Source: Health Products and Food Branch (CA) Revision Year: 2022
Pharmacotherapeutic group: Anticonvulsant and mood-stabilizing drug
ATC Code: N03AG01
DEPAKENE (valproic acid) has anticonvulsant properties. Although its mechanism of action has not yet been established, it has been suggested that its activity is related to increased brain levels of gammaaminobutyric acid (GABA). The effect on the neuronal membrane is unknown.
A good correlation has not been established between daily dose, serum level and therapeutic effect of DEPAKENE. In epilepsy, the therapeutic plasma concentrations range is believed to be from 50 to 100 mcg/mL (350 to 700 micromole/L) of total valproate. Occasional patients may be controlled with serum levels lower or higher than this range (see 4 DOSAGE AND ADMINISTATION).
Valproic acid is rapidly absorbed after oral administration. Peak serum levels occur approximately 1 to 4 hours after a single oral dose. A slight delay in absorption occurs when the drug is administered with meals but this does not affect the total absorption.
Valproic acid is rapidly distributed throughout the body and the drug is strongly bound (90%) to human plasma proteins. Increases in dose may result in decreases in the extent of protein binding and variable changes in valproic acid clearance and elimination.
The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, in hyperlipidemic patients, and in the presence of other drugs (e.g., acetylsalicylic acid). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). See 9 DRUG INTERACTIONS for more detailed information on the pharmacokinetic interactions of valproate with other drugs.
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (ranging from 7 to 25% of total concentration).
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial (beta)-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
Due to the saturable plasma protein binding, the relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather increases to a lesser extent. The kinetics of unbound drug are linear.
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m² and 11 L/1.73 m², respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m² and 92 L/1.73 m², respectively. These estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing AEDs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproic acid clearance, monitoring of valproate and concomitant drug concentrations should be intensified whenever enzyme-inducing drugs are introduced or withdrawn.
Elimination of valproic acid and its metabolites occurs principally in the urine, with minor amounts in the feces and expired air. Very little unmetabolized parent drug is excreted in the urine.
The serum half-life (t½) of valproic acid is typically in the range of 6 to 16 hours. Half-lives in the lower part of the above range are usually found in patients taking other AEDs capable of enzyme induction.
No microbiological information is required for this drug product.
Valproic acid has been shown to be effective against several types of chemically and electrically induced convulsions in a variety of animal species. These included maximal electroshock, low frequency electroshock, CO2 withdrawal, pentylene tetrazole, cobalt, bemegride, bicuculline and 1-glutamate. Many forms of photic and auditory induced seizures are also effectively blocked by valproic acid.
In animal studies, valproic acid at doses of 175 mg/kg or less had no effect on locomotor activity and conditioned responses to positive reinforcement.
Doses greater than 175 mg/kg inhibited spontaneous and conditioned behaviour in mice and rats and interfered with coordination of hind limbs in rats. Suppression of spontaneous and evoked brain potentials was also demonstrated at these higher dose levels.
Valproic acid at doses of 175 mg/kg or less had little or no effect on the autonomic nervous system, cardiovascular system, respiration, body temperature, inflammatory responses, smooth muscle contraction or renal activity. Intravenous doses of 22, 43 and 86 mg/kg in animals caused very transient decreases followed by compensatory increases in blood pressure.
Sodium valproate injectable caused decreased activity, ataxia, dyspnea, prostration and death in rats and mice acutely exposed to dosages exceeding 200 mg/kg.
The initial animal testing was done with sodium valproate, whereas most of the recent research has been with valproic acid. The conversion factor is such that 100 mg of the sodium salt is equivalent to 87 mg of the acid. References to dosage are in terms of valproic acid activity.
Acute toxicity has been determined in several animal species using oral, intravenous, intraperitoneal and subcutaneous routes. The oral median lethal dose in adult rats and dogs was about 1 to 2 g/kg. Toxicity was similar for both sexes; however, it tended to be greater in newborn and 14-day old rats and in young adult rats. The signs of toxicity were those of central nervous system depression. Specific organ damage was limited to cellular debris in reticuloendothelial tissue and slight fatty degeneration of the liver.
Large oral doses (more than 500 mg/kg) produced irritation of the gastrointestinal tract of rats.
In adult male mice, the oral medial lethal dose of divalproex sodium was 1.66 g/kg (equal to approximately 1.54 g/kg valproic acid).
Pulverized divalproex sodium enteric-coated tablets (equivalent to 250 mg valproic acid), suspended in 0.2% methylcellulose, were administered orally to mice and rats of both sexes (10/sex/species/group) in dosages ranging from 1.74 to 4.07 g/kg. The oral median lethal dose (LD50) ranged from 2.06 to 2.71 g/kg. No consistent sex-related or species-related differences were observed.
Signs of central nervous system depression, such as decreased activity, ataxia, and sleep, were observed. At necropsy, discolouration and/or thickening of the glandular mucosa were observed in only 2 female rats treated with 2.71 g/kg that died acutely.
When mature rats and dogs were administered up to 240 mg/kg/day or 120 mg/kg/day, respectively, for at least four consecutive weeks, no significant toxicologic effects were reported. However, significant reductions in testicular weights and total white cell counts in rats given 240 mg/kg/day were considered as evidence of subtle toxicity from sodium valproate injectable. Therefore, 90 mg/kg/day in rats and 120 mg/kg/day in dogs were considered the highest non-toxic doses.
