Valproic acid

Generic Name

Valproic acid

Other Forms and Related Compounds

Divalproex sodium (enteric-coated extended-release formulation)

Sodium valproate

Valproate semisodium

Brand Names

Depakene (valproic acid)

Depakote (divalproex sodium)

Epilim (sodium valproate)

Convulex

Valcote

Orfiril

Stavzor

Epival

Drug Class

Anticonvulsant

Mood stabilizer

Histone deacetylase (HDAC) inhibitor

Fatty acid derivative

Mechanism of Action

Valproic acid increases brain concentrations of gamma-aminobutyric acid GABA

Enhances GABA-mediated neurotransmission through inhibition of GABA transaminase and succinic semialdehyde dehydrogenase

Modifies voltage-gated sodium channels by prolonging their inactivated state

Blocks T-type calcium channels in thalamic neurons

These multiple mechanisms stabilize neuronal membranes and reduce neuronal excitability

Also functions as a histone deacetylase HDAC inhibitor which may contribute to its mood-stabilizing and neuroprotective properties

Indications

Epilepsy

Monotherapy or adjunctive therapy for complex partial seizures

Simple and complex absence seizures

Generalized tonic-clonic seizures

Juvenile myoclonic epilepsy

Status epilepticus intravenous form

Bipolar disorder

Treatment of acute manic or mixed episodes

Maintenance therapy in bipolar I disorder

Migraine prophylaxis

Off-label uses

Schizoaffective disorder

Borderline personality disorder

Agitation in dementia

Neuropathic pain

Post-traumatic stress disorder PTSD

Tardive dyskinesia

Dosage and Administration

Initial dose for epilepsy

10 to 15 mgkgday orally

Increased by 5 to 10 mgkgweek as needed

Maximum dose up to 60 mgkgday

Maintenance dose individualized to clinical response and serum valproate levels

For bipolar disorder

Starting dose 750 mgday in divided doses

Adjusted to response

Target serum levels 50 to 125 mcgmL

For migraine prophylaxis

250 to 500 mg twice daily

Maximum 1000 mgday

IV formulation

Used for status epilepticus or when oral route is not feasible

Rate not to exceed 20 mgmin

Administered slowly due to risk of hypotension

Oral formulations

Immediate-release capsules or syrup

Extended-release tablets

Delayed-release tablets and sprinkle capsules for swallowing or opening

Should be taken with food to reduce gastrointestinal irritation

Not to be used interchangeably without dose adjustment between valproic acid and divalproex

Pharmacokinetics

Absorption

Well absorbed orally with peak levels in 1 to 4 hours

Delayed with food but not reduced

Protein binding

Extensively bound to albumin 80 to 90 percent

Saturable binding at higher doses leads to increased free drug

Metabolism

Hepatic metabolism via glucuronidation and mitochondrial beta-oxidation

CYP450 minor pathway

Excretion

Primarily urinary as metabolites

Half-life

6 to 16 hours depending on age liver function and formulation

Clearance may be increased in children and decreased in elderly or liver disease

Contraindications

Known hypersensitivity to valproate

Significant hepatic impairment

Mitochondrial disorders caused by POLG mutations

Urea cycle disorders

Pregnancy for migraine prophylaxis absolute contraindication

Pancreatitis history associated with prior valproate therapy

Use in pediatric patients under 2 years of age with metabolic disorders is contraindicated due to hepatotoxicity risk

Warnings and Precautions

Black box warning for hepatotoxicity especially in children under 2 years or with mitochondrial disease

Monitor liver function tests frequently during first 6 months

Risk of pancreatitis which can be fatal

Hyperammonemia may occur even without liver dysfunction

Can lead to encephalopathy especially with topiramate or urea cycle disorders

Neural tube defects and other major congenital malformations in exposed pregnancies

Avoid in women of childbearing age unless no suitable alternatives

Monitor for suicidal ideation or behavior

Use with caution in patients with bleeding disorders or thrombocytopenia

Monitor complete blood counts and coagulation parameters

Weight gain and metabolic syndrome potential with long-term use

Cognitive effects in pediatric populations and developmental delay risk with in utero exposure

