Carcinogenicity studies in rats were negative; 24-month studies in mice showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested which ranged from approximately 5 to 8 times the average steady-state plasma concentrations in humans during prophylaxis of malaria. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the Mouse Lymphoma mutagenesis assay, and the Cultured Human Lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.
No evidence of a carcinogenic effect was observed in 24-month studies conducted in CD-1 mice (doses up to 1.5 times the average systemic human exposure based on AUC) and in Wistar Hannover rats (doses up to 1.1 times the average systemic human exposure).
Proguanil was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay and the Mouse Lymphoma mutagenesis assay. No evidence of genotoxicity was observed in the in vivo Mouse Micronucleus assay.
Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil, a dihydrofolate reductase inhibitor, were significantly reduced or abolished with folinic acid supplementation.
Genotoxicity studies have not been performed with atovaquone in combination with proguanil. Effects of MALARONE on male and female reproductive performance are unknown.