valproic acid
Depakene, Epival ◆

divalproex sodium
Depakote, Depakote ER, Depakote Sprinkle

valproate sodium
Depacon

Available forms
Available by prescription only
valproic acid
Capsules: 250 mg
Syrup: 250 mg/5 ml
divalproex sodium
Capsules (sprinkle): 125 mg
Tablets (delayed-release): 125 mg, 250 mg, 500 mg
Tablets (extended-release): 500 mg
valproate sodium
Injection: 5 ml single-dose vials, 100 mg/ml

Indications and dosages
Doses of divalproex sodium (Depakote) and valproate sodium are expressed as valproic acid.
 Complex partial seizures. Adults and children age 10 and older: Initially, 10 to 15 mg/kg daily as monotherapy or adjunctive therapy when being added to a current therapeutic regimen. Increase by 5 to 10 mg/kg weekly until seizures are controlled or adverse effects preclude further increases. Maximum, 60 mg/kg daily.
 Simple and complex absence seizures. Adults and children: Initially, 15 mg/kg daily; may increase by 5 to 10 mg/kg daily at weekly intervals until seizures are controlled or adverse effects prevent further increases in dose. Maximum, 60 mg/kg daily. If daily dose is greater than 250 mg, give drug in two or more divided doses.
 Mania. Adults: 750 mg P.O. in divided doses (divalproex sodium). Maximum, 60 mg/kg daily.
 Migraine prophylaxis. divalproex sodium only Adults: 250 mg P.O. b.i.d. Some patients benefit from doses up to 1 g daily. Or 500 mg ( extended-release tablets) once daily for 1 week; dose may be increased to 1 g/day.
Elderly patients: If using Depakote delayed- release tablets, start at lower dose. Increase dose slowly and monitor patient closely for adverse events.
 Status epilepticus refractory to I.V. diazepam ◇. Adults: 400 to 600 mg P.R. q 6 hours.

Pharmacodynamics
Anticonvulsant action: Mechanism unknown; effects may be from increased brain levels of gamma-aminobutyric acid (GABA), an inhibitory transmitter. Also may decrease GABA’s enzymatic catabolism. Onset of therapeutic effects may require a week or longer. May be used with other anticonvulsants.

Pharmacokinetics
Absorption: Valproate sodium and divalproex sodium quickly convert to valproic acid after administration of oral dose; plasma levels peak in 1 to 5 hours, 15 minutes to 2 hours with syrup, and immediately with I.V.; same bioavailability for all dose forms.
Distribution: Distributed rapidly throughout body; 80% to 95% protein-bound.
Metabolism: Metabolized by liver.
Excretion: Excreted in urine; some drug excreted in feces and exhaled air. Breast milk levels are 1% to 10% of serum levels.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug. Use cautiously in patients with history of hepatic dysfunction. Don’t give valproate sodium injection to patients with hepatic disease, significant hepatic dysfunction, or acute head trauma.
  Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorder (UCD), a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.

Interactions
Drug-drug. Antidepressants, MAO inhibitors, oral anticoagulants: Potentiated effects of these drugs. Monitor patient closely.
Carbamazepine: Decreased carbamazepine levels and increased metabolite levels. Monitor patient.
Clonazepam: Increased risk of absence seizures. Avoid use together.
Diazepam: Valproate displaces diazepam from albumin binding sites and inhibits its metabolism. Monitor patient.
Ethosuximide: Valproate inhibits ethosuximide metabolism. Monitor plasma levels of both drugs.
Felbamate, lamotrigine, salicylates: Increases valproate levels. Monitor valproate levels.
Phenobarbital, phenytoin, primidone: Increases serum levels of these drugs; causes excessive somnolence. Monitor patient carefully.
Rifampin: Increases oral clearance of valproate. Adjust valproate dosage, if necessary.
Drug-lifestyle. Alcohol use: Decreases valproic acid effectiveness; increases adverse CNS effects. Discourage alcohol use.

