divalproex sodium

Action

Increases level of gamma-aminobutyric acid in brain, reducing seizure activity

Availability

valproate sodium

Injection: 100 mg/ml in 5-ml vial

Syrup: 250 mg/5 ml

valproic acid

Capsules (delayed-release): 125 mg, 250 mg, 500 mg

Capsules (liquid-filled): 250 mg

divalproex sodium

Capsules (containing coated particles or sprinkles): 125 mg

Tablets (enteric-coated, delayed-release): 125 mg, 250 mg, 500 mg

Tablets (extended-release): 250 mg, 500 mg

Indications and dosages

➣ Complex partial seizures

Adults and children older than age 10: Initially, 10 to 15 mg/kg/day P.O. or I.V. (valproate sodium). May increase by 5 to 10 mg/kg/day q week until blood drug level is 50 to 100 mcg/ml or adverse reactions occur; don't exceed 60 mg/kg/day. If daily dosage exceeds 250 mg, give in two divided doses.

➣ Simple or complex absence seizures

Adults and children older than age 10: Initially, 15 mg/kg/day P.O. or I.V. (valproate sodium). May increase by 5 to 10 mg/kg/day at weekly intervals until therapeutic blood drug level is reached or adverse reactions occur; don't exceed 60 mg/kg/day. If daily dosage exceeds 250 mg, give in two divided doses.

➣ Mania associated with bipolar disorder

Adults: Initially, 750 mg (divalproex or valproic acid delayed-release) P.O. daily in divided doses. Titrate rapidly to desired effect or trough level of 50 to 125 mcg/ml. Don't exceed 60 mg/kg/day.

➣ To prevent migraine

Adults: 250 mg (divalproex or valproic acid delayed-release) P.O. b.i.d. Or 500 mg (divalproex extended-release) P.O. daily for 1 week (up to 1 g/day). Maximum dosage is 1 g/day.

Off-label uses

• Chorea

• Photosensitivity-related seizures

• Sedative-hypnotic withdrawal

Contraindications

• Hypersensitivity to drug or tartrazine (some products)

• Hepatic impairment

• Urea cycle disorders

Precautions

Use cautiously in:

• bleeding disorders, organic brain disease, bone marrow depression, renal impairment

• posttraumatic seizures caused by head injury (use not recommended)

• history of hepatic disease

• elderly patients

• pregnant or breastfeeding patients

• children.

Administration

• Give I.V. only when oral therapy isn't feasible.

• For I.V. use, dilute valproate sodium in at least 50 ml of dextrose 5% in water, lactated Ringer's solution, or normal saline solution. Infuse over 1 hour at a rate slower than 20 mg/minute.

• Know that I.V. and P.O. dosages and dosing frequencies are identical. However, patient should be switched to oral therapy as soon as possible.

• Give oral forms with food.

• Be aware that divalproex extended-release and delayed-release forms are not bioequivalent.

• Make sure patient swallows divalproex extended-release tablets and valproic acid capsules whole without chewing or crushing.

• If patient can't swallow capsule containing coated particles, sprinkle entire contents of capsule onto about 5 ml of semisolid food, such as pudding or applesauce, immediately before giving.

• Don't give syrup in carbonated beverages (may cause mouth and throat irritation).

Adverse reactions

CNS: confusion, dizziness, headache, sedation, ataxia, paresthesia, asthenia, tremor, drowsiness, emotional lability, abnormal thinking, amnesia, hyperammonemic encephalopathy, suicidal behavior or ideation

EENT: amblyopia, blurred vision, nystagmus, tinnitus, pharyngitis

GI: nausea, vomiting, diarrhea, abdominal pain, dyspepsia, anorexia, pancreatitis

Hematologic: leukopenia, thrombocytopenia

Hepatic: hepatotoxicity

Metabolic: hyperammonemia

Musculoskeletal: back pain

Respiratory: dyspnea

Skin: rash, alopecia, bruising

Other: abnormal taste, increased appetite, weight gain, flulike symptoms, infection, infusion site pain and reaction, multiorgan hypersensitivity reaction

