Valproate Sodium

ED / ICU / Transport

• Benzodiazepine-refractory convulsive status epilepticus: a second-line option when benzodiazepines have failed, alongside levetiracetam and fosphenytoin. The evidence is ESETT (off-label; not an FDA-labeled indication). The AES 2016 guideline rates the second therapy as less effective than the first in adults (Level A). ESETT is the trial that put the three second-line drugs head to head
• Epilepsy when oral valproate is temporarily not feasible: the label lists IV valproate for complex partial and absence seizures. Move to oral as soon as you can

Need the other two? Each has its own page: levetiracetam and fosphenytoin.

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

• Valproate sodium injection, USP: 100 mg/mL (equal to 100 mg valproic acid per mL) in 5 mL single-dose vials (500 mg per vial). No preservative. Discard whatever you don't use.
• Oral products: Valproic acid and divalproex sodium are different dosage forms. Don't treat them as one drug under two names. When you switch, match the total daily dose (see the Replacement row below).

Check the volume before you hang it. 3,000 mg is 30 mL of 100 mg/mL. Confirm mg and mL on the label and on the pump every time the dose changes.

Adult Dosing

Renal and hepatic dosing, and which weight to use, are covered under Special Populations.

Pediatric Dosing

Preparation & Administration

• Dilution: Use at least 50 mL of a compatible diluent: dextrose 5%, 0.9% sodium chloride or lactated Ringer's. It stays stable for at least 24 hr at 15–30 °C in glass or PVC. Look for particles and discoloration before it goes in.
• Push rate (maintenance): A 60-min infusion, never faster than 20 mg/min. Rapid infusion is associated with more adverse reactions. The label has limited experience with infusions under 60 min.
• Load rate: ESETT pushed 40 mg/kg over 10 min by pump: 4 mg/kg/min, up to 300 mg/min at the 3,000 mg cap. The label's limit is 20 mg/min, and ESETT ran well above it. A label safety study gave about 90 patients single 5–10 min infusions at 1.5–3 mg/kg/min. It was not built to test effectiveness. In that fast group, somnolence hit 10.7% and dizziness 7.1%. Standard infusions gave 1.7% and 5.2%. Your local protocol sets the load rate.
• Line: The label has no Y-site compatibility data. Check with pharmacy before you co-infuse anything.
• Storage: store vials at 20–25 °C (68–77 °F); excursions 15–30 °C (59–86 °F) permitted.

Contraindications

• Hepatic disease or significant hepatic dysfunction
• Known mitochondrial disorder caused by POLG mutations (for example, Alpers-Huttenlocher syndrome)
• Children under 2 yr with a suspected POLG-related disorder
• Known urea cycle disorder
• Known hypersensitivity to valproate
• Migraine prophylaxis only: pregnancy, or childbearing potential without effective contraception

Precautions

• Pregnancy and childbearing potential: The boxed warning applies. Use it only when other drugs have failed. In pregnant women with epilepsy, don't stop it abruptly. Status epilepticus is the risk.
• Children under 2 yr: No IV safety data for this age. Sole agent only.
• Older adults: Expect more somnolence. Start low and titrate slowly.
• Critical illness: Low albumin, uremia and propofol raise the free fraction. A total level can mislead you here.
• Acute head trauma: Not for seizure prophylaxis. In the label's post-traumatic seizure study, death ran 13% on IV valproate versus 8.5% on IV phenytoin (label 5.14). Many of those patients were critically ill. Treat active seizures per protocol.
• Males: Male infertility has been reported (label 8.3).
• Before planned surgery: Check blood counts and coagulation tests first. Evidence of hemorrhage, bruising or a hemostasis disorder is your cue to reduce the dose or stop (label 5.7).

Hold / Reassess If

• Significant hepatic dysfunction, suspected or apparent: discontinue immediately.
• Ammonia increased: discontinue valproate, treat and evaluate for a urea cycle disorder (label).
• Pancreatitis diagnosed: ordinarily discontinue (label).
• Platelets falling or bleeding: total level 110 mcg/mL (female) or 135 mcg/mL (male) or more; reassess the dose.
• Core temperature below 35 °C (95 °F): check ammonia.
• DRESS (rash, fever, eosinophilia, organ involvement): discontinue (label).

Common

• Intravenous trials (N = 463): dizziness 5.2%, headache 4.3%, injection-site pain 2.6%, somnolence 1.7%, nausea 3.2%.
• Oral high-dose monotherapy (divalproex, lower-dose comparison): tremor 57%, nausea 34%, somnolence 30%; thrombocytopenia 24% (1% in the lower-dose group).
• The oral data also report alopecia, asthenia and weight gain.

ESETT safety: life-threatening hypotension (1.6% valproate, 0.7% levetiracetam, 3.2% fosphenytoin) did not differ significantly among the three groups. Neither did life-threatening arrhythmia or death.

Serious / Life-Threatening

Overdose & Toxicity Management

• Signs: Look for somnolence, heart block, deep coma and hypernatremia. Recovery has been reported even at levels as high as 2,120 mcg/mL.
• Immediate: supportive care, attention to urine output, ECG for conduction block, and airway protection.
• Naloxone: It has been reported to reverse CNS depression. It may also reverse the antiseizure effect, so use it with caution in epilepsy (see naloxone).
• Extracorporeal removal: Hemodialysis, or hemodialysis with hemoperfusion, can pull significant drug out (see hemodialysis).
• Hyperammonemia: Stop valproate. Treat with the toxicology and metabolic teams. L-carnitine rests mainly on case series, per a 2026 systematic review. A valproate toxicity cohort showed no kinetic or survival advantage. It may be considered in severe toxicity with hyperammonemia or hepatotoxicity. No dose is established.

