Antiepileptics. Fatty acid derivatives
ATC code: N03AG01 (Valproic acid)
Brand names
Depakote, Depakote ER, Depakene, Stavzor, Depacon
Enhances GABAergic transmission, blocks sodium channels, inhibits T-type calcium channels. Used for generalized epilepsy, absences, bipolar disorder, migraine prophylaxis. Category X teratogen: neural tube defects and IQ reduction in the fetus – contraindicated in pregnancy and in women of reproductive age without reliable contraception.
First line
For typical absence seizures in children and adolescents, valproate and ethosuximide are first-line. Comparative RCTs (Glauser 2010) showed similar efficacy; ethosuximide has better cognitive profile and is used for isolated absences. Valproate is preferred when generalized tonic-clonic seizures coexist.
First line
Valproate is used for acute mania in bipolar disorder and maintenance therapy. CG185 and RANZCP 2022 list valproate as a first-line option for acute mania alongside lithium and atypical antipsychotics. Efficacy in mania is comparable to lithium per meta-analyses. Not used in women of reproductive age without strict indications.
In women of reproductive age with bipolar disorder, valproate is not used except in cases of intolerance or ineffectiveness of alternatives and under strict contraception.
Sources
First line
Valproate is first-line for idiopathic generalized epilepsy in men and postmenopausal women. NG217 and ILAE consider valproate the most effective drug for generalized tonic-clonic, myoclonic seizures, and juvenile myoclonic epilepsy. Effective in 70–80% of patients. In women of reproductive age, prescribed only when alternatives are unsuitable and Pregnancy Prevention Programme is strictly followed.
In women of reproductive age, prescription is allowed only within a Pregnancy Prevention Programme (annual signed informed consent, mandatory effective contraception, pregnancy testing).
Sources
Second line
Valproate is included in international guidelines (/AHS, EHF) as a drug with proven efficacy in episodic migraine prophylaxis. Reduces attack frequency by 50% in some patients. Used when first-line agents (beta-blockers, topiramate, anti-CGRP monoclonal antibodies) are ineffective or intolerable. Not used in women of reproductive age due to teratogenicity.
Not recommended
Use of valproate in women of reproductive age without strict contraception and without compelling indication is not supported by international regulators. 2018 and MHRA Pregnancy Prevention Programme require annual signed informed consent, mandatory effective contraception, and regular pregnancy testing. Valproate is among the most teratogenic antiepileptics: neural tube defect risk approximately 10%, average IQ reduction of 7–10 points in offspring.
This block reiterates the Pregnancy Prevention Programme information and is essential to prevent inappropriate prescribing without proper procedures.
Valproate reduces plasma L-carnitine via conjugation with glycine and urinary excretion. Carnitine deficiency is linked to hyperammonemic encephalopathy and hepatotoxicity. When symptoms appear (lethargy, vomiting, altered consciousness) or ammonia rises, measure carnitine level and administer L-carnitine IV (100–200 mg/kg/day) or orally (50–100 mg/kg/day).
Source: FDA: Depakote (divalproex sodium) prescribing information (2022)
Boxed warning
FDA triple boxed warning: 1) Hepatotoxicity, especially in children under 2 and with polytherapy – risk of fatality. 2) Teratogenicity: valproate is not used in women of reproductive age for conditions other than epilepsy if alternatives exist. 3) Pancreatitis. EMA 2018 introduced a Pregnancy Prevention Programme: annual informed consent, mandatory effective contraception, pregnancy testing.
valproic acid is evaluated for the following indications with varying evidence strength: Generalized epilepsy (evidence tier A), Absence seizures (evidence tier A), Bipolar disorder (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of valproic acid (≥ 1 in 100): Nausea, vomiting, dyspepsia, Weight gain, Tremor, Alopecia, Drowsiness, Elevated liver transaminases (usually asymptomatic). See the Safety section for uncommon and serious reactions.
FDA category X. FDA category X for migraine prophylaxis and bipolar disorder; category D for epilepsy. One of the most teratogenic antiepileptics. First-trimester use carries risks of neural tube defects (1–2%), cardiac defects, cleft palate, hypospadias, and average IQ reduction of 7–10 points. When planning pregnancy, switch to alternatives (levetiracetam, lamotrigine) with folic acid 4–5 mg/day for 1–3 months preconception.
Passes into breast milk in small amounts (1–10% of maternal plasma level). LactMed lists valproate as generally compatible with breastfeeding under infant monitoring (sedation, hepatotoxicity, thrombocytopenia).
valproic acid is contraindicated in: Hypersensitivity to valproate; Acute and chronic hepatitis, hepatic insufficiency; Hepatic porphyria; Mitochondrial disorders (POLG mutations); Urea cycle disorders. Full list in the Safety section.
FDA category X for migraine prophylaxis and bipolar disorder; category D for epilepsy. One of the most teratogenic antiepileptics. First-trimester use carries risks of neural tube defects (1–2%), cardiac defects, cleft palate, hypospadias, and average IQ reduction of 7–10 points. When planning pregnancy, switch to alternatives (levetiracetam, lamotrigine) with folic acid 4–5 mg/day for 1–3 months preconception.
Passes into breast milk in small amounts (1–10% of maternal plasma level). LactMed lists valproate as generally compatible with breastfeeding under infant monitoring (sedation, hepatotoxicity, thrombocytopenia).
FDA triple boxed warning: 1) Hepatotoxicity, especially in children under 2 and with polytherapy – risk of fatality. 2) Teratogenicity: valproate is not used in women of reproductive age for conditions other than epilepsy if alternatives exist. 3) Pancreatitis. EMA 2018 introduced a Pregnancy Prevention Programme: annual informed consent, mandatory effective contraception, pregnancy testing.
in women of reproductive age, use is strictly limited due to high teratogenicity. Neural tube defects 1–2%, average IQ reduction 7–10 points.
average gain 5–15 kg in the first year. Linked to increased appetite and insulin resistance. Persists in most patients during therapy.
when planning pregnancy, switch to alternatives 1–3 months ahead with concomitant folic acid.