Adverse reactions
Because drug usually is used with other anticonvulsants, adverse reactions may not be caused by valproic acid alone.
CNS: sedation, emotional upset, depression, psychosis, aggressiveness, hyperactivity, behavioral deterioration, tremor, ataxia, headache, dizziness, incoordination, asthenia.
EENT: nystagmus, diplopia.
GI: nausea, vomiting, indigestion, diarrhea, abdominal cramps, constipation, increased appetite and weight gain, anorexia, pancreatitis.
Hematologic: thrombocytopenia, increased bleeding time, petechiae, bruising, eosinophilia, hemorrhage, leukopenia, bone marrow suppression.
Hepatic: toxic hepatitis.
Musculoskeletal: muscle weakness.
Skin: rash, alopecia, pruritus, photosensitivity, erythema multiforme.

Effects on lab test results
• May increase ALT, AST, and bilirubin levels.
• May increase eosinophil count and bleeding time. May decrease platelet and WBC counts.

Overdose and treatment
Signs and symptoms of overdose include heart block, somnolence, and coma.
 Treat supportively. Maintain adequate urine output, and monitor vital signs and fluid and electrolyte balance carefully. Naloxone reverses CNS and respiratory depression but also may reverse anticonvulsant effects of valproic acid. Hemodialysis and hemoperfusion have been used.

Special considerations
 ALERT Evaluate patients with risk factors associated with UCD before initiation of valproate therapy. Patients who develop symptoms of unexplained hyperammonemic encephalopathy during valproate therapy should have drug discontinued; undergo prompt, appropriate treatment; and be evaluated for underlying UCD.
• Administer drug with food to minimize GI irritation.
• Administer I.V. as 60-minute infusion at no more than 20 mg/minute.
• Use of valproate sodium injection for periods of longer than 14 days hasn’t been studied. Switch patients to oral products as soon as clinically feasible. When switching from I.V. to oral therapy or from oral to I.V. therapy, the total daily dose should be equivalent and given with the same frequency.
• Don’t withdraw drug abruptly.
• Valproic acid may cause false-positive test results for urinary ketones.
• Divalproex sodium extended-release tablets and divalproex sodium delayed-release tablets aren’t bioequivalent.
• Valproic acid reportedly alters thyroid function test results. Clinical significance is unknown.
• A ketone metabolite in the urine of patients taking valproic acid may produce a false-positive result for urine ketones.
• Monitor plasma level and make dosage adjustments as needed; therapeutic range of drug is 50 to 100 mcg/ml.
• Watch for tremors; they may indicate need for dosage reduction.
• Evaluate liver function, platelet count, and PT at baseline and monthly intervals-especially during first 6 months of therapy.
Breast-feeding patients
• Drug appears in breast milk. An alternative to breast-feeding is recommended during therapy.
Pediatric patients
• Not recommended for use in children younger than age 2; this age-group is at highest risk for adverse effects.
• Hyperexcitability and aggressiveness have occurred in a few children.
• Divalproex sodium extended-release tablets aren’t recommended for children.
Geriatric patients
• Drug is eliminated more slowly in elderly patients; lower dosages are recommended. Increase dosages more slowly with regular monitoring of fluid and nutritional intake, dehydration, somnolence, and other adverse effects.

Patient education
• Tell patient to swallow tablets or capsules whole to avoid local mucosal irritation. If necessary, tell patient to take with food but not carbonated beverages because tablet may dissolve before swallowing, causing irritation and unpleasant taste.
• Warn patient to avoid alcohol while taking drug; it may decrease drug effectiveness and increase adverse CNS effects.
• Advise patient to avoid tasks that require mental alertness until CNS sedative effects are known. Drowsiness and dizziness may occur. Bedtime administration of drug may minimize CNS depression.
• Teach patient signs and symptoms of hypersensitivity and adverse effects and the need to report them.
• Advise patient not to stop drug suddenly, not to alter dosage without approval, and to call before changing brand or using generic drug because therapeutic effect may change.
• Encourage patient taking anticonvulsants to wear a medical identification bracelet or necklace that lists drug and seizure disorder.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use