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Valproic acid

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.2.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Others
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)



    VALPROIC ACID

    International Programme on Chemical Safety
    Poisons Information Monograph 551
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Valproic acid

        1.2  Group

             Antiepileptic (N03)/Fatty acid derivatives (N03AG)

        1.3  Synonyms

             Abbott-44089;
             2-Propylpentanoic acid;
             2-Propylvaleric acid;
             Di-n-dipropylacetic acid

        1.4  Identification numbers

             1.4.1  CAS number

                    99-66-1

             1.4.2  Other numbers

                    CAS number:
                    Sodium Valproate      1069-66-5
                    Semisodium Valproate  76584-70-8
                    Valproate Pivoxil     77372-61-3
                    Valpromide            2430-27-5

                    RTECS Valproic acid  YV7875000

        1.5  Brand names, Trade names

             Convulex, Convulexette (Belgium)
    
             Promonta, Mylproin, Valcote (Germany)
    
             Byk, Propymal (Netherlands)
    
             Gerot (Switzerland)
    
             Depakene (Canada, Japan, USA, Philippines)
    
             Depakin (Italy)
    

             Depakine (Belgium, France, Netherlands, Spain, Switzerland)
    
             Depamide (France, Italy, Netherlands, Spain)
    
             Deparkine (Denmark, Norway)
    
             Epilim (Australia, South Africa, UK)
    
             Epival (Canada)
    
             Leptilan (Denmark, Germany)
    
             Ergenyl, Leptilen, Orfilept (Sweden)
    
             Logical (Argentina)
    
             Orfiril (Denmark, Germany, Norway, Switzerland)
    
             Vistora (Spain)

        1.6  Manufacturers, Importers

             Promonta (Germany)
             Sigmatau (Italy)
             Labanz (France, Spain, Switzerland, Germany, South Africa)
             Labanz Sanofi (Netherlands, UK)
             Reckitt and Colman (Australia)
             Geigy (Denmark, Germany)
             Leo Rhodia (Sweden)
             Rhône Poulenc (Switzerland, Denmark)
             Vita (Spain)

    2.  SUMMARY

        2.1  Main risks and target organs

             After oral administration, the drug is rapidly absorbed
             from the gastrointestinal tract and metabolized in the
             liver.
    
             Fatal hepatic failure has been reported in patients on
             valproic acid therapy, especially those on chronic use.
    
             Central nervous system depression and convulsions may
             occur.
    
             The drug crosses the placental barrier and has been found in
             breastmilk.
    
             Pancreatitis has also been reported, usually seen in patients
             receiving normal therapeutic dosage.

        2.2  Summary of clinical effects

             Reports showed that acute toxicity is rare, and usually
             follows a benign course (Ellenhorn, 1988).
    
             Fatal hepatic failure is usually seen following chronic use
             of valproic acid. 
    
             The most commonly reported adverse effects are anorexia,
             nausea and vomiting.
    
             Gastrointestinal:
    
             Nausea, vomiting, diarrhoea, pancreatitis (usually receiving
             normal therapeutic doses).
    
             Central nervous system:
    
             Drowsiness, possibly apathy and withdrawal, confusion,
             restlessness, hyperactivity. Less frequently, seizures and
             coma may occur.  Asterixis of both hands and feet.  Delayed
             cerebral oedema.
    
             Sedative effects are more pronounced when drug is used
             together with other anti-epileptic agents.
    
             Liver:
    
             Hepatic failure (centrilobular necrosis).
    
             Haematopoietic system:
    
             Thrombocytopenia, abnormal bleeding time and partial
             thromboplastin time with decreased fibrinogen levels and
             prolonged prothrombin time leading to bruising, petechiae,
             haematoma, and epistaxis.
    
             Skin:
    
             Pruritic macular rashes.
    
             Hair:
    
             Transient alopecia.
    
             Metabolic:
    
             Hyperammonaemia, hypocalcaemia, metabolic acidosis.
    
             Endocrine system:
    
             Altered thyroid functions (clinical significance is unknown).

