VALPROIC ACID (DIVALPROEX SODIUM, SODIUM VALPROATE)

(val-proe'ic)

Depacon, Depakene, Depakote, Depakote ER, Depakote Sprinkle, Epival

, Zalkote
Classifications: anticonvulsant; gamma-aminobutyric acid (gaba) inhibitor;
Therapeutic: anticonvulsant
Pregnancy Category: D

Availability

250 mg capsules; 125 mg sprinkle capsules; 125 mg, 250 mg, 500 mg delayed release tablets; 500 mg sustained release tablets; 250 mg/5 mL syrup; 100 mg/mL injection

Action

Anticonvulsant whose mechanism of action is believed to be related to increased bioavailability of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to brain neurons. It may also suppress repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.

Therapeutic Effect

Depresses abnormal neuron discharges in the CNS, thus decreasing seizure activity.

Uses

Alone or with other anticonvulsants in management of absence (petit mal) and mixed seizures; mania; migraine headache prophylaxis.

Unlabeled Uses

Status epilepticus refractory to IV diazepam, petit mal variant seizures, febrile seizures in children, other types of seizures including psychomotor (temporal lobe), myoclonic, akinetic and tonic-clonic seizures, photosensitivity seizures, and those refractory to other anticonvulsants.

Contraindications

Hypersensitivity to valproate sodium; thrombocytopenia, patient with bleeding disorders or liver dysfunction or disease; cirrhosis, pancreatitis; congenital metabolic disorders, those with severe seizures, or on multiple anticonvulsant drugs; encephalopathy; AIDS; pregnancy (category D); child <2 y; children <18 y for treatment of mania.

Cautious Use

History of kidney disease, renal impairment or failure; adjunctive treatment with other anticonvulsants; congenital metabolic disorders, those with severe epilepsy, use as sole anticonvulsant drug; HIV; hypoalbuminemia; organic brain syndrome.

Route & Dosage

Note: May need to increase dose when converting from immediate release to extended release products

Management of Seizures
Adult/Child (≥10 y): PO/IV 10–15 mg/kg/d in divided doses when total daily dose >250 mg, increase at 1 wk intervals by 5–10 mg/kg/d until seizures are controlled or adverse effects develop (max: 60 mg/kg/d)

Migraine Headache Prophylaxis
Adult: PO 250 mg b.i.d. (max: 1000 mg/d) or Depakote ER 500 mg q.d. x 1 wk, may increase to 1000 mg q.d.

Mania
Adult: PO 250 mg t.i.d. (max: 60 mg/kg/d)

Hepatic Impairment
Dose reduction recommended.

Administration

Oral

Give tablets and capsules whole; instruct patient to swallow whole & not to chew. Instruct to swallow sprinkle capsules whole or sprinkle entire contents on teaspoonful of soft food, and instruct to not chew food.
Avoid using a carbonated drink as diluent for the syrup because it will release drug from delivery vehicle; free drug painfully irritates oral and pharyngeal membranes.
Reduce gastric irritation by administering drug with food because serious GI adverse effects can lead to discontinuation of therapy. Enteric-coated tablet or syrup formulation is usually well tolerated.

Intravenous

PREPARE: IV Infusion: Dilute each dose in 50 mL or more of D5W, NS, or RL.

ADMINISTER: IV Infusion: Give a single dose over at least 60 min (≤20 mg/min). Avoid rapid infusion.

INCOMPATIBILITIES Solution/additive: Should avoid mixing with other drugs.

Adverse Effects (≥1%)

CNS: Breakthrough seizures, sedation, drowsiness, dizziness, increased alertness, hallucinations, emotional upset, aggression; deep coma, death (with overdose). GI: Nausea, vomiting, indigestion (transient), hypersalivation, anorexia with weight loss, increased appetite with weight gain, abdominal cramps, diarrhea, constipation, liver failure, pancreatitis. Hematologic: Prolonged bleeding time, leukopenia, lymphocytosis, thrombocytopenia, hypofibrinogenemia, bone marrow depression, anemia. Skin: Skin rash, photosensitivity, transient hair loss, curliness or waviness of hair. Endocrine: Irregular menses, secondary amenorrhea. Metabolic: Hyperammonemia (usually asymptomatic) hyperammonemic encephalopathy in patients with urea cycle disorders. Respiratory: Pulmonary edema (with overdose).

Diagnostic Test Interference

Valproic acid produces false-positive results for urine ketones, elevated AST, ALT, LDH, and serum alkaline phosphatase, prolonged bleeding time, altered thyroid function tests.

Interactions

Drug: Alcohol and other cns depressants potentiate depressant effects; other anticonvulsants, barbiturates increase or decrease anticonvulsant and barbiturate levels; haloperidol, loxapine, maprotiline, maois, phenothiazines, thioxanthenes, tricyclic antidepressants can increase CNS depression or lower seizure threshold; aspirin, dipyridamole, warfarin increase risk of spontaneous bleeding; clonazepam may precipitate absence seizures; salicylates, cimetidine, isoniazid may increase valproic acid levels and toxicity. Mefloquine can decrease valproic acid levels; meropenem may decrease valproic acid levels; cholestyramine may decrease absorption. Herbal: Ginkgo may decrease anticonvulsant effectiveness.

Pharmacokinetics

Absorption: Readily from GI tract. Peak: 1–4 h valproic acid; 3–5 h divalproex. Therapeutic Range: 50–100 mcg/mL. Distribution: Crosses placenta; distributed into breast milk. Metabolism: In liver. Elimination: Primarily in urine; small amount in feces and expired air. Half-Life: 5–20 h.

Nursing Implications

Assessment & Drug Effects

Monitor for therapeutic effectiveness achieved with serum levels of valproic acid at 50–100 mcg/mL.
Monitor patient alertness especially with multiple drug therapy for seizure control. Evaluate plasma levels of the adjunctive anticonvulsants periodically as indicators for possible neurologic toxicity.
Monitor patient carefully during dose adjustments and promptly report presence of adverse effects. Increased dosage is associated with frequency of adverse effects.
Lab tests: Perform baseline platelet counts, bleeding time, and serum ammonia, then repeat at least q2mo, especially during the first 6 mo of therapy.
Multiple drugs for seizure control increase the risk of hyperammonemia, marked by lethargy, anorexia, asterixis, increased seizure frequency, and vomiting. Report such symptoms promptly to physician. If they persist with decreased dosage, the drug will be discontinued.

Patient & Family Education

Do not discontinue therapy abruptly; such action could result in loss of seizure control. Consult physician before you stop or alter dosage regimen.
Note to diabetic patients: Drug may cause a false-positive test for urine ketones. Notify physician if this occurs; a differential diagnostic blood test may be indicated.
Notify physician promptly if spontaneous bleeding or bruising occurs (e.g., petechiae, ecchymotic areas, otorrhagia, epistaxis, melena).
Withhold dose and notify physician for following symptoms: visual disturbances, rash, jaundice, light-colored stools, protracted vomiting, diarrhea. Fatal liver failure has occurred in patients receiving this drug.
Avoid alcohol and self-medication with other depressants during therapy.
Consult physician before using any OTC drugs during anticonvulsant therapy. Combination drugs containing aspirin, sedatives, and medications for hay fever or other allergies are particularly UNSAFE.
Do not drive or engage in potentially hazardous activities until response to drug is known.
Inform doctor or dentist before any kind of surgery that you are taking valproic acid.
Carry medical identification card at all times. It needs to indicate medical diagnosis, medication(s), physician's name, address, and telephone number.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug

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