Use cautiously with other CNS depressants

Adverse Effects

Very common

Nausea

Vomiting

Tremor

Weight gain

Alopecia

Somnolence

Dizziness

Increased appetite

Common

Hepatotoxicity

Pancreatitis

Hyperammonemia

Thrombocytopenia

Leukopenia

Amenorrhea

Polycystic ovary syndrome

Hair thinning or color change

Photosensitivity

Rare but serious

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Aplastic anemia

Liver failure

Pancreatic failure

Encephalopathy

Suicidal thoughts or behavior

Teratogenicity including spina bifida and decreased IQ in offspring

Teratogenicity and Pregnancy

Valproic acid is one of the most teratogenic anticonvulsants

Associated with neural tube defects spina bifida

Facial dysmorphism cleft palate cardiovascular defects

Neurodevelopmental disorders and reduced cognitive function in exposed children

FDA and EMA recommend avoiding use in pregnancy unless absolutely necessary

Effective contraception required during treatment in women of reproductive age

Pregnancy prevention programs mandatory in some countries

Overdose

Symptoms

CNS depression

Respiratory depression

Metabolic acidosis

Hypernatremia

Coma

Management

Supportive care

Activated charcoal if early ingestion

Naloxone may reverse CNS depression

Hemodialysis in severe cases due to low molecular weight and protein binding saturation

Drug Interactions

CNS depressants including benzodiazepines enhance sedation

Enzyme inducers carbamazepine phenytoin phenobarbital reduce valproate levels

Valproate may increase serum levels of lamotrigine risk of Stevens-Johnson syndrome

Displaces phenytoin from protein binding sites raising free phenytoin levels

Inhibits CYP2C9 increasing levels of some drugs like diazepam

Increases serum levels of amitriptyline nortriptyline zidovudine

Warfarin effect may be increased due to protein displacement and enzyme inhibition

Concomitant aspirin may increase free valproate levels and bleeding risk

Topiramate may increase risk of hyperammonemia

Antacids may affect absorption rate but not extent

Use in Special Populations

Pregnancy

Strongly discouraged unless other options are ineffective

High risk of congenital malformations

Lactation

Excreted in breast milk

Considered compatible but monitor infant for sedation or liver dysfunction

Pediatrics

High risk of hepatotoxicity under 2 years

Dose based on body weight

Geriatrics

Increased sensitivity

Lower doses may be needed

Renal Impairment

No significant dose adjustment

Monitor for toxicity

Hepatic Impairment

Contraindicated in severe impairment

Monitoring Parameters

Serum valproate levels

Target range 50 to 100 mcgmL for seizures

May require higher levels for mania up to 125 mcgmL

Liver function tests baseline and periodically

Platelet count and CBC baseline and periodically

Serum ammonia if altered mental status

Weight and metabolic profile during long-term therapy

Pregnancy status and contraceptive use in females of reproductive age

Comparative Pharmacology

Compared to carbamazepine

Less risk of hyponatremia but more teratogenic

Compared to lamotrigine

More effective for mania but more risk of weight gain and teratogenicity

Compared to lithium

Fewer renal side effects but less effective in depression phase

Compared to levetiracetam

More adverse effects related to metabolism and liver

Broader spectrum of seizure control

Formulations Available

Valproic acid capsules and syrup 250 mg5 mL

Divalproex sodium tablets delayed-release 125 mg 250 mg 500 mg

Extended-release tablets 250 mg 500 mg

Sprinkle capsules

IV injection solution for acute care

Available globally as brand and generic

Regulatory and Legal Status

Prescription-only medicine

Approved by FDA EMA and other authorities

Classified as teratogenic

Subject to pregnancy prevention programs in EU

Black box warnings for hepatotoxicity teratogenicity pancreatitis and suicidal ideation

Not a controlled substance

Included on WHO Model List of Essential Medicines for epilepsy and bipolar disorder