Medication Guide App

Valproic Acid (Systemic)

This monograph includes information on the following:

1) Divalproex
2) Valproate Sodium 
3) Valproic Acid


INN:
Divalproex Sodium— Valproate Semisodium

BAN:
Divalproex Sodium—Semisodium Valproate


JAN:
Valproate Sodium—Sodium Valproate

VA CLASSIFICATION
Divalproex
Primary: CN400
Secondary: CN105; CN900

Valproate Sodium
Primary: CN400

Valproic Acid
Primary: CN400


Commonly used brand name(s): Alti-Valproic3; Depacon2; Depakene3; Depakote1; Depakote Sprinkle1; Deproic3; Dom-Valproic3; Epival1; Med Valproic3; Novo-Valproic3; Nu-Valproic3; PMS-Valproic Acid3; Penta-Valproic3; pms-Valproic Acid3; pms-Valproic Acid E.C.3

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Anticonvulsant—

antimanic—

migraine headache prophylactic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Epilepsy, absence seizure pattern (treatment)—Valproic acid, divalproex, and valproate sodium are indicated in the treatment of simple and complex absence (petit mal) seizures. {09} {10} {11} {12} {13} {14} {46} Although these agents may be used alone or with other anticonvulsant medication {09} {10} {11} {12} {13}, monotherapy with valproic acid, divalproex, or valproate sodium is preferred whenever possible because of unpredictable interactions with hepatic enzyme–inducing anticonvulsants {01} and because of the increased risk of hepatotoxicity {03}.

Epilepsy, mixed seizure pattern (treatment adjunct)—Valproic acid, divalproex, and valproate sodium are indicated as adjuncts in conditions of multiple seizures that include absence seizures. {09} {10} {11} {12} {13}

[Epilepsy, myoclonic seizure pattern (treatment)]—Valproic acid, divalproex, and valproate sodium are used as primary agents for myoclonic seizures. {14}

[Epilepsy, simple partial seizure pattern (treatment)] or
Epilepsy, complex partial seizure pattern (treatment)—Valproic acid, divalproex, and valproate sodium may be useful in patients with partial seizures that are refractory to other anticonvulsants. {17} {25}

[Epilepsy, tonic-clonic seizure pattern (treatment)]—Valproic acid, divalproex, and valproate sodium are used as primary agents in the treatment of tonic-clonic (grand mal) seizures. {10} {12} {14} {46}

Bipolar disorder, manic episodes (treatment)—Divalproex is indicated for the treatment of manic episodes associated with bipolar disorder. {40}

[Bipolar disorder (prophylaxis and treatment)]—Valproic acid and divalproex may be useful in the prophylaxis and treatment of manic-depressive illness refractory to treatment with lithium or other agents. {19} {20} {32} {33} {34} {35} {36}

Migraine headaches (prophylaxis)1—Divalproex is indicated in the prophylaxis of migraine headaches. {40} There is no evidence that it may be useful in the treatment of acute migraine. {40}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Divalproex sodium is a stable coordination compound composed of equal parts of valproic acid and sodium valproate. In the gastrointestinal tract, divalproex sodium dissociates into valproate and then produces the bioequivalent pharmacologic activity of valproic acid {16}. Equivalent oral doses of divalproex sodium and valproic acid capsules deliver systemically equivalent quantities of valproate ion {16}. Valproate sodium injection exists as the valproate ion in the blood and yields plasma levels equivalent to those of the oral valproic acid and divalproex products {42}. In this monograph, the term valproate is used to designate the valproate ion in the body, whether administered as valproic acid, divalproex sodium, or valproate sodium.


Physicochemical characteristics:
Molecular weight—
    Divalproex sodium: 310.41 {41}
    Valproate sodium: 166.2 {42}
    Valproic acid: 144.21 {41}

pKa—
    Valproic acid: 4.8 {37}


pH
    Valproate sodium injection: 7.6 {42}.

Mechanism of action/Effect:

The mechanism of action has not been established {09} {10} {11} {12} {13} {42}; however, it is thought to be related to a direct or secondary increase in concentrations of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) {09} {10} {11} {12} {13} {42}, possibly caused by its decreased metabolism or decreased reuptake in brain tissues. Another hypothesis is that valproate acts on postsynaptic receptor sites to mimic or enhance the inhibitory action of GABA. The effect on the neuronal membrane is not completely understood. {09} {10} {11} {12} {13} Some studies suggest a possible direct effect on membrane activity related to changes in potassium conductance. {01} {02} Also, valproate has been shown in animal studies to block sustained neuronal bursting responses by reducing the amplitude of sodium-dependent action potentials in a voltage- and use-dependent manner. {17} {18}


Other actions/effects:

Valproate is a weak inhibitor of some hepatic P450 isoenzymes, as well as epoxide hydrase and glucuronosyl transferase. {10} {42}

Absorption:

Divalproex sodium—Enteric coating on the tablet delays absorption for about 1 {11} to 4 hours after ingestion; concomitant administration with food may significantly {06} slow the rate, but not the extent, of absorption. {11} {12} {16}

Valproic acid—Rapid absorption from gastrointestinal tract {09} {10} {13} {43} {44} {45} {46}; slight delay when taken with food. {09} {10} {13} {44} {46}



Distribution:

Valproate concentrations in the cerebrospinal fluid approximate unbound concentrations in plasma, which is about 10% of the total concentration. {42} Valproate is distributed into breast milk in concentrations ranging from 1 to 10% of total maternal serum concentrations. {09} {10} {11} {12} {13} {42}

Protein binding:

High (90 {09} {10} {11} {12} {13} {44} {45} to 95 {06} {46}%) at serum concentrations up to 50 micrograms (mcg) per mL; as the concentration increases from 50 to 100 mcg per mL, the percentage bound decreases to 80 to 85% and {06} the free fraction becomes progressively larger, thus increasing the concentration gradient into the brain. Protein binding of valproate is reduced in the elderly {42}, in patients with hypoalbuminemia {08}, in patients with chronic hepatic diseases {42}, and in patients with renal function impairment. {42}

Biotransformation:

Primarily hepatic. {09} {10} {11} {12} {13} {42} {44} Some metabolites may have pharmacologic or toxic activity. Rate of metabolism is faster in children and in patients concurrently using hepatic enzyme–inducing medications, such as carbamazepine, phenobarbital, phenytoin, and primidone {03}.

