An antiepileptic capsule for absence seizures and complex partial seizures, alone or with other seizure drugs. Its boxed warning covers fatal liver failure, pancreatitis, and serious harm to an unborn baby, so liver tests are checked and it is avoided in pregnancy unless nothing else works.
Labeled use. Complex partial seizures from age 10, and simple and complex absence seizures, alone or as add-on therapy.
A broad-spectrum antiseizure drug, effective for generalized epilepsies including absence, myoclonic, and generalized tonic-clonic seizures, and, as divalproex, for bipolar mania and migraine prevention. Avoid in women who could become pregnant, where lamotrigine or levetiracetam is preferred, and in liver disease. Ethosuximide is first-line for childhood absence epilepsy without other seizure types.
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Valproic acid dissociates to the valproate ion in the gut. Its mechanism is not established; antiseizure activity may relate to higher brain GABA concentrations. It is cleared mainly by hepatic glucuronidation and beta-oxidation, with CYP oxidation a minor path, so enzyme inducers such as phenytoin, carbamazepine, and phenobarbital can double its clearance. It is a weak inhibitor of some CYP isozymes, epoxide hydrase, and glucuronosyltransferases.
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Narrow therapeutic index. The label directs checking plasma levels against the accepted target range of 50 to 100 mcg/mL when response is unsatisfactory, and thrombocytopenia rises at higher levels.
Doses come from the FDA label. Study tool, not for clinical decisions.
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No labeled dose change. Protein binding falls in renal failure, so total levels can mislead.
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Contraindicated in hepatic disease or significant hepatic dysfunction.
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Life-threatening adverse reactions. Hepatotoxicity, including fatal liver failure, usually in the first 6 months; children under 2 and patients with mitochondrial disorders are at higher risk, so check liver tests before and frequently during therapy. Fetal risk: neural tube defects, other major malformations, and decreased IQ. Pancreatitis, including fatal hemorrhagic cases.
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No specific antidote. Give supportive care and maintain urine output; hemodialysis, or hemodialysis with hemoperfusion, can remove significant drug in overdose. Naloxone has reversed CNS depression but may also reverse its antiseizure effect, so use it cautiously in epilepsy.
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Can cause neural tube defects such as spina bifida, other major malformations, and decreased IQ, often very early in pregnancy. Do not use in pregnancy or in women planning pregnancy unless other medicines have failed; use effective contraception. Do not stop it abruptly in a pregnant woman with epilepsy, because status epilepticus threatens mother and baby. Folic acid before conception lowers neural tube defect risk in general.
Passes into milk at 1% to 10% of maternal serum levels. Monitor the breastfed infant for jaundice and unusual bruising or bleeding.
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Children under 2 have a much higher risk of fatal hepatotoxicity; use with extreme caution and as a sole agent. Children 3 months to 10 years clear it 50% faster per kg than adults and may need larger doses; after age 10, kinetics approach adult values.
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