Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Aventis Pharma Limited, One Onslow StreetGuildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Valproic acid pharmacotherapeutic group: Anti-epileptics, Fatty acid derivatives
ATC code: N03AG01
Sodium valproate and valproic acid are anti-convulsants.
The most likely mode of action for Epilim 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 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.
In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels (see also section 4.2).
The reported effective therapeutic range for plasma valproic acid levels is 40–100 mg/litre (278–694 micromol/litre). 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. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.
The pharmacological (or therapeutic) effects of Epilim Chronosphere may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.
The major pathway of valproate biotransformation is glucuronidation (~40%), mainly via UGT1A6, UGT1A9, and UGT2B7.
The half-life of Epilim is usually reported to be within the range of 8–20 hours. It is usually shorter in children.
Inter-individual variability has been noted. There are insufficient data to establish a robust PK-PD relationship resulting from this PK interaction.
Epilim Chronosphere is a prolonged (or modified) release formulation of Epilim which reduces peak concentration and ensures more even plasma concentrations throughout the day, comparable with other modified release Epilim formulations.
Epilim Chronosphere has been shown to be bioequivalent to Epilim Chrono tablets. Compared with immediate release forms of Epilim, Epilim Chrono is characterized at an equivalent dose by:
Steady-state pharmacokinetic data indicate that the peak concentration (Cmax) and trough concentration (Cmin) of Epilim Chronosphere lie within the effective therapeutic range of plasma levels found in pharmacokinetic studies with Epilim Enteric Coated tablets.
In cases where measurement of plasma levels is considered necessary, the pharmacokinetics of Epilim Chronosphere make the measurement of plasma levels less dependent upon time of sampling.
The peak plasma level is achieved approximately 7 hours after administration, with an elimination half-life of approximately 16 hours.
This pharmacokinetic profile is not affected by taking the drug with food.
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
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