valproic acid (Rx)

>10%

Nausea (31%)

Headache (<31%)

Increased bleeding time (26-30%)

Thrombocytopenia (26-30%)

Tremor (25%)

Alopecia (<24%)

Asthenia (16-20%)

Infection (16-20%)

Somnolence (16-20%)

Amblyopia (11-15%)

Diarrhea (11-15%)

Diplopia (11-15%)

Dizziness (11-15%)

Dyspepsia (11-15%)

Nystagmus (11-15%)

Tinnitus (11-15%)

Vomiting (11-15%)

1-10%

Ataxia (<8%)

Increased appetite (<6%)

Rash (<6%)

Abdominal pain (<5%)

Tremor (<5%)

Back pain (<5%)

Mood changes (<5%)

Anxiety (<5%)

Confusion (<5%)

Abnormal gait (<5%)

Paresthesia (<5%)

Hallucinations (<5%)

Catatonia (<5%)

Dysarthria (<5%)

Tardive dyskinesia (<5%)

Vertigo (<5%)

Irregular menses (<5%)

Weight gain (4%)

Frequency Not Defined

Anorexia

Acute pancreatitis (may be life-threatening)

Hepatic toxicity

Hyperammonemia

Weight loss

Fractures

Osteoporosis

Osteopenia

Decreased bone mineral density

Cerebral pseudoatrophy (acute or subacute cognitive decline and behavioral changes (apathy or irritability)

Postmarketing Report

Hair texture change

Hair color change

Photosensitivity

Erythema multiforme

Toxic epidermal necrolysis

Stevens-Johnson syndrome

Elevated testosterone level

Hyperandrogenism

Hirsutism

Nail and nailbed disorders

Weight gain

Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology

Paradoxical convulsion

Parkinsonism

Contraindications

Hypersensitivity

Liver disease, significant hepatic impairment

Urea cycle disorder

Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase-gamma (POLG; eg, Alpers-Huttenlocher Syndrome) and children <2 years of age who are suspected of having a POLG-related disorder

Migraine headache prevention in women who are pregnant or plan to become pregnant

Cautions

Probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations exceed 110 mcg/mL in females and 135 mcg/mL in males

Bleeding and other hematopoietic disorders may occur; monitor platelet counts and coagulation tests

Hepatotoxic (age <2 years, higher risk of fatal hepatotoxicity); evaluate high risk populations and monitor serum liver tests; risk factors include organic brain disease, mental retardation with severe seizure disorders, congenital metabolic disorders, and patients on multiple anticonvulsants; discontinue immediately with signs/symptoms of significant or suspected impairment

POLG mutations; see Contraindications and Black Box Warnings

Discontinue if hyperammonemia occurs; check ammonia level if emesis occurs or if the patient displays lethargy or abnormal behavior; evaluate patient for urea cycle disorder (see Contraindications) or hepatotoxicity (see Black Box Warnings)

Pancreatitis, including fatalities reported (see Black Box Warnings)

Porphyria may occur

May produce false-positive urine ketone test and alter TFTs

May cause CNS depression, which may impair physical or mental to perform tasks requiring mental alertness

Birth defects and decreased IQ following in utero exposure compared with 3 other common AEDs (carbamazepine, lamotrigine, phenytoin); only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential; reversible and irreversible cerebellar atrophy reported; monitor motor and cognitive function routinely

Drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity reaction reported; discontinue therapy; monitor for possible disparate manifestations associated with lymphatic, renal, hepatic, and/or hematologic organ systems;

Not recommended for post-traumatic seizure prophylaxis in patients with acute head trauma (may increase mortality

Hypothermia reported during valproate therapy with or without associated hyperammonemia; this adverse reaction can also occur in patients using concomitant topiramate

Somnolence in the elderly can occur; valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake

Irreversible and reversible brain atrophhy reported; routinely monitor motor and cognitive function to assess for signs and symptoms of brain atrophy

Serious, sometimes fatal drug reaction with eosinophilia and systemic symptoms (DRESS) reported; monitor for symptoms; may require discontinuation and conversion to alternate therapy

Suicidal thoughts, behavior may occur; monitor patients for changes in behavior that might indicate suicidal thoughts or depression

Mechanism of Action

May increase levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in brain; may enhance or mimic action of GABA at postsynaptic receptor sites; may also inhibit sodium and calcium channels

Absorption

Bioavailability: Extended-release 81-89% of delayed-release

Peak plasma time: 2 hr (Stavzor)

Peak plasma concentration: 115-145 mcg/mL (IV)

Distribution

Protein bound: 80-90%

Vd: 92 L/1.73 m²

Metabolism

Metabolized by liver

Enzymes inhibited: CYP2C9

Metabolites: 2-propyl-3-ketopentanoic acid

Elimination

Half-life: 7-13 hr (>2 months); 9-16 hr (adults)

Dialyzable: Yes

Total body clearance: 4.6 L•hr/1.73 m² (50% higher in children <10 years)

Excretion: Urine (30-50%)

IV Preparation

Dilute with at least 50 mL of compatible diluent (eg, D5W; NS; LR)

Stable for at least 24 hr when stored in glass or PVC at 15-30°C (59-86°F)

IV Administration

Infuse over 60 min at <20 mg/min

Has been administered as rapid infusion over 5-10 min (1.5-3 mg/kg/min) (not per label; rapid infusion associated with increased AE risk, but in limited studies was well-tolerated) 

Oral Administration

Swallow whole, do not chew or crush

Capsules may be opened and sprinkled on spoonful of soft food immediately before administration

If dose is skipped, do not double next dose

If daily oral dose >250 mg/day, give as divided dose

Storage

Store vials at 15-30°C (59-86°F)