EPILIM CHRONO TABLET 500mg FOR ORAL USE

Product Information

Registration Status: Active

EPILIM CHRONO TABLET 500mg is approved to be sold in Singapore with effective from 1995-11-04. It is marketed by SANOFI-AVENTIS SINGAPORE PTE LTD, with the registration number of SIN08112P.

This product contains Valproic Acid 333mg in the form of TABLET, FILM-COATED. It is approved for ORAL use.

This product is manufactured by SANOFI WINTHROP INDUSTRIE in FRANCE.

It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Description

Valproic acid, supplied as the sodium salt valproate semisodium or divalproex sodium, is a fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage dependent sodium channels. Typically supplied in the sodium salt form (CAS number: 76584-70-8). Valproic Acid is also a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.

Indication

For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome.

Mechanism of Action

Valproic Acid dissociates to the valproate ion in the gastrointestinal tract and then binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. It is also a histone deacetylase inhibitor. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection.

Pharmacokinetics

Absorption: Rapid absorption from gastrointestinal tract. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Food has a greater influence on the rate of absorption of the Depakote tablet (increases Tmax from 4 to 8 hours) than on the absorption of Depakote sprinkle capsules (increase Tmax from 3.3 to 4.8 hours). Furthermore, studies suggest that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control.
Distribution: * 11 L/1.73 m2 [total valproate] * 92 L/1.73 m2 [free valproate]
Metabolism: Valproic Acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
Elimination

Clearance

* 0.56 L/hr/1.73 m2 [plasma clearance, total valproate] * 4.6 L/hr/1.73 m2 [plasma clearance, free valproate] * 4.8 ± 0.17 L/hr/1.73 m2 [males, unbound clearance] * 4.7 ± 0.07 L/hr/1.73 m2 [females, unbound clearance]

Toxicity

Oral, mouse: LD₅₀ = 1098 mg/kg; Oral, rat: LD₅₀ = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems. The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults.

Active Ingredient/Synonyms

Source of information: Drugbank (External Link). Last updated on: 3^rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.