General

divalproex sodium
(dye-val-PROE-exSOE -dee-um)

• Apo-Divalproex [Canada]

• Depakote

• Depakote ER

• DOM-Divalproex [Canada]

• Epival [Canada]

• Gen-Divalproex [Canada]

• Novo-Divalproex [Canada]

• Nu-Divalproex [Canada]

• PHL-Divalproex [Canada]

• PMS-Divalproex [Canada]

valproate sodium
(val-PROE-ateSOE -dee-um)

• Depacon

valproic acid
(val-PROE-ikAS -id)

• Apo-Valproic [Canada]

• Depakene

• DOM-Valproic Acid [Canada]

• PHL-Valproic Acid [Canada]

• PMS-Valproic Acid [Canada]

• Ratio-Valprox [Canada]

Pregnancy Category
Category D

Ther. class.
anticonvulsants
vascular headache suppressants

Indications

• Monotherapy and adjunctive therapy for simple and complex absence seizures

• Monotherapy and adjunctive therapy for complex partial seizures

• Adjunctive therapy for patients with multiple seizure types, including absence seizures

• Divalproex sodium only:

» Manic episodes associated with bipolar disorder

» Prevention of migraine headache

Action

Increase levels of GABA, an inhibitory neurotransmitter in the CNS

Therapeutic Effect(s):

• Suppression of seizure activity

• Decreased manic episodes

• Decreased frequency of migraine headaches

Pharmacokinetics

Absorption: Well absorbed following oral administration; divalproex is enteric-coated, and absorption is delayed. ER form produces lower blood levels. IV administration results in complete bioavailability

Distribution: Rapidly distributed into plasma and extracellular water. Cross blood-brain barrier and placenta; enters breast milk

Protein Binding: 80–90%, decreased in neonates, elderly, renal impairment, or chronic hepatic disease

Metabolism and Excretion: Mostly metabolized by the liver; minimal amounts excreted unchanged in urine

Half-life: Adults: 9–16 hr

TIME/ACTION PROFILE (onset = anticonvulsant effect; peak = blood levels)

ROUTE	ONSET	PEAK	DURATION
PO—liquid	2–4 days	15–120 min	6–24 hr
PO—capsules	2–4 days	1–4 hr	6–24 hr
PO—delayed-release products	2–4 days	3–5 hr	12–24 hr
PO—extended-release products	2–4 days	7–14 hr	24 hr
IV	2–4 days	end of infusion	6–24 hr

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity

• Hepatic impairment

• Known/suspected urea cycle disorders (may result in fatal hyperammonemic encephalopathy)

Use Cautiously in:

• Bleeding disorders

• History of liver disease

• Organic brain disease

• Bone marrow depression

• Renal impairment

• Geri: risk of adverse effects

• OB: Use during pregnancy is linked to congenital anomalies, neural tube defects, clotting abnormalities, and hepatic dysfunction in the neonate. Use with extreme caution. Lactation: Pass into breast milk. Consider discontinuing nursing when valproates are administered to the nursing mother

• Pedi: Children, especially <2 yr (at risk for potentially fatal hepatotoxicity)

Adverse Reactions/Side Effects

CNS: agitation, dizziness, headache, insomnia, sedation, confusion, depression.

CV: peripheral edema.

EENT: visual disturbances.

GI: HEPATOTOXICITY, PANCREATITIS, abdominal pain, anorexia, anorexia, diarrhea, indigestion, nausea, vomiting, constipation, increased appetite.

Derm: alopecia, rashes.

Endo: weight gain.

Hemat: leukopenia, thrombocytopenia.

Metabolic: HYPERAMMONEMIA.

Neuro: HYPOTHERMIA, tremor, ataxia.

*CAPITALS indicates life-threatening.
*italic indicates most frequent.

