Sign Out
Pharmacotherapeutic group: Anti-epileptics. ATC Code: N03AG01.
Pharmacology: Pharmacodynamics: Sodium valproate is an anti-convulsant.
The most likely mode of action for Epilim is potentiation of the inhibitory action of gamma aminobutyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.
In certain in-vitro studies it was reported that Epilim could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that Epilim does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of Epilim on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.
Pharmacokinetics: The reported effective therapeutic range for plasma valproic acid levels is 40 - 100 mg/L (278 - 694 μmol/L). This reported range may depend on time of sampling and presence of co-medication.
Distribution: The percentage of free (unbound) drug is usually between 6-15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.
The pharmacological (or therapeutic) effects of Epilim may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.
Placental transfer (see Use in Pregnancy & Lactation): Valproate crosses the placental barrier in animal species and in humans: In animal species, valproate crosses the placenta to a similar extent as in humans; In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism: The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9 and UGT2B7.
Elimination: The half-life of Epilim is usually reported to be within the range 8-20 hours.
Epilim EC, Syr and Chrono tab: It is usually shorter in children.
Special populations: Renal insufficiency: In patients with severe renal insufficiency, it may be necessary to alter dosage in accordance with free plasma valproic acid levels.
Paediatric population: Epilim IV: 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 1-67 hours. In children aged 2-10 years, valproate clearance is 50% higher than in adults.
Interaction with oestrogen-containing products: Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.
Toxicology: Preclinical safety data: Valproate was neither mutagenic in bacteria, nor in the mouse lymphoma assay in vitro and did not induce DNA repair in primary rat hepatocyte cultures. In vivo, however, contradictory results were obtained at teratogenic doses depending on the route of administration. After oral administration, the predominant route of administration in humans, valproate did not induce chromosome aberrations in rat bone marrow or dominant lethal effects in mice. Intraperitoneal injection of valproate increased DNA strand-breaks and chromosomal damage in rodents. In addition, increased sister-chromatid exchanges in epileptic patients exposed to valproate as compared to untreated healthy subjects have been reported in published studies. However, conflicting results were obtained when comparing data in epileptic patients treated with valproate with those in untreated epileptic patients. The clinical relevance of these DNA/chromosome findings is unknown.
Non-clinical data reveal no special hazard for humans based on conventional carcinogenicity studies.
Reproductive and developmental toxicity: Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.
Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
Behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioural changes have also been observed in the second generation and those were less pronounced in the third generation of mice following acute in utero exposure of the first generation to teratogenic valproate doses. The underlying mechanisms and the clinical relevance of these findings are unknown.
