)] basis, these doses are, respectively, 4.3 and 2.7 times the systemic exposure [AUC(0-∞)] in humans receiving the MRHD (10/320 mg/60 kg).
Studies with valsartan and 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 are, respectively, 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 amg/m2 basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide in a 60-kg patient.)
Fetotoxicity was observed in association with maternal toxicity in rats at valsartan/hydrochlorothiazide doses ≥200/63 mg/kg/day andin rabbits at valsartan/hydrochlorothiazide doses of 10/3mg/kg/day. Evidence of fetotoxicity in rats consisted of decreased fetal weight and fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Evidence of 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 of the valsartan/hydrochlorothiazide combination in mice, rats and rabbits were 600/188, 100/31 and 3/1mg/kg/day, respectively. These doses in mice, rats and rabbits are, respectively, 9, 3 and 0.18 times the MRHD ofvalsartan and 38, 13 and 0.5 times the MRHD of hydrochlorothiazide on amg/m2 basis. (Calculations assume an oral dose of 320mg/day valsartan in combination with 25mg/day hydrochlorothiazide in a 60-kg patient.)
14 CLINICAL STUDIES
Exforge HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of 2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg,valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation patients assigned to the two-component arms received lower doses of their treatment combination while patients assigned to the Exforge HCT arm received 160/12.5 mg valsartan/hydrochlorothiazide. After one week, Exforge HCT patients were titrated to 5/160/12.5 mg amlodipine/valsartan/hydrochlorothiazide, while all other patients continued receiving their initial doses. After two weeks, all patients were titrated to their full treatment dose. A total of 55% of patients were male, 14%were 65 years or older, 72% were Caucasian, and 17% were Black.
At week 8, the triple combination therapy produced greater reductions in blood pressure than each of the three dual combination treatments (p<0.0001 for both diastolic and systolic blood pressures reductions). The reductions in systolic/diastolic blood pressure with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on the maximal dose of Exforge HCT (see Figure 2 and Figure 3). As the pivotal study was an active controlled trial, the treatment effects shown in Figure 1, 2, and 3 include a placebo effect of unknown size.
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