Valproic Acid and Derivatives (Sodium valproate, divalproex sodium)

A to Z Drug Facts

 Action Believed to work by increasing brain levels of GABA. It may also inhibit catabolism of GABA, potentiate postsynaptic GABA responses, and affect potassium channels or directly stabilize membranes.

 Indications Sole and adjunctive therapy in simple (petit mal) and complex absence seizures. Adjunctive therapy in multiple seizure types including absence seizures. Divalproex sodium is used for manic episodes associated with bipolar disorder.

Treatment of atypical absence, myoclonic and tonic-clonic (grand mal) seizures, and atonic, complex partial, elementary partial, and infantile spasm seizures; prevention of recurrent pediatric febrile seizures; intractable status epilepticus in patients who have not responded to other therapies; treatment of minor incontinence after ileoanal anastomosis (subchronic administration); migraine prophylaxis; management of anxiety disorders and panic attacks.

 Contraindications Hepatic disease dysfunction; known urea cycle disorders.

 Route/Dosage

Epilepsy

Adults and Children: PO 15 mg/kg/day in divided doses if total dose is more than 250 mg/day; increase at 1-wk intervals by 5 to 10 mg/kg/day until seizures are controlled; side effects preclude further increases or a maximum dose of 60 mg/kg/day. Titrate and individualize based on outcomes or side effects.

Mania (Divalproex Sodium)

Adults: PO 750 mg/day in divided doses. Increase as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect. Maximum dosage 60 mg/kg/day.

 Interactions

Alcohol, CNS depressants: Enhanced CNS depression.

Barbiturates: May increase barbiturate levels and actions.

Carbamazepine, hydantoins: May result in increased levels of these drugs and reduced efficacy of valproic acid.

Charcoal: May reduce absorption of valproic acid.

Chlorpromazines, cimetidine, salicylates: May increase valproic acid levels.

Felbamate: Increased valproic acid levels.

Lamotrigine: Decreased valproic acid levels; increased lamotrigine levels.

Zidovudine: Increased AUC of valproic acid.

 Lab Test Interferences Valproic acid may yield false-positive results on urine ketone tests; altered thyroid function tests.

 Adverse Reactions

CARDIOVASCULAR: Hypertension; hypotension; palpitations; posturual hypotension; tachycardia; vascular anomaly; vasodilation. CNS: Abnormal dreams; abnormal gait; aggression; agitation; ataxia; behavioral deterioration; catatonic reaction; coma; confusion; depression; diplopia; dizziness; dysarthria; emotional upset; hallucinations; headache; hyperactivity; hypertonia; hypokinesia; incoordination; insomnia; paresthesia; psychosis; reflexes increased; sedation; somnolence; tardive dyskinesia; thinking abnormalities; tremor; vertigo. DERMATOLOGIC: Alopecia; discoid lupus erythematosus; dry skin; erythema multiforme; furunculosis; generalized pruritus; maculopapular rash; petechiae; photosensitivity; seborrhea; skin rash; Stevens-Johnson syndrome; transient hair loss. EENT: Asterixis; diplopia; nystagmus; “spots before eyes.” GI: Abdominal cramps; anorexia with weight loss; constipation; diarrhea; flatulence; gastroenteritis; glossitis; fecal incontinence; increased appetite with weight gain; indigestion; nausea; periodontal abscess; vomiting. GU: Dysmenorrhea; dysuria; enuresis; irregular menses; secondary amenorrhea, urinary incontinence. HEMATOLOGIC: Acute intermittent porphyria; altered bleeding time; anemia; bone marrow suppression or toxicity (suggestive of myelodysplastic syndrome); bruising; eosinophilia; Ecchymosis; hematoma formation; hemorrhage; hypofibrinogenemia; leukopenia; lymphocytosis; macrocytosis; reduced platelet aggregation; thrombocytopenia. HEPATIC: Minor elevations of AST, ALT, and LDH; increase in serum bilirubin; abnormal LFT results; severe hepatotoxicity; possibly death. METABOLIC: Abnormal thyroid function test results; hyponatremia; inappropriate ADH secretion; Fanconi's syndrome; hypocarnitinemia; parotid gland swelling; breast enlargement; galactorrhea; hyperammonemia; hyperglycemia; edema; peripheral edema. MUSCULOSKELETAL: Arthralgia; arthrosis; leg cramps; twitching. RESPIRATORY: Dyspnea; rhinitis. OTHER: Abnormal vision; accidental injury; acute pancreatitis; amblyopia; chest pain, chills, chills with fever, cyst, fever, infection, neck pain, neck rigidity (mania); conjunctivitis; deafness; dry eyes; ear disorder; ear pain; extremity edema; eye pain; fever; lupus erythematosus; tinnitus; weakness.

