Pronunciation:

(val PROE ik AS id & dah RIV ah tives)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Mania associated with bipolar disorder (Depakote®)

Migraine prophylaxis (Depakote®, Depakote® ER)

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

Cases of life-threatening pancreatitis, occurring at the start of therapy or following years of use, have been reported in adults and children. Some cases have been hemorrhagic with rapid progression of initial symptoms to death.

May cause teratogenic effects such as neural tube defects (eg, spina bifida). Use in women of childbearing potential requires that benefits of use in mother be weighed against the potential risk to fetus, especially when used for conditions not associated with permanent injury or risk of death (eg, migraine).

Hyperammonemic encephalopathy, sometimes fatal, has been reported following the initiation of valproate therapy in patients with known or suspected urea cycle disorders (UCD), particularly those with ornithine transcarbamylase deficiency. Although a rare genetic disorder, UCD evaluation should be considered for the following patients, prior to the start of therapy: History of unexplained encephalopathy or coma; encephalopathy associated with protein load; pregnancy or postpartum encephalopathy; unexplained mental retardation; history of elevated plasma ammonia or glutamine; history of cyclical vomiting and lethargy; episodic extreme irritability, ataxia; low BUN or protein avoidance; family history of UCD or unexplained infant deaths (particularly male); signs or symptoms of UCD (hyperammonemia, encephalopathy, respiratory alkalosis). Patients who develop symptoms of hyperammonemic encephalopathy during therapy with valproate should receive prompt evaluation for UCD and valproate should be discontinued.

Hyperammonemia may occur with therapy and may be present with normal liver function tests. Ammonia levels should be measured in patients who develop unexplained lethargy and vomiting, or changes in mental status. Discontinue therapy if ammonia levels are increased and evaluate for possible UCD.

In vitro studies have suggested valproate stimulates the replication of HIV and CMV viruses under experimental conditions. The clinical consequence of this is unknown, but should be considered when monitoring affected patients.

Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; valproate should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Concomitant use with clonazepam may induce absence status.

CNS depression may occur with valproate use. Patients must be cautioned about performing tasks which require mental alertness (operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated.

Adverse Reactions:

Adverse reactions reported when used as monotherapy for complex partial seizure:

>10%:

Central nervous system: Somnolence (18% to 30%), dizziness (13% to 18%), insomnia (9% to 15%), nervousness (7% to 11%)

Dermatologic: Alopecia (13% to 24%)

Gastrointestinal: Nausea (26% to 34%), diarrhea (19% to 23%), vomiting (15% to 23%), abdominal pain (9% to 12%), dyspepsia (10% to 11%), anorexia (4% to 11%)

Hematologic: Thrombocytopenia (1% to 24%)

Neuromuscular & skeletal: Tremor (19% to 57%), weakness (10% to 21%)

Respiratory: Respiratory tract infection (13% to 20%), pharyngitis (2% to 8%), dyspnea (1% to 5%)

1% to 10%

Cardiovascular: Hypertension, palpitation, peripheral edema (3% to 8%), tachycardia, chest pain

Central nervous system: Amnesia (4% to 7%), abnormal dreams, anxiety, confusion, depression (4% to 5%), malaise, personality disorder

Dermatologic: Bruising (4% to 5%), dry skin, petechia, pruritus, rash

Endocrine & metabolic: Amenorrhea, dysmenorrhea

Gastrointestinal: Eructation, flatulence, hematemesis, increased appetite, pancreatitis, periodontal abscess, taste perversion, weight gain (4% to 9%)

Genitourinary: Urinary frequency, urinary incontinence, vaginitis

Hepatic: Increased AST and ALT

Neuromuscular & skeletal: Abnormal gait, arthralgia, back pain, hypertonia, incoordination, leg cramps, myalgia, myasthenia, paresthesia, twitching

Ocular: Amblyopia/blurred vision (4% to 8%), abnormal vision, nystagmus (1% to 7%)

Otic: Deafness, otitis media, tinnitus (1% to 7%)

Respiratory: Epistaxis, increased cough, pneumonia, sinusitis

Additional adverse effects: Frequency not defined:

Cardiovascular: Bradycardia

Central nervous system: Aggression, ataxia, behavioral deterioration, cerebral atrophy (reversible), dementia, emotional upset, encephalopathy (rare), fever, hallucinations, headache, hostility, hyperactivity, hypesthesia, incoordination, Parkinsonism, psychosis, vertigo

Dermatologic: Cutaneous vasculitis, erythema multiforme, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (rare)

Endocrine & metabolic: Breast enlargement, galactorrhea, hyperammonemia, hyponatremia, inappropriate ADH secretion, irregular menses, parotid gland swelling, polycystic ovary disease (rare), abnormal thyroid function tests

