Valproic acid
Valproic acid (Depakene)
Valproic acid
(val- PROH-ick)
Pregnancy Category: D Alti-Valproic Depakene Deproic Gen-Valproic Novo-Valproic PMS-Valproic Acid (Rx)
Divalproex sodium
Valproic acid
(die-val- PROH-ex)
Pregnancy Category: D Depakote Epival (Rx)

Classification: Anticonvulsant, miscellaneous

See Also: See also Anticonvulsants .

Action/Kinetics: The following information also applies to divalproex sodium (Depakote, Epival ). The precise anticonvulsant action is unknown; may increase brain levels of the neurotransmitter GABA. Other possibilities include acting on postsynaptic receptor sites to mimic or enhance the inhibitory effect of GABA, inhibiting an enzyme that catabolizes GABA, affecting the potassium channel, or directly affecting membrane stability. Absorption is more rapid with the syrup (sodium salt) than capsules. Peak levels, with syrup: 15 min-2 hr. Equivalent PO doses of divalproex sodium and valproic acid deliver equivalent amounts of valproate ion to the system. Peak serum levels, capsules and syrup: 1-4 hr (delayed if the drug is taken with food); peak serum levels, enteric-coated tablet (divalproex sodium): 3-4 hr. t 1/2: 9-16 hr, with the lower time usually seen in clients taking other anticonvulsant drugs (e.g., primidone, phenytoin, phenobarbital, carbamazepine). t 1/2, children less than 10 days: 10-67 hr; t 1/2, children over 2 months: 7-13 hr. t 1/2, cirrhosis or acute hepatitis: Up to 18 hr. Therapeutic serum levels: 50-100 mcg/mL. Approximately 90% bound to plasma protein. Metabolized in the liver and inactive metabolites are excreted in the urine; small amounts of valproic acid are excreted in the feces.

Uses: Alone or in combination with other anticonvulsants for treatment of simple and complex absence seizures (petit mal). As an adjunct in multiple seizure patterns that include absence seizures. Alone or as adjunct to treat complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium delayed release used for the acute treatment of manic episodes in bipolar disorder and for prophylaxis of migraine headaches. Investigational: Alone or in combination to treat atypical absence, myoclonic, and grand mal seizures; also, atonic, complex partial, elementary partial, and infantile spasm seizures. Prophylaxis of febrile seizures in children, to treat anxiety disorders/panic attacks, and subchronically to treat minor incontinence after ileoanal anastomosis. Management of anxiety disorders or panic attacks.

Contraindications: Liver disease or dysfunction.

Special Concerns: Use with caution during lactation. Use with caution in children 2 years of age or less as they are at greater risk for developing fatal hepatotoxicity. Use lower doses in geriatric clients because they may have increased free, unbound valproic acid levels in the serum. Safety and efficacy of divalproex sodium have not been determined for treating acute mania in children less than 18 years of age or for treating migraine in children less than 16 years of age.

Side Effects: GI: (most frequent): N&V;, indigestion. Also, abdominal cramps, abdominal pain, dyspepsia, diarrhea, constipation, anorexia with weight loss or increased appetite with weight gain. CNS: Sedation, psychosis, depression, emotional upset, aggression, hyperactivity, deterioration of behavior, tremor, headache, dizziness, somnolence, dysarthria, incoordination, coma (rare). Ophthalmologic: Nystagmus, diplopia, ``spots before eyes.'' Hematologic: Thrombocytopenia, leukopenia, eosinophilia, anemia, bone marrow suppression, relative lymphocytosis, hypofibrinogenemia, myelodysplastic-type syndrome. Dermatologic: Transient alopecia, petechiae, erythema multiforme, skin rashes. photosensitivity, pruritus, Stevens-Johnson syndrome. Hepatic: Hepatotoxicity. Also, minor increases in AST, ALT, LDH, serum bilirubin, and serum alkaline phosphatase values. Endocrine: Menstrual irregularities, secondary amenorrhea, breast enlargement, galactorrhea, swelling of parotid gland, abnormal thyroid function tests. Miscellaneous: Also asterixis, weakness, asthenia, bruising, hematoma formation, frank hemorrhage, acute pancreatitis, hyperammonemia, hyperglycinemia, hypocarnitinemia, edema of arms and legs, weakness, inappropriate ADH secretion, Fanconi's syndrome (rare and seen mostly in children), lupus erythematosus, fever, enuresis, hearing loss.

