t.)
Hydrochlorothiazide: Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats represent 608 and 405 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)
14CLINICAL STUDIES
14.1 Hypertension
Valsartan-Hydrochlorothiazide: In controlled clinical trials including over 7600 patients, 4372 patients were exposed to valsartan (80, 160 and 320mg) and concomitant hydrochlorothiazide (12.5 and 25mg). Two factorial trials compared various combinations of 80/12.5mg, 80/25mg, 160/12.5mg, 160/25mg, 320/12.5mg and 320/25mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14-21/8-11mmHg at 80/12.5mg to 320/25mg, compared to 7-10/4-5mmHg for valsartan 80mg to 320mg and 5-11/2-5mmHg for hydrochlorothiazide 12.5mg to 25mg, alone.
Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80mg to valsartan 320mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4-12/2-5mmHg.
The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.
In long-term follow-up studies (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide appeared to be maintained for up to two years. The antihypertensive effect is independent of age or gender. The overall response to the combination was similar for Black and non-Black patients.
There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.
Valsartan: The antihypertensive effects of valsartan were demonstrated principally in 7placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160mg/day; comparison of peak and trough effects; comparison (in pooled data) of resonse by gender, age, and race; and eva luation of incremental effects of hydrochlorothiazide.
Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2hours, and maximum reduction of blood pressure is achieved within 6hours. The antihypertensive effect persists for 24hours after dosing, but there is a decrease from peak effect at lower doses (40mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained afte |
