d in breast milk.
Metabolism
Valsartan: The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism.
Hydrochlorothiazide: Is not metabolized.
Excretion
Valsartan: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.
Following intravenous administration, plasma clearance of valsartan is about 2L/h and its renal clearance is 0.62L/h (about 30% of total clearance).
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24hours. The elimination half-life is between 5.8 and 18.9hours.
13NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Valsartan-Hydrochlorothiazide: No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. However, these studies have been conducted for valsartan as well as hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide.
Valsartan: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2years at doses up to 160 and 200mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320mg/day and a 60-kg patient.)
Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests withSalmonella(Ames) and E. coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.
Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200mg/kg/day. This dose is about 6times the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320mg/day and a 60-kg patient.)
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 TA 98, 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 leth |
