DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility
The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram VALTREX given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.
Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.
In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.
Valacyclovir was mutagenic in a mouse micronucleus assay.
Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.
Pregnancy
Teratogenic Effects
Pregnancy Category B. Valacyclovir was not teratogenic in rats or rabbits at 10 and 7 times human plasma levels, respectively, during the period of major organogenesis.
There are no adequate and well-controlled studies of VALTREX or ZOVIRAX in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. VALTREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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