Valproic Acid and Derivatives

( Divalproex Sodium , Sodium Valproate )

Pronunciation: val-PROE-ik AS-id
Class: Anticonvulsant Divalproex Sodium

Trade Names

Depakote
- Tablets, delayed-release 125 mg
- Tablets, delayed-release 250 mg
- Tablets, delayed-release 500 mg
- Capsules, sprinkle 125 mg

Depakote ER
- Tablets, ER 250 mg
- Tablets, ER 500 mg

Sodium Valproate

Depacon
- Injection 100 mg/mL

Depakene
- Capsules 250 mg (as valproic acid)
- Syrup 250 mg per 5 mL

Stavzor
- Capsules, delayed-release 125 mg (as valproic acid)
- Capsules, delayed-release 250 mg (as valproic acid)
- Capsules, delayed-release 500 mg (as valproic acid)

Apo-Divalproex (Canada)
Apo-Valproic Acid (Canada)
Epival (Canada)
Gen-Valproic (Canada)
Nu-Divalproex (Canada)
PMS-Valproic Acid (Canada)
PMS-Valproic Acid E.C. (Canada)
ratio-Valproic (Canada)
Sandoz Valproic (Canada)

Pharmacology

Believed to work by increasing brain levels of GABA.

Pharmacokinetics

Absorption

Valproic acid is rapidly absorbed in the GI tract. Divalproex and valproic acid dissociates into valproate ion in the GI tract. T _max is 4 to 17 h (ER tablets).

Distribution

Vd of total or free valproic acid is 11 and 92 L per 1.73 m ² , respectively. 80% to 90% protein bound (concentration-dependent).

Metabolism

Metabolized primarily in the liver.

Elimination

30% to 50% excreted as glucuronide conjugate in the urine. The half-life is 9 to 16 h for valproate.

Special Populations

Renal Function Impairment

Protein binding in renal failure patients is substantially reduced.

Hepatic Function Impairment

Cl may be decreased and unbound fraction of valproate may be increased.

Elderly

Intrinsic Cl is reduced 39%; the free fraction is increased 44%.

Children

Children between 3 and 10 yr of age have a 50% higher Cl than adults. Older than the age of 10 yr, pharmacokinetic parameters in children approximate those of adults.

Gender

Adjusted unbound Cl similar between men and women.

Race

Pharmacokinetics have not been studied.

Indications and Usage

Monotherapy and adjunctive therapy in treating patients with complex partial seizures that occur either in isolation or in association with other types of seizures; sole and adjunctive therapy in treating simple and complex absence seizures and adjunctively in patients with multiple seizure types that include absence seizures.

Divalproex sodium delayed-release tablets

Treatment of manic episodes associated with bipolar disorder; prophylaxis of migraine headache.

Divalproex sodium ER tablets

Treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features; prophylaxis of migraine headache.

Valproic acid delayed-release capsules

Treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy in patients with multiple seizure types that include absence seizures; prophylaxis of migraine headaches.

Unlabeled Uses

Bipolar disorder, borderline personality disorder, rectal administration.

Contraindications

Hepatic disease or dysfunction; known urea cycle disorders; hypersensitivity to the drug.

Dosage and Administration

Therapeutic serum levels for most patients with seizures range from 50 to 100 mcg/mL; however, a good correlation has not been established between daily dose, serum level, and therapeutic effect.

Complex Partial Seizures
Adults and children 10 yr of age and older Monotherapy

PO / IV Start at 10 to 15 mg/kg daily and increase by 5 to 10 mg/kg/wk to achieve optimal clinical response, which usually occurs below 60 mg/kg daily.

Conversion to monotherapy

PO / IV Start at 10 to 15 mg/kg daily and increase by 5 to 10 mg/kg/wk to achieve optimal clinical response, which usually occurs below 60 mg/kg daily. Concomitant antiepilepsy drug dosage can usually be reduced approximately 25% every 2 wk. The reduction may be started at initiation of therapy or delayed by 1 to 2 wk if there is a concern that reductions may result in seizures.

Adjunctive therapy

PO / IV Divalproex sodium or valproic acid may be added to the patient's regimen at a dosage of 10 to 15 mg/kg daily. The dosage may be increased by 5 to 10 mg/kg/wk to achieve optimal response, which usually occurs below 60 mg/kg daily. If the total daily dose exceeds 250 mg, administer in divided doses.

Conversion from Depakote to Depakote ER
Adults and children 10 yr of age and older

Patients with epilepsy previously receiving Depakote should be administered Depakote ER daily using a dose that is 8% to 20% higher than the daily dose of Depakote . For patients whose Depakote total daily dose cannot be directly converted to Depakote ER , consider, at the clinician's discretion, an increase in the patient's Depakote total daily dose to the next higher dosage before converting to the appropriate total daily dose of Depakote ER .