        2.3  Diagnosis

             Clinical diagnosis is difficult because of multiorgan
             toxicity.
    
             Serum, urine, plasma and breastmilk can be used as samples
             for determining valproic acid and its metabolites using
             either gas chromatography, gas chromatography-mass
             spectrophotometry and high pressure liquid chromatography.

        2.4  First aid measures and management principles

             Assess airway, breathing, circulation and neurological
             status of the patient.  Maintain a clear airway, aspirate
             secretions.  If respiratory depression is present, intubate
             and ventilate.
    
             Emesis with syrup of ipecac is not advisable since, although
             the patient may be conscious on admission, he/she may rapidly
             deteriorate and become somnolent and stuporous.  Gastric
             lavage should be considered, if the patient is seen within 1
             to 2 hours after ingestion. However, if the patient is
             comatose, convulsing or has lost the gag reflex, endotracheal
             intubation is needed.  This procedure, however, is of limited
             value when the drug was taken in syrup form due to rapid
             absorption of the drug.  The use of activated charcoal may be
             considered after oral overdosage.
    
             Enhancement of elimination either by forced alkaline
             diuresis, haemodialysis or haemoperfusion may be of little
             value, because of its high protein binding.
    
             Supportive therapy is the mainstay in the management of
             valproic acid overdose.
    
             If the patient is stuporous, drowsy or somnolent, but
             otherwise with normal vital signs and baseline liver function
             tests are within normal, then simple observation with
             supportive therapy and good nursing care for 24 to 72 hours
             may be sufficient (Ellenhorn & Barceloux, 1988).

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Valproic acid may be synthesized from 4-heptanol by
             successive conversions to 4-bromoheptane with HBr, to
             4-cyanoheptane with HCN and to 2-propyl pentanoic (valproic)
             acid by alkaline hydrolysis of the 4-cyanoheptane (Gennaro,
             1985).

        3.2  Chemical structure

             Molecular formula:
    
             Valproic acid          C8H16O2
             Sodium Valproate       C8H15NaO2
             Semisodium Valproate   C16H31NaO4
             Valproate Pivoxil      C14H26O4
             Valpromide             C8H17NO
    
             Molecular weight:
    
             Valproic acid           144.2
             Sodium Valproate        166.2
             Semisodium Valproate     310.4
             Valproate Pivoxil        258.4
             Valpromide               143.2
    
             Chemical names:
    
             Valproic acid
             2-Propylpentanoic acid
             2-Propylvaleric acid
             Di-n-dipropylacetic acid
    
             Sodium Valproate
             Sodium 2-propylvalerate
             Sodium 2-propylpentanoate
    
             Semisodium Valproate
             2-Propylvaleric acid-sodium 2-propylvalerate
             Sodium hydrogen bis(2-propylvalerate)
    
             Valproate Pivoxil 
             Hydroxymethyl 2-propylvalerate pivalate
    
             Valpromide
             Dipropylacetamide
             2-propylvaleramide
    
             (Reynolds, 1989; USP, 1990)

        3.3  Physical properties

             3.3.1  Colour

                    Colourless to pale yellow

             3.3.2  State/Form

                    Liquid-viscous liquid

             3.3.3  Description

                    It is slightly soluble in water (1.2 mg/mL);
                    fully soluble in acetone, chloroform, ether and methyl
                    alcohol.
    
                    (Ellenhorn & Barceloux, 1988; Reynolds, 1989)

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No data available.

             3.4.2  Storage conditions

                    Store in airtight containers and protect from
                    light.  Valproic acid capsules should be stored at 15
                    to 30°C and freezing should be avoided. (Reynolds,
                    1989; McEvoy, 1991).

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Antiepileptic preparation
                    Antiepileptic drug
                    Fatty acid derivative; antiepileptic

             4.2.2  Description

                    Valproic acid is used solely or in combination
                    with other anticonvulsants in the treatment of simple
                    (petit mal) and complex absence seizures.
    
