Drug reference

Valproic Acid

Antiepileptic

Also known as Sodium Valproate, Divalproex Sodium, Valproate Semisodium

START

Confirm seizure type or bipolar mania. Baseline CBC, LFTs, ammonia, pregnancy test (women of childbearing potential). Rule out urea cycle disorders and hepatic disease. Start 10-15 mg/kg/day.

TYPICAL MAX

60 mg/kg/day; 3000-4000 mg/day absolute max. Therapeutic range: 50-100 μg/mL.

STOP IF

ALT/AST >3x ULN, signs of hepatic failure (jaundice, coagulopathy), pancreatitis (severe abdominal pain, elevated lipase), hyperammonemic encephalopathy (confusion, vomiting, asterixis), severe thrombocytopenia (<50,000)

WATCH

LFTs at baseline and every 3-6 months, CBC/platelets (every 3 months), ammonia (if symptoms), serum levels (trough: 50-100 μg/mL), weight, pregnancy status (monthly counseling), tremor

CDSCO approvedSchedule HJan AushadhiATC N03AG01

Dose laddermg/d

Renal dose adjustmenteGFR mL/min/1.73m²

KDIGO 2024 + manufacturer label

Pharmacokineticsplasma · t hours

ONSET: 45min · absorption onset
PEAK: 3h · 1-4 h (IR); 7-14 h (ER)
t½: 14h · 8-20 h (adults); longer in neonates/elderly
DURATION: 12h · 6-12 h (IR); 24 h (ER)

EXCRETION

~30-50% renal (glucuronides); hepatic glucuronidation/beta-oxidation; NOT CYP-dependent

route + CYP

INTERACTIONS

12 major

SEVERE in our sources

PREGNANCY

FDA PLLR: HIGH RISK of teratogenicity. Can cause neural tube defects, craniofacial defects, cardiovascular malformations, and cognitive impairment in offspring (lower IQ). Contraindicated for migraine prophylaxis in pregnancy. For epilepsy/bipolar: use only if no effective alternatives. Women of childbearing potential must use effective contraception. Pregnancy registry available.

FDA category + note

Top interactionssee all 12 →

AspirinSevereDatabaseKimi deep-research + Cla
BexaroteneSevereDatabaseDDInter
BuprenorphineSevereDatabaseDDInter
CarbamazepineSevereDatabaseKimi deep-research + Cla

Available in India

190 branded formulations and 228 fixed-dose combinations. Look up specific brands in the Drugs workspace.

Jan Aushadhi — generic available at GoI pharmacies

Mechanism

Valproic acid (and its sodium salt, valproate) is a broad-spectrum antiepileptic drug with multiple proposed mechanisms. Its primary mechanism involves inhibition of voltage-gated sodium channels, which limits sustained repetitive neuronal firing. It also enhances GABAergic neurotransmission by: (1) inhibiting GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), the enzymes responsible for GABA degradation; (2) increasing glutamic acid decarboxylase (GAD) activity, which synthesizes GABA; and (3) possibly blocking GABA reuptake. Additionally, valproate inhibits T-type calcium channels and may modulate histone deacetylases (HDACs), affecting gene expression. The combination of enhanced GABAergic transmission and sodium channel blockade provides broad-spectrum efficacy against multiple seizure types.

Indications

Complex partial seizures (with/without secondary generalization)Absence seizures (petit mal)Simple and complex absence seizuresMixed seizure typesManic episodes associated with bipolar disorderMigraine prophylaxisAcute mania (in combination with antipsychotics)Bipolar maintenance (off-label, but widely used)

Dosing

Adult: Seizures: Start 10-15 mg/kg/day; increase by 5-10 mg/kg/week; usual 30-60 mg/kg/day; max 60 mg/kg/day. Mania: Start 750 mg/day in divided doses; max 60 mg/kg/day. Migraine: 250 mg BID; max 1000 mg/day. IV (Depacon): same total daily dose as oral, divided q6h.
Pediatric: Seizures (≥10 years): 10-15 mg/kg/day; increase by 5-10 mg/kg/week; max 60 mg/kg/day. <2 years: contraindicated (fatal hepatotoxicity risk).
Renal adjustment: No adjustment required (not renally eliminated).
Hepatic adjustment: CONTRAINDICATED in hepatic disease. If mild impairment: reduce dose by 50%; monitor LFTs and ammonia closely.
Geriatric: Start at lower dose; reduce initial dose; slower titration. Monitor for somnolence, tremor, ataxia.
Max dose: 60 mg/kg/day; 3000-4000 mg/day absolute maximum

Pharmacokinetics

Onset

Anticonvulsant effect: within days. Therapeutic levels typically achieved within 1-2 weeks.

Peak effect

Immediate-release: peak at 1-4 hours. Delayed-release: 3-5 hours. Extended-release: 7-14 hours.

Duration

6-12 hours (IR); 12-24 hours (ER).

Half-life

8-20 hours (adults; mean ~12-16 hours). Neonates: 30-60 hours. Shorter in patients taking enzyme inducers (carbamazepine, phenytoin).

Bioavailability

~90% (oral; nearly complete absorption).