Half-life:

Variable, from 6 to 16 hours {09} {10} {11} {12} {13} {44} {45}; may be considerably longer in patients with hepatic function impairment, in the elderly {03}, and in children up to 18 months of age; may be considerably shorter in patients receiving hepatic enzyme–inducing anticonvulsants.

Mean terminal half-life for valproate monotherapy following a 60-minute intravenous infusion of 1000 mg was 16 ± 3 hours. {42}

Time to peak serum concentration

Capsules and syrup—1 to 4 hours. {09} {10} {13} {46}

Delayed-release capsules and tablets—3 to 4 hours. {11} {12} {16}

Injection—At the end of a 1-hour intravenous infusion. {42}

Therapeutic plasma concentrations

Variable. The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg per mL (347 to 693 micromoles per L) of total valproate, although some patients may require higher or lower plasma concentrations. {09} {10} {42} {43} {45} {46}

The relationship between plasma concentration and clinical response is not well documented. {42} {43} {44} {46} One contributing factor is the nonlinear, concentration-dependent protein binding of valproate, which affects the clearance of the medication. {42} Monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. {42}

Elimination:
    Renal {09} {10} {11} {12} {13} {44} {45}, mainly as glucuronide conjugate {09} {10} {11} {12} {13} {44}; small amounts excreted in feces and expired air. {09} {10} {11} {12} {13} {44} {45}


Precautions to Consider

Carcinogenicity/Tumorigenicity

Studies in rodents given valproic acid doses of 0, 80, and 170 mg per kg of body weight (mg/kg) a day for 2 years showed a variety of neoplasms and an increase in the incidence of subcutaneous fibrosarcomas in male rats receiving high doses, as well as a dose-related trend for benign pulmonary adenomas in male mice. The significance of these findings humans is not known {04} {09} {11} {13} {40} {42}.

Mutagenicity

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats {42}. Increased frequency of sister chromatid exchange (SCE) has been reported in a study of epileptic children taking valproate, but this association was not observed in another study in adults {42}. There is some evidence that increased SCE frequencies may be associated with epilepsy {42}. The biological significance of an increase in SCE frequency is not known {42}.

Pregnancy/Reproduction
Fertility—
Long-term toxicity studies in rats given doses greater than 200 mg/kg a day and dogs given doses greater than 90 mg/kg a day have shown reduced spermatogenesis and testicular atrophy. Segment I fertility studies in rats given up to 350 mg/kg a day for 60 days have shown no effect on fertility. However, the effect of valproate on the development of the testes and on sperm production and fertility in humans is unknown. {04} {09} {10} {11} {12} {13} {42}

Pregnancy—
First trimester: Valproate crosses the placenta and has been reported to have caused teratogenic effects, including neural tube defects (anencephaly, meningomyelocele {23}, and spina bifida) in the fetus when the mother received valproate during the first trimester of pregnancy. {09} {10} {11} {12} {13} {14} {42} Risk-benefit must be carefully considered when these medications are required to treat epilepsy in pregnant patients for whom other medications are ineffective or cannot be used. {42}

Studies in rodents have shown that skeletal abnormalities, primarily involving ribs and vertebrae, occurred in the offspring when the mother received doses exceeding 65 mg/kg per day during pregnancy. {09} {11} {13}

FDA Pregnancy Category D. {42}

Breast-feeding

Valproate is distributed into breast milk {09} {10} {11} {12} {13} {42} {45}. Concentrations in breast milk have been reported to be l to 10% of the total maternal serum concentration {09} {10} {11} {12} {13} {42} {44}.

Pediatrics

Children are at an increased risk of developing serious or fatal hepatotoxicity {01} {02} {09} {10} {11} {12} {13} {45}. Patients up to 2 years of age {01} {02} {09} {10} {11} {12} {13}, especially those on polytherapy {01} {02} {09} {10} {11} {12} {13} {45}, those with congenital metabolic disorders {42} {45}, those with severe seizure disorders accompanied by mental retardation {42} {45}, and those with organic brain disease {42} {45}, appear to be at greatest risk. Experience in patients with epilepsy has shown that the risk of fatal hepatotoxicity decreases with advancing age {01} {02} {09} {10} {11} {12} {13} {42}.


