Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t1/2) ranged from 8-16hours following oral administration.

Pharmacokinetics in Special Populations

Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children <6years of age, systemic exposure was about 50% lower than in adults.

Geriatric: The pharmacokinetics of deferasirox have not been studied in geriatric patients (65years of age or older).

Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Renal Insufficiency: Deferasirox is minimally (8%) excreted via the kidney.

Hepatic Impairment: Deferasirox is principally excreted by glucuronidation and is minimally (8%) metabolized by oxidative cytochrome P450 enzymes. Exjade treatment has been initiated in patients with baseline liver transaminase levels up to 5times the upper limit of the normal range. The pharmacokinetics of deferasirox were not influenced by such transaminase levels.

The average AUC of deferasirox in 6 subjects with mild hepatic impairment (Child-Pugh A) increased 16% over that found in 6 subjects with normal hepatic function, while the average AUC of deferasirox in 6 subjects with moderate hepatic impairment (Child-Pugh B) increased 76% over that found in 6 subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment increased 22% over that found in subjects with normal hepatic function. The impact of severe hepatic impairment (Child-Pugh C) was assessed in only one subject [see Dosage and Administration (2.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.7)].

12.6 QT Prolongation
The effect of 20 and 40mg/kg per day of deferasirox on the QTinterval was eva luated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTcinterval was observed in this study.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60mg/kg per day (0.48times the MRHD (Maximum Recommended Human Dose) on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200mg/kg per day (0.81times the MRHD on a mg/m2 basis) in males and 300mg/kg per day (1.21times the MRHD on a mg/m2 basis) in females.

Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1of3 in-viv