Moderate CYP3A4 inhibitors  

 

Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with LEVITRA 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of LEVITRA 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 (Cmax) of vardenafil when co-administered with 20 mg LEVITRA in healthy volunteers.

 

7.3 Effects of Vardenafil on Other Drugs

 

In vitro studies

 

Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar). Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing. The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 Cmax values after an 80 mg vardenafil dose.

 

In vivo studies 

 

Nifedipine: Vardenafil 20 mg, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the AUC or Cmax of nifedipine, a drug that is metabolized via CYP3A4. Nifedipine did not alter the plasma levels of LEVITRA when taken in combination. In these patients whose hypertension was controlled with nifedipine, LEVITRA 20 mg produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mmHg compared to placebo.

 

Ritonavir and Indinavir: Upon concomitant administration of 5 mg of LEVITRA with 600 mg BID ritonavir, the Cmax and AUC of ritonavir were reduced by approximately 20%. Upon administration of 10 mg of LEVITRA with 800 mg TID indinavir, the Cmax and AUC of indinavir were reduced by 40% and 30%, respectively.

 

Aspirin: LEVITRA (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

 

Other interactions: LEVITRA had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B