Geriatrics


Geriatric patients tend to have increased free, unbound valproate concentrations and lowered intrinsic clearances, indicating a reduction of valproate metabolizing capacity and a fall in serum albumin {06}. Therefore, these patients should receive a lower daily dosage, and the serum concentrations should be kept in the lower therapeutic range. {45}


Dental

Valproate inhibits the secondary phase of platelet aggregation {09} {10} {11} {12} {13}, which may be reflected in prolonged bleeding time and/or frank hemorrhaging. {04} {09} {10} {11} {12} {13}

In addition, the leukopenic and thrombocytopenic effects of valproate may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work, whenever possible, should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Surgical

Because of the thrombocytopenic effects of valproate, as well as its inhibition of the secondary phase of platelet aggregation and production of abnormal coagulation parameters (e.g., low fibrinogen), monitoring of platelet counts and coagulation tests are recommended in patients prior to scheduled surgery. {42} {44} {45}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: In addition to the interactions listed below, additive or multiple effects leading to impaired blood clotting and/or increased risk of bleeding may occur if valproic acid, divalproex, or valproate sodium is used concurrently with any other medication having a significant potential for inhibiting platelet aggregation or for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol{09}{10}{11}{12}{13}{43}{45} or
» Central nervous system (CNS) depression–producing medications, other{09}{10}{11}{12}{13} (see Appendix II )    (concurrent use with valproic acid, divalproex, or valproate sodium may potentiate CNS depressant effects)


Anticoagulants, coumarin- or indandione-derivative{09}{10}{11}{12}{13} or
» Heparin or
» Thrombolytic agents    (valproate-induced hypoprothrombinemia may increase the activity of coumarin- and indandione-derivative anticoagulants and may increase the risk of bleeding in patients receiving heparin or thrombolytic agents)

    (inhibition of platelet aggregation and reduction of platelet numbers or thrombocytopenia {07} may increase the risk of hemorrhage in patients receiving anticoagulant or thrombolytic therapy)


Antidepressants, tricyclic{29} or
Bupropion{29} or
Clozapine{29} or
Haloperidol{29} or
Loxapine{29} or
Maprotiline{29} or
Molindone{29} or
Monoamine oxidase (MAO) inhibitors{29} or
Phenothiazines{29} or
Pimozide{29} or
Thioxanthenes{29}    (in addition to enhancing CNS depression when used concurrently with valproic acid, divalproex, or valproate sodium, these medications may lower the seizure threshold; dosage adjustments may be necessary to control seizures)


» Barbiturates or
» Primidone{09}{10}{11}{12}{13}{42}{45}{46}    (concurrent use with valproate causes higher serum concentrations of barbiturates or primidone, leading to increased CNS depression and neurological toxicity because of protein binding displacement of the barbiturate {07} and reduced barbiturate metabolism; half-life of valproate is decreased; dosage adjustment of barbiturates or primidone may be necessary)


» Carbamazepine{09}{11}{13}{42}{44}    (concurrent use may result in decreased serum concentrations and half-life of valproate due to increased metabolism induced by hepatic microsomal enzyme activity; valproate causes an increase in the active 10,11-epoxide metabolite of carbamazepine by inhibiting its breakdown {06} {07}; monitoring of serum concentrations as a guide to dosage is recommended, especially when either medication is added to or withdrawn from an existing regimen)


Clonazepam{09}{10}{11}{12}{13}{42}{45}{46}    (concurrent use with valproic acid, divalproex, or valproate sodium may produce absence status)


Diazepam{42}    (valproate may displace diazepam from its plasma albumin binding sites and may inhibit its metabolism; coadministration was found to increase the free fraction of diazepam by 90% in healthy volunteers; plasma clearance of free diazepam was reduced by 25% and volume of distribution of free diazepam was reduced by 20% in the presence of valproate; the elimination half-life of diazepam remained unchanged {42})


Ethosuximide, and possibly other succinimide anticonvulsants{14}{15}{42}    (concurrent use with valproic acid, divalproex, or valproate sodium has been reported to both increase and decrease ethosuximide concentrations; monitoring of serum concentrations as a guide to dosage is recommended)


» Felbamate{40}{42}    (coadministration of felbamate may increase valproate plasma concentrations by 35 to 50%; a decrease in valproic acid, divalproex, or valproate sodium dosage may be needed when felbamate therapy is initiated)


» Hepatotoxic medications, other (see Appendix II )    (concurrent use with valproic acid, divalproex, or valproate sodium may increase the risk of hepatotoxicity; patients on prolonged therapy or with a history of liver disease should be carefully monitored)


» Lamotrigine{42}    (elimination half-life of lamotrigine was increased from 26 to 70 hours in a steady-state study in volunteers receiving both lamotrigine and valproate; when coadministered with valproate, the dose of lamotrigine should be reduced {42}; concurrent use of lamotrigine with valproate may increase the risk of dangerous dermatologic reactions {47})


Levocarnitine    (requirements for carnitine may be increased in patients receiving valproic acid or divalproex {38} {39})


» Mefloquine    (concurrent use with valproic acid, divalproex, or valproate sodium may result in low valproate serum concentrations and loss of seizure control; monitoring of valproate serum concentrations is recommended and dosage adjustments may be necessary during and after therapy with mefloquine {27} {28})


» Phenytoin, and possibly other hydantoin anticonvulsants{09}{10}{11}{12}{13}{42}{45}    (concurrent use with valproic acid, divalproex, or valproate sodium has resulted in breakthrough seizures or phenytoin toxicity because valproate may interfere with phenytoin protein binding, and phenytoin, through enzyme induction, will lower valproate levels {03}; valproate increases unbound phenytoin concentrations and decreases intrinsic clearance by inhibiting metabolism of phenytoin {01} {02} {44}; concurrent use requires close monitoring of the patient since variable serum phenytoin concentrations have resulted {01} {02} {44}; total phenytoin serum concentrations may not reflect unbound phenytoin activity, and unbound phenytoin concentrations may be more reliable; dosage of phenytoin should be adjusted as required by clinical situation)


