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

FDA-approved for

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

Off-label

aggression/impulsivity

FDA label

Read the full label on DailyMed ↗

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
cap 125 mg
DR cap 125 mg
ER tab 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).