Valproic Acid and Derivatives

|Valproic Acid and Derivatives

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Valproic Acid and Derivatives

( Sodium Valproate , Divalproex Sodium ) Pronouncation: (VAL-pro-ik acid)
Class: Anticonvulsant Sodium Valproate

Trade Names:
- Capsules 250 mg (as valproic acid)
- Syrup 250 mg per 5 mL

Trade Names:
- Injection 100 mg/mL

Alti-Valproic (Canada)
Apo-Divalproex (Canada)
Apo-Valproic (Canada)
Epiject (Canada)
Gen-Valproic (Canada)
Novo-Divalproex (Canada)
Novo-Valproic (Canada)
Nu-Divalproex (Canada)
Nu-Valproic (Canada)
PMS-Valproic Acid (Canada)
ratio-Valproic (Canada)
Rhoxal-valproic (Canada)
Rhoxal-valproic EC (Canada)
Divalproex Sodium

Trade Names:
- Tablets, delayed-release 125 mg
- Tablets, delayed-release 250 mg
- Tablets, delayed-release 500 mg
- Capsules, sprinkle 125 mg

Trade Names:
Depakote ER
- Tablets, extended-release 250 mg
- Tablets, extended-release 500 mg

Mechanism of Action


Believed to work by increasing brain levels of gamma-aminobutyric acid (GABA). It may also inhibit catabolism of GABA, potentiate postsynaptic GABA responses, and affect potassium channels or directly stabilize membranes.



Valproic acid is rapidly absorbed in the GI tract. Divalproex dissociates into valproic acid in the GI tract. T max is 4 to 17 hr (extended-release tablets).


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).


Metabolized primarily in the liver.


30% to 50% excreted as glucuronide conjugate in the urine. The t ½ is 9 to 16 hr 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.


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

Indications and Usage

Sole and adjunctive therapy in simple (petit mal) and complex absence seizures; adjunctive therapy in multiple seizure types, including absence seizures; monotherapy and adjunctive therapy in complex partial seizures that occur in isolation or with other seizure types; manic episodes associated with bipolar disorder (divalproex sodium delayed-release tablets); prophylaxis of migraine headaches (divalproex sodium delayed-release and extended-release [ER] tablets).

Unlabeled Uses

Treatment of atypical absence, myoclonic, and tonic-clonic (grand mal) seizures and atonic, elementary partial, and infantile spasm seizures; prevention of recurrent pediatric febrile seizures; intractable status epilepticus in patients who have not responded to other therapies; treatment of minor incontinence after ileoanal anastomosis (subchronic administration); management of anxiety disorders and panic attacks.


Hepatic disease 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 per 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 per wk to achieve optimal clinical response, which usually occurs below 60 mg/kg daily. Concomitant antiepilepsy drug dosage can usually be reduced approximately 25% q 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. If the total daily dose exceeds 250 mg, administer in divided doses.

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 per 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 , consideration may be given, at the clinician"s discretion, to 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 (Divalproex Sodium Delayed-Release Tablets)

PO 750 mg daily in divided doses. Increase dose as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect (max, 60 mg/kg daily).

Migraine (Divalproex Sodium)
Divalproex sodium delayed-release tablets

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

Divalproex sodium ER tablets

PO Start with 500 mg daily for 1 wk, thereafter increasing 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 side effects 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 dose forms 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 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer"s solution.
  • Do not administer if particulate matter, cloudiness, or discoloration 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.


Store syrup, tablets, and unopened injection vials at controlled room temperature (59° to 86°F). Store capsules and sprinkle capsules at temperature less than 77°F. Diluted injection may be stored at controlled room temperature for up to 24 hr.

Drug Interactions

Alcohol, CNS depressants

Enhanced CNS depression.

Amitriptyline/Nortriptyline, barbiturates, diazepam, ethosuximide

May increase levels and actions of these drugs.

Carbamazepine, hydantoins

May result in increased levels of these drugs and reduced efficacy of valproic acid.

Charcoal, cholestyramine

May reduce absorption of valproic acid.

Chlorpromazine, cimetidine, erythromycin, rifampin, salicylates

May increase valproic acid levels.


May increase risk of absence status in patients with history of absence-type seizures.


Increased valproic acid levels.


Decreased valproic acid levels; increased lamotrigine levels.


May decrease valproic acid levels.


Increased AUC of zidovudine.

Laboratory Test Interactions

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

Adverse Reactions


Hypertension, hypotension, postural hypotension, palpitation, tachycardia, bradycardia (more than 1% and less than 5%).


Tremor (57%); somnolence (30%); asthenia (21%); dizziness (18%); insomnia (15%); nervousness (11%); amnesia (7%); headache (5% or more); depression (5%); ataxia, emotional lability, abnormal thinking, paresthesia (1% to 5%); anxiety, confusion, abnormal gait, hypertonia, incoordination, abnormal dreams, personality disorder, agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, increased reflexes, tardive dyskinesia, speech disorder, vertigo (more than 1% and less than 5%).


