Source: Υπουργείο Υγείας (CY) Revision Year: 2023 Publisher: Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, France
Pharmacotherapeutic group: Antiepileptics
ATC code: N03AG01
Sodium valproate is an anticonvulsant.
The most likely mode of action for valproate is potentiation of the inhibitory action of gamma amino-butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.
In certain in-vitro studies it was reported that sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed, the effect of sodium valproate 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.
The reported effective therapeutic range for plasma valproic acid levels is 40-100 mg/litre (278-694 micromole/litre). This reported range might depend on time of sampling and presence of co-medication.
The percentage of free (unbound) drug is usually between 6% and 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 Depakine may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.
Valproate crosses the placental barrier in animal species and in humans:
The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7.
The half-life of sodium valproate is usually reported to be within the range of 8-20 hours. It is usually shorter in children.
In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free serum valproic acid levels.
DEPAKINE CHRONO formulations are slow release formulations which demonstrate in pharmacikinetic studies less fluctuation in plasma concentration compared with other established conventional and modified release DEPAKINE formulations.
In case where measurement of plasma levels is considered necessary, the pharmacikinetics of DEPAKINE CHRONO make the measurement of plasma levels dependent upon time of sampling.
The DEPAKINE CHRONO formulations are bioequivalent to DEPAKINE solution and DEPAKINE gastro-resistant formulations with respect to mean areas under the plasma concentrations time curves. Steady-state pharmacokinetic data indicate that the peak concentration (Cmax) and trough concentration (Cmin) of DEPAKINE CHRONO lie within the effective therapeutic range of plasma levels found in pharmacikinetic studies with DEPAKINE gastro-resistant.
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.
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 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.
Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits.
Behavioral abnormalities have been reported in first generation offspring of mice and rats after in utero exposure. Some behavioral changes have been also observed in the 2nd generation and those were less pronounced in the 3rd 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.
Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
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).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
