Divalproex ER

DEPAKOTE ER

Open Divalproex ER in the interactive console ↗

What it isExtended-release divalproex modulates sodium and T-type calcium channels; migraine (its original 2000 approval), mania, and seizures.

Why this oneER delivers less drug than DR, so converting DR to ER means RAISING the total daily dose 8-20% per the label.

What limits itAvoid in pregnancy; monitor liver, blood counts, and levels. Pancreatitis and hyperammonemic encephalopathy can be severe.

FDA-approved for

migraine prophylaxis (2000)
bipolar mania (~2005)
seizures (~2006)

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 / mixed episodes (bipolar disorder)	Adults	25 mg/kg/day QD	Increase as rapidly as possible to lowest effective dose; trough 85-125 mcg/mL	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	500 mg QD x 1 week	Then 1,000 mg QD (effective range of DR product 500-1,000 mg/day)	1,000 mg/day

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

Renal Undefined

Hepatic Contraindicated in hepatic disease or significant hepatic dysfunction

DR-to-ER conversion: total daily dose 8-20% higher, given once daily. No conversion factor above DR 3,125 mg/day.

Instructions

Once-daily; swallow whole, do not crush or chew
Conversion from Depakote (DR): give Depakote ER QD at a total daily dose 8-20% higher (per label Table 1); if not directly convertible, may round DR dose up to next strength first; Cmin on average equivalent but varies — check level if response unsatisfactory
If smaller dose adjustments are needed than ER strengths allow, use Depakote (DR) instead; elderly starts <250 mg only possible with DR
Medication residue in stool reported (rarely, some with diarrhea): check plasma valproate level and monitor clinically
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

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
Post-marketing: SJS/TEN, angioedema, hyperammonemia, PCOS/menstrual irregularities, decreased bone density/fractures, pancytopenia, reversible cerebral pseudoatrophy, male infertility, medication residue in stool

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).

⚠ BOXED WARNINGS