Exforge

Following oral administration of Exforge in normal healthy adults, peak plasma concentrations of valsartan and amlodipine are reached in 3 and 6-8 hours, respectively. The rate and extent of absorption of valsartan and amlodipine from Exforge are the same as when administered as individual tablets.

Special Populations

Geriatric

Studies with Amlodipine : Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40%-60%; therefore a lower initial dose of amlodipine may be required.

Studies with Valsartan : Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.

Gender

Studies with Valsartan: Pharmacokinetics of valsartan does not differ significantly between males and females.

Renal Insufficiency

Studies with Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Studies with Valsartan: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.

Hepatic Insufficiency

Studies with Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40%-60%; therefore, a lower initial dose of amlodipine may be required.

Studies with Valsartan: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease.

Studies with A mlodipine

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 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/m basis).

Studies with V alsartan

There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to p