Clinically Significant Interactions

IV Compatibility

• Preferred diluents: dextrose 5%, 0.9% sodium chloride and lactated Ringer's (at least 50 mL per dose).
• Stability: physically compatible and chemically stable for at least 24 hr at 15–30 °C in glass or PVC bags.
• Y-site: The label has no Y-site data. Verify with your institution's compatibility resource.

• Pediatrics: The risk of fatal hepatotoxicity is highest under 2 yr. IV safety hasn't been studied under 2 yr, and a suspected POLG disorder is a contraindication. ESETT enrolled children 2 yr and older. The label reports no unique safety concerns in 35 children aged 2–17 yr. Doses are in the Pediatric Dosing table.
• Neonates: Half-life runs 10–67 hr in children under 10 days (label). Maternal use has been linked to neonatal hypoglycemia, hemorrhagic complications and fatal hepatic failure in infants.
• Pregnancy: The boxed warning covers this. Valproate causes neural tube defects and other major malformations, plus decreased IQ and neurodevelopmental disorders after in utero exposure. The malformation rate is about four times that of other antiseizure monotherapies (label). Use it only when other drugs have failed. Encourage enrollment in the North American Antiepileptic Drug Pregnancy Registry.
• Lactation: It is excreted in human milk at 1–10% of maternal serum levels. Breastfed infants had 1–6% of maternal levels. A published study followed children up to age 6 yr and reported no adverse developmental effects (label). Weigh the benefits of breastfeeding against the mother's need for the drug.
• Older Adults: Unbound clearance is lower, and somnolence is more common. Start low, titrate slowly, and watch fluid and nutritional intake. The 2023 AGS Beers Criteria list antiepileptics to avoid in older adults with a history of falls or fractures, except for seizures and mood disorders. Valproate is not named individually.
• Renal Impairment: No dosage adjustment appears necessary (label). Unbound clearance fell 27% at creatinine clearance under 10 mL/min. Hemodialysis lowers levels by about 20%.
• Hepatic Impairment: Contraindicated with significant hepatic dysfunction. In chronic liver disease, protein binding drops, so a total level can mislead. Free levels are needed.
• Obesity / Dosing Weight: The label sets no IV dosing-weight rule. ESETT used measured, stated or estimated weight for the 40 mg/kg load, with the cap at 3,000 mg (reached at 75 kg).
• Critical Illness (free valproate): In one ICU cohort, hypoalbuminemia, uremia and propofol exposure went with disproportionate free elevation. Free levels should be measured directly.

• Scope: It varies by state and agency protocol. Check whether yours allows transport to receive or continue the infusion.
• Storage & Stability: 20–25 °C (68–77 °F); excursions 15–30 °C permitted. Protect from vehicle heat or cold.
• Carried Concentration: 100 mg/mL (500 mg in 5 mL). On every bag and syringe, confirm mg versus mL. 3,000 mg is 30 mL.
• Infusions in Transport: Use a pump. Maintenance runs no more than 20 mg/min, over at least 60 min. Every dose needs at least 50 mL of diluent, so pack enough bag volume for the trip.
• Altitude / Environment: The label says nothing about altitude.
• Handoff Essentials: time and total dose in mg and mg/kg, with dosing weight; infusion start and expected end time; any seizure since the load; last total or free level and its time; interacting drugs, especially carbapenems, enzyme inducers and propofol.

Mechanism of Action

• It appears to raise brain GABA concentrations (suggested). The exact antiseizure mechanism is not established (label).
• Protein binding depends on concentration. The free fraction climbs from about 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. At high levels, a total level underestimates the free effect.
• Glucuronidation and beta-oxidation do most of the clearing. Cytochrome P450 oxidation is a minor pathway, so CYP inhibitors have little effect (label).

Pharmacokinetics

• Half-life: 16 ± 3 hr after a single 1,000 mg IV dose (monotherapy); 10–67 hr under 10 days of age; 7–13 hr over 2 months of age.
• Metabolism: glucuronidation and beta-oxidation; enzyme inducers can double clearance.
• Elimination: total clearance 0.56 L/hr per 1.73 m²; volume of distribution 11 L per 1.73 m² (label).
• Protein binding / Vd: free fraction about 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Free fraction rises with hypoalbuminemia and uremia.

Generic Name

Valproate sodium (sodium salt of valproic acid)

Brand Names

No current US brand-name injection label found on DailyMed or openFDA (Depacon not listed); the IV product is marketed as generic valproate sodium injection. Oral forms are different dosage forms: divalproex sodium (Depakote, AbbVie) and valproic acid

Pharmacologic Class

Branched-chain fatty acid (2-propylpentanoate), antiseizure agent

Therapeutic Class

Antiseizure medication

Controlled Substance

Not controlled

ISMP High-Alert

No. Not on the ISMP List of High-Alert Medications in Acute Care Settings (2024 edition)

Look-Alike / Sound-Alike

None commonly reported

Error-Prone Abbreviations to Avoid

None listed