Schedule H

Oral, Intravenous

• Oral tablets: 200 mg, 300 mg, 500 mg

• Oral controlled-release tablets: 200 mg CR, 300 mg CR, 500 mg CR

• Oral syrup: 200 mg/5 mL

• Injection (IV): 100 mg/mL (5 mL vial = 500 mg)

• Note: Valproate semisodium (divalproex sodium) also available — refer separate entry

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Epilepsy — Generalised and Focal Seizures

Adults:

Parameter Recommendation

Starting dose 10–15 mg/kg/day orally in 2–3 divided doses

Titration Increase by 5–10 mg/kg every 5–7 days based on response

Usual maintenance dose 20–30 mg/kg/day

Maximum dose 60 mg/kg/day (specialist supervision for refractory cases)

Clinical notes:

• CR formulations preferred for once or twice daily dosing and improved tolerability

• Target therapeutic plasma level: 50–100 μg/mL

• Syrup formulation useful for dose flexibility

1. Status Epilepticus (IV) — When first-line agents fail

Adults:

Parameter Recommendation

Loading dose 20–40 mg/kg IV over 10–15 minutes

Maintenance 1–2 mg/kg/hour continuous infusion OR transition to oral when feasible

Maximum infusion rate 6 mg/kg/min

Clinical notes:

• Specialist/ICU setting only

• Avoid rapid bolus to reduce hypotension risk

• Alternative when phenytoin contraindicated

1. Bipolar Disorder — Acute Mania

Adults:

Parameter Recommendation

Starting dose 750–1000 mg/day orally in 2–3 divided doses

Titration Increase by 250–500 mg every 3–5 days

Usual maintenance dose 1000–2000 mg/day

Maximum dose 60 mg/kg/day

Target plasma level 50–125 μg/mL

Clinical notes:

• Not recommended for maintenance monotherapy in bipolar disorder

• Avoid in women of childbearing potential unless pregnancy prevention programme in place

Secondary Indications — Adults Only (Off-label)

Indication Dose Duration Notes

Migraine prophylaxis — OFF-LABEL 500–1000 mg/day in divided doses 3–6 months trial Specialist initiation; supported by RCT evidence; avoid in women of childbearing age

Behavioural disturbance in dementia — OFF-LABEL 250–500 mg/day Variable Specialist-only; limited evidence; use with extreme caution in frail elderly

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

1. Epilepsy — Generalised and Focal Seizures

Age: ≥1 month

Weight Starting Dose Maintenance Dose Maximum Dose

<20 kg 10–15 mg/kg/day in 2–3 divided doses 20–30 mg/kg/day 40 mg/kg/day

≥20 kg 300–600 mg/day in 2–3 divided doses 20–35 mg/kg/day 60 mg/kg/day (refractory cases)

Clinical notes:

• Use syrup formulation for accurate dosing in infants and young children

• Titrate by 5–10 mg/kg/week

• Target plasma levels: 50–100 μg/mL

1. Status Epilepticus (IV)

Paediatric Neurologist supervision mandatory

Parameter Recommendation

Loading dose 20–30 mg/kg IV over 10–15 minutes

Maintenance 1–2 mg/kg/hour IV OR transition to oral

Secondary Indications — Paediatrics (Off-label)

Not routinely recommended for off-label indications in paediatric population.

Paediatric Safety Alert

⚠️ Avoid use in children <2 years unless absolutely essential and under specialist supervision — significantly increased risk of fatal hepatotoxicity, particularly with:

• Polytherapy with other antiepileptics

• Underlying metabolic disorders

• Developmental delay

Mild–Moderate impairment No dosage adjustment required

Severe impairment/Dialysis Monitor free (unbound) valproate levels; total levels may be misleading due to decreased protein binding

Haemodialysis Valproate is not significantly dialysed; supplemental dosing generally not required

• Active liver disease or significant hepatic dysfunction

• Family history of severe hepatic dysfunction (especially drug-related)

• Known hypersensitivity to valproate or any excipient

• Urea cycle disorders (risk of hyperammonaemic encephalopathy)

• Known mitochondrial disorders caused by POLG mutations

• Porphyria

• Women of childbearing potential for psychiatric indications or migraine (unless adequate contraception and informed consent)

• Age <2 years — highest risk of fatal hepatotoxicity

• Concomitant use with other antiepileptics (increased hepatotoxicity and ADR risk)

• Elderly — increased sensitivity, fall risk, cognitive effects

• Pre-existing thrombocytopenia or bleeding disorders

• History of pancreatitis

• Systemic lupus erythematosus

• Renal impairment (monitor free drug levels)

• Patients at risk of suicidal ideation — monitor closely

• Before elective surgery — assess bleeding risk

Aspect Guidance

Overall risk High teratogenic potential — neural tube defects (1–2%), craniofacial abnormalities, developmental delay, autism spectrum disorder

Epilepsy indication Avoid if safer alternatives exist; if essential, use lowest effective dose as monotherapy (preferably <1000 mg/day)

Psychiatric/Migraine indication CONTRAINDICATED

Preconception High-dose folic acid (5 mg/day) at least 3 months prior

Monitoring Detailed anomaly scan at 18–20 weeks; serial growth scans

Counselling Mandatory informed consent regarding teratogenic risks before initiating in any woman of childbearing potential

