EpilepsyRx

Valproate / divalproex

Depakote · Depakene

DailyMed-verified antiseizure indications

Indication / use

Label / evidence summary
Divalproex and valproic acid: monotherapy or adjunctive therapy for complex partial seizures and simple or complex absence seizures; adjunctive therapy for multiple seizure types that include absence. Depakote ER epilepsy labeling starts at age 10 years; other products have separate age information. IV valproate is a temporary alternative when oral treatment is not feasible, not a labeled status-loading regimen.
Role
Maintenance
Class
Multiple proposed mechanisms, including increased GABA availability

Indications checked 26 September 2026. Product, route, age, and treatment-role limits apply. A DailyMed listing alone does not establish FDA approval.

Formulations & strengths

U.S. products unless another country is named. Strengths are per unit or stated volume.

Brand & formulation labels

Each link names the product and formulation it covers. Archived labels do not establish current availability.

Dosing & administration

Adult / product-specific schedule
DR divalproex / immediate-release valproic acid: focal seizures start 10–15 mg/kg/day; absence usually 15 mg/kg/day; increase 5–10 mg/kg/day weekly, maximum 60 mg/kg/day. Give in divided doses when the product label directs. Depakote ER is once daily; do not apply a divided-dose instruction to ER.
Pediatric
Epilepsy dosing is product/indication-specific. Depakote DR complex focal use is described from age 10; ER epilepsy use from age 10. Younger use requires the appropriate product label/specialist assessment. Highest fatal-hepatotoxicity risk is under age 2.
Titration / repeat dosing
Depakote DR → ER (≥10 years): once-daily ER total dose 8–20% higher, using the label conversion table below; some strengths cannot be converted directly. IV replacement: equivalent total daily oral dose, 60-minute infusion at ≤20 mg/min, same frequency with divided dosing if >250 mg/day; monitor levels. Equivalence was evaluated with 6-hourly IV dosing; less frequent dosing may need trough monitoring.

Valproate: formulation-specific administration

ProductStarting / replacement scheduleAdministration
Depakote delayed-release (DR)Complex focal: 10–15 mg/kg/day; absence: 15 mg/kg/day. Increase 5–10 mg/kg/day weekly; maximum 60 mg/kg/day.Follow divided-dose instructions; swallow DR tablets whole.
Depakote extended-release (ER)Once-daily epilepsy regimen; DR conversion requires 8–20% higher total daily dose and the table below.Once daily; swallow whole. Do not crush or chew. Do not apply the DR >250 mg divided-dose instruction to ER.
Valproic acid oral solution (250 mg/5 mL)Full label §2.1: focal start 10–15 mg/kg/day; absence 15 mg/kg/day, weekly increments 5–10 mg/kg/day; max 60 mg/kg/day.Use a calibrated oral measuring device. The linked full label directs divided doses when total daily dose exceeds 250 mg.
Valproate sodium IV (temporary oral replacement)Equivalent total daily oral dose; infuse over 60 minutes, no faster than 20 mg/min.Use a divided regimen when >250 mg/day. Steady-state equivalence was studied every 6 hours; less frequent regimens require close trough monitoring. Not an IV status-loading protocol.

Doses expressed as valproic acid equivalent. Product labels are linked below; the oral-solution highlights abbreviate absence initiation differently from full §2.1, which is the schedule summarized here. Switching formulations requires prescriber review.

Depakote DR → Depakote ER conversion (label Table 1)

DR total mg/dayER mg once daily
500*–625750
750*–8751,000
1,000*–1,1251,250
1,250–1,3751,500
1,500–1,6251,750
1,7502,000
1,875–2,0002,250
2,125–2,2502,500
2,3752,750
2,500–2,7503,000
2,8753,250
3,000–3,1253,500

*500, 750 and 1,000 mg/day cannot directly achieve an 8–20% increase with available ER strengths. The prescriber may first adjust DR to the next higher dose per label. This table does not cover doses above 3,125 mg/day. Assess response and concentrations after conversion.