» Platelet aggregation inhibitors, other{09}{10}{11}{12}{13}{42} (see Appendix II )    (concurrent use with valproic acid, divalproex, or valproate sodium may increase the risk of hemorrhage because of additive or multiple actions that may decrease blood-clotting ability)

    (the gastrointestinal ulcerative or hemorrhagic potential of aspirin, anti-inflammatory analgesics, or sulfinpyrazone may increase the risk of hemorrhage in patients receiving valproic acid, divalproex, or valproate sodium)

    (in addition, aspirin may displace valproic acid, divalproex, or valproate sodium from protein binding sites, as well as altering valproate metabolism and excretion, resulting in increased levels of free [unbound] valproate, which may cause toxic effects {21} {22} {26})


Rifampin{42}    (unpublished data obtained by the manufacturer suggest that increased clearance of single-dose oral valproate occurs following pretreatment with oral rifampin; dosage adjustments may be necessary if valproate and rifampin are used concurrently {42} {49})


Sodium benzoate and sodium phenylacetate combination{30}{31}    (valproate-induced hyperammonemia may exacerbate urea cycle enzymopathy deficiency and antagonize the efficacy of sodium benzoate and sodium phenylacetate combination {30} {31})


Zidovudine{42}    (in six HIV-positive patients, the clearance of zidovudine was decreased by 38% following administration of valproate; the half-life of zidovudine was unaffected {42})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Metyrapone test    (increased metabolism of metyrapone by a hepatic enzyme inducer such as valproic acid, divalproex, or valproate sodium may decrease the response to metyrapone)


Thyroid function tests{09}{10}{11}{12}{13}{42}{46}    (test results may be altered; decreased T 4, and free T 3 and T 4 concentrations have been reported {03}; clinical significance is unknown {09} {10} {11} {12} {13} {45})


Urine ketone tests    (use of valproic acid, divalproex, or valproate sodium may produce false-positive results because of a ketone metabolite excreted in urine {09} {10} {11} {12} {13} {42} {45} {46})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH)    (minor elevations of serum concentrations occur frequently and appear to be dose-related; elevations may indicate asymptomatic hepatotoxicity {09} {10} {11} {12} {13})


Amino acid screening    (increases in glycine may occur {09} {10} {11} {12} {13})


Bilirubin    (serum concentrations may be increased; increase may indicate potentially serious hepatotoxicity {09} {10} {11} {12} {13})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Hepatic disease{09}{10}{11}{12}{13}{40}{43}{44}{46} or
» Hepatic function impairment, significant{09}{10}{11}{12}{13}{40}{46}{43}    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
Blood dyscrasias or
Brain disease, organic or
Hepatic disease, history of{09}{10}{11}{12}{13}{43}    (may be exacerbated)


Hypoalbuminemia{08}    (alterations in protein binding may affect serum levels)


Renal function impairment    (metabolites may accumulate; valproate binding to serum albumin is decreased {07} and volume of distribution is increased {03})


Sensitivity to valproic acid, divalproex, or valproate sodium{09}{10}{11}{12}{13}{42}{46}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Ammonia concentrations, serum{10}{12}{42}{45}{46}    (therapy should be discontinued if hyperammonemia occurs, with or without lethargy or coma)


Bleeding time determinations{09}{10}{11}{12}{13}{42}{44}{45} and
Blood cell counts, including platelets{09}{10}{11}{12}{13}{42}{44}{45} and
Renal function determinations    (recommended prior to therapy and periodically during therapy)


Hepatic function determinations    (should be performed prior to therapy and periodically thereafter, especially during the first 6 months of therapy; valproic acid, divalproex, or valproate sodium should be discontinued immediately if significant hepatic function impairment is apparent or suspected {09} {10} {11} {12} {13} {45} {46})


Valproate concentrations, serum    (since therapeutic concentrations {07} vary widely, morning trough concentrations with values ranging from 50 to 100 mcg per mL [347 to 693 micromoles per L] may be useful when initiating therapy; doses may be raised gradually until patient achieves a predose serum concentration of at least 50 mcg per mL [347 micromoles per L], the dose then being increased as needed {03})

    (total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males significantly increase the probability of thrombocytopenia {42}; risk-benefit must be considered)

    (since serum valproate concentrations do not always correspond with therapeutic effect, evaluation of dose adjustments must be based on total clinical assessment of the patient {09} {10} {11} {12} {13} {43})




Side/Adverse Effects

Note: Hepatic failure resulting in death has occurred in patients receiving valproic acid and divalproex. {09} {10} {11} {12} {13} {14} {43} {44} {46} These incidents usually have occurred during the first 6 months of treatment. {09} {10} {11} {12} {13} {44} Patients at greatest risk are children receiving other anticonvulsants along with valproic acid, divalproex, or valproate sodium. {01} {12} {14} {42} {44} Serious or fatal hepatotoxicity may be preceded by nonspecific symptoms such as loss of seizure control, malaise, weakness, lethargy, Reye's-like syndrome, anorexia, vomiting, jaundice, and edema {03} {09} {10} {11} {12} {13} {45} {46}. In some cases, hepatic function impairment has progressed despite discontinuation of medication. {09} {10} {11} {12} {13} {45} {46}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Behavioral, mood, or mental changes {09} {10} {11} {12} {13}
    
hepatotoxicity or hyperammonemia {09} {10} {11} {12} {13} {14} (increase in frequency of seizures; loss of appetite ; continuing nausea or vomiting; swelling of face; tiredness and weakness; yellow eyes or skin)
    
ophthalmological effects, specifically diplopia {09} {10} {11} {12} {13} (double vision ), nystagmus {09} {10} {11} {12} {13} (continuous, uncontrolled back-and-forth and/or rolling eye movements), or spots before eyes {09} {10} {11} {12} {13}
    
pancreatitis {09} {10} {11} {12} {13} {14} (severe abdominal or stomach cramps; continuing nausea and vomiting)
    
platelet aggregation inhibition or thrombocytopenia {09} {10} {11} {12} {13} {14} {46} (unusual bleeding or bruising)
Note: Evidence of hemorrhage, bruising, or a disorder of coagulation or hemostasis is an indication for reduction of dosage or discontinuation of therapy. {09} {10} {11} {12} {13}





Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal or stomach cramps, mild {09} {10} {11} {12} {13} —may also indicate a risk of pancreatitis; less frequent with divalproex {01}
    
anorexia {09} {10} {11} {12} {13} (loss of appetite)
    
change in menstrual periods {09} {10} {11} {12} {13}
    
diarrhea {09} {10} {11} {12} {13}
    
hair loss {09} {10} {11} {12} {13}
    
indigestion {09} {10} {11} {12} {13}
    
nausea and vomiting {09} {10} {11} {12} {13}
    
trembling of hands and arms {09} {10} {11} {12} {13} {14}
    
unusual weight loss or gain {09} {10} {11} {12} {13}

Incidence less frequent or rare
    
Ataxia {09} {10} {11} {12} {13} (clumsiness or unsteadiness)
    
constipation {09} {10} {11} {12} {13}
    
dizziness {09} {10} {11} {12} {13}
    
drowsiness {09} {10} {11} {12} {13}
    
headache {09} {10} {11} {12} {13} {14}
    
skin rash {09} {10} {11} {12} {13} {14}
    
unusual excitement, restlessness, or irritability {09} {10} {11} {12} {13}





Overdose
For specific information on the agents used in the management of valproic acid overdose, see:    • Naloxone (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Treatment of overdose consists primarily of supportive {09} {10} {11} {12} {13} and symptomatic measures.

To decrease absorption—The effectiveness of emesis or gastric lavage will depend upon the time elapsed since ingestion {09} {10} {11} {12} {13}. The enteric-coated tablets will delay absorption about 1 to 4 hours.

To enhance elimination—Hemodialysis, or tandem hemodialysis and hemoperfusion, may result in significant reductions in valproate serum concentrations {42} {44}.

Specific treatment—Maintenance of adequate urinary output must be ensured {09} {10} {11} {12} {13} {42} {46}. Naloxone has been administered to counteract severe CNS depression, but it also theoretically reverses the anticonvulsant effect and should be used with caution {09} {10} {11} {12} {13} {42} {44} {46}.

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Valproic Acid (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to valproic acid, divalproex, or valproate sodium

Pregnancy—Pregnancy studies in animals have shown skeletal abnormalities involving ribs and vertebrae in offspring of mothers given large doses; in humans, crosses placenta in first trimester and may cause neural tube defects in fetus





Breast-feeding—Distributed into breast milk at concentrations up to 10% of the total maternal serum concentration





Use in children—Children are at an increased risk of serious hepatotoxicity






Use in the elderly—Elderly patients tend to have higher serum concentrations of free (unbound) valproic acid; lower daily dosages recommended





Dental—Prolonged bleeding time and/or hemorrhaging; leukopenia and thrombocytopenia may result in increased incidence of microbial infection, delayed healing, and gingival bleeding

Surgical
Prolonged bleeding time and/or hemorrhaging may occur; leukopenia and thrombocytopenia may cause surgical complications
Other medications, especially alcohol or other CNS depression–producing medications, heparin or thrombolytic agents, barbiturates, primidone, carbamazepine, felbamate, other hepatotoxic medications, lamotrigine, mefloquine, phenytoin, or other platelet aggregation inhibitors
Other medical problems, especially significant hepatic disease or hepatic function impairment

Proper use of this medication

Proper administration

For valproic acid capsules
Swallowing capsules whole with water only; not breaking, chewing, or crushing

For divalproex sodium delayed-release capsules
Swallowing capsules whole, or sprinkling the contents on a small amount of cool, soft food (such as applesauce or pudding) and swallowing, not chewing, immediately after preparation

For divalproex sodium delayed-release tablets
Swallowing tablets whole; not breaking, chewing, or crushing

For valproic acid syrup
Mixing with any liquid or adding to a small amount of food to enhance palatability

For all oral products
Taking with food if necessary to reduce gastrointestinal side effects
» Compliance with therapy; taking exactly as directed by physician

» Proper dosing
Missed dose: If dosing schedule is—

• One dose a day: Taking as soon as possible; not taking if not remembered until next day; not doubling doses


• Two or more doses a day: Taking if remembered within 6 hours; taking remaining doses for that day at equally spaced intervals; not doubling doses


» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress of therapy

» Checking with physician before discontinuing medication; gradual dosage reduction may be necessary

» Possible prolonged bleeding or hemorrhage: caution if any kind of surgery, dental treatment, or emergency treatment is required

» Avoiding use of alcoholic beverages or other CNS depressants during therapy

Diabetic patients: When testing for urine ketones, possible false-positive test results

Caution if any laboratory tests required; possible interference with results of metyrapone or thyroid function tests

Possible need for carrying medical identification card or bracelet

» Possible drowsiness; caution when driving or doing other things requiring alertness


Side/adverse effects
Signs of potential side effects, especially behavioral, mood, or mental changes; hepatotoxicity; hyperammonemia; ophthalmological effects; pancreatitis; platelet aggregation inhibition; or thrombocytopenia


General Dosing Information
Patients at primary risk for fatal liver failure with valproic acid, divalproex, or valproate sodium treatment include:    • Children up to 2 years of age, especially those on polytherapy, those with congenital metabolic disorders, those with severe epilepsy accompanied by mental retardation, and those with organic brain disease {09} {10} {11} {12} {13} {42}.
   • All patients receiving concomitant anticonvulsants, especially those that enhance production of a toxic metabolite through induction of hepatic P450 isoenzymes (e.g., carbamazepine {09} {11} {13} {42}, felbamate {40} {42}, lamotrigine {42}, phenobarbital {09} {10} {11} {12} {13} {42}, phenytoin {09} {10} {11} {12} {13} {42}, primidone {09} {10} {11} {12} {13} {42})
   • Patients with familial liver disease.


