valproic acid

valproic acid

(val proe' ik)

valproic acid

Capsules:

Depakene

sodium valproate

Syrup:

Depakene

valproate acid

Injection:

Depacon

divalproex sodium

Tablets, enteric coated:

Depakote, Depakote ER, Depakote Sprinkle, Divalproex, 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, 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; treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features

·        Adjunctive therapy with multiple seizure types, including absence seizures

·        Depakote ER: Treatment of bipolar mania

·        Depakote, Depacote ER: Prophylaxis of migraine headaches

·        Divalproex, sodium valproate injection: Treatment of complex partial seizures as monotherapy or with other antiepileptics

·        Unlabeled uses: Adjunct in symptom management of schizophrenia, treatment of aggressive outbursts in children with attention-deficit hyperactivity disorder, 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—250, 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.

·        Acute mania or bipolar disorder: Initially, 25 mg/kg/day PO once daily. Dose should be increased rapidly to achieve the lowest therapeutic dose. Maximum dose 60 mg/kg/day PO (Depakote ER only).

·        Bipolar mania: 750 mg PO daily in divided doses; do not exceed 60 mg/kg/day (Divalproex 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 > 10 YR

10-15 mg/kg/day PO.

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; T_1/2: 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 LFTs, 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, LFTs, 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.

·        WARNING: Reduce dosage, discontinue, or substitute other antiepileptics gradually; abrupt discontinuation of all antiepileptics may precipitate absence seizures.

·        WARNING: Arrange for frequent LFTs; discontinue drug immediately with significant hepatic dysfunction, suspected or apparent; hepatic dysfunction has progressed in spite of drug discontinuation.

·        WARNING: 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 ofhemostasis.

·        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.

·        WARNING: Discontinue drug at any sign of pancreatitis.

·        WARNING: 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 health care provider.

·        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 health care provider.

·        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.

·        You may experience these side effects: 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.