The acute intravenous toxicity of sodium valproate injectable formulation containing the equivalent of 100 mg valproic acid/mL was evaluated in both sexes of mice and rats. Groups of mice and rats (five/sex/species/group) were treated at dosages ranging from 0.5 to 9.0 mL/kg (50 to 900 mg valproate/kg). No overt signs of toxicity were present in rats and mice given 0.5mL/kg (50 mg valproate/kg). LD50 values for the test solution in mice and rats (data combined for both sexes) were 7.3 and 7.0 mL/mg (730 and 700 mg valproate/kg), respectively.
Subacute and chronic toxicity studies consisted of 1, 3, 6 and 18 months studies in rats and 3, 6 and 12 months studies in dogs. Pathologic changes included suppression of the hematopoietic system, depletion of lymphocytes from lymphoid tissues and the loss of germinal epithelial cells from seminiferous tubules. Reduced spermatogenesis and testicular atrophy occurred in dogs at doses greater than 90 mg/kg/day and in rats at doses greater than 350 mg/kg/day. In rats, the first indication of toxicity at 350 mg/kg/day was decreased food consumption and growth.
Two hundred rats were given valproic acid in the diet for 107 weeks. Mean doses consumed in the treatment period were: 81 mg/kg/day (males) and 85 mg/kg/day (females), in the low dose group; 161 mg/kg/day (males) and 172 mg/kg/day (females) in the high dose group (approximately 10 to 50% of the maximum human daily dose on a mg/m² basis). Control animals received corn oil in the diet. The chief finding in the study was an increased incidence of skin fibrosarcomas in treated males of the highdose group. There were 2 such neoplasms in the low dose group, 5 in the high dose group and none in control males. Fibrosarcomas in rats are relatively infrequent, usually occurring in less than 3% of animals.
Valproic acid was also administered in the diet to female mice for nearly 19 months at doses of 81 and 163 mg/kg/day and to male mice for nearly 23 months at doses of 80 and 159 mg/kg/day. A significant dose related trend occurred in male mice in the incidence of bronchoalveolar adenomas, and when the data were adjusted for the times of death, the incidence in the high dose group was significantly increased.
Depending on the method of statistical analysis, the incidence of hepatocellular carcinomas and/or adenomas also showed significant or almost significant increases for the corresponding observations. The results of these two studies indicate that valproic acid is a weak carcinogen or promoter in rats and mice. The significance of these findings for humans is unknown at present.
Subcutaneous fibrosarcomas were observed in male rats and hepatocellular carcinomas and bronchiolo-alveolar adenomas were observed in male mice at incidences slightly higher than concurrent study controls but comparable to those in registries of historical controls.
Valproate was not mutagenic in bacteria (Ames test), or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay), and did not induce DNA repair activity in primary culture of rat hepatocytes. After oral administration, valproate did not induce either chromosome aberrations in rat bone marrow, or dominant lethal effects in mice.
In literature, after intraperitoneal exposure to valproate, increased incidences of DNA and chromosome damage (DNA strand-breaks, chromosomal aberrations or micronuclei) have been reported in rodents. However, the clinical significance of the results obtained with the intraperitoneal route of administration is unknown.
Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in epileptic children exposed to valproate as compared to healthy children or epileptic children not exposed to valproate. However, contradictory results were reported in another study conducted in a mixed population of adults and children who showed similar SCE frequencies in treated or untreated epileptic patients. The clinical significance of an increase in SCE frequency is not known.
Studies in rats have shown placental transfer of the drug. Teratogenic effects (malformations of multiple organ systems) have been demonstrated in mice, rats, and rabbits. Doses greater than 65 mg/kg/day given to rats, mice and rabbits produced an increased incidence of skeletal abnormalities of the ribs, vertebrae and palate. Animal studies show that in utero exposure to valproate results in morphological and functional alterations of the auditory system in rats and mice.
Doses greater than 150 mg/kg/day given to pregnant rabbits produced fetal resorptions and (primarily) soft-tissue abnormalities in the offspring.
In rats, there was a dose related delay in onset of parturition. Post-natal growth and survival of the progeny were adversely affected, particularly when drug administration spanned the entire gestation and early lactation period. Embryolethality or major developmental abnormalities occurred in rats and rabbits at doses of 350 mg/kg/day.
Survival among pups born to the high dose females was very poor but was improved when pups were transferred to control dams shortly after birth.
In published literature, behavioral abnormalities have been reported in first generation offspring of mice and rats after in utero exposure to clinically relevant doses/exposures of valproate. In mice, behavioral changes have also been observed in the 2nd and 3rd generations, albeit less pronounced in the 3rd generation, following an acute in utero exposure of the first generation from dams dosed with valproate at 300 mg/kg (i.p.) or 500 mg/kg (s.c.) valproate on GD 10 or 10.5, respectively. The relevance of these findings for humans is unknown.
Chronic toxicity studies in adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of valproic acid of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m² basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m² basis). Segment I fertility studies in rats have shown that oral doses up to 350 mg/kg/day (approximately equal to the maximum human daily dose on a mg/m² basis) for 60 days have no effect on fertility.
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). There are insufficient data to determine the effect of valproate on testicular development in humans (see 8.5 Post-Market Adverse Reactions, Reproductive Findings).
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