Recommendations for reducing the risk of serious hepatotoxicity with valproate include:    • Avoiding the administration of valproate with other anticonvulsants whenever possible {09} {10} {11} {12} {13}, especially in children up to 3 years of age, unless monotherapy has failed or the benefits of polytherapy outweigh the risks.
   • Avoiding valproate therapy in patients with pre-existing liver disease or a family history of childhood hepatic disease. {09} {10} {11} {12} {13}
   • Administering valproate in as low a dose as possible to achieve seizure control. {10} {12}
   • Avoiding concurrent administration with other hepatotoxic medications, especially salicylates. {09} {10} {11} {12} {13} {42}
   • Monitoring for prodromal symptoms (e.g., nausea {07} or vomiting, headache, edema, jaundice, or seizure breakthrough, especially after a febrile illness) {05}.
   • Avoiding administration to patients with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease. {09} {10} {11} {12} {13}


When valproic acid, divalproex, or valproate sodium is to be discontinued, dosage should be reduced gradually since abrupt withdrawal may precipitate seizures or status epilepticus. {09} {11} {44}

The serum concentration of valproate does not always correspond with therapeutic effect; therefore, the evaluation of the patient's progress must be based on total clinical assessment. {09} {10} {11} {12} {13}

When valproic acid, divalproex, or valproate sodium is used to replace or supplement other anticonvulsant therapy, the dosage should be increased gradually to achieve therapeutic serum concentrations, while that of the replaced medication is decreased gradually in order to maintain seizure control. The addition of valproic acid, divalproex, or valproate sodium may cause increases {03} in the serum concentrations of hepatic enzyme–inducing anticonvulsants (e.g., carbamazepine {09} {11} {13} {42}, felbamate {40} {42}, lamotrigine {42}, phenobarbital {09} {10} {11} {12} {13} {42}, phenytoin {09} {10} {11} {12} {13} {42}, primidone {09} {10} {11} {12} {13} {42})

The possible prolongation of bleeding time, in addition to potentiation of depressant effect by CNS depressants, should be considered when surgery, dental treatment, or emergency treatment is required. {09} {11} {13}

Diet/Nutrition
Valproic acid or divalproex may be taken with food to reduce gastrointestinal side effects. {09} {10} {11} {12} {13} {14} {44} {45}

The contents of divalproex sodium delayed-release capsules may be sprinkled on a small amount of cool, soft food (such as applesauce or pudding) and swallowed, not chewed, immediately after preparation. {16} {24}

Valproic acid syrup may be mixed with a small amount of food or liquid to enhance the palatability. {09} {10}

Requirements for carnitine may be increased in patients receiving valproic acid, divalproex, or valproate sodium. {38} {39}

DIVALPROEX


Oral Dosage Forms

DIVALPROEX SODIUM DELAYED-RELEASE CAPSULES

Usual adult and adolescent dose
Anticonvulsant
Monotherapy: Oral, the equivalent of valproic acid—Initially, 5 to 15 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated. {16}

Polytherapy: Oral, the equivalent of valproic acid—Initially, 10 to 30 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated {01}.

Note: If the total daily dose exceeds 250 mg, it should be divided into two or more doses {16} (usually given every 12 hours {01}) to lessen the possibility of gastrointestinal irritation.
Geriatric patients may need lower doses.
Patients also taking a hepatic enzyme–inducing medication may need higher dosages depending on predose serum concentrations. {03}



Usual adult prescribing limits
60 mg per kg of body weight a day. {16}

Usual pediatric dose
Anticonvulsant: Children 1 to 12 years of age
Monotherapy: Oral, the equivalent of valproic acid—Initially, 15 to 45 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated.

Polytherapy: Oral, the equivalent of valproic acid—30 to 100 mg per kg of body weight a day.

Note: Dosage adjustments depend on clinical response and serum anticonvulsant concentrations.



Usual geriatric dose
Geriatric patients may need lower doses {42}. See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—



The equivalent of valproic acid


125 mg (Rx) [Depakote Sprinkle]

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F), preferably between 15 and 30 °C (59 and 86 °F) in a tight, light-resistant container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Do not chew contents of capsule.


DIVALPROEX SODIUM DELAYED-RELEASE TABLETS

Usual adult dose
Anticonvulsant
Monotherapy: Oral, the equivalent of valproic acid—Initially, 5 to 15 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated. {40}

Polytherapy: Oral, the equivalent of valproic acid—Initially, 10 to 30 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated {01}.

Antimanic
Oral, initially 750 mg a day in divided doses {40}. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect or a desired trough plasma concentration within the range of fifty to one hundred twenty-five micrograms/mL {40}.