Protein binding

~80-90% (concentration-dependent; bound primarily to albumin). Saturation occurs at higher concentrations (>80 μg/mL), increasing free fraction and toxicity risk.

Metabolism

Extensive hepatic via multiple pathways: glucuronide conjugation (~50%), beta-oxidation (~40%), and minor omega-oxidation to toxic 4-ene-VPA metabolite. NOT primarily CYP-dependent (some CYP2C9/2C19/2A6 involvement in minor pathways).

Excretion

Renal: ~30-50% (as glucuronide conjugates). Minimal unchanged drug in urine.

Contraindications

Hypersensitivity to valproate
Hepatic disease or significant hepatic dysfunction
Urea cycle disorders (UCD) — can cause fatal hyperammonemic encephalopathy
Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (POLG; e.g., Alpers-Huttenlocher syndrome) — fatal hepatotoxicity
Pregnancy (for migraine prophylaxis — absolute contraindication; for epilepsy/bipolar — use only if no alternatives due to teratogenicity)
Known ornithine transcarbamylase (OTC) deficiency

Side effects

Common

Nausea, vomiting, diarrhea (GI upset — dose-related, often transient)Tremor (dose-related; often fine postural tremor)Sedation, somnolenceWeight gain (metabolic effect; dose-related)Alopecia (hair loss — often transient; reversible on dose reduction)Thrombocytopenia (dose-related; usually mild)Elevated liver enzymes (transient, usually asymptomatic)

Serious

Hepatotoxicity (fatal hepatic failure — idiosyncratic, not dose-related; highest risk <2 years, polytherapy, metabolic disorders). FDA black box warning.
Pancreatitis (can be fatal; may occur without hepatic toxicity)
Teratogenicity (neural tube defects, craniofacial defects, cognitive impairment — FDA black box warning for pregnancy)
Hyperammonemic encephalopathy (can occur with normal LFTs; symptoms: lethargy, vomiting, cognitive changes, focal neurological deficits, asterixis)
Thrombocytopenia (severe, with bleeding)
Bone marrow suppression (pancytopenia, aplastic anemia — rare)
Stevens-Johnson syndrome, toxic epidermal necrolysis
Hypothermia (rare, in combination with topiramate)
Polycystic ovary syndrome (PCOS) with chronic use in women
Suicidal ideation and behavior (FDA warning for all AEDs)

Pregnancy & lactation

Pregnancy

Lactation

Excreted in breast milk (infant dose ~1-10% of maternal). May cause infant hepatotoxicity, thrombocytopenia. Monitor infant for jaundice, poor feeding, bruising. Use lowest effective maternal dose.

Drug interactions

Aspirin

Severe

Database

Aspirin displaces valproate from albumin binding sites, increasing free (unbound) valproate fraction and risk of toxicity (tremor, somnolence, ataxia, hepatotoxicity) even with normal total levels.

Avoid concurrent use if possible. If necessary, monitor free valproate levels (not just total) and clinical signs of toxicity. Reduce valproate dose by 20-30%.

Source: Kimi deep-research + Cla

Bexarotene

Severe

Database

Drug interaction classified as: synergy

Source: DDInter

Buprenorphine

Severe

Database

Drug interaction classified as: synergy

Source: DDInter

Carbamazepine

Severe

Database

Enzyme inducers increase valproate clearance, reducing valproate levels. Valproate inhibits epoxide hydrolase, increasing carbamazepine-epoxide (active metabolite) levels. Complex bidirectional interaction.

Monitor valproate and carbamazepine-epoxide levels. May need to increase valproate dose by 50%. Watch for toxicity from carbamazepine-epoxide (diplopia, dizziness, ataxia).

Source: Kimi deep-research + Cla

Carbapenems

Severe

Database

Carbapenems dramatically reduce valproic acid serum concentrations by 50-100% within 24-48 hours, causing breakthrough seizures. Mechanism involves inhibition of intestinal absorption and increased hepatic clearance.

AVOID combination in seizure patients. If carbapenem essential for infection, add alternative anticonvulsant (levetiracetam, lacosamide) and monitor for seizures. Valproate levels recover 1-2 weeks after carbapenem discontinuation.

Source: Kimi deep-research + Cla · p1159

Dextropropoxyphene

Severe

Database

Clinical effect not specified

Source: DDInter

Doripenem

Severe

Database

Carbapenems markedly reduce valproate levels → breakthrough seizures

Avoid combination; if unavoidable use alternative anticonvulsant + monitor levels

Source: Kimi deep-research + Cla

Ertapenem

Severe

Database

Carbapenems markedly reduce valproate levels → breakthrough seizures

Avoid combination; alternative anticonvulsant + monitor levels

Source: Kimi deep-research + Cla

Faropenem

Severe

Database

Significant reduction in serum valproic acid levels, leading to loss of seizure control or worsening of psychiatric symptoms.

Concomitant use is generally contraindicated. If co-administration is unavoidable, consider alternative antiepileptics or closely monitor valproic acid levels and clinical response, with potential for significant dose adjustments. Alternative antibiotics should be considered.

Glycerol Phenylbutyrate

Severe

Database

Clinical effect not specified

Source: DDInter

Imipenem

Severe

Database

Clinical effect not specified

Source: DDInter

Leflunomide

Severe