Dose adjustment & concentrations

Renal impairment
No routine adjustment, but reduced protein binding makes total levels harder to interpret.
Hepatic impairment
Contraindicated in hepatic disease/significant dysfunction and specified mitochondrial disorders.
Serum reference information
Epilepsy label: total valproate usually 50–100 mcg/mL. Mayo VALPG reports total 50 (trough)–125 (peak) mcg/mL and free 5–25 mcg/mL. These are different reference contexts, not interchangeable targets. Consider a measured free level when albumin is low, binding is altered, or toxicity conflicts with the total level.

Safety

Boxed warning
Boxed warnings: potentially fatal hepatotoxicity, fetal malformations and adverse neurodevelopment, and potentially fatal pancreatitis. Hepatotoxicity risk is highest under age 2, especially with multiple ASMs or mitochondrial disease.
Contraindications
Hepatic disease/significant dysfunction; known POLG mitochondrial disorder or suspected POLG disorder under age 2; urea-cycle disorders; hypersensitivity. Pregnancy/ineffective contraception is a contraindication for migraine prevention; epilepsy has separate stringent restrictions.
Serious precautions & monitoring
Hepatotoxicity (especially under age 2 and mitochondrial disease), pancreatitis, thrombocytopenia/coagulopathy and hyperammonemia. Baseline and frequent early liver tests; blood counts/coagulation as indicated; ammonia for unexplained lethargy/vomiting/mental-status change.

Common / selected adverse effects

  • Nausea
  • Headache
  • Somnolence
  • Tremor
  • Vomiting
  • Alopecia, depending on study
  • Weight gain

Drug interactions: toxicity & clinical action

Partner / combinationClinical effectClinical action
LamotrigineMore than doubles lamotrigine exposure through impaired clearance; serious rash risk increases.Use the lamotrigine valproate-specific titration. Reassess dose if either drug starts/stops; promptly assess rash or systemic hypersensitivity symptoms.
Phenobarbital / primidone / phenytoinPhenobarbital may accumulate; free phenytoin may rise despite a misleading total concentration.Monitor sedation/ataxia; check phenobarbital or free phenytoin when indicated and adjust partner dose.
Topiramate / cannabidiolTopiramate: hyperammonemic encephalopathy/hypothermia. Cannabidiol: increased liver-injury risk.Check ammonia for compatible symptoms; monitor liver tests with cannabidiol and review dose reduction/withdrawal.
Carbapenem antibiotics (e.g., meropenem)Rapid, substantial fall in valproate can cause breakthrough seizures; dose escalation alone may not overcome the interaction.Prefer an alternative antibiotic or additional/alternative ASM with specialist input; monitor during and after the antibiotic.
Lorazepam / rufinamide / ganaxolone / aspirin or anticoagulantsExposure to sedating partner drugs may increase; aspirin may increase free valproate, and bleeding risk can be compounded.Use partner-specific dose adjustments, concentration/clinical monitoring and platelet/coagulation assessment as indicated.

Pregnancy & contraception

Fetal / neonatal risk
Valproate increases major-malformation, neural-tube-defect and adverse neurodevelopmental risks. For epilepsy in pregnancy or planned pregnancy, the U.S. label restricts use to situations where alternatives fail or are unacceptable. AAN/AES/SMFM advises avoidance when clinically feasible. Do not stop abruptly after pregnancy recognition.
Contraception
Use effective contraception when valproate is required. Estrogen-containing contraceptives may lower valproate concentrations; monitor response and levels when they are started or stopped.

Clinical evidence

Research summaries describe studied populations and outcomes; they do not add indications or constitute treatment recommendations.

