valproates

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: ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, alopecia, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), ERYTHEMA MULTIFORME, rash, STEVENS JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

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

Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA)

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.
Carbamazepine, ertapenem, imipenem, meropenem, methotrexate, phenobarbital, phenytoin, estrogen-containing contraceptives, or rifampin may ↓ levels and effectiveness.
May ↑ levels and 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 risk of toxicity of propofol; ↓ propofol dose.
Topiramate may ↑ risk of hypothermia and hyperammonemia, with or without encephalopathy.
Cholestyramine may ↓ levels and effectiveness; separate administration by 3 hr.
Cannabidiol may ↑ risk of liver enzyme elevation; monitor liver enzymes closely during concurrent therapy.

Availability ⬆ ⬇

Valproic Acid

(Generic available)

Capsules: 250 mg
Oral solution: 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
Extended-release tablets (Depakote ER): 250 mg; 500 mg
Sprinkle capsules: 125 mg

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.
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.

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.

US Brand Names ⬆ ⬇

divalproex sodium: Depakote, Depakote ER, Depakote Sprinkle,

valproate sodium: ~~Depacon,~~

valproic acid: ~~Depakene~~

Action ⬆ ⬇

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

Therapeutic effects:

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

Classifications ⬆ ⬇

Therapeutic Classification: anticonvulsants, vascular headache suppressants

Pharmacokinetics ⬆ ⬇

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, older adults, 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.

Canadian Brand Names ⬆ ⬇

divalproex sodium: Epival

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

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Advise to take 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 notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications, especially CNS depressants or opioids. Caution patient to avoid alcohol during therapy.
May cause drowsiness or dizziness. Advise patient to avoid driving or other activities requiring alertness until effects of medication are known. Explain to patient not to resume driving until physician gives clearance based on control of seizure disorder.
Advise patient and family/caregiver to notify health care provider 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 ↑ in activity and talking, or other unusual changes in behavior or mood occur.
Instruct patient to notify health care provider of medication regimen prior to treatment or surgery.
Advise patient to notify health care provider 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.
Advise patient to carry identification at all times describing medication regimen.
Emphasize the importance of routine exams to monitor progress.
Rep: May cause fetal harm. Advise women of reproductive potential to use effective contraception during therapy and to notify health care provider immediately if pregnancy is planned or suspected or if breastfeeding. Dietary folic acid supplementation prior to conception and during 1st trimester of pregnancy ↓ 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 ↑ in autism spectrum disorders and attention-deficit hyperactivity disorder, ↓ 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 outcomes by calling 1-888-233-2334 or visiting www.aedpregnancyregistry.org; patient must enroll themselves. May cause male infertility. Monitor breastfed infant for signs of liver damage, including jaundice and unusual bruising or bleeding.

section name header

Indications ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Availability ⬆ ⬇

Route/Dosage ⬆ ⬇

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Classifications ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Canadian Brand Names ⬆ ⬇

Time/Action Profile ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Pronunciation ⬆