Alopecia (7%); rash (6%); dry skin, pruritus, petechiae, discoid lupus erythematosus, furunculosis, maculopapular rash, seborrhea (more than 1% and less than 5%); erythema multiforme, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (rare).


Pharyngitis, amblyopia, blurred vision (8%); nystagmus, tinnitus (7%); diplopia, taste perversion (1% to 5%); abnormal vision, deafness, otitis media, conjunctivitis, dry eyes, ear pain/disorder, eye pain (more than 1% and less than 5%).


Nausea (34%); diarrhea, vomiting (23%); dyspepsia (13%); abdominal pain (12%); anorexia (11%); increased appetite (6%); constipation (1% to 5%); flatulence, hematemesis, eructation, periodontal abscess, fecal incontinence, gastroenteritis, glossitis, periodontal abscess, dry mouth, GI disorder, stomatitis, tooth disorder (more than 1% and less than 5%).


Amenorrhea, dysmenorrhea, urinary frequency, urinary incontinence, vaginitis, cystitis, metrorrhagia, vaginal hemorrhage (more than 1% and less than 5%).




Thrombocytopenia (24% [high dose]); ecchymosis (5%); frank hemorrhage; relative lymphocytosis; macrocytosis; leucopenia; eosinophilia; anemia; bone marrow suppression; pancytopenia; aplastic anemia; acute intermittent porphyria.

Lab Tests

Increase ALT, AST, LDH, bilirubin.


Weight gain (9%); edema (more than 1% and less than 5%); hyperammonemia; Fanconi syndrome (primarily in children); hyperglycemia.


Arthralgia, leg cramps, myalgia, myasthenia, twitching arthrosis (more than 1% and less than 5%).


Infection (20%); flu-like syndrome (12%); rhinitis; dyspnea (1% to 5%); epistaxis, pneumonia, sinusitis, increased cough (more than 1% and less than 5%).


Infection (15%); back pain (8%); injection site pain (3%); injection site reaction (2%); fever, chest pain, vasodilation, peripheral edema, accidental injury, chills, face edema, viral infection (1% to 5%); malaise (more than 1% and less than 5%); lupus erythematosus; anaphylaxis.




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.


Can produce teratogenic effects such as neural tube defects (eg, spina bifida).


Category D .


Excreted in breast milk.


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 have not been established in patients younger than 18 yr of age. Safety and efficacy of divalproex sodium for the prophylaxis of migraines have not been established in patients younger than 16 yr of age. Safety and efficacy of divalproex sodium ER tablets for the prophylaxis of migraine headaches in pediatric patients have not been established. Safety and efficacy of divalproex ER for the treatment of complex partial seizures, simple and complex absence seizures, and multiple seizure types that include absence seizures have not been established in pediatric patients younger than 10 yr of age. Safety and efficacy of valproate sodium injection have not been established in children younger than 2 yr of age.


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.


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.


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


May occur with or without lethargy and coma and contribute to hepatotoxicity.


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


Life-threatening pancreatitis has been reported.


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



Motor restlessness, somnolence, heart block, visual hallucinations, asterixis, deep coma, death.

Patient Information

  • Explain name, dose, action, and potential side effects of drug.
  • Advise patient, family, or caregiver to read the Patient Information leaflet before starting therapy and with each refill.
  • Instruct patient, family, or caregiver 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 without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient, family, or caregiver that if a dose is missed to skip that dose and not to double up on the next dose.
  • Instruct patient, family, or caregiver to immediately contact health care provider if any of the following occur: loss of seizure control in epileptic patient, general body discomfort, weakness, lethargy, facial swelling, appetite loss, persistent nausea or vomiting, sudden onset of stomach pain, mental status changes.
  • 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.
  • Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding.
  • 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 side effects (eg, drowsiness, indigestion) occur.
  • Advise diabetic patient that medication may interfere with urine ketone tests.
  • Advise patient, family, or caregiver not to take (give) any prescription or OTC medications or dietary supplements unless advised by health care provider.
  • Advise patient, family, or caregiver that laboratory tests and follow-up visits will be required to monitor therapy and to keep appointments.
  • Syrup
  • Advise patient, family, or caregiver to measure prescribed dose using dosing spoon or dosing syringe.
  • Tablets, delayed-release tablets, and extended-release tablets
  • Advise patient to swallow whole and not to crush, chew, or divide.
  • Advise patient, family, or caregiver that extended-release 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) that should be swallowed immediately without chewing and then washed down with a fluid (eg, water, juice). Caution patient, family, or caregiver not to prepare 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 professional 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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