al, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies with amlodipine/valsartan/hydrochlorothiazide: No carcinogenicity, mutagenicity or fertility studies have been conducted with this combination. However, these studies have been conducted for amlodipine, valsartan and hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any toxicologically significant adverse interaction between these components.
Studies with amlodipine:Rats and mice treated with amlodipine maleate in the diet for up totwo years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mgamlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse,the highest dose was, on mg/m2basis, similar to the maximum recommended human dose[MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, abouttwo and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects ateither the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day(about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
Studies with valsartan:There was no evidence of carcinogenicity when valsartan wasadministered in the diet to mice and rats for up to 2 years at concentrations calculated toprovide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats areabout 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m2basis.(Calculations based on a 60 kg patient.)
Mutagenicity assays did not reveal any valsartan-related effects at either the gene orchromosome level. These assays included bacterial mutagenicity tests with Salmonella and E.coli, a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinesehamster ovary cells, and a rat micronucleus test.
Valsartan had no adverse effects on the reproductive performance of male or female rats atoral doses of up to 200 mg/kg/day. This dose is about 6 times the maximum recommendedhuman dose on a mg/m2basis.
Studies with hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600mg/kg/day) or in male and female rats (at doses of up to approximately 100mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays and in the Aspergillus Nidulans non-disjunction assay.
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