valproic acid

(val proe' ik)

valproic acid
Capsules:
Alti-Valproic (CAN), Depakene, Deproic (CAN)

sodium valproate
Syrup:
Depakene

valproate acid
Injection:
Depacon

divalproex sodium
Tablets, enteric coated:
Depakote, Depakote ER, Depakote Sprinkle, Epival (CAN)

Pregnancy Category D

Drug class
Antiepileptic

Therapeutic actions
Mechanism of action not understood: antiepileptic activity may be related to the
metabolism of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA);
divalproex sodium is a compound containing equal proportions of valproic acid and
sodium valproate.

Indications
• Sole and adjunctive therapy in simple (petit mal) and complex absence seizures
• Depakote ER: Treatment of epilepsy in children > 10 yr
• Adjunctive therapy with multiple seizure types, including absence seizures
• Divalproex: Treatment of mania
• Divalproex-DR tablets: Prophylaxis of migraine headaches
• Divalproex, sodium valproate injection: Treatment of complex partial seizures as
monotherapy or with other antiepileptics
• Unlabeled uses: Sole and adjunctive therapy in atypical absence, myoclonic and
grand mal seizures; possibly effective therapy in atonic, elementary partial, and
infantile spasm seizures; prophylaxis for recurrent febrile seizures in children,
adjunct in symptom management of schizophrenia, relief of tardive dyskinesia in
 patients receiving long-term antipsychotics, treatment of aggressive outbursts in
children with ADHD, organic brain syndrome

Contraindications and cautions

• Contraindicated with hypersensitivity to valproic acid, hepatic disease or
significant hepatic dysfunction.
• Use cautiously with children < 18 mo; children < 2 yr, especially with multiple
antiepileptics, congenital metabolic disorders, severe seizures accompanied by
severe mental retardation, organic brain disorders (higher risk of developing fatal
hepatotoxicity); pregnancy (fetal neural tube defects; do not discontinue to
prevent major seizures; discontinuing such medication is likely to precipitate
status epilepticus, hypoxia and risk to both mother and fetus); lactation.

Available forms
Capsules—250 mg; syrup—250 mg/5 mL; DR tablets—125, 250, 500 mg; sprinkle
capsules—125 mg; injection—100 mg/mL; ER tablets—500 mg

Dosages
ADULTS
Dosage is expressed as valproic acid equivalents. Initial dose is 10–15 mg/kg/day PO,
increasing at 1-wk intervals by 5–10 mg/kg/day until seizures are controlled or side
effects preclude further increases. Maximum recommended dosage is 60 mg/kg/day PO.
If total dose > 250 mg/day, give in divided doses.
• Mania: 750 mg PO daily in divided doses; do not exceed 60 mg/kg/day (DR
tablets only).
• Migraine: 250 mg PO bid; up to 1,000 mg/day has been used (divalproex DR
tablets); 500 mg ER tablet once a day.
PEDIATRIC PATIENTS
Use extreme caution. Fatal hepatotoxicity has occurred. Children < 2 yr are especially
susceptible. Monitor all children carefully.

Pharmacokinetics
Route Onset Peak
Oral Varies 1–4 hr
IV Rapid 1 hr

Metabolism: Hepatic; T1/2: 6–16 hr

Distribution: Crosses placenta; enters breast milk
Excretion: Urine

IV facts
Preparation: Dilute vial in 5% dextrose injection, 0.9% sodium chloride injection or
lactated Ringer's injection. Stable for 24 hr at room temperature. Discard unused portions.
Infusion: Administer over 60 min, not more than 20 mg/min. Do not use > 14 days;
switch to oral products as soon as possible.

