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RAPAMUNE® (sirolimus) Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings.

Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

When female rats were treated by oral gavage with sirolimus and mated to untreated males, female fertility was decreased at 0.5 mg/kg (2.5-fold the clinical dose of 2 mg, on a body surface area basis) due to decreased implantation. In addition, reduced ovary and uterus weight were observed. The NOAEL for female rat fertility was 0.1 mg/kg (0.5-fold the clinical dose of 2 mg).

When male rats were treated by oral gavage with sirolimus and mated to untreated females, male fertility was decreased at 2 mg/kg (9.7-fold the clinical dose of 2 mg, on a body surface area basis). Atrophy of testes, epididymides, prostate, seminiferous tubules, and reduced sperm counts were observed. The NOAEL for male rat fertility was 0.5 mg/kg (2.5-fold the clinical dose of 2 mg).

Testicular tubular degeneration was also seen in a 4-week intravenous study of sirolimus in monkeys at 0.1 mg/kg (1-fold the clinical dose of 2 mg, on a body surface area basis).

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