divalproex sodium: dye-val-PROE-ex SOE-dee-um

valproate sodium: val-PROE-ate SOE-dee-um

valproic acid: val-PROE-ik AS-id

• 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.

• Increase levels of GABA, an inhibitory neurotransmitter in the CNS.

• Suppression of seizure activity.
• Decreased manic episodes.
• Decreased frequency of migraine headaches.

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/Excretion: Mostly metabolized by the liver; minimal amounts excreted unchanged in urine.

Half-life: Adults: 9–16 hr.

Contraindicated in:

• Hypersensitivity
• Hepatic impairment
• Known/suspected urea cycle disorders (may result in fatal hyperammonemic encephalopathy)
• Mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (↑ risk for potentially fatal hepatotoxicity)
• Rep: Women of reproductive potential not using effective contraception (for migraine prophylaxis only)
• OB: Pregnancy (may cause fetal harm) (for migraine prophylaxis only)
• Lactation: Lactation
• Pedi: Children <2 yr with suspected mitochondrial disorder caused by mutations in mitochondrial DNA polymerase gamma (↑ risk for potentially fatal hepatotoxicity).

Use Cautiously in:

• All patients (may ↑ risk of suicidal thoughts/behaviors)
• Bleeding disorders
• History of liver disease
• Organic brain disease
• Bone marrow depression
• Renal impairment
• Rep: Women of reproductive potential (use for seizure disorders or bipolar disorders only if other medications are ineffective, poorly tolerated, or inappropriate).
• OB: Pregnancy (may cause fetal harm including ↓ IQ, neurodevelopmental disorders [including autism spectrum disorders and attention deficit/hyperactivity disorder], neural tube defects, hearing impairment/loss, and other major congenital malformations); use for seizure disorders or bipolar disorders only if other medications are ineffective, poorly tolerated, or inappropriate
• Geri: ↑risk of adverse effects in older adults.

CV: peripheral edema.

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), alopecia, rashes.

EENT: visual disturbances.

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

Hemat: thrombocytopenia, leukopenia.

Metab: HYPERAMMONEMIA, weight gain.

Neuro: HYPOTHERMIA, tremor, ataxia , SUICIDAL THOUGHTS, agitation, dizziness, headache, insomnia, sedation, confusion, depression.

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, estrogen-containing contraceptives, or rifampin may ↓ valproate levels.
• May ↑ levels of carbamazepine, diazepam, amitriptyline, nortriptyline, ethosuximide, lamotrigine, phenobarbital, phenytoin, rufinamide, topiramate, or zidovudine; dosage adjustments of these medications may be necessary.
• May ↑ levels of propofol; ↓ dose of propofol.
• Concurrent use with topiramate may ↑ risk of hypothermia and hyperammonemia with or without encephalopathy.
• Ertapenem, imipenem, or meropenem may ↓ valproate levels.
• Cholestyramine may ↓ valproate levels; separate administration by 3 hr.

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 dose 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 dose 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 every 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.

• 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. DNC: Extended-release and delayed-release tablets and capsules should be swallowed whole, do not open, 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 dose. 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 Administration:

• 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 an infusion of 15 mg/kg over 5–10 min (1.5–3 mg/kg/min). Rapid loading doses of doses of 20 to 40 mg/kg have been administered over 1 to 5 min. In pediatric patients, an infusion rate of 1.5 to 3 mg/kg/minute has been recommended.
• Y-Site Compatibility:
  • cefepime
  • ceftazidime
  • meropenem
  • naloxone
• Y-Site Incompatibility:
  • vancomycin
.

divalproex sodium: Depakote, Depakote ER, Depakote Sprinkle

valproate sodium: Depacon

valproic acid: Depakene

divalproex sodium: Epival

Therapeutic Classification: anticonvulsants, vascular headache suppressants

Valproic Acid

(generic available)

• Capsules: 250 mg; 500 mg;
  • Cost: Generic— $37.90/100.
• Syrup: 250 mg/5 mL;

Valproate Sodium

(generic available)

• Solution for injection: 100 mg/mL;

Divalproex Sodium

(generic available)

• Delayed-release tablets (Depakote): 125 mg; 250 mg; 500 mg;
  • Cost: 125 mg; $89.72/100 250 mg; $176.23/100 500 mg; $324.97/100.
• Extended-release tablets (Depakote ER): 250 mg; 500 mg;
  • Cost: 250 mg; $167.91/100 500 mg; $295.36/100.
• Sprinkle capsules: 125 mg;
  • Cost: $137.53/100.

(onset = anticonvulsant effect; peak = blood levels)

• Seizures: Assess location, duration, and characteristics of seizure activity. Institute seizure precautions.
• Bipolar Disorder: Assess mood, ideation, and behavior frequently.
• Migraine Prophylaxis: Monitor frequency and intensity of migraine headaches.
• Geri: Assess geriatric patients for excessive somnolence.
• Assess for suicidal tendencies, especially during early therapy. Restrict amount of drug available to patient. Risk may be increased in children, adolescents, and adults 24 yr.
• Monitor for signs and symptoms of pancreatitis (abdominal pain, nausea, vomiting, anorexia). If pancreatitis occurs, valproates should be discontinued and alternate therapy initiated.
• Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis, eosinophilia). If symptoms occur and DRESS is confirmed, discontinue valproate and do not restart.

• 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.

• Therapeutic serum levels range from 50–100 mcg/mL (50–125 mcg/mL for mania). Doses are gradually ↑ until a pre-dose 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. Monitor patients receiving near the maximum recommended 60 mg/kg/day for toxicity.

• 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. Advise patient to read the Medication Guide before starting therapy and with each Rx refill in case of changes.
• 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.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially CNS depressants. Caution patient to avoid alcohol during therapy.
• Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide; new or worse depression; new or worse anxiety; feeling very agitated or restless; panic attacks; trouble sleeping; new or worse irritability; acting aggressive; being angry or violent; acting on dangerous impulses; an extreme increase in activity and talking, other unusual changes in behavior or mood occur.
• Instruct patient to notify health care professional of medication regimen prior to treatment or surgery.
• 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.
• Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during therapy and to notify health care professional immediately if pregnancy is planned or suspected, or if breast feeding. May cause abnormal clotting and hepatic failure in pregnant woman and neonate. May cause adverse effects on neurodevelopment, including increases in autism spectrum disorders and attention deficit/hyperactivity disorder (ADHD), decreased IQ, neural tube defects, and hearing impairment/loss. Advise pregnant patients taking valproates to enroll in the NAAED Pregnancy Registry to monitor pregnancy outcomes by calling 1-888-233-2334; call must be made by patient. Registry website is . May cause male infertility. Monitor breast-fed infant for signs of liver damage including jaundice and unusual bruising or bleeding.
• Advise patient to carry identification at all times describing medication regimen.
• Emphasize the importance of routine exams to monitor progress.

• Decreased seizure activity.
• Decreased incidence of manic episodes in patients with bipolar disorders.
• Decreased frequency of migraine headaches.