Valproate

Sodium valproate is effective in controlling generalised tonic-clonic seizures, particularly in primary generalised epilepsy. It is a drug of choice in primary generalised epilepsy, generalised absences and myoclonic seizures, and may be tried in atypical absence, atonic, and tonic seizures. Controlled trials in partial epilepsy suggest that it has similar efficacy to that of carbamazepine and phenytoin. The maximum response to valproate may not be seen for some weeks after steady-state has been achieved in some patients.^1,2

• Both generalised seizures, partial seizures and other forms of epilepsy.¹ Valproate is effective over the complete range of seizure types, with particular value in the idiopathic generalised epilepsies.
• Valproic acid is also licensed for acute mania associated with bipolar disorder - but prescribed as Depakote® , not as Epilim® or sodium valproate.³

• Active liver disease
• Family history of severe hepatic dysfunction
• Porphyria

• Liver function:
  • Should be monitored before therapy and during first 6 months especially in patients most at risk.
  • Raised liver enzymes are not uncommon during valproate treatment and are usually transient but patients should be reassessed clinically and liver function (including prothrombin time) monitored until return to normal.
  • An abnormally prolonged prothrombin time requires discontinuation of treatment. Any concomitant use of salicylates should be stopped.
  • Ensure no undue potential for bleeding before starting valproate, and before surgery.
• Renal impairment
• Pregnancy:
  • Women of childbearing potential should only be started on valproate on the advice of a neurologist and provided with adequate counselling with regard to the risks associated with pregnancy and the potential teratogenic risk to the fetus.¹
  • The concentration of antiepileptic drugs in the blood can change during pregnancy, particularly in the later stages. The dose of antiepileptics should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
  • First trimester: increased risk of congenital malformations and developmental delay. To counteract the risk of neural tube defects, adequate folate supplements are advised for women before and during pregnancy. Women should receive folic acid 5 mg daily, as soon as contraception is discontinued.¹
  • Third trimester: neonatal bleeding and neonatal hepatotoxicity have been reported. Routine injection of vitamin K at birth effectively counteracts any antiepileptic-associated risk of neonatal haemorrhage.
  • It is possible that valproate may be more teratogenic than other commonly used antiepileptic drugs.
• Systemic lupus erythematosus
• False-positive urine tests for ketones
• Avoid sudden withdrawal

Avoid the following if possible, or monitor frequently:

• Sodium valproate can inhibit a range of hepatic metabolic processes. Targets include other antiepileptic drugs, particularly phenytoin, phenobarbitone, carbamazepine and lamotrigine.
• Sometimes lowers plasma concentration of an active metabolite of oxcarbazepine.
• Often raises plasma concentration of an active metabolite of carbamazepine, and of lamotrigine, primidone, phenobarbital and phenytoin (but may also lower phenytoin concentration).
• Sometimes raises plasma concentration of ethosuximide, and primidone (and tendency for significant increase in phenobarbital level).
• Aspirin displaces sodium valproate from its binding sites on plasma protein and inhibits its metabolism.
• Sodium valproate does not interfere with the hormonal components of the oral contraceptive pill.¹

• Common side effects include weight gain, tremor, thinning or loss of hair (usually temporary) and menstrual irregularities including amenorrhoea.
• Polycystic ovarian syndrome has been reported in some patients.

Other side-effects

• Sedation is uncommon. Stupor and encephalopathy are rare but can occur.
• Hepatotoxicity, histologically similar to that found in Reye's syndrome, affects less than one in 20,000 exposed individuals. Children under three years of age receiving more than one antiepileptic drug are the highest risk group.
• Hyperammonaemia without hepatic damage occurs in approximately 20% of patients receiving the drug. This is usually transient, but occasionally can present with confusion, nausea and vomiting, and clouding of consciousness.
• Other sporadic problems include thrombocytopenia and pancreatitis.

• The starting dose of sodium valproate for adults and adolescents should be 500 mg/day for one or two weeks, increasing in most patients to 500 mg twice daily. The controlled release formulation can be given once daily.
• The maintenance dose is between 500 mg and 2500 mg daily.
• Alterations thereafter should be made according to clinical need. Since the drug can take several weeks to become fully effective, frequent dosage adjustments shortly after initiating therapy may be unwarranted.

• Sodium valproate does not exhibit a clear-cut concentration-effect-toxicity relationship and the daily variation in the level at a given dose is wide. Therefore routine monitoring is not helpful unless used as a check of compliance.
• The target range for valproic acid is up to 700 micromol/L.
• Saliva valproic acid concentrations do not generally correlate with blood concentrations.