Renal Impairment 

 

In male volunteers with CLcr = 50–80 mL/min, the pharmacokinetics of vardenafil were similar to those observed in a control group with CLcr >80 mL/min. In male volunteers with CLcr = 30–50 mL/min or CLcr<30 mL/min renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in a control group with CLcr>80 mL/min). Vardenafil pharmacokinetics have not been eva luated in patients requiring renal dialysis. [See Dosage and Administration (2.3), Warnings and Precautions (5.9), and Use in Specific Populations (8.7).] 

 

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

 

Carcinogenesis

 

Vardenafil was not carcinogenic in rats and mice when administered daily for 24 months. In these studies systemic drug exposures (AUCs) for unbound (free) vardenafil and its major metabolite were approximately 400- and 170-fold for male and female rats, respectively, and 21- and 37-fold for male and female mice, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg. 

 

Mutagenesis

 

Vardenafil was not mutagenic as assessed in either the in vitro bacterial Ames assay or the forward mutation assay in Chinese hamster V79 cells. Vardenafil was not clastogenic as assessed in either the in vitro chromosomal aberration test or the in vivo mouse micronucleus test. 

Impairment of Fertility

 

Vardenafil did not impair fertility in male and female rats administered doses up to 100 mg/kg/day for 28 days prior to mating in male, and for 14 days prior to mating and through day 7 of gestation in females. In a corresponding 1-month rat toxicity study, this dose produced an AUC value for unbound vardenafil 200 fold greater than AUC in humans at the MRHD of 20 mg.

14 CLINICAL STUDIES

 

LEVITRA was eva luated in four major double-blind, randomized, placebo-controlled, fixed-dose, parallel design, multicenter trials in 2431 men aged 20-83 (mean age 57 years; 78% White, 7% Black, 2% Asian, 3% Hispanic and 10% Other/Unknown). The doses of LEVITRA in these studies were 5 mg, 10 mg, and 20 mg. Two of these trials were conducted in the general erectile dysfunction (ED) population and two in special ED populations (one in patients with diabetes mellitus and one in post-prostatectomy patients). LEVITRA was dosed without regard to meals on an as needed basis in men with ED, many of whom had multiple other medical conditions. The primary endpoints were assessed at 3 months.

 

Primary efficacy assessment in all four major trials was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3).