Antiepileptic

Valproate (Depacon)

Also called Depacon

Reviewed by Alex G, BSN, RN, CEN, CCRN, CMC, NREMT-P · From the Reference tab of the app

Indications

Established status epilepticus after a benzodiazepine (off-label; 40 mg/kg, max 3,000 mg, over 10 min in ESETT 2019: 46% response, similar to levetiracetam and fosphenytoin; AES 2016 second-line option, Level B)
IV replacement for oral valproate in focal, absence and generalized seizures when oral dosing is temporarily not feasible (the injection's only labeled use; same total daily dose and frequency as oral, each dose over 60 min and no faster than 20 mg/min, with limited label experience of faster rates; not studied beyond 14 days; the label gives no status epilepticus or loading dose)
Manic or mixed episodes of bipolar disorder (oral divalproex label)
Migraine prophylaxis (oral divalproex label; contraindicated in pregnancy and in women of childbearing potential without effective contraception)
Refractory nonconvulsive status, absence or myoclonic status and status in known generalized epilepsy, where sodium-channel drugs can worsen seizures (off-label)

Dosing

Where	Dose
Seizures and neuro	Valproate: 40 mg/kg (max 3,000 mg) over 10 min

Mechanism of action

Valproate works through several targets, and the label says its mechanism is not established. It raises brain GABA by inhibiting GABA transaminase and succinic semialdehyde dehydrogenase, limits sustained high-frequency firing by slowing recovery of voltage-gated sodium channels, and reduces T-type calcium currents in thalamic neurons, which explains its breadth against absence, myoclonic and generalized seizures. It also inhibits histone deacetylase, which is linked to its teratogenicity. As a branched fatty acid it enters mitochondrial β-oxidation, ties up carnitine and coenzyme A and lowers N-acetylglutamate, the activator of carbamoyl phosphate synthetase I, so ammonia can rise even when the liver is otherwise normal.

Pharmacology

CNS: drowsiness, tremor, ataxia and diplopia, dose-related; less sedation than phenobarbital at loading doses; hyperammonemic encephalopathy (lethargy, vomiting, confusion, asterixis, coma) with normal LFTs
Cardiovascular and respiratory: little hypotension or respiratory depression at ESETT loading doses, which makes it useful when blood pressure is fragile; no QTc effect
Hematologic: dose-related thrombocytopenia (platelets ≤75,000 in 27% at about 50 mg/kg/day), platelet dysfunction and low fibrinogen; can add to bleeding risk around surgery
Hepatic and GI: nausea and vomiting; transaminase rises; rare fatal hepatotoxicity, usually in the first 6 months; pancreatitis, including hemorrhagic cases, at any time
Metabolic: carnitine depletion, hypothermia (with or without high ammonia, and with topiramate), weight gain and hair loss with long use
Other: inhibits glucuronidation and CYP2C9, raising lamotrigine, phenobarbital and free phenytoin; teratogenic (neural tube defects, lower IQ, autism risk)

Pharmacokinetics

Onset	Level peaks at the end of the infusion; a 40 mg/kg load reaches the therapeutic range at once
Half-life	16 ± 3 h after 1 g IV in monotherapy; much shorter (often 6–9 h) with phenytoin, carbamazepine or phenobarbital, which can double clearance
Distribution	Vd about 11 L/1.73 m² for total drug (roughly 0.15 L/kg, plasma and extracellular water); CSF levels match free plasma levels (about 10% of total); crosses the placenta
Protein binding	About 90% to albumin at 40 mcg/mL, falling to about 81.5% at 130 mcg/mL (saturable); less in hypoalbuminemia, kidney or liver disease, older adults and with aspirin
Metabolism	Liver: glucuronidation 30–50%, mitochondrial β-oxidation over 40%, CYP oxidation (2C9, 2A6, 2B6) under 15–20%, which makes the hepatotoxic 4-ene-valproate
Elimination	Urine, mostly as the glucuronide; under 3% unchanged
Levels	Total trough 50–100 mcg/mL; thrombocytopenia becomes more likely above 110 mcg/mL in women and 135 in men
Low albumin	Total levels underestimate free drug as albumin falls and the free fraction rises; in critical illness, uremia or liver disease measure a free level (commonly quoted target about 5–15 mcg/mL)
Nonlinear binding	Doubling the dose less than doubles the total level, while free drug rises in proportion; a faster infusion gives a higher free peak
Bioavailability	Oral products nearly complete; IV and oral doses are interchangeable at the same total daily dose
Overdose	Free fraction rises steeply, so hemodialysis removes meaningful drug in severe poisoning; patients have survived levels of 2,120 mcg/mL

