13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.

In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.

No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.

13.2 Animal Toxicology and/or Pharmacology

CNS Toxicity

CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.

A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52-day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately ≥1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (≥250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.