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Elimination Mean plasma clearance and volume of distribution for total valproate are 0.56 L/ hr/ 1.73 m 2 and 11 L/ 1.73 m 2 , respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/ hr/ 1.73 m 2 and 92 L/ 1.73 m 2 . Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Text Continues Below
Special Populations Effect of Age: Pediatric - The valproate pharmacokinetic profile following administration of DEPAKOTE ER was characterized in a multiple-dose, non-fasting, open-label, multi-center study in children and adolescents. DEPAKOTE ER once-daily doses ranged from 250 to 1750 mg. Once-daily administration of DEPAKOTE ER in pediatric patients (10-17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in adults. Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly (see DOSAGE AND ADMINISTRATION). Effect of Gender: There are no differences in the body surface area adjusted unbound clearance between males and females (4.8± 0.17 and 4.7± 0.07 L/ hr per 1.73 m 2 , respectively). Effect of Race: The effects of race on the kinetics of valproate have not been studied. Effect of Disease: Liver Disease -
(see BOXED WARNING, CONTRAINDICATIONS, and WARNINGS). Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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