Aspect Guidance

Compatibility Generally compatible with breastfeeding

Excretion in milk Low (1–10% of maternal serum concentration)

Infant monitoring Observe for excessive sedation, poor feeding, jaundice

Preferred alternative If mother requires valproate for epilepsy, breastfeeding acceptable with monitoring

Aspect Recommendation

Starting dose 250–500 mg/day

Titration Slow (increase every 5–7 days)

Cautions Increased risk of sedation, tremor, gait instability, falls

Monitoring Baseline and periodic LFTs, platelet count; monitor for encephalopathy symptoms

Special considerations Risk of SIADH-like hyponatraemia (rare); cognitive impairment may be exacerbated

Interacting Drug Effect Management

Lamotrigine Valproate inhibits lamotrigine metabolism — markedly increased lamotrigine levels and risk of serious rash (SJS/TEN) Reduce lamotrigine dose by 50%

Carbapenem antibiotics (meropenem, imipenem) Rapid and significant reduction in valproate levels (up to 60–90%) Avoid combination; use alternative antibiotic or AED

Topiramate Additive risk of hyperammonaemia and encephalopathy Monitor ammonia levels; avoid if possible

Phenytoin Mutual interaction — unpredictable changes in levels of both Monitor levels of both drugs; dose adjustment likely needed

Carbamazepine Enzyme induction decreases valproate levels May need to increase valproate dose; monitor levels

Warfarin Valproate displaces warfarin from protein binding — increased bleeding risk Monitor INR closely; adjust warfarin dose

Interacting Drug Effect Management

Aspirin (high-dose) Increased free valproate fraction; increased toxicity risk Use with caution, especially in children

Benzodiazepines Additive CNS depression Monitor for excessive sedation

Rifampicin May reduce valproate efficacy via enzyme induction Monitor clinical response and serum levels

Cholestyramine Reduced valproate absorption Separate administration by at least 3 hours

Cimetidine Inhibits valproate metabolism; increased levels Monitor for toxicity

Erythromycin May increase valproate levels Monitor

• Nausea, vomiting, dyspepsia

• Weight gain

• Tremor (dose-related)

• Transient hair loss (reversible on dose reduction)

• Drowsiness, lethargy

• Asymptomatic elevation of liver transaminases

• Peripheral oedema

Adverse Effect Clinical Notes

Hepatotoxicity Highest risk in children <2 years, polytherapy, metabolic disorders; can be fatal; monitor LFTs; discontinue if symptomatic liver dysfunction

Pancreatitis Can occur at any time; may be fatal; discontinue immediately if suspected

Thrombocytopenia Dose-related; check platelet count if bruising or bleeding

Hyperammonaemic encephalopathy Altered consciousness, lethargy, vomiting; can occur without LFT abnormalities; check ammonia levels

Severe cutaneous reactions SJS/TEN (rare); discontinue immediately

Teratogenicity Neural tube defects, developmental delay — see Pregnancy section

Phase Parameters

Baseline LFTs, CBC with platelets, serum ammonia (if symptoms), coagulation profile, pregnancy test (if applicable)

During titration LFTs and CBC at 2–4 weeks

Therapeutic drug monitoring Target: 50–100 μg/mL (epilepsy); 50–125 μg/mL (mania); check if toxicity suspected, non-response, or drug interactions

Long-term LFTs and CBC every 3–6 months

Special populations More frequent monitoring in children <2 years, elderly, hepatic impairment

• Encorate®, Encorate Chrono® (Sun Pharma)

• Valparin®, Valparin Chrono® (Sanofi)

• Epilex®, Epilex Chrono® (Abbott)

• Valance® (Intas)

• Sodival® (Micro Labs)

• Multiple generic formulations widely available

Note: Not currently on NLEM 2022 for psychiatric indications; included for epilepsy.

• Hepatotoxicity risk is highest in children <2 years on polytherapy — avoid unless no alternatives; monitor LFTs rigorously

• Mandatory pregnancy counselling — all women of childbearing potential must be counselled about teratogenic risks before initiation; document informed consent

• CR formulations improve compliance and reduce peak-related adverse effects (tremor, sedation)

• Tremor and hair loss are dose-dependent — often improve with dose reduction or zinc supplementation (for hair loss)

• IV valproate is a useful second-line agent in status epilepticus when phenytoin is contraindicated (cardiac disease, hypotension)

• Avoid carbapenem antibiotics in patients on valproate — dramatic reduction in levels can precipitate seizures

• Check ammonia levels if unexplained lethargy or confusion develops, even with normal LFTs

sodium valproate; epilepsy; broad-spectrum antiepileptic; bipolar mania; status epilepticus; teratogenic; hepatotoxicity; paediatric caution; pregnancy contraindicated; India

RxIndia v1.0 — 04 May 2025

• CDSCO approved prescribing information

• National Formulary of India (NFI) 2021

• Indian Epilepsy Society Guidelines

• NIMHANS Psychiatry Protocols

• API Textbook of Medicine

• AIIMS Neurology Protocols

• IAP Guidelines (Paediatric dosing)

• ICMR Guidelines for Reproductive Health (teratogenicity)

• Published RCTs/meta-analyses (migraine prophylaxis — off-label basis)