Extrapolation Direct pivotal trial Guideline-supported off-label use

Trial summary

Study design / duration
Older active-controlled monotherapy and adjunctive complex-partial-seizure studies predated current Phase 3 conventions; endpoints included time to exit for seizure deterioration and seizure-frequency comparisons.
Primary endpoint
No single pivotal endpoint is identified in the cited source.
Results
Introduced before modern Phase 3 conventions. Controlled monotherapy data in complex partial seizures found efficacy comparable to carbamazepine; absence-seizure evidence derives largely from older trials and later comparative studies rather than a single contemporary placebo-controlled Phase 3 program.

Trial publications

Comparative evidence

Findings
Childhood absence randomized double-blind trial: freedom from treatment failure at 16–20 weeks was 53% ethosuximide, 58% valproate and 29% lamotrigine; this composite is not a seizure-freedom rate. SANAD II randomized 520 patients aged ≥5 years with newly diagnosed generalized or unclassified epilepsy. Levetiracetam failed the prespecified non-inferiority criterion for time to 12-month remission; the per-protocol analysis favored valproate. Open-label design, mixed syndromes and 65% male participation limit extrapolation to every patient with IGE.

Mechanism of action

  • Divalproex sodium dissociates to valproate; it is not an ester prodrug analogous to eslicarbazepine acetate. Different formulations deliver the same active valproate moiety.
  • The precise antiseizure mechanism is unknown. Increased brain GABA availability is a proposed contributor, rather than direct benzodiazepine-site GABA-A potentiation.
  • Sodium-current and T-type calcium-current effects have been demonstrated in experimental preparations. Their importance at clinical exposures varies with the model and is not established as a fixed three-target mechanism.

Pharmacology

Adult values unless specified. Vd/F denotes apparent oral distribution volume.

Pharmacokinetics

Bioavailability
Near-complete systemic availability for conventional oral products. Depakote ER: approximately 90% absolute bioavailability after a meal and approximately 89% relative to an equal daily delayed-release dose. IV: 100%.
Elimination half-life
Approximately 9–16 hours during adult monotherapy; altered by enzyme inducers, liver function, age and protein binding.
Volume of distribution
Total valproate: mean 11 L/1.73 m²; free valproate: 92 L/1.73 m² in the U.S. label. The different values reflect the concentration measure used and must not be interchanged.
Active metabolite(s)
Some metabolites are pharmacologically active in preclinical studies, including trans-2-en-valproate. Their contribution to human antiseizure efficacy is not established; other metabolites may contribute toxicity.
Active-metabolite half-life
No well-established human half-life for active trans-2-en-valproate is provided in the cited clinical label/primary evidence. Do not reuse the parent 9–16-hour value for the metabolite.
Protein binding
~90% and concentration-dependent
Metabolism / elimination
Extensive hepatic glucuronidation and mitochondrial beta-oxidation

Free fraction increases with concentration and can rise with low albumin or displacement; total levels alone can mislead.

Molecular structure

Molecular structure of Valproic acid — parent acid of valproate
The neutral acid is shown. Valproate is predominantly ionized at physiological pH; divalproex is a formulation supplying valproate.
NIH PubChem structure and record ↗

Product history

Initial U.S. approval
1978 (valproic acid); 1983 (divalproex)
Market / formulation history
1978; divalproex 1983
Brands
Depakote · Depakene
Manufacturer / marketer
AbbVie (Depakote); brand availability varies (Depakene)
Generic availability
Yes
Related drugs
Divalproex dissociates to valproate; valproic acid, sodium valproate, and divalproex share the active valproate ion.

Sources & review status

Representative sources are selected product labels, not an exhaustive list of generic manufacturers. Consult the exact product and formulation prescribed. Brand-name package inserts are linked separately.

Brand references: Depakote delayed-release tablets ↗ · Depakote ER ↗ · Depakote Sprinkle ↗ · Depakene — archived brand label ↗

Indications and DailyMed PDFs checked: 2026-09-26. Other profile sources reviewed: 2026-09-15 · label revision noted at that review: 3/2026. This is a draft reference; final review is pending.

Send a comment · Privacy & traffic measurement