about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (Tmax about 2 hours).The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change change in the kinetics of hydrochlorothiazide on repeated dosing and accumulation is minimal when dosed once daily. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of hydrochlorothiazide is 60-80 % after oral administration.
Distribution: The apparent volume of distribution is 4-8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 1.8 times the level in plasma.
Biotransformation: Hydrochlorothiazide is eliminated as unchanged drug.
Elimination: More than 95% of the absorbed dose is being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule. The terminal half-life is 6-15 hours.
Special populations
Paediatric patients (age below 18 years)
No pharmacokinetic data are available in the paediatric population.
Elderly (age 65 years or over)
Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.
Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Since the three components are equally well tolerated in younger and elderly patients, normal dose regimens are recommended (see section 4.2).
Renal impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan.
Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see sections 4.2 and 4.4).
Hepatic impairment
Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that found in healthy |