Mania

Increase dose as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect (max, 60 mg/kg/day).

Adults Divalproex sodium delayed-release tablets, valproic acid delayed-release capsules

PO 750 mg daily in divided doses.

Divalproex sodium ER tablets

PO 25 mg/kg/day once daily.

Migraine (Divalproex Sodium)
Adults and Children 16 yr of age and older Divalproex sodium delayed-release tablets

PO Start with 250 mg twice daily (max, 1,000 mg daily).

Adults Divalproex sodium ER tablets

PO Start with 500 mg daily for 1 wk, thereafter increasing to 1,000 mg daily.

Migraine (Valproic Acid)
Adults

PO Valproic acid delayed-release capsules: Start with 250 mg twice daily. Some patients may benefit from dosages of up to 1,000 mg daily.

Simple and Complex Absence Seizures

PO / IV Start at 15 mg/kg daily, increasing at 1-wk intervals by 5 to 10 mg/kg daily until seizures are controlled or adverse reactions preclude further increases (max, 60 mg/kg daily). If the total daily dose exceeds 250 mg, administer in divided doses.

General Advice

• Injection and oral doseforms are interchangeable on a mg-for-mg basis.

• Injection
• Administer by IV route only. Not for intradermal, subcutaneous, or IM administration.
• Dilute prescribed dose in at least 50 mL of dextrose 5% injection, sodium chloride 0.9% injection, or Ringer's lactate.
• Do not administer if particulate matter, cloudiness, or discoloration is noted.
• Administer prescribed dose as a 60-min infusion or at a rate not to exceed 20 mg per min.
• Discard any unused portion of vial. Do not save for future use.

• Oral
• Divalproex ER tablets and valproic acid delayed-release capsules: must be swallowed whole; do not break, crush, or chew.
• Divalproex sprinkle capsules: May be swallowed whole or sprinkled on a teaspoonful of soft food (eg, applesauce, pudding) and swallowed immediately without chewing.
• Patients who experience GI irritation may benefit from taking the medication with food or by slowly increasing the dose from the initial dose.

Storage/Stability

Capsules

Store at 59° to 77°F.

Sprinkle capsules

Store below 77°F.

Oral solution, delayed-release tablets

Store below 86°F.

Delayed-release capsules, ER tablets

Store at 59° to 86°F.

Injection

Store at 59° to 86°F. Parenteral solutions may be stored for at least 24 h at 59° to 86°F when stored in glass or polyvinyl chloride bags.

Drug Interactions

Alcohol, CNS depressants

Enhanced CNS depression.

Amitriptyline/Nortriptyline, barbiturates, diazepam, ethosuximide, hydantoins (eg, phenytoin), phenobarbital, primidone, zidovudine

Plasma levels of these drugs may be increased.

Carbamazepine

Carbamazepine plasma levels may be decreased while carbamazepine-10,11-epoxide levels may be increased; decreased valproic acid levels.

Carbapenem antibiotics (eg, ertapenem, imipenem, meropenem), charcoal, cholestyramine, rifampin

May decrease valproic acid levels.

Chlorpromazine, erythromycin, felbamate, fluoxetine, salicylates

May increase valproic acid levels.

Clonazepam

Absence status may be induced in patients with a history of absence-type seizures.

Hormonal contraceptives

Valproic acid plasma concentrations may be reduced, decreasing the efficacy.

Lamotrigine

Decreased valproic acid levels; increased lamotrigine levels.

Lorazepam

Lorazepam plasma levels may be increased.

Olanzapine

Risk of hepatic adverse reactions may be increased; olanzapine levels may be decreased.

Tolbutamide

May be displaced from binding site by valproate, transiently increasing tolbutamide levels. Clinical importance is not known.

Topiramate

Coadministration with valproic acid has been associated with hyperammonemia with and without encephalopathy. Plasma levels of both drugs may be decreased.

Warfarin

Warfarin may be displaced from its protein binding site, transiently increasing the anticoagulant effect.

Laboratory Test Interactions

Valproic acid may yield false-positive results on urine ketone tests; altered thyroid function tests.

Adverse Reactions

Cardiovascular

Arrythmia, hypertension, hypotension, palpitation, postural hypotension, tachycardia, vasodilation (more than 1% and less than 5%); bradycardia (postmarketing).