 Precautions

Pregnancy: Category D. Risk of neural tube defects may be increased during first trimester. Lactation: Excreted in breast milk. Children: In children younger than 2 yr, use drug with extreme caution. This patient group is at considerably increased risk of developing fatal hepatotoxicity. Safety and efficacy of divalproex sodium for treatment of acute mania have not been studied in patients younger than 18 yr. Safety and efficacy of long-term use (more than 3 wk) have not been systematically evaluated. If used for extended periods, continually reevaluate the drug's usefulness. Younger children, especially if receiving enzyme-inducing drugs, will require larger maintenance doses to reach targeted drug concentrations. Elderly: Reduce starting dose and base therapeutic dose on clinical response. Acute head injuries: Because IV valproic acid has been associated with a higher incidence of death than IV phenytoin, do not use in the prevention of posttraumatic seizures in patients with acute head injuries. Bioavailability: Bioavailability problems may occur when converting to generic forms. Concurrent anticonvulsant use: Valproic acid may interact with other anticonvulsant medications. Discontinuation: Abrupt discontinuation may precipitate status epilepticus with attendant life-threatening hypoxia in patients receiving valproic acid to prevent major seizures. GI irritation: Sustained-release divalproex sodium may be less irritating to GI system than valproic acid. Hematologic effects: Drug may cause bleeding disorders. Hepatotoxicity: Hepatic failure resulting in fatalities has occurred. Children younger than 2 yr are at increased risk of developing fatal hepatotoxicity. Reactions usually occur within first 6 mo of therapy preceded by symptoms such as lost seizure control, malaise, weakness, lethargy, facial edema, anorexia, jaundice, and vomiting. Use drug with caution in patients with prior history of liver disease. Monitor results of LFTs frequently. Pancreatitis: Life-threatening pancreatitis has been reported in adults and children. Hyperammonemia: May occur with or without lethargy and coma and contribute to hepatotoxicity. Dose-related adverse reactions: Frequency of adverse reactions (particularly elevated liver enzymes, thrombocytopenia) may be dose related. Mania: Clinical data from long-term studies (more than 3 wk) are not available.

 Administration/Storage

• Administer orally with food if GI upset occurs.
• Instruct patient to swallow tablets or capsules whole and not to chew or crush them.
• Give once a day at bedtime to reduce effects of CNS depression.
• For sprinkle capsule administration, have patient swallow whole or sprinkle on 1 tsp of semisolid food (eg, applesauce) and have patient swallow immediately without chewing. Discard unused portion.
• Do not administer oral syrup in carbonated drinks as unpleasant taste and local irritation results.
• Store at room temperature in tight container. Do not freeze syrup.

 Assessment/Interventions

• Obtain patient history, including drug history and any known allergies. Note sensitivity to anticonvulsant drugs and history of seizures.
• Observe for development of side effects (eg, GI intolerance, CNS changes, abnormal bleeding or bruising, hair loss).
• Determine platelet counts and bleeding times before therapy, periodically during therapy, and before surgery.
• Immediately notify health care provider of the following symptoms of hepatotoxicity: lethargy, coma, jaundice.
• Report symptoms of bleeding disorders or abnormal platelet count or bleeding times to health care provider. Dosage reduction or withdrawal of therapy may be required.
• When drug is administered concomitantly with other anticonvulsant medication, determine drug serum levels before therapy and periodically during treatment.
• Perform LFTs prior to therapy and at frequent intervals thereafter, especially during first 6 mo of therapy.
• Monitor BP, pulse, and respirations.
• Maintain adequate fluid intake.

 Patient/Family Education

• Advise patient to take with food if GI upset occurs.
• Instruct patient to take once-daily dose at bedtime to reduce CNS depression.
• Advise patient not to chew tablets or capsules, swallow them whole.
• When sprinkle capsules have been prescribed, inform patient that capsules may be swallowed whole or sprinkled on 1 tsp of semisolid food and swallowed immediately without chewing. Instruct patient to discard unused portion.
• Advise patient to carry identification (eg, edi-Alert) indicating condition and medication regimen.
• Caution patient to avoid intake of alcoholic beverages and other CNS depressants.
• Inform diabetic patient that drug may cause false-positive results for urine ketones.
• Instruct patient not to take OTC or prescription medications, especially those containing aspirin, without consulting health care provider.
• Instruct patient to report the following symptoms to health care provider: unusual bruising or bleeding, skin eruptions, jaundice, lethargy, abdominal pain, anorexia, nausea, vomiting, diarrhea.
• Advise patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness.

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Copyright © 2003 Facts and Comparisons
David S. Tatro
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