                    Valproate may be effective against myoclonic and
                    atonic seizures in young children and considered by
                    some experts as the agent of choice.
                    (Gilman et al., 1990).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Oral
    
                    Initial dose of sodium valproate in the UK is 600 mg
                    daily in divided doses, increased every other 3 days
                    by 200 mg daily to a usual range of 1 to 2 g daily (20

                    to 30 mg/kg/day); further increase to a maximum of
                    2.5 g daily may be necessary if adequate control has
                    not been achieved.
    
                    In the USA, doses are expressed in terms of valproic
                    acid with an initial dose of 15 mg/kg/day increased at
                    one-week intervals by 5 to 10 mg/kg/day to a maximum
                    of 60 mg/kg/day.
    
                    The dose for valpromide is from 600 mg to 1800 mg
                    daily in divided doses.
    
                    Parenteral
    
                    Sodium valproate may be administered by slow
                    intravenous infusion or injection.  The suggested
                    initial dose is up to 10 mg/kg followed by further
                    doses as necessary, up to a total of 2.5 g/day.
                    (Reynolds, 1993).

             4.2.2  Children

                    Oral
    
                    A suggested initial dose for children weighing more
                    than 20 kg is 400 mg daily (irrespective of weight) in
                    divided dose, gradually increased until control is
                    achieved, with the usual range of 20 to 30 mg/kg/day;
                    children weighing less than 20 kg may be given a dose
                    of 20 mg/kg/day which may be increased to 40 mg/kg/day
                    in severe cases.  It has been recommended that the
                    dose of 40 mg/kg/day should only be exceeded in
                    patients where plasma concentration, clinical
                    chemistry and haematological parameters are being
                    monitored (Reynolds, 1993).

        4.3  Contraindications

             Valproic acid should not be used in patients with
             hepatic disease and substantial hepatic dysfunction.
    
             Children younger than 2 years and patients receiving multiple
             anticonvulsant therapy or those with congenital metabolic
             disorder or organic brain disease may be at particular risk
             of hepatotoxicity, thus valproic acid should be used with
             extreme caution; the benefits of seizure control must be
             weighed against the risks.
    
             Hypersensitivity to the drug is also a contraindication.
    

             Since the drug crosses the placental barrier and is also
             found in breastmilk, its use in pregnant women is
             contraindicated, however, there is no known effect on nursing
             infants.
    
             (Physician's Desk Reference, 1990)

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Valproic acid is administered orally either as a tablet,
             a syrup or a capsule.

        5.2  Inhalation

             No data available.

        5.3  Dermal

             No data available.

        5.4  Eye

             No data available.

        5.5  Parenteral

             May be given as slow intravenous injection or infusion
             in the form of sodium valproate powder 400 mg (provided with
             diluent).

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             The drug is well absorbed after oral ingestion. 
    
             The extent of availability (i.e. the percentage of an oral
             dose that reaches the arterial blood in an active form to
             produce pharmacological actions) is estimated at 100% (Gilman
             et al., 1990; Moffat, 1986).
    
             Tablets and syrup are rapidly absorbed from the
             gastrointestinal tract.  Blood concentrations of 50 to 100
             mg/mL may be reached at therapeutic dose levels.  Peak plasma
             levels occur from 15 to 60 minutes after ingestion of the
             syrup, and 1 to 4 hours after a single oral tablet dose. 

             After a meal, enteric-coated capsules are absorbed within 1
             to 4.5 hours with peak plasma levels reached at 3 to 7.5
             hours post-ingestion (McEvoy, 1991; Ellenhorn & Barceloux,
             1988).

        6.2  Distribution by route of exposure

             The apparent volume of distribution is about 0.2 L/kg. 
             The bound drug is restricted to the circulation and rapidly
             exchangeable extracelluar water.  The apparent volume of
             distribution of the free drug in the plasma is 1 L/kg which
             indicates some penetration and binding.
    
             Protein binding at therapeutic concentration is about 90%. 
             At higher blood concentration, protein binding decreases,
             thereby causing changes in the clearance and elimination.
    
