Source: Health Products and Food Branch (CA) Revision Year: 2022
DEPAKENE (valproic acid) is indicated for:
In accorda nce with the International Classification of Seizures, simple absence is defined as a very brief clouding of the sensorium or loss of consciousness (lasting usually 2 to 15 seconds), accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity for statement regarding serious or fatal hepatic dysfunction.
Pediatrics (<18 years of age): When DEPAKENE is used in children under the age of 2 years, it should be used with extreme caution and as a sole agent. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. For a brief discussion, see 7.1.3 Pediatrics.
Geriatrics (≥65 years of age): The safety and efficacy of DEPAKENE in elderly patients with epilepsy has not been evaluated in clinical trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience with DEPAKENE in this population. For a brief discussion, see 7.1.4 Geriatrics, 4.1 Dosing Considerations, Dosing in Elderly Patients and 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics.
Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered (see 9 DRUG INTERACTIONS).
As the dosage of DEPAKENE (valproic acid) is titrated upward, blood concentrations of phenobarbital, and/or phenytoin may be affected (see 9 DRUG INTERACTIONS).
Antiepileptic drugs (AEDs) should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
Any changes in dosage and administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
When changing therapy involving drugs known to induce hepatic microsomal enzymes (e.g., carbamazepine) or other drugs with valproate interactions, (see 9 DRUG INTERACTIONS), it is advisable to monitor serum valproate concentrations.
Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, urinary tract infection, and other adverse events. Dose reductions or discontinuation of DEPAKENE should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of clinical response (see 7.1.4 Geriatrics).
The frequency of adverse events (particularly elevated liver enzymes and thrombocytopenia) may be dose related. The probability of thrombocytopenia appears to increase significantly at total valproate concentration of ≥110 mcg/mL [females] or ≥135 mcg/mL [males] (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Dosing-related Adverse Reactions: Thrombocytopenia). Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects.
DEPAKENE (valproic acid) is administered orally. The recommended initial dosage is 15 mg/kg/day, increasing at one-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.
The maximum recommended dosage is 60 mg/kg/day. When the total daily dose exceeds 250 mg, it should be given in a divided regimen (Table 1).
Table 1. Initial Doses by Weight (based on 15 mg/kg/day):
| Weight | Total Daily Dose (mg) | Teaspoonful of Oral Solution | |||
|---|---|---|---|---|---|
| kg | lb | Dose 1 | Dose 2 | Dose 3 | |
| 10 to 24.9 | 22 to 54.9 | 250 | 0 | 0 | 1 |
| 25 to 39.9 | 55 to 87.9 | 500 | 1 | 0 | 1 |
| 40 to 59.9 | 88 to 131.9 | 750 | 1 | 1 | 1 |
| 60 to 74.9 | 132 to 164.9 | 1,000 | 1 | 1 | 2 |
| 75 to 89.9 | 165 to 197.9 | 1,250 | 2 | 1 | 2 |
A good correlation has not been established between daily dose, total serum valproate concentration and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with epilepsy will range from 50 to 100 mcg/mL (350 to 700 micromole/L). Some patients may be controlled with lower or higher serum concentrations (see 7 WARNINGS AND PRECAUTIONS).
EPIVAL (divalproex sodium) enteric-coated tablets dissociate to the valproate ion in the gastrointestinal tract. EPIVAL tablets are uniformly and reliably absorbed, however, because of the enteric coating, absorption is delayed by an hour when compared to DEPAKENE.
In patients previously receiving DEPAKENE therapy, EPIVAL should be initiated at the same daily dosing schedule. After the patient is stabilized on EPIVAL, a dosing schedule of two or three times a day may be chosen in selected patients. Changes in the dosing of EPIVAL or concomitant medications should be accompanied by increased monitoring of plasma concentrations of valproate and other medications, as well as the patient’s clinical status.
Valproic Acid treatment must be initiated and supervised by a specialist experienced in the management of epilepsy. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, Pregnancy Prevention Program, and7.1.1 Pregnant Women).
Valproate is prescribed and dispensed according to the Valproate Pregnancy Prevention Program (see 7 WARNINGS AND PRECAUTIONS, Pregnancy Prevention Program).
In the exceptional circumstance when valproate is the only treatment option during pregnancy in epileptic women, valproic acid should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. During pregnancy, the daily dose of immediate release formulations should be divided into at least two single doses.
Available data show an increased risk of major congenital malformations and neurodevelopmental disorders in the children of mothers treated during pregnancy with either valproate monotherapy or valproate polytherapy, compared to the population not exposed to valproate.
DEPAKENE may be taken with or without food.
Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by a progressive increase of the dose from an initial low level. Co-administration of DEPAKENE with food should cause no clinical problems in the management of patients with epilepsy.
The patient should not abruptly stop taking their medication because of the risk of increasing their seizures.
If the patient misses a dose, they should not try to make up for it by doubling up on their next dose. They should take their next regularly scheduled dose and try not to miss any more doses.
Overdosage with DEPAKENE (valproic acid) may result in somnolence, muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, hypotension, metabolic acidosis, heart block, deep coma and circulatory collapse/shock. Cases of intracranial hypertension related to cerebral oedema have been reported. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2,120mcg/mL.
The presence of sodium content in the valproate formulations may lead to hypernatremia when taken in overdose.
In a reported case of overdosage with DEPAKENE after ingesting 36 g in combination with phenobarbital and phenytoin, the patient presented in deep coma. An electroencephalogram (EEG) recorded diffuse slowing, compatible with the state of consciousness. The patient made an uneventful recovery.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. As valproic acid is absorbed very rapidly, gastric lavage may be of limited value. General supportive measures should be applied with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of DEPAKENE overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of DEPAKENE, it should be used with caution.
For management of a suspected drug overdose, contact your regional poison control centre.
Store DEPAKENE (valproic acid) oral solution between 15 and 30°C.
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