valproates

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

Distribution: Rapidly distributed into plasma and extracellular water. Cross blood-brain barrier.

Protein Binding: 80–90% (↓ in neonates, elderly, renal impairment, or chronic hepatic impairment).

Metabolism/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

Contraind./Precautions ⬆ ⬇

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 (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;
Renal impairment;
Hepatic impairment;
Organic brain disease;
Bone marrow depression;
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.

Adv. Reactions/Side Effects ⬆ ⬇

CV: peripheral edema

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

EENT: visual disturbances

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

Hemat: thrombocytopenia, leukopenia

Metab: ↑appetite, HYPERAMMONEMIA, weight gain

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

Interactions ⬆ ⬇

Drug-drug:

↑risk of bleeding with warfarin.
Aspirin, carbamazepine, chlorpromazine, cimetidine, erythromycin, or felbamate may ↑ levels and the risk of toxicity.
↑risk of 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, ertapenem, imipenem, meropenem, methotrexate, phenobarbital, phenytoin, estrogen-containing contraceptives, or rifampin may ↓ levels and effectiveness.
May ↑ levels and the risk of toxicity of carbamazepine, diazepam, amitriptyline, nortriptyline, ethosuximide, lamotrigine, phenobarbital, phenytoin, rufinamide, topiramate, or zidovudine; dosage adjustments of these medications may be necessary.
May ↑ levels and the risk of toxicity of propofol; ↓ dose of propofol.
Concurrent use with topiramate may ↑ the risk of hypothermia and hyperammonemia with or without encephalopathy.
Cholestyramine may ↓ levels and effectiveness; separate administration by 3 hr.
Concurrent use with cannabidiol may ↑ risk of liver enzyme elevation; monitor liver enzymes closely during concomitant therapy.

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

Seizure Disorders

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.
(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.

Bipolar Disorder

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

Valproate Sodium

Divalproex Sodium

Capsules: 250 mg
Oral solution: 250 mg/5 mL
Solution for injection: 100 mg/mL
Delayed-release tablets (Depakote): 125 mg; 250 mg; 500 mg
Extended-release tablets (Depakote ER): 250 mg; 500 mg
Sprinkle capsules: 125 mg

Assessment ⬆ ⬇

Seizures: Assess location, duration, frequency, 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 older adults 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.

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. Monitor patients receiving near the maximum recommended 60 mg/kg/day for toxicity.

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. DNC: Swallow extended-release and delayed-release tablets and capsules 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.
- Reduce starting dose in older adults. Increase doses more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.
- Shake liquid preparations well before pouring. Use calibrated measuring device to ensure accurate dose. Oral solution 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.
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 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.

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. 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 or opioids. 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 breastfeeding. Dietary folic acid supplementation prior to conception and during first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 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, decreased IQ, neural tube defects, and hearing impairment/loss. Advise pregnant patients taking valproates to enroll in the North American Anti Epileptic Drug Pregnancy Registry to monitor pregnancy outcomes by calling 1-888-233-2334; call must be made by patient. Registry website is www.aedpregnancyregistry.org. May cause male infertility. Monitor breastfed 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.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