             Valproic acid appears to localize in structures with the
             highest levels of gamma-aminobutyric acid degradative
             enzymes.  It is distributed mainly to the serum, liver,
             lungs, spleen, skeletal muscles, kidney and the gut.  The
             concentration of valproic acid detected in the CSF is
             approximately 10% that of the plasma.  Its concentration in
             the saliva is 0.5 to 4%.  It crosses the placental barrier
             and appears in breastmilk (1 to 10%).
    
             (Gilman et al., 1990; Ellenhorn & Barceloux, 1988; McEvoy,
             1991).

        6.3  Biological half-life by route of exposure

             A half-life of 7 to 15 hours (Gilman et al.,1990,
             estimate 14 hours) is observed in healthy normal individuals.
             It may be longer in elderly patients, patients with cirrhosis
             and neonates, and in epileptics on valproic acid alone.  The
             half-life is the same after a single or multiple doses. When
             other anticonvulsants are used with valproic acid, the mean
             half-life may be reduced.
    
             In children the half-life of valproic acid alone is 10  to 11
             hours; when other medications are added, half-life may be
             reduced to 8 to 9 hours.  Half-lives of up to 30 hours have
             been reported in overdosage.
    
             (Ellenhorn & Barceloux, 1988; McEvoy, 1991)

        6.4  Metabolism

             Valproic acid is metabolized principally in the liver by
             the beta and omega oxidation.  There is no evidence that it
             can enhance its own metabolism, but metabolism may be
             enhanced by other drugs which induce hepatic microsomal
             enzymes.
    

             More than 10 metabolites have been identified in human blood
             and urine, but only 2-propyl 2-pentanoic acid (2-en-VPA) has
             been shown to accumulate in the brain and is 1.3 times more
             potent than its parent compound and it contributes
             significantly to the anti-convulsant effect of chronically
             administered valproic acid.

        6.5  Elimination and excretion

             The total systemic clearance of the drug from plasma is
             0.11 mL/min/kg. About 1.8% per cent of the administered dose
             is excreted unchanged in the urine of a healthy young adult
             (Gilman et al., 1990).
    
             Valproic acid is eliminated by first order kinetics. Plasma
             clearance after a therapeutic dose is 5 to 10 mL/min and is
             independent of liver blood flow. The free drug is cleared
             much more rapidly about 77 mL/min.  Excretion occurs
             partially in the form of ketone bodies (Ellenhorn &
             Barceloux, 1988).
    
             Metabolites are excreted in the urine as unchanged valproic
             acid 1 to 3%; valproic acid glucuronide 20%; 3-oxovalproic
             acid 3 to 60% and omega oxidation products 2 to 30%. 
             Elimination also occurs by faecal excretion 2 to 3% and in
             expired air.  About 7% of the dose undergoes enterohepatic
             recirculation - results of studies in rats (Ellenhorn &
             Barceloux, 1988; Reynolds, 1989; McEvoy, 1991).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    No data available.

             7.1.2  Pharmacodynamics

                    The mechanism of action of valproic acid is
                    unknown.  Effects of the drug may be related, at least
                    in part, to increased brain concentrations of the
                    inhibitory neurotransmitter GABA.  Animal studies have
                    shown that valproic acid inhibits GABA transferase and
                    succinic aldehyde dehydrogenase, enzymes which are
                    important for GABA catabolism.  Results of one study
                    indicate the drug inhibits neuronal activity by
                    increasing potassium conductance.  In animals,
                    valproic acid protects against seizure induced by
                    electrical stimulation, as well as those induced by
                    pentylenetetrazol (McEvoy, 1991).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Toxic effects are frequently
                             associated with daily doses of over 1,800 mg
                             per day and blood levels of over 100 mg/mL.
                             Unconsciousness occurs when more than 200
                             mg/kg has been ingested.  Death has been
                             associated with blood levels of 1970 mg/mL
                             and recovery at blood levels at 218 mg/mL. 
                             However, plasma concentration and clinical
                             effects are not correlated sufficiently
                             closely to be of value clinically (Ellenhorn
                             & Barceloux, 1988).