Migraine headache prophylactic
Oral, initially 250 mg two times a day. {40} The dose may be increased as needed and tolerated; some patients may benefit from doses up to 1000 mg a day. {40} However, daily doses above 1000 mg have not demonstrated increased efficacy in clinical trials. {40}


Note: If the total daily dose exceeds 250 mg, it should be divided into two or more doses {16} (usually given every 12 hours {01}) to lessen the possibility of gastrointestinal irritation.
Geriatric patients may need lower doses. {40}
Patients also taking a hepatic enzyme–inducing medication may need higher dosages depending on predose serum concentrations. {03}


Usual adult prescribing limits
See Divalproex Sodium Delayed-release Capsules.

Usual pediatric dose
See Divalproex Sodium Delayed-release Capsules.

Usual geriatric dose
Geriatric patients may need lower doses {42}. See Usual adult dose .

Strength(s) usually available
U.S.—



The equivalent of valproic acid


125 mg (Rx) [Depakote]


250 mg (Rx) [Depakote]


500 mg (Rx) [Depakote]

Canada—



The equivalent of valproic acid


125 mg (Rx) [Epival (enteric-coated)]


250 mg (Rx) [Epival (enteric-coated)]


500 mg (Rx) [Epival (enteric-coated)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Swallow tablets whole. Do not break or chew.


VALPROATE SODIUM


Parenteral Dosage Forms

VALPROATE SODIUM INJECTION

Usual adult and adolescent dose
Anticonvulsant


Initial exposure to valproate:
Monotherapy—Intravenous infusion: Initially, 5 to 15 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated {09} {10} {13}.

Polytherapy—Intravenous infusion: Initially, 10 to 30 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated {01}.



Replacement for oral therapy:
Intravenous infusion—The total daily dose should be equivalent to the total daily dose of the oral valproic acid or divalproex product and should be administered at the same frequency as the oral product {42}. If the total daily dose exceeds 250 mg, it should be given in divided doses {42}.


Note: Valproate sodium injection should be administered as a 60-minute intravenous infusion; the rate of infusion should not exceed 20 mg per minute {42}. Plasma concentration monitoring and dosage adjustments may be necessary {42}. Patients receiving doses approaching the maximum recommended daily dose of 60 mg per kg of body weight per day should be monitored closely, particularly those not receiving hepatic enzyme–inducing medications {42}. Patients should be switched to oral valproate products as soon as clinically feasible {42}.
Geriatric patients may need lower doses {42}.
Patients also taking a hepatic enzyme–inducing medication may need higher dosages, depending on predose serum valproate concentrations {03}.



Usual adult prescribing limits
60 mg per kg of body weight a day. {09} {10} {13} {42}

Usual pediatric dose
Anticonvulsant: Children 1 to 12 years of age
Monotherapy: Oral, initially, 15 to 45 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated {48}.

—Polytherapy: Oral, 30 to 100 mg per kg of body weight a day {48}.

Note: Dosage adjustments depend on clinical response and serum anticonvulsant concentrations {48}.



Usual geriatric dose
Geriatric patients may need lower doses {42}. See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—



Equivalent to valproic acid


100 mg per mL (Rx) [Depacon (edetate disodium 0.4 mg per mL)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer {42}.

Preparation of dosage form:
Valproate sodium injection should be diluted with at least 50 mL of 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, or Lactated Ringers Injection USP {42}. The product should be inspected visually for particulate matter and discoloration prior to administration {42}.

Stability:
Valproate sodium injection is stable in 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, or Lactated Ringers Injection USP for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature {42}. Any valproate sodium remaining in the vial after preparing the intravenous infusion should be discarded {42}.


VALPROIC ACID


Oral Dosage Forms

VALPROIC ACID CAPSULES USP

Usual adult and adolescent dose
Anticonvulsant
Monotherapy: Oral, initially, 5 to 15 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated. {09} {10} {13}

Polytherapy: Oral, initially, 10 to 30 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated. {01}

Note: If the total daily dose exceeds 250 mg, it should be divided into two or more doses {09} {10} {13} {44} {45} (usually given every 12 hours {01}) to lessen the possibility of gastrointestinal irritation.
Geriatric patients may need lower doses.
Patients also taking a hepatic enzyme–inducing medication may need higher dosages depending on predose serum concentrations. {03}



Usual adult prescribing limits
60 mg per kg of body weight a day. {09} {10} {13} {44} {45}

Usual pediatric dose
Anticonvulsant—Children 1 to 12 years of age
Monotherapy: Oral, initially, 15 to 45 mg per kg of body weight a day, the dosage being increased at one-week intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated.

Polytherapy: Oral, 30 to 100 mg per kg of body weight a day.

Note: Dosage adjustments depend on clinical response and serum anticonvulsant concentrations.



Usual geriatric dose
Geriatric patients may need lower doses {42}. See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


250 mg (Rx) [Depakene (parabens)][Generic]

Canada—


250 mg (Rx) [Alti-Valproic] [Depakene (parabens)] [Deproic (parabens)] [Dom-Valproic] [Med Valproic] [Novo-Valproic] [Nu-Valproic] [Penta-Valproic] [pms-Valproic Acid]


500 mg (Rx) [Alti-Valproic (enteric-coated)] [Depakene (enteric-coated) (parabens) (tartrazine)] [Deproic (enteric-coated)] [Dom-Valproic (enteric-coated)] [Novo-Valproic (enteric-coated)] [pms-Valproic Acid E.C. (enteric-coated)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.
   • Swallow capsules whole. Do not break or chew.


VALPROIC ACID SYRUP USP

Usual adult and adolescent dose
See Valproic Acid Capsules USP.

Usual adult prescribing limits
See Valproic Acid Capsules USP.

Usual pediatric dose
See Valproic Acid Capsules USP.