Interactions

Drug-drug. Activated charcoal, cholestyramine: decreased valproate absorption

Antiplatelet agents (including abciximab, aspirin and other nonsteroidal anti-inflammatory drugs, eptifibatide, tirofiban), cefamandole, cefoperazone, cefotetan, heparin, thrombolytics, warfarin: increased risk of bleeding

Barbiturates, primidone: decreased metabolism and greater risk of toxicity of these drugs, decreased valproate efficacy

Carbamazepine: increased carbamazepine blood level, decreased valproate blood level, poor seizure control

Chlorpromazine: decreased valproate clearance and increased trough level

Cimetidine: decreased valproate clearance

Clonazepam: absence seizures in patients with history of these seizures

CNS depressants (such as antihistamines and antidepressants, MAO inhibitors, opioid analgesics, sedative- hypnotics): additive CNS depression

Diazepam: displacement of diazepam from binding site, inhibited diazepam metabolism

Erythromycin, felbamate: increased valproate blood level, greater risk of toxicity

Ethosuximide: inhibited ethosuximide metabolism

Lamotrigine: decreased valproate blood level, increased lamotrigine blood level

Phenytoin: increased phenytoin effects and risk of toxicity, decreased valproate effects

Salicylates (large doses in children): increased valproate effects

Topiramate: increased risk of hyperammonemia with and without encephalopathy and hypothermia

Tricyclic antidepressants: increased blood levels of these drugs, greater risk of adverse reactions

Zidovudine: decreased zidovudine clearance in patients with human immunodeficiency virus

Drug-diagnostic tests. Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin: increased levels

Bleeding time: prolonged

Ketone bodies: false-positive results

Platelets, white blood cells: decreased counts

Thyroid function tests: interference with results

Drug-behaviors. Alcohol use: additive CNS depression

Patient monitoring

Closely monitor neurologic status. Watch for seizures and suicidal behavior or ideation.

If hyperammonemia or hyperammonemic encephalopathy (unexplained lethargy and vomiting or changes in mental status) is suspected, measure ammonia level.

Evaluate GI status. Stay alert for signs and symptoms of pancreatitis. Consider discontinuing drug if pancreatitis is diagnosed.

Watch for diverse signs and symptoms of multiorgan hypersensitivity reaction, such as fever and rash associated with other organ system involvement (lymphadenopathy, hepatitis, liver function test abnormalities, hematologic abnormalities, pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia). Discontinue drug if multiorgan hypersensitivity reaction occurs.

• Monitor I.V. infusion site for local reactions.

• Assess CBC (including platelet count), prothrombin time, International Normalized Ratio, and liver function tests.

• Monitor valproate blood level; therapeutic range is 50 to 100 mcg/ml.

Patient teaching

• Instruct patient to take with food to minimize GI upset.

• Tell patient taking extended-release tablets or valproic acid capsules to swallow them whole without chewing or breaking.

• Inform patient taking capsules with delayed-release pellets that he may swallow them whole or open them and sprinkle contents onto a teaspoon of semisolid food, such as pudding or applesauce.

• Tell patient (or parents) that valproate syrup shouldn't be taken with carbonated beverages.

Advise patient to immediately report signs and symptoms of liver dysfunction (such as malaise, weakness, lethargy, appetite loss, vomiting, or yellowing of skin or eyes), signs and symptoms of pancreatitis (such as abdominal pain, nausea, vomiting, loss of appetite), or suicidal behavior or ideation.

Tell patient to immediately report unexplained signs and symptoms that may reflect hypersensitivity reaction (fever, rash, hepatitis signs and symptoms, bleeding or bruising, itching, urinary problems, muscle pains, or weakness).

• If patient is taking drug for seizure control, tell him to avoid driving and other hazardous activities.

Caution patient not to stop therapy abruptly.

• Instruct patient to avoid alcohol.

• Stress importance of follow-up laboratory tests.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and behaviors mentioned above.