                    7.2.1.2  Children

                             In a study of 88 paediatric patients
                             receiving sodium valproate monotherapy, side
                             effects were noted in 71 patients and
                             although average doses in these patients were
                             significantly higher than in the 17 patients
                             with no side effects, no difference in plasma
                             concentration was noted.  Behavioural
                             alterations, digestive disorders, and
                             neurological changes were the common side
                             effects observed.  None of the children
                             showed hepatic or pancreatic dysfunction
                             except for 2 cases who had transient increase
                             in their transaminases (Reynolds, 1989).

             7.2.2  Relevant animal data

                    LD50 oral (rats) (valproic acid) 670
                    mg/kg
    
                    LD50 oral (mice) (sod. valproate) 1700 mg/kg
    
                    (Budavari, 1989)
    
                    In 2-year rat and chronic mouse studies using dosages
                    of 80 to 170 mg/kg/day, an increased incidence of
                    subcutaneous fibrosarcoma occurred in male rats at the
                    higher dosage level and a dose-related trend for an
                    increased incidence of benign pulmonary adenomas was
                    observed in male mice.  The importance of these
                    findings to humans is not known (McEvoy, 1991).

             7.2.3  Relevant in vitro data

                    No relevant data available.

        7.4  Teratogenicity

             Safe use of valproic acid during pregnancy has not been
             established.  Adverse foetal effects have been observed in
             reproduction studies in rats and mice.  Although several
             reports suggest an association between the use of valproic
             acid in pregnant epileptic women and an increased incidence
             of birth defects (particularly neural tube defects) in
             children born to these women, a causal relationship remains
             to be established (McEvoy, 1991).

        7.5  Mutagenicity

             Studies to date have not shown any evidence of mutagenic
             potential for the drug (McEvoy, 1991).

        7.6  Interactions

             Phenobarbital levels increase when valproic acid is
             given concomitantly, enhancing sedative effects.  Mechanism
             is unknown.  Phenobarbital dose should be reduced.
    
             Carbamazepine serum concentration is increased when valproic
             acid is added to the treatment regimen.  This is largely due
             to an increase in the carbamazepine epoxide level.
    
             Phenobarbital, primidone, phenytoin and carbamazepine may
             produce enzyme inducing effects that can lower the half life
             of valproic acid.
    
             Valproic acid increases the half life of levodopa.
    
             Valproic acid potentiates the CNS depressant effects of
             alcohol.
    
             Administration of clonazepam and valproic acid has been
             reported to produce absence status epilepticus.
    
             Valproic acid inhibits the secondary phase of platelet
             aggregation reflected in an altered bleeding time.  Caution
             is recommended when it is administered with acetylsalicylic
             acid or warfarin.
    
             Cimetidine and ranitidine slightly increase the half life of
             valproic acid when they are added in the treatment regimen. 
             They do not affect volume of distribution or clearance of
             valproic acid.
    

             Valproic acid may potentiate the effects of MAO inhibitors
             and other anti-depressant drugs.  Dosage reduction of these
             drugs may be necessary when given with valproic acid.
    
             Serum protein binding of diazepam is competitively inhibited
             by valproic acid.
    
             (Ellenhorn & Barceloux, 1988; Reynolds, 1989; Griffin, 1988).

        7.7  Main adverse effects

             Gastrointestinal
    
             The most frequent effects of valproic acid are nausea, and
             vomiting.  These adverse effects are usually transient,
             rarely require discontinuation of the drug, and can be
             minimized by administering the drug with meals or by
             gradually increasing the dose. Hypersalivation, anorexia with
             weight loss, increased appetite with weight gain, abdominal
             cramps, diarrhoea and constipation have been reported in
             patients receiving valproic acid.  Acute pancreatitis has
             also been reported (McEvoy, 1991).
    
             These transitory gastrointestinal disturbances are dose-
             related and occurs approximately in 16% of patients treated
             with the drug.
    