Chemistry

Valproic acid is 2-propylpentanoic acid, an eight-carbon branched-chain fatty acid with no ring and no nitrogen, unlike other antiepileptics; molecular weight 144
Achiral; a weak carboxylic acid (pKa about 4.8) that is fully ionized at body pH yet lipid soluble enough as the acid to cross membranes
Divalproex sodium (oral) is a 1:1 coordination compound of valproic acid and sodium valproate; all forms deliver the same valproate ion, dosed as valproic acid
Injection: valproate sodium equivalent to 100 mg/mL valproic acid in 5 mL single-dose vials, with edetate disodium, pH 7.6, no preservative; dilute in at least 50 mL of D5W, saline or lactated Ringer's (stable 24 h at room temperature); store at 20–25 °C

Adverse effects and cautions

Safety

Boxed warning: hepatotoxicity, sometimes fatal, mostly in the first 6 months; highest risk under age 2, on multiple antiepileptics, and with mitochondrial disease; contraindicated in hepatic disease and in POLG disorders such as Alpers-Huttenlocher, where it can cause fatal liver failure
Boxed warning: fetal risk (neural tube and other major malformations, lower IQ, autism); avoid in women who could become pregnant unless other drugs have failed, and use effective contraception
Boxed warning: pancreatitis, including hemorrhagic cases; check lipase for abdominal pain or vomiting and stop the drug if confirmed
Hyperammonemic encephalopathy, even with normal LFTs: check ammonia for unexplained lethargy, vomiting, confusion or hypothermia; stop valproate and give levocarnitine (StatPearls for overdose with altered mental status: 100 mg/kg IV load, then 50 mg/kg every 8 h; evidence is from case series); contraindicated in urea cycle disorders
Thrombocytopenia and coagulation defects: platelets and coagulation tests before surgery and when bleeding
Carbapenems (meropenem, ertapenem, imipenem) can drop levels to subtherapeutic with loss of seizure control (label), by about 60% within 24 h in one retrospective series, where raising the valproate dose did not restore therapeutic levels (Wu 2016): choose a different antibiotic or antiepileptic, or monitor levels often if the pair cannot be avoided
Interactions: lamotrigine half-life rises from 26 to 70 h (halve the lamotrigine dose; SJS/TEN risk); valproate displaces phenytoin from albumin and inhibits its metabolism, so free phenytoin rises while total looks normal or low; topiramate adds hyperammonemia and hypothermia; aspirin raises free valproate; enzyme inducers lower levels; it can raise the INR on warfarin and propofol levels
DRESS and other hypersensitivity; drowsiness in older adults, so start lower; do not stop abruptly

In the one-pagers

Practice Neuro: ICP and Stroke questions free55 exam-style questions with rationales on the topic where Valproate comes up most. No account or download needed.

In the algorithms

Practice free in your browser2,450+ exam-style questions with rationales. No account, no ads. Also free on the App Store and Google Play.

Sources

FDA label: valproate sodium injection, Sagent (2026)
Kapur 2019, ESETT (NEJM)
Glauser 2016, AES status epilepticus guideline
Mancl 2009 (carbapenem interaction)
Wu 2016 (carbapenem interaction, Ther Drug Monit)
Brown 2018 (levocarnitine case series)
StatPearls: Valproate Toxicity (levocarnitine dose)

For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow your local protocols and medical direction.