Adverse effects
 • CNS: Sedation, tremor (may be dose-related), emotional upset, depression,
psychosis, aggression, hyperactivity, behavioral deterioration, weakness
• Dermatologic: Transient increases in hair loss, rash, petechiae
• GI: Nausea, vomiting, indigestion, diarrhea, abdominal cramps, constipation,
anorexia with weight loss, increased appetite with weight gain, life-threatening
pancreatitis, hepatic failure
• GU: Irregular menses, secondary amenorrhea
• Hematologic: Slight elevations in AST, ALT, LDH; increases in serum bilirubin,
abnormal changes in other liver function tests, altered bleeding time;
thrombocytopenia; bruising; hematoma formation; frank hemorrhage; relative
lymphocytosis; hypofibrinogenemia; leukopenia, eosinophilia, anemia, bone
marrow suppression

Interactions
Drug-drug
• Increased serum phenobarbital, primidone, ethosuximide, diazepam, zidovudine
levels
• Complex interactions with phenytoin; breakthrough seizures have occurred with
the combination of valproic acid and phenytoin
• Increased serum levels and toxicity with salicylates, cimetidine, chlorpromazine,
erythromycin, felbamate
• Decreased effects with carbamazepine, rifampin, lamotrigine
• Decreased serum levels with charcoal
• Increased sedation with alcohol, other CNS depressants
Drug-lab test
• False interpretation of urine ketone test

Nursing considerations
CLINICAL ALERT!
Confusion has occurred between delayed release Depakote and Depakote
ER. Dosage is very different and serious adverse effects can occur; use
extreme caution.

Assessment
• History: Hypersensitivity to valproic acid; hepatic dysfunction; pregnancy,
lactation
• Physical: Weight; skin color, lesions; orientation, affect, reflexes; bowel sounds,
normal output; CBC and differential, bleeding time tests, hepatic function tests,
serum ammonia level, exocrine pancreatic function tests, EEG

Interventions
• Give drug with food if GI upset occurs; substitution of the enteric-coated
formulation also may be of benefit; have patient swallow SR tablet whole; do not
cut, crush, or chew.
 • Reduce dosage, discontinue, or substitute other antiepileptics gradually; abrupt
discontinuation of all antiepileptics may precipitate absence seizures.
• Arrange for frequent liver function tests; discontinue drug immediately with
significant hepatic dysfunction, suspected or apparent; hepatic dysfunction has
progressed in spite of drug discontinuation.
• Arrange for patient to have platelet counts, bleeding time determination before
therapy, periodically during therapy, and prior to surgery. Monitor patient
carefully for clotting defects (bruising, blood-tinged toothbrush). Discontinue if
there is evidence of hemorrhage, bruising, or disorder of hemostasis.
• Monitor ammonia levels, and discontinue if there is clinically significant
elevation in level.
• Monitor serum levels of valproic acid and other antiepileptic drugs given
concomitantly, especially during the first few weeks of therapy. Adjust dosage on
the basis of these data and clinical response.
• Arrange for counseling for women of childbearing age who wish to become
pregnant.
• Discontinue drug at any sign of pancreatitis.
• Evaluate for therapeutic serum levels—usually 50–100 mcg/mL.

Teaching points
• Take this drug exactly as prescribed. Do not chew tablets or capsules before
swallowing them. Swallow them whole to prevent local irritation of mouth and
throat. Sprinkle tablets may be opened and sprinkled on applesauce or pudding.
• Do not discontinue this drug abruptly or change dosage, except on the advice of
your physician.
• Avoid alcohol and sleep-inducing and over-the-counter drugs. These could cause
dangerous effects.
• Have frequent checkups, including blood tests, to monitor your drug response.
Keep all appointments for checkups.
• Use contraceptive techniques at all times. If you wish to become pregnant, you
should consult your physician.
• Wear a medical ID tag to alert emergency medical personnel that you have
epilepsy and are taking antiepileptic medication.
• If you have diabetes, this drug may interfere with urine tests for ketones.
• These side effects may occur: Drowsiness (avoid driving or performing other
tasks requiring alertness; take at bedtime); GI upset (take with food or milk, eat
frequent small meals; if problem persists, substitute enteric-coated drug); transient
increase in hair loss.
• Report bruising, pink stain on the toothbrush, yellowing of the skin or eyes, pale
feces, rash, pregnancy; abdominal pain with nausea, vomiting, anorexia.

Adverse effects in Italic are most common; those in Bold are life-threatening.