             Nervous system
    
             Sedation and drowsiness may occur with valproic acid therapy,
             especially in patients receiving other anticonvulsants.  Some
             patients have reported increased alertness during valproic
             acid therapy.  Rarely paraesthesia, ataxia, headache,
             nystagmus, diplopia spots before the eyes, tremors,
             asterixis, dysarthria, dizziness and incoordination have been
             reported.  Anxiety, confusion, emotional upset, mental
             depression, hallucinations and other behavioural disturbances
             have been reported in a few children receiving valproic acid
             (McEvoy, 1991).
    
             Hepatic
    
             Minor elevation in serum transaminases and lactate
             dehydrogenase occur frequently in patients receiving valproic
             acid.  Occasionally, increases in serum bilirubin
             concentrations and abnormal changes in other hepatic
             functions may reflect potentially serious hepatoxicity
             (McEvoy, 1991).
    
             Prodromal symptoms include anorexia, vomiting followed by
             jaundice, ascites then hepatic encephalopathy eventually by
             death after a few weeks.
    

             Metabolic
    
             Hyperammonaemia with or without lethargy or coma may occur in
             patients receiving valproic acid and may occur in the absence
             of abnormal liver function.  Hyperglycaemia has also been
             reported in valproic acid therapy (McEvoy, 1991).
    
             Haematological
    
             Valproic acid inhibits the secondary phase of platelet
             aggregation and may prolong bleeding time.  Thrombocytopenia,
             petechiae, bruising, haematoma, epistaxis, otorrhagia,
             lymphocytosis, leucopenia, eosinophilia, decreased fibrinogen
             levels, anaemia and bone marrow depression have been reported
             (McEvoy, 1991).
    
             Dermatological
    
             Transient alopecia, curliness of the hair, generalized
             pruritus, photosensitivity and erythema multiforme have been
             reported in valproic acid therapy (McEvoy, 1991).
    
             Others
    
             Rare adverse effects include muscular weakness, enuresis and
             fatigue, irregular menses and secondary amenorrhoea.  Altered
             thyroid function has been reported but the clinical
             significance is not known (McEvoy, 1991; Physician's Desk
             Reference, 1990).

    8.  TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

             Sample collection
    
             Blood collected on EDTA for plasma sample.  Other samples
             used are serum, urine and breastmilk.  Blood samples should
             be collected 1 to 4 hours post-ingestion.
    
             Biomedical analysis
    
             Gas chromatography mass spectrophotometry is a useful and
             accurate method of measuring valproic acid and its
             metabolites.
    
             Toxicological analysis
    
             Measuring blood levels of valproic acid and its metabolites
             is not considered to be of practical assistance in the
             clinical management of valproic acid poisoning since plasma
             concentrations and clinical effects do not correlate closely.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Toxic effects are frequently associated with
                    dose levels over 1,800 mg per day and blood levels of
                    >100 mg/mL.  Unconsciousness occurs when 200 mg/kg
                    has been ingested (Ellenhorn & Barceloux, 1988).

             9.1.2  Inhalation

                     No data available.

             9.1.3  Skin exposure

                    No data available.

             9.1.4  Eye contact

                    No data available.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Hepatoxicity associated with valproic acid use
                    manifests itself in 3 ways:
    
                    Asymptomatic elevation in serum concentration of liver
                    enzymes (fairly common).
    
                    Hyperammonaemia associated with lethargy, vomiting,
                    stupor or coma but generally not accompanied with
                    hepatocellular damage.
    
                    Acute hepatoxicity that may terminate fatally, usually
                    seen in children and adolescents during the first six
                    months of therapy.  Its frequency is 1 in 5,000
                    children.  Hepatic failure has been observed
                    displaying a Reye's syndrome like illness (Ellenhorn &
                    Barceloux, 1988).

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Acute valproic acid poisoning is observed relatively
             infrequently compared to other anticonvulsants.  Reports have
             shown that in most patients the poisoning follows a benign
             course.  Death is rare but if it occurs it results from
             cardio-pulmonary arrest secondary to hepatic failure.
    
             Hepatoxicity following chronic use may be asymptomatic or may
             have a fulminant course (Ellenhorn & Barceloux, 1988).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension

             9.4.2  Respiratory

                    Depression; arrest in fulminant course.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Patient is usually drowsy, may be
                             apathetic and withdrawn, stuporous, confused,
                             restless, hyperactive.  Rarely seizures,
                             myoclonic movements, unconsciousness, coma. 
                             No dysarthria, nystagmus or ataxia. 
                             Asterixis.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Muscle weakness.