Interactions

Drug-Drug

• risk of bleeding with warfarin

• Blood levels and toxicity may be by aspirin, carbamazepine, chlorpromazine, cimetidine, erythromycin, or felbamate

• CNS depression with other CNS depressants, including alcohol, antihistamines, antidepressants, opioid analgesics, MAO inhibitors, and sedative/hypnotics

• MAO inhibitors and other antidepressants may seizure threshold and effectiveness of valproate

• Carbamazepine, meropenem, phenobarbital, phenytoin, or rifampin may valproate blood levels

• Valproate may toxicity of carbamazepine, diazepam, amitriptyline, nortriptyline, ethosuximide, lamotrigine, phenobarbital, phenytoin, topiramate, or zidovudine

• Concurrent use with topiramate may risk of hypothermia

• Ertapenem, imipenem, or meropenem may valproate blood levels

Route/Dosage

• Regular-release and delayed-release formulations usually given in 2–4 divided doses daily; extended-release formulation (Depakote ER) usually given once daily

Anticonvulsant

• PO (Adults and Children >10 yr):
Single-agent therapy (complex partial seizures)—Initial dose of 10–15 mg/kg/day in 1–4 divided doses; by 5–10 mg/kg/day weekly until therapeutic response achieved (not to exceed 60 mg/kg/day); when daily dosage exceeds 250 mg, give in divided doses.
Polytherapy (complex partial seizures)—Initial dose of 10–15 mg/kg/day; by 5–10 mg/kg/day weekly until therapeutic response achieved (not to exceed 60 mg/kg/day); when daily dosage exceeds 250 mg, give in divided doses.

• PO (Adults and Children >2 yr [>10 yr for Depakote ER]):
Simple and complex absence seizures-Initial dose of 15 mg/kg/day in 1–4 divided doses; by 5–10 mg/kg/day weekly until therapeutic response achieved (not to exceed 60 mg/kg/day); when daily dosage exceeds 250 mg, give in divided doses.

• IV (Adults and Children): Give same daily dose and at same frequency as was given orally; switch to oral formulation as soon as possible.

• Rect (Adults and Children): Dilute syrup 1:1 with water for use as a retention enema. Give 17–20 mg/kg load, maintenance 10–15 mg/kg/dose q 8 hr.

Mood Stabilizer

• PO (Adults):
Depakote—Initial dose of 750 mg/day in divided doses initially, titrated rapidly to desired clinical effect or trough plasma levels of 50–125 mcg/ml (not to exceed 60 mg/kg/day).
Depakote ER- Initial dose of 25 mg/kg once daily; titrated rapidly to desired clinical effect of trough plasma levels of 85–125 mcg/ml (not to exceed 60 mg/kg/day).

Migraine Prevention

• PO (Adults and Children >=16 yr):
Depakote—250 mg twice daily (up to 1000 mg/day).
Depakote ER—500 mg once daily for 1 wk, then to 1000 mg once daily.

Availability

Valproic Acid

• Capsules: 250 mg, 500 mg[canada]

» Cost:
Generic: $29.97/100.

• Syrup: 250 mg/5 ml

» Cost:
Generic: $17.99/150 ml.

Valproate Sodium

• Injection: 100 mg/ml in 5-ml vials

Divalproex Sodium

• Delayed-release tablets (Depakote): 125 mg, 250 mg, 500 mg

» Cost: 125 mg $85.85/100, 250 mg $159.98/100, 500 mg $296.66/100.

• Capsules-sprinkle: 125 mg

» Cost: $83.31/100.

• Extended-release tablets (Depakote ER): 250 mg, 500 mg

» Cost: 250 mg $134.97/90, 500 mg $225.97/90.

