (600 mg b.i.d.) co-administered with vardenafil hydrochloride tablets 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13­ fold increase in vardenafil C max. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 26 hours. Consequently, it is recommended not to exceed a single 2.5 mg vardenafil hydrochloride tablets dose in a 72-hour period when used in combination with ritonavir. [See Dosage and Administration (2.4) and Warnings and Precautions (5.2).] . 

Moderate CYP3A4 inhibitors

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C max when co­ administered with vardenafil hydrochloride tablets 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of vardenafil hydrochloride tablets in a 24-hour period when used in combination with erythromycin. [See Dosage and Administration (2.4) and Warnings and Precautions (5).] 

Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.

Other Drug Interactions

No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine. In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Cimetidine (400 mg b.i.d.) had no effect on vardenafil bioavailability (AUC) and maximum concentration (C max) of vardenafil when co-administered with 20 mg vardenafil hydrochloride tablets in healthy volunteers.