Divalproex DR

DEPAKOTE

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Divalproex DR ballicule: receptor binding, kinetics and half-life diagram — Mechanism of action: Divalproex DR ballicule

Divalproex DR DEPAKOTE mascot mnemonic cartoon — Visual mnemonic: Divalproex DR mascot
**“Dipsy”**
UGT inhibitor
Major teratogen

What it isSodium- and T-type calcium-channel modulator with SSADH and HDAC inhibition; seizures, bipolar mania, and migraine prevention.

Why this oneIts enteric-coated dimer of valproic acid + valproate sodium is dosed BID-TID and reduces gastric irritation versus straight valproic acid.

What limits itAvoid in pregnancy; monitor liver, blood counts and levels. Pancreatitis, hyperammonemia and carnitine depletion can be severe; it doubles lamotrigine levels.

Divalproex DR molecular structure (skeletal formula) — Molecular structure: Divalproex DR

Divalproex DR prescription history

Animated chart of estimated U.S. prescriptions per year, Bipolar disorder meds (1954–2026). Divalproex DR enters in 1983 (estimated).

FDA-approved for

seizures (1983)
bipolar mania (1995)
migraine prophylaxis (1996)

Off-label

aggression/impulsivity

Classes and tags

Clinical profile

Therapeutic safety burden2 / 4

Overdose danger2 / 4

Weight-gain liability3 / 4

Sedation liability2 / 4

QT / Torsades0 / 4

Direct muscarinic antagonism0 / 4

Embryofetal risk4 / 4

Legacy pregnancy categoryD

Defining liabilitySedation, dizziness and agent-specific rash, behavioral, hepatic, hematologic or teratogenic toxicity.

FDA label

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BOXED WARNING Fatal hepatotoxicity (highest risk age <2 yr and POLG mitochondrial disease — contraindicated; monitor LFTs, esp. first 6 mo), fetal risk (neural tube defects, major malformations, decreased IQ — contraindicated for migraine prophylaxis in pregnancy/childbearing potential without contraception), and life-threatening (incl. hemorrhagic) pancreatitis.

FDA dosing	Population	Start	Target	Max
Acute mania (bipolar disorder)	Adults	750 mg/day divided	Increase as rapidly as possible to lowest effective dose; trough 50-125 mcg/mL (max concentrations usually by day 14)	60 mg/kg/day
Complex partial seizures (mono- & adjunctive)	Adults & peds >=10 yr	10-15 mg/kg/day	Titrate to response; usual <60 mg/kg/day (plasma 50-100 mcg/mL); divide dose if >250 mg/day	60 mg/kg/day
Simple & complex absence seizures (sole & adjunctive; adjunctive in multiple seizure types incl. absence)	All ages studied	15 mg/kg/day	Titrate until seizures controlled or limiting side effects (plasma 50-100 mcg/mL); divide dose if >250 mg/day	60 mg/kg/day
Migraine prophylaxis	Adults	250 mg BID	Some benefit up to 1,000 mg/day; no evidence higher doses more effective	1,000 mg/day

Titration Epilepsy: increase by 5-10 mg/kg/day at 1-week intervals. Mania: increase as rapidly as possible to effect.

Renal Undefined

Hepatic Contraindicated in hepatic disease or significant hepatic dysfunction

Total daily dose >250 mg: give in divided doses. Long-term antimanic benefit (>3 wk) not demonstrated in controlled trials.

Instructions

Swallow tablets whole; do not crush or chew
Switching from valproic acid: start Depakote at same daily dose and schedule; once stable, BID-TID schedule may be used in selected patients
GI irritation: give with food or build dose up slowly
Do not discontinue abruptly when preventing major seizures — risk of status epilepticus
Conversion to monotherapy: reduce concomitant AED ~25% every 2 weeks
Elderly: reduce starting dose, increase more slowly; monitor fluid/nutrition, somnolence
On rufinamide: start valproate low and titrate to effect

Available strengths

DR tab 125, 250, 500 mg

Contraindications

Hepatic disease or significant hepatic dysfunction
Mitochondrial disorders caused by POLG mutations (e.g., Alpers-Huttenlocher); children <2 yr with suspected POLG-related disorder
Urea cycle disorders
Migraine prophylaxis: pregnancy, or childbearing potential without effective contraception

Cautions

Hepatotoxicity, incl. fatal — monitor serum liver tests before and frequently during therapy (esp. first 6 mo); age <2 yr, polytherapy, metabolic/organic brain disease at highest risk
Fetal risk: neural tube defects, major malformations, decreased IQ/neurodevelopmental disorders — avoid in women of childbearing potential unless other options failed; effective contraception + folate
Pancreatitis, incl. fatal hemorrhagic — discontinue if diagnosed
Hyperammonemic encephalopathy (evaluate for urea cycle disorders; risk increased with concomitant topiramate) — measure ammonia if unexplained lethargy/vomiting/mental-status change; hypothermia can co-occur
Dose-related thrombocytopenia, coagulation abnormalities (low fibrinogen, acquired von Willebrand) — CBC + coags at baseline, periodically, before surgery, and in pregnancy
Suicidal behavior/ideation (AED class effect, ~2x relative risk) — monitor mood/behavior
Hypothermia (<35 C), with or without hyperammonemia
DRESS/multiorgan hypersensitivity — discontinue
Somnolence in the elderly — reduce starting dose, titrate slowly, monitor intake/dehydration
Serious dermatologic reactions (SJS/TEN, sometimes fatal) and angioedema reported

Adverse reactions

>=15% (any indication): nausea, vomiting, abdominal pain, diarrhea, dyspepsia, somnolence, dizziness, tremor, asthenia, headache, insomnia, thrombocytopenia, alopecia, diplopia, infection
Mania trials add: sedation-spectrum, weight gain, appetite changes
Post-marketing: SJS/TEN, angioedema, hyperammonemia, PCOS/menstrual irregularities, decreased bone density/fractures, pancytopenia, reversible cerebral pseudoatrophy, male infertility

Pregnancy High teratogenicity: neural tube defects ~1-2% (registry major-malformation rate 9-11% at ~1,000 mg/day), craniofacial/cardiac/limb defects, hypospadias; decreased IQ, ASD/ID/ADHD risk; dose-dependent, no safe threshold. Contraindicated for migraine prophylaxis; epilepsy/bipolar only if other drugs failed. Do not stop abruptly (status epilepticus). Folate + NAAED registry (1-888-233-2334).

Lactation Excreted in milk at 1-10% of maternal serum levels (infant serum 0.7-4 mcg/mL, 1-6% of maternal); no adverse developmental/cognitive effects reported through age 6. Monitor breastfed infant for jaundice and unusual bruising/bleeding (hepatic failure and clotting abnormalities reported in valproate-exposed offspring).