CNS

Tremor (57%); headache (31%); somnolence (30%); asthenia (27%); dizziness (25%); insomnia (15%); nervousness (11%); ataxia (8%); amnesia (7%); abnormal thinking, emotional lability (6%); depression (5%); abnormal dreams, abnormal gait, agitation, anxiety, catatonic reaction, confusion, dysarthria, hallucinations, hypertonia, hypokinesia, incoordination, increased reflexes, paresthesia, personality disorder, speech disorder, tardive dyskinesia, vertigo (more than 1% and less than 5%); aggression, behavioral deterioration, cerebral atrophy, dementia, emotional upset, encephalopathy, hostility, hyperactivity, hypesthesia, parkinsonism, psychosis (postmarketing).

Dermatologic

Alopecia (24%); rash (6%); discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, petechiae, pruritus, seborrhea (more than 1% and less than 5%); bruising, cutaneous vasculitis, erythema multiforme, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

EENT

Diplopia (16%); amblyopia, blurred vision (12%); nystagmus, pharyngitis (8%); tinnitus (7%); abnormal vision, conjunctivitis, deafness, dry eyes, ear pain/disorder, epistaxis, eye pain, otitis media, photophobia, taste perversion (more than 1% and less than 5%); hearing loss, spots before eyes (postmarketing).

GI

Nausea (48%); vomiting (27%); abdominal pain, diarrhea (23%); dyspepsia (13%); anorexia (12%); increased appetite (6%); constipation (5%); dry mouth, eructation, fecal incontinence, flatulence, gastroenteritis, GI disorder, glossitis, hematemesis, increased appetite, pancreatitis, periodontal abscess, stomatitis, tooth disorder (more than 1% and less than 5%); abdominal cramps, acute pancreatitis (postmarketing).

Genitourinary

Amenorrhea, cystitis, dysmenorrhea, dysuria, metrorrhagia, urinary frequency, urinary incontinence, vaginal hemorrhage, vaginitis (more than 1% and less than 5%); breast enlargement, enuresis, galactorrhea, irregular menses, UTI (postmarketing).

Hematologic-Lymphatic

Thrombocytopenia (24% [high dose]); ecchymosis (5%); anemia, increased bleeding time, leukopenia (more than 1%); acute intermittent porphyria, agranulocytosis, aplastic anemia, bone marrow suppression, eosinophilia, frank hemorrhage, hematoma, hypofibrinogenemia, inhibition of platelet aggregation, macrocytosis, pancytopenia, relative lymphocytosis (postmarketing).

Hepatic

Hepatotoxicity (postmarketing).

Lab Tests

Increased ALT and AST (more than 1% and less than 5%); bilirubin, increased LDH (postmarketing).

Local

Injection-site pain (3%); injection-site reaction (2%).

Metabolic

Weight gain (9%); peripheral edema (8%); weight loss (6%); edema, hypoproteinemia (more than 1% and less than 5%); Fanconi syndrome (primarily in children), hyperammonemia, hyperglycemia, hypernatremia, SIADH (postmarketing).

Musculoskeletal

Back pain (8%); neck pain, neck rigidity (1% or more); arthralgia, leg cramps, myalgia, myasthenia, twitching (more than 1% and less than 5%); bone pain, weakness (postmarketing).

Respiratory

Flu-like syndrome (12%); bronchitis, dyspnea, rhinitis (5%); hiccup, increased cough, pneumonia, sinusitis (more than 1% and less than 5%).

Miscellaneous

Infection (20%); pain (11%); accidental injury, fever (6%); chest pain, chills, face edema, fungal infection, malaise, viral infection (more than 1% and less than 5%); abnormal thyroid function tests, anaphylaxis, coma, fever, hypothermia, lupus erythematosus, parotid gland swelling (postmarketing).

Precautions

Warnings Hepatotoxicity Increased risk in children younger than 2 yr of age, especially those on multiple anticonvulsants or those with congenital metabolic disorders, severe seizure disorders, mental retardation, or organic brain syndrome. Onset is typically during the first 6 mo. Pancreatitis, some cases life-threatening Occurs in children and adults after initial or long-term therapy. Teratogenicity Can produce teratogenic effects such as neural tube defects (eg, spina bifida).

Monitor Periodic plasma concentrations of valproate are recommended during the early course of therapy when drugs capable of enzyme induction are coadministered.

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Children

Use with extreme caution in children younger than 2 yr of age (see Warning Box). Safety and efficacy of divalproex sodium for treatment of acute mania not established in patients younger than 18 yr of age. Safety and efficacy of divalproex sodium for the prophylaxis of migraines not established in patients younger than 16 yr of age. Safety and efficacy of divalproex sodium ER tablets for the prophylaxis of migraine headaches in children have not been established. Safety and efficacy of divalproex ER tablets and valproic acid delayed-release capsules for the treatment of complex partial seizures, simple and complex absence seizures, and multiple seizure types that include absence seizures not established in children younger than 10 yr of age. Safety and efficacy of valproate sodium injection not established in children younger than 2 yr of age.