Genitourinary: Enuresis, urinary tract infection

Hematologic: Anemia, aplastic anemia, bone marrow suppression, eosinophilia, hematoma formation, hemorrhage, hypofibrinogenemia, intermittent porphyria, leukopenia, lymphocytosis, macrocytosis, pancytopenia

Hepatic: Bilirubin increased, hyperammonemic encephalopathy (in patients with UCD)

Neuromuscular & skeletal: Asterixis, bone pain, dysarthria

Ocular: Diplopia, "spots before the eyes"

Renal: Fanconi-like syndrome (rare, in children)

Miscellaneous: Anaphylaxis, decreased carnitine, hyperglycinemia, lupus

Postmarketing and/or case reports: Life-threatening pancreatitis (2 cases out of 2416 patients), occurring at the start of therapy or following years of use, has been reported in adults and children. Some cases have been hemorrhagic with rapid progression of initial symptoms to death. Cases have also been reported upon rechallenge.

Overdosage/Toxicology:

Drug Interactions:

Acyclovir: Serum levels of valproate may be reduced; monitor

Carbamazepine: Valproic acid may increase, decrease, or have no effect on carbamazepine levels; valproic acid may increase serum concentrations of carbamazepine - epoxide (active metabolite); valproic acid may induce the metabolism of carbamazepine; monitor

Cholestyramine: Cholestyramine (and possibly colestipol) may bind valproic acid in GI tract; monitor

Clonazepam: Absence seizures have been reported in patients receiving valproic acid and clonazepam

Clozapine: Valproic acid may displace clozapine from protein-binding site resulting in decreased clozapine serum concentrations

Diazepam: Valproic acid may increase serum concentrations; monitor

Isoniazid: May decrease valproic acid metabolism (limited documentation)

Lamotrigine: Valproic acid inhibits the metabolism of lamotrigine; combination therapy has been proposed to increase the risk of toxic epidermal necrolysis; monitor

Macrolide antibiotics: May decrease valproic acid metabolism (limited documentation); includes clarithromycin, erythromycin, troleandomycin; monitor

Mefloquine: Concomitant use with valproic acid may reduce seizure control by lowering plasma levels. Monitor.

Nimodipine: Valproic acid appears to inhibit the metabolism of nimodipine; monitor for increased effect

Phenobarbital: Valproic acid appears to inhibit the metabolism of phenobarbital; monitor for increased effect

Phenothiazines: Chlorpromazine may increase valproic acid concentrations. Other phenothiazines may share this effect; monitor

Phenytoin: Valproic acid may increase, decrease, or have no effect on phenytoin levels

Risperidone: A case report of generalized edema occurred during combination therapy

Salicylates: May displace valproic acid from plasma proteins, leading to acute toxicity

Tricyclic antidepressants: Valproate may increase serum concentrations and/or toxicity of tricyclic antidepressants

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Food may delay but does not affect the extent of absorption. Valproic acid serum concentrations may be decreased if taken with food. Milk has no effect on absorption.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased)

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Distribution: Total valproate: 11 L/1.73 m²; free valproate 92 L/1.73 m²

Protein binding (dose dependent): 80% to 90%

Metabolism: Extensively hepatic via glucuronide conjugation and mitochondrial beta-oxidation. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.

Bioavailability: Extended release: 90% of I.V. dose and 81% to 90% of delayed release dose

Half-life elimination: (increased in neonates and with liver disease): Children: 4-14 hours; Adults: 9-16 hours

Time to peak, serum: 1-4 hours; Divalproex (enteric coated): 3-5 hours

Excretion: Urine (30% to 50% as glucuronide conjugate, 3% as unchanged drug)

Dosage:

Seizures:

Children >10 years and Adults:

Oral: Initial: 10-15 mg/kg/day in 1-3 divided doses; increase by 5-10 mg/kg/day at weekly intervals until therapeutic levels are achieved; maintenance: 30-60 mg/kg/day. Adult usual dose: 1000-2500 mg/day. Note: Regular release and delayed release formulations are usually given in 2-4 divided doses/day, extended release formulation (Depakote® ER) is usually given once daily. Conversion to Depakote® ER from a stable dose of Depakote® may require an increase in the total daily dose between 8% and 20% to maintain similar serum concentrations.

Children receiving more than one anticonvulsant (ie, polytherapy) may require doses up to 100 mg/kg/day in 3-4 divided doses

I.V.: Administer as a 60-minute infusion (20 mg/minute) with the same frequency as oral products; switch patient to oral products as soon as possible. Alternatively, rapid infusions have been given: 15 mg/kg over 5-10 minutes (1.5-3 mg/kg/minute).