Usual geriatric dose
See Valproic Acid Capsules USP.

Strength(s) usually available
U.S.—


250 mg per 5 mL (Rx) [Depakene (parabens) (sorbitol) (sucrose)][Generic]

Canada—


250 mg per 5 mL (Rx) [Alti-Valproic] [Depakene (parabens) (sucrose)] [PMS-Valproic Acid]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.



Revised: 08/14/1998



References
  1. Panelist comment.
  1. Rimmer RM, Richens A. An update on sodium valproate. Pharmacotherapy 1985; 5(3): 171-84.
  1. Panelist comment, 9/87.
  1. Valproic acid (Depakene, Abbott). In: PDR Physician's Desk Reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company, 1988: 511.
  1. Penry JK. Valproate monotherapy in the treatment of epilepsy. Am J Med 1988; 84(Supp 1A): 1-41.
  1. Panelist comment, 9/88.
  1. Panelist comment, 9/88.
  1. Reviewer comment, 12/88.
  1. Valproic acid (Depakene, Abbott). In: PDR Physician's Desk Reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 511-3; 51st ed. 1997: 416-8.
  1. Valproic acid (Depakene, Abbott). In: Krough CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 292-3; 32nd ed. 1997: 427-9.
  1. Divalproex (Depakote, Abbott). In: PDR Physician's Desk Reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company, 1989: 513-4; 51st ed. 1997: 418-22.
  1. Divalproex (Epival, Abbott). In: Krough CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association, 1989: 372-3; 32nd ed. 1997: 538-40.
  1. Valproic acid capsules (Reid-Rowell—US) package insert, Rev 1/89; Rec 4/89.
  1. Drugs for epilepsy. Med Lett Drugs Ther 1986 (Sep 26); 28(723): 91-4.
  1. Ethosuximide package insert (Zarontin, Parke-Davis—US) Rev 6/89, Rec 11/89.
  1. Divalproex package insert (Depakote, Abbott—US) Rev 9/89, Rec 11/89.
  1. Panelist comment, 2/90.
  1. Macdonald RL. Antiepileptic drug actions. Epilepsia l989; 30(Suppl 1): S19-S28.
  1. Panelist comment, 2/90.
  1. Panelist comment, 2/90.
  1. Shinn AF, Shrewsbury RP. EDI, Evaluation of drug interactions. 3rd ed. St. Louis: Mosby, l985: 275.
  1. Reviewer comment, 12/88.
  1. Panelist comment, 2/90.
  1. Panelist comment, 2/90.
  1. Dean JC, Penry JK. Valproate monotherapy in 30 patients with partial seizures. Epilepsia 1988 (Mar-Apr); 29(2): 140-4.
  1. Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity induced by acetylsalicylic acid. Neurol 1987; 37: 1392-4.
  1. Mefloquine package insert (Lariam, Roche—US), Rev 11/89, Rec 4/90.
  1. Mefloquine for malaria. Med Lett Drugs Ther 1990; 31(Feb 9): 13-4.
  1. Reviewers" responses to Psychiatric Disease Advisory Panel Memo #6 of 9/16/91.
  1. Sodium benzoate and sodium phenylacetate package insert (Ucephan, Kendall McGaw—US), Rev. 12/87, Rec. 12/9/87.
  1. Watson A, et al. Transient idiopathic hyperammonaemia in adults. Lancet 12/7/85: 1271-4.
  1. Parks-Veal PM. Use of anticonvulsants for treatment of bipolar disorder. Hosp Pharm 1992; 27: 606, 609.
  1. Post RM. Introduction: Emerging perspectives on valproate in affective disorders. J Clin Psychiatry 1989; 50 (Suppl 3): 3-9.
  1. Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry 1990; 147: 431-4.
  1. McElroy SL, Keck PE, Pope HG. Sodium valproate: Its use in primary psychiatric disorders. J Clin Psychopharmacol 1987: 7: 16-24.
  1. McElroy SL, Keck PE Jr, Pope HG, Hudson JI. Valproate in the treatment of bipolar disorder: Literature review and clinical guidelines. J Clin Psychopharmacol 1992; 12: 42S-52S.
  1. Raymond GG, Born JL. An updated pKa listing of medicinal compounds. Drug Intell Clin Pharm 1986; 20: 683-6.
  1. Opala G, Winter S, Vance C, Vance H, Hutchison HT, Linn LS. The effect of valproic acid on plasma carnitine levels. Am J Dis Child 1991; 145: 999-1001.
  1. Shapira Y, Gutman A. Muscle carnitine deficiency in patients using valproic acid. J Pediatr 1991; 118(4): 646-9.
  1. Divalproex package insert (Depakote, Abbott—US), Rev 3/96, Rec 5/15/96.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1996: 244; 754.
  1. Valproate sodium injection package insert (Depacon, Abbott—US), Rev 1/97, Rec 3/24/97.
  1. Valproic acid product monograph (Alti-Valproic, Altimed—Canada), Rev 10/23/96, Rec 5/7/97.
  1. Valproic acid product monograph (pms-VALPROIC ACID and pms-VALPROIC ACID E.C., Pharmascience—Canada), Rev 2/14/97, Rec 3/24/97.
  1. Valproic acid product monograph (Deproic, Technilab—Canada), Rev 4/96, Rec 3/24/97.
  1. Valproic acid product monograph (NOVO-VALPROIC, Novopharm—Canada), Rev 4/15/96, Rec 3/25/97.
  1. Panel comment, 7/97.
  1. Panel consensus on review of monograph of 5/29/97.
  1. Personal communication, Abbott Laboratories, 7/23/97.
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