Elderly

Reduce starting dose and base therapeutic dose on clinical response.

Acute head injuries

Because IV valproic acid has been associated with a higher incidence of death than IV phenytoin, do not use in the prevention of posttraumatic seizures in patients with acute head injuries.

Discontinuation

Abrupt discontinuation may precipitate status epilepticus with attendant life-threatening hypoxia in patients receiving valproic acid to prevent major seizures.

Hematologic effects

Thrombocytopenia, inhibition of secondary phase of platelet aggregation, and abnormal coagulation parameters (eg, low fibrinogen) may occur. Risk of bleeding may be increased.

Hepatotoxicity

Reactions usually occur within first 6 mo of therapy and are preceded by symptoms such as anorexia, facial edema, jaundice, lethargy, lost seizure control, malaise, vomiting, and weakness. Use drug with caution in patients with history of liver disease. Monitor patients and perform LFTs frequently.

Hyperammonemia

May occur despite normal LFTs. In patients who develop unexplained lethargy and vomiting or changes in mental status, consider hyperammonemic encephalopathy and measure ammonia level. If ammonia is elevated, discontinue valproic acid.

Hypothermia

A decrease in body core temperature to less than 95°F has been reported in association with valproate therapy.

Mania

Clinical data from long-term studies (more than 3 wk) are not available.

Multiorgan hypersensitivity

Has been reported in close association with the initiation of valproate therapy.

Pancreatitis

Life-threatening pancreatitis has been reported.

Suicide

Suicidal ideation may be a manifestation of certain psychiatric disorders and may persist until significant remission of symptoms occurs.

Overdosage

Symptoms

Asterixis, death, deep coma, heart block, motor restlessness, somnolence, visual hallucinations.

Patient Information

• Advise patient, family, or caregiver to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient to continue to take other medications unless advised otherwise by health care provider.
• Advise patient, family, or caregiver that medication will be started at a low dose and gradually increased as tolerated until max benefit has been obtained.
• Instruct patient, family, or caregiver to take (give) exactly as prescribed and not change the dose or discontinue therapy unless advised by health care provider.
• Advise patient, family, or caregiver that each dose may be taken (given) without regard to meals but to take (give) with food if stomach upset occurs.
• Advise patient, family, or caregiver that fever associated with other organ involvement (eg, rash) may be drug-related and should be reported immediately to health care provider.
• Instruct patient, family, or caregiver to immediately contact health care provider if any of the following occur: appetite loss, facial swelling, general body discomfort, lethargy, loss of seizure control in epileptic patient, mental status changes, persistent nausea or vomiting, sudden onset of stomach pain, weakness.
• Advise patient, family, or caregiver that if medication needs to be discontinued, it will usually be slowly withdrawn over a period of 2 wk or more unless safety concerns (eg, rash) require a more rapid withdrawal.
• Caution patient that drug may cause dizziness or drowsiness and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
• Caution women of childbearing potential that medication may be harmful if taken while pregnant and to use effective contraception to avoid becoming pregnant.
• Instruct patient, family, or caregiver to contact health care provider if seizures get worse, new types of seizures occur, bipolar symptoms do not improve or worsen, or migraine headaches do not improve or worsen.
• Advise patient, family, or caregiver to contact health care provider if bothersome adverse reactions (eg, drowsiness, indigestion) occur.
• Advise diabetic patient that medication may interfere with urine ketone tests.

• Syrup
• Advise patient, family, or caregiver to measure prescribed dose using dosing spoon or dosing syringe.

• Tablets, delayed-release tablets, and ER tablets
• Advise patient to swallow whole and not to crush, chew, or divide.
• Advise patient, family, or caregiver that ER tablets given daily can be taken at night to reduce daytime sedation.

• Capsules
• Advise patient to swallow whole and not to open, crush, or chew to avoid local irritation of mouth and throat.

• Sprinkle capsules
• Advise patient, family, or caregiver that sprinkle capsules may be swallowed whole or the capsule can be opened and the entire contents of the capsule sprinkled on a small amount (eg, teaspoon) of soft food (eg, applesauce). Mixture should be swallowed immediately without chewing and then washed down with a fluid (eg, water, juice). Caution patient, family, or caregiver not to prepare mixture ahead of time and store for future use.

• Injection
• Advise patient, family, or caregiver that medication will be prepared and administered by a health care provider in a health care setting.
• Advise patient, family, or caregiver that injection will only be used to control seizures if it is not possible or not feasible to take medications by mouth.

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