Depakene Cap 500mg Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

DEPAKENE® (valproic acid) has anticonvulsant properties. Although its mechanism of action has not yet been established, it has been suggested that its activity is related to increased brain levels of gamma-aminobutyric acid (GABA). The effect on the neuronal membrane is unknown.

PHARMACOKINETICS

Valproic acid is rapidly absorbed after oral administration. Peak serum levels occur approximately one to four hours after a single oral dose. The serum half-life (t_1/2)

.

A good correlation has not been established between daily dose, serum level and therapeutic effect.

increases to a lesser extent. The kinetics of unbound drug are linear.

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (ranging from 7 to 25% of total concentration).

ne.

drawn.

Special Populations

Neonates/ Infants

onths.

Pediatrics

parameters that approximate those of adults. Elderly

Effect of Gender

², respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Hepatic Dysfunction

INDICATIONS AND CLINICAL USE

DEPAKENE® (valproic acid) is indicated for use as sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal, and is useful in primary generalized seizures with tonic-clonic manifestations. Valproic acid may also be used adjunctively in patients with multiple seizure types which include either absence or tonic-clonic seizures.

In accordance with the International Classification of Seizures, simple absence is defined as a very brief clouding of the sensorium or loss of consciousness (lasting usually 2 to 15 seconds), accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

CONTRAINDICATIONS

DEPAKENE® (valproic acid) should not be administered to patients with hepatic disease or significant hepatic dysfunction.

It is also contraindicated in patients with known hypersensitivity to the drug.

WARNINGS

Serious Skin Reactions

Serious or Fatal Hepatotoxicity

Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. The risk in this age group decreased considerably in patients receiving valproate as

.

Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia and vomiting. Patients should be monitored closely for appearance of these symptoms. Patients and parents should be instructed to report such symptoms. Because of the non-specific nature of some of the early signs, hepatotoxicity should be suspected in patients who become unwell, other than through obvious cause, while taking valproic acid.

Liver function tests should be performed prior to therapy and at frequent intervals thereafter especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproic acid to patients with a prior history of hepatic disease. Patients with various unusual congenital disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.

In high-risk patients, it might also be useful to monitor serum fibrinogen and albumin for decreases in concentration and serum ammonia for increases in concentration. If changes occur, valproic acid should be discontinued. Dosage should be titrated to and maintained at the lowest dose consistent with optimal seizure control.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Urea Cycle Disorders (UCD)

:

Somnolence in the elderly

ADMINISTRATION).

Usage in pregnancy

According to published

nt.

majority of mothers receiving antiepileptic medications deliver normal infants.

had children with neural tube defects (ANENCEPHALY AND SPINA BIFIDA).

Other congenital anomali

anomalies.

nancy.

anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproic acid is used in pregnancy, the clotting parameters should be monitored carefully.

regnancy.

embryo or fetus.

.

of anti-epileptic medication is in doubt, appropriate consultation is indicated.

.

Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving valproate.

epilepsy).

Nursing mothers

Fertility

Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at doses greater than 200 mg/kg/day in rats and 90 mg/kg/day in dogs. Segment 1 fertility studies in rats have shown that doses up to 350 mg/kg/day for 60 days have no effect on fertility. The effect of valproic acid on the development of the testis and on sperm production and fertility in humans is unknown.

Dose-related Adverse Reactions: Thrombocytopenia

.

Carcinogenicity

and mice. The significance of these findings for humans is unknown at present.

PRECAUTIONS

Hepatic dysfunction: See CONTRAINDICATIONS and WARNINGS.

General

).

ed.

n of valproic acid and phenytoin.

Valproic acid is partially eliminated in the urine as a ketone-containing metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproic acid: the clinical significance of these is unknown.

Suicidal ideation may be a manifestation of preexisting psychiatric disorders, and close supervision of high risk patients should accompany initial drug therapy.

Patients with Special Diseases and Conditions

unknown.

Thrombocytopenia

a). Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with hyperammonemia.

TIONS, General).

Multi-organ Hypersensitivity Reaction

his to be a possibility.

Hepatic Dysfunction

See CONTRAINDICATIONS and WARNINGS.

Renal Impairment

Renal impairment is associated with an increase in the unbound fraction of valproate. In several studies, the unbound fraction of valproat

Use in Pediatric Patients

Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (See WARNINGS). When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproic acid concentrations. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic concentrations. Interpretation of valproic acid concentrations in children should include

affect hepatic metabolism and protein binding.

Use in the Elderly

).

.

).

Monitoring Valproate Concentrations

in

Driving and hazardous occupations

Valproic acid may produce CNS depression, especially when combined with another CNS depressant, such as alcohol. Therefore, patients should be advised not to engage in hazardous occupations, such as driving a car or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Drug Interactions

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronyl transferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on valproate monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P₄₅₀ isozymes, e.g. antidepressants, may be expected to have little effect on valproate clearance because cytochrome P₄₅₀ microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.

The concomitant administration of valproic acid with drugs that exhibit extensive protein binding (e.g., aspirin, carbamazepine, dicumarol, warfarin, tolbutamide, and phenytoin) may result in alteration of serum drug levels.

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy and whenever enzyme-inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Please note that drugs may be listed under specific name, family or pharmacologic class. Reading the entire section is recommended.

Acetaminophen

Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Alcohol

Valproate may potentiate the CNS depressant action of alcohol.

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males

Antacids

A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Aspirin

A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. Caution should be observed when valproate is administered with drugs affecting coagulation , (e.g., aspirin and warfarin).

Benzodiazepines

Valproic acid may decrease oxidative liver metabolism of some benzodiazepines, resulting in increased serum concentrations (see Diazepam and Lorazepam).

Carbamazepine/carbamazepine-10,11-Epoxide

Concomitant use of carbamazepine with valproic acid may result in decreased serum concentrations and half-life of valproate due to increased metabolism induced by hepatic microsomal enzyme activity. Monitoring of serum concentrations is recommended when either medication is added to or withdrawn from an existing regimen. Changes in the serum concentration of the 10,11-epoxide metabolite of carbamazepine, however, will not be detected by routine serum carbamazepine assay.

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

Chlorpromazine

A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg b.i.d) revealed a 15% increase in trough plasma levels of valproate.

Cimetidine

Cimetidine may decrease the clearance and increase the half-life of valproic acid by altering its metabolism. In patients receiving valproic acid, serum valproic acid levels should be monitored when treatment with cimetidine is instituted, increased, decreased, or discontinued. The valproic acid dose should be adjusted accordingly.

Clonazepam

The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.

Clozapine

In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.

Diazepam

Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.

Ethosuximide

Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Felbamate

A study involving the co-administration of 1200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 µg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean valproate peak concentration to 133 µg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Lower doses of valproate may be necessary when used concomitantly with felbamate.

Haloperidol

A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg b.i.d) revealed no significant changes in valproate trough plasma levels.

Lamotrigine

The effects of sodium valproate on lamotrigine were investigated in six healthy male subjects. Each subject received a single oral dose of lamotrigine alone and with valproic acid 200 mg every 8 hours for six doses starting 1 hour before the lamotrigine dose was given. Valproic acid administration reduced the total clearance of lamotrigine by 21% and increased the plasma elimination half-life from 37.4 hours to 48.3 hours (p < 0.005). Renal clearance of lamotrigine

(e.g. carbamazepine, phenytoin, phenobarbital, or primidone) demonstrated a mean lamotrigine plasma elimination half-life of 14 hours while the elimination half-life was 30 hours in patients taking sodium valproate plus an enzyme inducing antiepileptic agent. The latter value is similar to the lamotrigine half-life during monotherapy indicating that valproic acid may counteract the effect of the enzyme inducer. If valproic acid is discontinued in a patient receiving lamotrigine and an enzyme inducing antiepileptic serum lamotrigine concentrations may decrease. Patients receiving combined antiepileptic therapy require careful monitoring when another agent is started, stopped or when the dose is altered.

Lithium

In a double-blind placebo-controlled multiple dose crossover study in 16 healthy male volunteers, pharmacokinetic parameters of lithium were not altered by the presence or absence of valproate. The presence of lithium, however, resulted in an 11% to 12% increase in the AUC and C_max of valproate. T_max was also reduced. Although these changes were statistically significant, they are not likely to have clinical importance.

Co-administration of valproate (500 mg b.i.d) and lithium carbonate (300 mg t.i.d) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg b.i.d) and lorazepam (1 mg b.i.d) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Meropenem

Subtherapeutic valproic acid levels have been reported when meropenem was co-administered.

Oral Contraceptive Steroids

Evidence suggests that there is an association between the use of certain antiepileptic drugs capable of enzyme induction and failure of oral contraceptives. One explanation for this interaction is that enzyme-inducing drugs effectively lower plasma concentrations of the relevant steroid hormones, resulting in unimpaired ovulation. However, other mechanisms, not related to enzyme induction, may contribute to the failure of oral contraceptives. Valproic acid is not a significant enzyme inducer and would not be expected to decrease concentrations of steroid hormones. However, clinical data about the interaction of valproic acid with oral contraceptives are minimal.

Administration of a single-dose of ethinyloestradiol (50 µg)/levonorgestrel (250 µg) to 6 women on valproate (200 mg b.i.d) therapy for 2 months did not reveal any pharmacokinetic interaction. Phenobarbital

Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg b.i.d for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in the presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.

Phenytoin

Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg t.i.d) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.

Primidone

Primidone is metabolized into a barbiturate, and therefore, may also be involved in a similar or identical interaction with valproate as phenobarbital.

Rifampin

A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Selective Serotonin Re-Uptake Inhibitors (SSRI's)

Some evidence suggests that SSRI's inhibit the metabolism of valproate, resulting in higher than expected levels of valproate.

Tolbutamide

From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.

Topiramate

Warfarin

In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown, however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants.

Caution is recommended when valproate is administered with drugs affecting coagulation (See ADVERSE REACTIONS).

Zidovudine

In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected.

Other - Antipsychotics, MAO Inhibitors and Tricyclic Antidepressants

In addition to enhancing central nervous system (CNS) depression when used concurrently with valproic acid, antipsychotics, tricyclic antidepressants and MAO inhibitors may lower the seizure threshold. Dosage adjustments may be necessary to control seizures.

ADVERSE REACTIONS

The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since DEPAKENE® (valproic acid) has usually been used with other anti-epileptics, it is not possible in most cases to determine whether the adverse reactions mentioned in this section are due to valproic acid alone or to the combination of drugs.

Gastrointestinal:

CNS Effects:

.

Encephalopathy, with or without fever or hyperammonemia, has been reported without evidence of hepatic dysfunction or inappropriate valproate plasma levels. Most patients recovered, with noted improvement of symptoms, upon discontinuation of the drug.

Reversible cerebral atrophy and dementia have been reported in association with valproate therapy.

Dermatologic: Transient increases in hair loss have been observed. Skin rash, petechiae, photosensitivity, generalized pruritus, erythema multiforme, Stevens-Johnson syndrome, and petechiae have rarely been noted.

Endocrine: There have been reports of irregular menses, secondary amenorrhea, breast enlargement, galactorrhea and parotid gland swelling in patients receiving valproic acid.

Abnormal thyroid function tests have been reported (see PRECAUTIONS).

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.

Psychiatric: Emotional upset, depression, psychosis, aggression, hyper-activity, hostility, and behavioural deterioration have been reported.

Musculoskeletal: Weakness has been reported.

Genitourinary: Enuresis and urinary tract infection

Hematopoietic: Thrombocytopenia has been reported. Valproic acid inhibits the second phase of platelet

d

Hepatic: Minor elevations of transaminases (e.g. SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory tests also show increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity (see WARNINGS).

Metabolic: Hyperammonemia, hyponatremia, and inappropriate ADH secretion.(see

). There have been rare reports of Fanconi syndrome

Pancreatic:

,

Special Senses: Hearing loss, either reversible or irreversible, has been reported;

however, a cause and effect relationship has not been established. Ear pain has also been reported.

Other:

s

fever and hypothermia have

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2120 mcg/mL.

In a reported case of overdosage with DEPAKENE® (valproic acid) after ingesting 36 g in combination with phenobarbital and phenytoin, the patient presented in deep coma. An EEG recorded diffuse slowing, compatible with the state of consciousness. The patient made an uneventful recovery.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. As valproic acid is absorbed very rapidly, gastric lavage may be of limited value. General supportive measures should be applied with particular attention to the prevention of hypovolemia and the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproic acid overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproic acid it should be used with caution.

DOSAGE AND ADMINISTRATION

DEPAKENE® (valproic acid) is administered orally. The recommended initial dosage is 15 mg/kg/day, increasing at one-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.

The maximal recommended dosage is 60 mg/kg/day. When the total daily dose exceeds 250 mg, it should be given in a divided regimen (see Table 1). A 500 mg enteric-coated capsule may be substituted for two 250 mg capsules.

The frequency of adverse effects (particularly elevated liver enzymes) may increase with increasing dose. Therefore, the benefit gained by improved seizure control must be weighed against the increased incidence of adverse effects.

Therapeutic Blood Levels

r

).

t

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced. Dosage should be increased

.

Dose-Related Adverse Events

mcg/mL (males) (See

G.I. Irritation

Conversion from DEPAKENE® to EPIVAL®:

AVAILABILITY

DEPAKENE® (valproic acid) is available as orange-coloured, soft gelatin capsules of 250 mg in bottles of 100 and 500 capsules; pale yellow, oval, soft gelatin enteric-coated capsules of 500 mg in bottles of 100 and 500 capsules; and as a red syrup containing the equivalent of 250 mg valproic acid, as the sodium salt, per 5 mL in bottles of 480 mL.

PHARMACEUTICAL INFORMATION

DEPAKENE® (valproic acid) is chemically a carboxylic acid designated as 2-propylpentanoic acid, also known as dipropylacetic acid. Its structural formula is as follows:

It is a colourless liquid, slightly soluble in water and very soluble in organic solvents.

Storage Recommendations

Store capsules between 15° and 25°C.

Store syrup between 15° and 25°C.

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2. 2.

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3. 3.

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14. 15.

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15. 16.

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16. 17. Swinyard EA. The Pharmacology of Dipropylacetic Acid Sodium with Special Emphasis on its Effects on the Central Nervous System. 1974. (Available from Abbott Laboratories on request).
17. 18.

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18. 19. Shakir RA. Comparison of Sodium Valproate and Phenytoin as Single Drug Treatment in Epilepsy. Epilepsia. 1981;22:27-33.
19. 20.

    Shakir RA. Comparative Trial of Falproate Sodium and Clonazepam in Chronic

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20. 21. Turnbull DM, Rawlins MD, Weightman D, Chadwick DW. A Comparison of Phenytoin and Valproate in Previously Untreated Adult Epileptic Patients. J. Neurol Neurosur. Psychiat. 1982;45:55-59.
21. 22.

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22. 23. Cramer JA, Mattson RH. Valproic Acid: In Vitro Plasma Protein Binding and Interaction with Phenytoin. Ther. Drug. Monit. 1979;1(1):105-116.
23. 24.

    Bowdle TA, Patel JH, Levy RH. Valproic Acid Dosage and Plasma Protein Binding and

    Clearance. Clin. Pharmacol. Ther. 1980;28(4):487-492.

24. 25.

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25. 26.

    Kapetamovic IM, Kupferberg HJ. Inhibition of Microsomal Phenobarbital Metabolism of

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26. 27.

    Patel IH, Levy RH. Phenobarbital - Valproic Acid Interaction. Clin. Pharmacol. Ther.

    1979;27(4):515-521.

27. 28.

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    1980;30:94-97.

28. 29.

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    Properties and Therapeutic Efficacy in Epilepsy. Drugs. 1977;B:81-123.

29. 30.

    Millet Y, Sinty JM. Problems Created by Combining Phenobarbital and Sodium

    Dipropylacetate Therapeutically: Case Report. Europ. Toxicol. 1976;9(6)6:381-383.

30. 31.

    Rai PV. Acute Intoxication During a Combined Treatment of Sodium Valproate and

    Phenobarbitone. (In) Epileptology. 1978;366-369.

31. 32.

    Dreifus FE, Santille N. Valproic Acid Hepatic Fatalities: Analysis of U.S. Cases,

    Presented at The Annual Meeting of the Am. Acad. of Neurology. April 30, 1986.