Assessment

Seizures

• Assess location, duration, and characteristics of seizure activity. Institute seizure precautions

Bipolar Disorder

• Assess mood, ideation, and behavior frequently

Migraine Prophylaxis

• Monitor frequency of migraine headaches

• Geri: Assess geriatric patients for excessive somnolence

Lab Test Considerations

• Monitor CBC, platelet count, and bleeding time prior to and periodically during therapy. May cause leukopenia and thrombocytopenia

» Monitor hepatic function (LDH, AST, ALT, and bilirubin) and serum ammonia concentrations prior to and periodically during therapy. May cause hepatotoxicity; monitor closely, especially during initial 6 mo of therapy; fatalities have occurred. Therapy should be discontinued if hyperammonemia occurs

» May interfere with accuracy of thyroid function tests

» May cause false-positive results in urine ketone tests

Toxicity and Overdose

• Therapeutic serum levels range from 50–100 mcg/ml (50–125 mcg/ml for mania). Doses are gradually until a predose serum concentration of at least 50 mcg/ml is reached. However, a good correlation among daily dose, serum level, and therapeutic effects has not been established. Patients receiving near the maximum recommended 60 mg/kg/day should be monitored for toxicity

Potential Nursing Diagnoses

• Risk for injury (Indications)

Implementation

• Do not confuse Depakote ER and regular dose forms. Depakote ER produces lower blood levels than Depakote dosing forms. If switching from Depakote to Depakote ER, increase dose by 8-20%

» Single daily doses are usually administered at bedtime because of sedation

• PO: Administer with or immediately after meals to minimize GI irritation. Extended-release and delayed-release tablets should be swallowed whole, do not break or chew; will cause mouth or throat irritation and destroy extended release mechanism. Do not administer tablets with milk or carbonated beverages (may cause premature dissolution). Delayed-release divalproex sodium may cause less GI irritation than valproic acid capsules

» Shake liquid preparations well before pouring. Use calibrated measuring device to ensure accurate dosage. Syrup may be mixed with food or other liquids to improve taste

» Sprinkle capsules may be swallowed whole or opened and entire capsule contents sprinkled on a teaspoonful of soft, cool food (applesauce, pudding). Do not chew mixture.Administer immediately; do not store for future use

» To convert from valproic acid to divalproex sodium, initiate divalproex sodium at same total daily dose and dosing schedule as valproic acid. Once patient is stabilized on divalproex sodium, attempt administration 2–3 times daily

• Rect: Dilute syrup 1:1 with water for use as a retention enema

IV Adminstration:

• Intermittent Infusion:

Diluent: May be diluted in at least 50 ml of D5W, 0.9% NaCl, or LR. Solution is stable for 24 hr at room temperature
Concentration: 2 mg/ml.

• Rate:
Infuse over 60 min (<=20 mg/min). Rapid infusion may cause increased side effects. Has been given as a one-time infusion of 1000 mg over 5-10 min @ 3 mg/kg/min up to 15 mg/kg in patients with no detectable valproate levels

Patient/Family Teaching

• Instruct patient to take medication as directed. If a dose is missed on a once-a-day schedule, take as soon as remembered that day. If on a multiple-dose schedule, take it within 6 hr of the scheduled time, then space remaining doses throughout the remainder of the day. Abrupt withdrawal may lead to status epilepticus

• May cause drowsiness or dizziness. Caution patient to avoid driving or other activities requiring alertness until effects of medication are known. Tell patient not to resume driving until physician gives clearance based on control of seizure disorder

• Caution patient to avoid taking alcohol, CNS depressants, OTC medications or herbal products concurrently with valproates without consulting health care professional

• Instruct patient to notify health care professional of medication regimen prior to treatment or surgery

• Advise patient to carry identification at all times describing medication regimen

• Advise patient to notify health care professional if anorexia, abdominal pain, severe nausea and vomiting, yellow skin or eyes, fever, sore throat, malaise, weakness, facial edema, lethargy, unusual bleeding or bruising, pregnancy, or loss of seizure control occurs. Children <2 yr of age are especially at risk for fatal hepatotoxicity

• Emphasize the importance of routine exams to monitor progress

Evaluation/Desired Outcomes

• Decreased seizure activity

• Decreased incidence of manic episodes in patients with bipolar disorders

• Decreased frequency of migraine headaches

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