Rectal (unlabeled): Dilute syrup 1:1 with water for use as a retention enema; loading dose: 17-20 mg/kg one time; maintenance: 10-15 mg/kg/dose every 8 hours

Status epilepticus (unlabeled use): Adults:

Loading dose: I.V.: 15-25 mg/kg administered at 3 mg/kg/minute.

Maintenance dose: I.V. infusion: 1-4 mg/kg/hour; titrate dose as needed based upon patient response and evaluation of drug-drug interactions

Mania: Adults: Oral: 750-1500 mg/day in divided doses; dose should be adjusted as rapidly as possible to desired clinical effect; a loading dose of 20 mg/kg may be used; maximum recommended dosage: 60 mg/kg/day

Migraine prophylaxis: Adults: Oral:

Extended release tablets: 500 mg once daily for 7 days, then increase to 1000 mg once daily; adjust dose based on patient response; usual dosage range 500-1000 mg/day

Delayed release tablets: 250 mg twice daily; adjust dose based on patient response, up to 1000 mg/day

Elderly: Elimination is decreased in the elderly. Studies of elderly patients with dementia show a high incidence of somnolence. In some patients, this was associated with weight loss. Starting doses should be lower and increases should be slow, with careful monitoring of nutritional intake and dehydration. Safety and efficacy for use in patients >65 years have not been studied for migraine prophylaxis.

Dosing adjustment in renal impairment: A 27% reduction in clearance of unbound valproate is seen in patients with Clcr<10 mL/minute. Hemodialysis reduces valproate concentrations by 20%, therefore no dose adjustment is needed in patients with renal failure. Protein binding is reduced, monitoring only total valproate concentrations may be misleading.

Dosing adjustment/comments in hepatic impairment: Reduce dose. Clearance is decreased with liver impairment. Hepatic disease is also associated with decreased albumin concentrations and 2- to 2.6-fold increase in the unbound fraction. Free concentrations of valproate may be elevated while total concentrations appear normal.

Administration:

Depakote® ER: Swallow whole, do not crush or chew. Patients who need dose adjustments smaller than 500 mg/day for migraine prophylaxis should be changed to Depakote® delayed release tablets. Sprinkle capsules may be swallowed whole or open cap and sprinkle on small amount (1 teaspoonful) of soft food and use immediately (do not store or chew).

Depacon®: Following dilution to final concentration, administer over 60 minutes at a rate of 20 mg/minute. Alternatively, single doses up to 15 mg/kg have been administered as a rapid infusion over 5-10 minutes (1.5-3 mg/kg/minute).

Monitoring Parameters:

Reference Range:

Therapeutic:

Epilepsy: 50-100 mcg/mL (SI: 350-690 mol/L)

Mania: 50-125 mcg/mL (SI: 350-860 mol/L)

Toxic: Some laboratories may report >200 mcg/mL (SI: >1390 mol/L) as a toxic threshold, although clinical toxicity can occur at lower concentrations.

Seizure control: May improve at levels >100 mcg/mL (SI: 690 mol/L), but toxicity may occur at levels of 100-150 mcg/mL (SI: 690-1040 mol/L)

Mania: Clinical response seen with trough levels between 50-125 mcg/mL; risk of toxicity increases at levels >125 mcg/mL

Test Interactions:

Dietary Considerations:

Coated particles of divalproex sodium may be mixed with semisolid food (eg, applesauce or pudding) in patients having difficulty swallowing; particles should be swallowed and not chewed

Valproate sodium oral solution will generate valproic acid in carbonated beverages and may cause mouth and throat irritation; do not mix valproate sodium oral solution with carbonated beverages; sodium content of valproate sodium syrup (5 mL): 23 mg (1 mEq)

Patient Education:

Additional Information:

Anesthesia and Critical Care Concerns/Other Considerations:

Symptoms of overdose include coma, somnolence, motor restlessness, visual hallucinations, and heart block. Naloxone has been used to reverse toxic CNS depressant effects but may block anticonvulsant effects.

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Dosage Forms:

Capsule, as valproic acid (Depakene®): 250 mg

Capsule, sprinkles, as divalproex sodium (Depakote® Sprinkle®): 125 mg

Injection, solution, as valproate sodium (Depacon®): 100 mg/mL (5 mL)

Syrup, as valproic acid: 250 mg/5 mL (5 mL, 480 mL)

Depakene®: 250 mg/5 mL (480 mL)

Tablet, delayed release, as divalproex sodium (Depakote®): 125 mg, 250 mg, 500 mg

Tablet, extended release, as divalproex sodium (Depakote® ER): 250 mg, 500 mg

International Brand Names: