Pravachol - Patient Info

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CNS Toxicity

CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononu-clear 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 human dose 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 mea-sured 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.

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/ m 2 and at approximately 4 times the human dose, 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 human dose 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 human dose 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 con-version assay using Saccharomyces cerevisiae.