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DIOVAN HCT(valsartan and hydrochlorothiazide) tablet, film c(十五)
al trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300mcgm/mL, and in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4mg/kg, respectively, prior to mating and throughout gestation.These doses of hydrochlorothiazide in mice and rats represent 19 and 1.5times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 25mg/day and a 60-kg patient.)
13.3Developmental Toxicity StudiesValsartan-Hydrochlorothiazide: There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100 and 10mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31 and 3mg/kg/day. These non-teratogenic doses in mice, rats and rabbits, respectively, represent 9, 3.5 and 0.5 times the maximum recommended human dose (MRHD) of valsartan and 38, 13 and 2 times the MRHD of hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide and a 60-kg patient.)
Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of ≥200 and 10mg/kg/day, respectively, in combination with hydrochlorothiazide doses of ≥63 and 3mg/kg/day. Fetotoxicity in rats was considered to be related to decreased fetal weights and included fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Fetotoxicity in rabbits included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses and decreased number of live fetuses. The no observed adverse effect doses in mice, rats and rabbits for valsartan were 600, 100 and 3mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 188, 31 and 1mg/kg/day. These no adverse effect doses in mice, rats and rabbits, respectively, represent 9, 3 and 0.18 times the MRHD of valsartan and 38, 13 and 0.5 times the MRHD of hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide and a 60-kg patient.)
Valsartan: No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6 and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patien |
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