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

Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity

Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation

Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess

Hemic and Lymphatic System: Ecchymosis

Metabolic and Nutritional Disorders: Edema, peripheral edema, SGOT increase, and SGPT increase

Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching, myalgia

Nervous System: Abnormal dreams, depression, hypertonia, hypokinesia, insomnia, reflexes increased, thinking abnormalities,

Respiratory System: Dyspnea, rhinitis, cough increased, and sinusitis

Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea, pruritus, and rash

Special Senses: Conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus, taste perversion

Urogenital System: Dysmenorrhea, dysuria, urinary incontinence, cystitis, metrorrhagia, and vaginal hemorrhage

Hemic and Lymphatic System: Ecchymosis

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; because of reports of cytopenias, inhibition of secondary phase of platelet aggregation, and abnormal coagulation parameters (eg, low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease)

Measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals; recommended that patients receiving drug be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy; evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy

Medication residue in the stool reported; some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times; in some reports, medication residues have occurred in the context of diarrhea; recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition monitored; If clinically indicated, may consider alternative treatment

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; therapy should be discontinued and not be resumed if an alternative etiology for signs or symptoms cannot be established

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

Pregnancy

A pregnancy exposure registry monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), during pregnancy; encourage women on therapy during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/.; must be done by the patient herself

Although available studies have methodological limitations, the weight of evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention-deficit/hyperactivity disorder (ADHD); because studies were observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder and ADHD cannot be considered definitive

Contraindicated for use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception; for epilepsy or bipolar disorder, drug should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable

Women with epilepsy who become pregnant while taking valproate should not discontinue therapy abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life; discontinuation of the drug may be considered prior to and during pregnancy in individual cases if seizure disorder severity and frequency do not pose serious threat to patient

Maternal valproate use during pregnancy for any indication increases risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations)

Risk is dose-dependent; a threshold dose below which no risk exists cannot be established; valproate polytherapy with other AEDs has been associated with increased frequency of congenital malformations compared with AED monotherapy; risk of major structural abnormalities is greatest during first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy

There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy

Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases risk for congenital neural tube defects in general population; not known whether risk of neural tube defects or decreased IQ in offspring of women receiving valproate is reduced by folic acid supplementation; dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate

There have been reports of male infertility coincident with valproate therapy; in animal studies, oral administration at clinically relevant doses resulted in adverse reproductive effects in males

Lactation

Drug is excreted in human milk; data in the published literature describe presence of valproate in human milk; there are no data to assess effects of drug on milk production or excretion

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Monitor breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding; there have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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)