Source: Health Products Regulatory Authority (ZA) Publisher: Ruby Pharmaceuticals (PTY) LTD, P.O. Box 431, Pinetown 3600
Pharmacotherapeutic group: Antiepileptics
ATC Code: N03AG01
Pharmacological classification: Anticonvulsants, including anti-epileptics
Sodium valproate has anticonvulsant properties. The exact mode of action is unknown. However, 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.
Peak plasma concentrations are observed in 1 to 4 hours after sodium valproate liquid, but this can be delayed for several hours if valproic acid is administered in enteric-coated tablets, in prolonged release formulation, or is ingested with meals.
Sodium valproate bioavailability is close to 100% following oral or IV administration.
Valproic acid concentration in cerebrospinal fluid is close to free plasma concentration.
Steady state plasma concentration is reached after 3 to 4 days, following oral administration. Valproate is highly bound to plasma proteins; protein binding is dose dependent and saturable. When given in therapeutic doses, most of the medicine is converted to the conjugate ester of glucuronic acid, while mitochondrial metabolism, principally by means of beta-oxidation, accounts for the remainder. Some of the metabolites have anticonvulsant activity. Sodium valproate is mainly excreted in urine following metabolism via glucuroconjugation and beta-oxidation.
Sodium valproate does not increase its own degradation, neither that of other medicines such as oestrogen and progestogen containing medicines.
The elimination half-life of sodium valproate varies from approximately 8 to 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 plasma valproic acid levels.
The reported effective therapeutic range for plasma valproic acid levels in epilepsy is considered to be between 30 and 100 μg/ml. This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of total plasma levels.
The pharmacological (or therapeutic) effects of RUBILIM CR are not clearly correlated with the total or free (unbound) plasma valproic acid levels.
In cases where measurement of plasma levels is considered necessary, trough plasma levels should be used for therapeutic monitoring.
Valproate induced teratogenic effects (malformations of multiple organ systems) in mice, rats and rabbits. (see section 4.6)
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.
© 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.
