EPIVAL Prolonged-release tablet Ref.[50749] Active ingredients: Valproic acid

Absorption

Valproate is well absorbed. The absolute bioavailability is almost 100%. Peak plasma levels are obtained at ca. 1-6 hours, depending on the pharmaceutical form. For Epival CR prolonged-release tablets, mean peak plasma levels are obtained at ca. 6-14 hours. Steady state plasma levels are achieved within 3-4 days. Effective therapeutic plasma levels are in the range of 40-100 mg/l (278-694 µmol/l). A high inter- and intra-individual variability in plasma levels is observed.

Distribution

Valproic acid binding to serum proteins is approximately 80-95%. At plasma levels above 100 mg/l, the free fraction increases. Valproic acid is mainly distributed into blood. The concentration of valproic acid in the cerebrospinal fluid is comparable with the free valproic acid concentration in plasma. Valproic acid passes the placenta, and is excreted into breast milk (1-10% of the total serum concentration).

Biotransformation

Valproic acid is metabolised in the liver, mainly glucuronidated. Valproic acid inhibits the cytochrome P450 enzyme system.

Elimination

Valproic acid is mainly excreted into the urine as glucuronidates. The plasma elimination half-life is 10-15 hours and is significantly shorter in children, namely 6-10 hours.

Epival CR prolonged-release tablets are a prolonged-release formulation which in pharmacokinetic studies demonstrates less fluctuation in plasma concentration compared to other established conventional formulations of valproic acid. For Epival CR prolonged-release tablets, the pharmacological effects may not be clearly correlated with the total or free (unbound) plasma valproic acid levels. In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of Epival CR prolonged-release tablets make the measurement of plasma levels less dependent upon time of sampling.

Special patient groups

Elderly patients

Pharmacokinetics of valproic acid may be altered in elderly patients due to an increased distribution volume and a decrease in protein binding, which may result in an increase in free drug concentration.

Patients with renal insufficiency

Pharmacokinetics of valproic acid may be altered in patients with renal insufficiency, due to a decrease in protein binding, resulting in an increase in free drug concentrations.

Patients with hepatic dysfunction

Elimination half-lives in patients with cirrhosis and in patients recovering from acute hepatitis were significantly prolonged compared with controls, indicating impaired clearance in patients with liver dysfunction.

Epival CR prolonged-release tablets are bioequivalent to other prolonged release valproate formulations with respect to the mean areas under the plasma concentration time curves. Steady-state pharmacokinetic data indicate that the peak concentration (C_max) and trough concentration (Cmin) of Epival CR prolonged-release tablets lie within the effective therapeutic range of plasma levels as generally accepted for sodium valproate.

Above the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. In paediatric patients below the age of 10 years, the systemic clearance of valproate varies with age. In neonates and infants up to 2 months of age, valproate clearance is decreased when compared to adults and is lowest directly after birth. In a review of the scientific literature, valproate half-life in infants under two months showed considerable variability ranging from 1 to 67 hours. In children aged 2-10 years, valproate clearance is 50% higher than in adults.

Chronic toxicity studies with valproic acid demonstrated reduced spermatogenesis and testicular atrophy in rats and dogs.

In repeat-dose toxicity studies, testicular degeneration/atrophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration at doses of 1250 mg/kg/day and 150 mg/kg/day, respectively.

In juvenile rats, a decrease in testes weight was only observed at doses exceeding the maximum tolerated dose (from 240 mg/kg/day by intraperitoneal or intravenous route) and with no associated histopathological changes. No effects on the male reproductive organs were noted at tolerated doses (up to 90 mg/kg/day). Based on these data, juvenile animals were not considered more susceptible to testicular findings than adults. Relevance of the testicular findings to paediatric population is unknown.

In a fertility study in rats, valproate at doses up to 350 mg/kg/day did not alter male reproductive performance. However, male infertility has been identified as an undesirable effect in humans (see sections 4.6 and 4.8).

Genotoxicity testing revealed no mutagenic potential. In studies on the carcinogenic potential an increased incidence of subcutaneous fibrosarcomas was observed in male rats. The significance of these findings for humans is unknown. Valproic acid was shown to be a potent animal teratogen.