Laboratory Test Alterations: False + for ketonuria. Altered thyroid function tests.

Overdose Management: Symptoms: Motor restlessness, asterixis, visual hallucinations, somnolence, heart block, deep coma. Treatment: Perform gastric lavage if client is seen early enough (valproic acid is absorbed rapidly). Undertake general supportive measures making sure urinary output is maintained. Naloxone has been used to reverse the CNS depression (however, it could also reverse the anticonvulsant effect). Hemodialysis and hemoperfusion have been used with success.

Drug Interactions: Alcohol / Incidence of CNS depression Carbamazepine / Variable changes in carbamazepine levels with possible loss of seizure control Charcoal / Valproic acid absorption from the GI tract Chlorpromazine / Clearance and t 1/2 of valproic acid pharmacologic effects Cimetidine / Clearance and t 1/2 of valproic acid pharmacologic effects Clonazepam / Chance of absence seizures (petit mal) and toxicity CNS depressants / Incidence of CNS depression Diazepam / Diazepam effect R/T plasma binding and metabolism Erythromycin / Serum valproic acid levels valproic acid toxicitiy Ethosuximide / Ethosuximide effect R/T metabolism Felbamate / Mean peak valproic acid levels Lamotrigine / Valproic acid serum levels and lamotrigine serum levels; reduce dose of lamotrigine Phenobarbital / Phenobarbital effect R/T liver breakdown Phenytoin / Phenytoin effect R/T liver breakdown or effect of valproic acid R/T metabolism Salicylates (aspirin) / Effect of valproic acid R/T plasma protein binding and metabolism Warfarin sodium / Effect of valproic acid R/T plasma protein binding. Also, additive anticoagulant effect Zidovudine / Clearance in HIV-seropositive clients

How Supplied: Valproic acid: Capsule: 250 mg; Syrup: 250 mg/5 mL; Divalproex sodium: Enteric Coated Capsule: 125 mg; Enteric Coated Tablet: 125 mg, 250 mg, 500 mg

Dosage
?Capsules, Syrup, Enteric-Coated Capsules and Tablets (Divalproex) Complex partial seizures.
Adults and children 10 years and older: 10-15 mg/kg/day. Increase by 5-10 mg/kg/week until seizures are controlled or side effects occur, up to a maximum of 60 mg/kg/day. If the total daily dose exceeds 250 mg, divide the dose. Dosage of concomitant anticonvulsant drugs can usually be reduced by about 25% every 2 weeks. Divalproex sodium may be added to the regimen at a dose of 10-15 mg/kg/day; the dose may be increased by 5-10 mg/kg/week to achieve the optimal response (usually less than 60 mg/kg/day).
Simple and complex absence seizures.
Initial: 15 mg/kg/day, increasing at 1-week intervals by 5-10 mg/kg/day until seizures are controlled or side effects occur.
Acute manic episodes in bipolar disorder (use divalproex).
Initial: 250 mg t.i.d.; then increase dose q 2-3 days until a trough serum level of 50 mcg/mL is reached. The maximum dose is 60 mg/kg/day.
Prophylaxis of migraine (divalproex sodium).
250 mg/day b.i.d., although some may require up to 1,000 mg daily.
?Rectal Intractable status epilepticus that has not responded to other treatment.
Adults: 200-1,200 mg q 6 hr rectally with phenytoin and phenobarbital. Children: 15-20 mg/kg.