             9.4.4  Gastrointestinal

                    Nausea, vomiting, diarrhoea and pancreatitis.

             9.4.5  Hepatic

                    Centrilobular necrosis, hepatic failure.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Nocturnal enuresis.

                    9.4.6.2  Others

             9.4.7  Endocrine and reproductive systems

                    Irregular menses and secondary amenorrhoea.
    
                    Altered thyroid function test (clinical significance
                    is not known).

             9.4.8  Dermatological

                    Macular pruritic rashes.

             9.4.9  Eye, ear, nose, throat

                    Pupils may pinpoint and sluggishly reactive to
                    light. 

                    Tablets may cause irritating sensation in the throat
                    if accidentally chewed.

             9.4.10 Haematological

                    Petechiae, bruising, haematoma, epistaxis.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Metabolic acidosis has been
                             reported (Dupuis et al., 1990).

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hypocalcaemia (Dupuis et al.,
                             1990).

                    9.4.12.3 Others

                             Hyperammonaemia with or without
                             lethargy, or coma with or without deranged
                             liver function.

             9.4.13 Allergic reactions

                    Pruritic rash

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy
    
                    Increased risk of neural tube defects (spina bifida)
                    if used during first trimester.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Establish the airway and breathing and evaluate
             circulatory status.  If respiration is depressed on
             admission, then perform endotracheal intubation and support
             ventilation using appropriate mechanical device.  Supportive
             treatment is the mainstay in the management of valproic acid
             overdose.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Supportive treatment is the mainstay of valproate
             overdose.  Maintenance of adequate urine output and
             discontinuation of all anticonvulsive drugs and all hepatic
             enzyme inducers will be sufficient for rapid recovery within
             24 to 72 hours.  Hepatic and pancreatic function should be
             monitored by appropriate biochemical investigations.
    

             The drug should be discontinued and seizures should be
             managed by the use of intravenous diazepam (0.1 to 0.3 mg/kg)
             to a maximum of 20 mg in an adult.  This may be repeated in
             10 to 20 minutes if required.
    
             If patients are stuporous, somnolent, or drowsy, but
             otherwise have normal vital signs and liver function tests,
             then simple observation with good nursing care and supportive
             therapy for 24 to 72 hours in a hospital intensive care unit
             may be sufficient.

        10.3 Decontamination

             Emesis with syrup of ipecac is not ordinarily advisable
             since although the patient may be awake on admission, he/she
             may deteriorate rapidly and become somnolent or stuporous and
             aspiration is possible.
    
             Gastric lavage may be considered.  However, if the patient is
             comatose, convulsing, or has lost the gag reflex,
             endotracheal intubation is needed.  This procedure  may be of
             limited value if the drug was taken in syrup form because of
             the very rapid absorption of the drug.
    
             Activated charcoal (adults, 50 to 100 g; children, 15 to 30
             g) may adsorb valproate still in the gut after the overdose. 
             Cathartics are no longer recommended.

        10.4 Enhanced elimination

             No systematic studies are available to support the
             usefulness of forced alkaline diuresis, haemodialysis,
             peritoneal dialysis, exchange transfusion, or haemoperfusion. 
             The high degree of protein binding, minimal amount of
             unchanged drug excreted through the kidneys, and short
             spontaneous course to recovery with supportive treatment
             alone would tend to preclude the need for such
             measures.

        10.5 Antidote treatment

             10.5.1 Adults

                    No data available.

             10.5.2 Children

                    No data available.

        10.6 Management discussion

             The use of naloxone at a dose of 0.01 mg/kg
             intravenously given in patients who are unconscious following
             ingestion of large amount of valproic acid has been reported
             to cause improvement in a 19-month-old male who ingested 2.25
             g of valproic acid (serum level of 185 mg/ml) and presented
             as unconsciousness with poorly reactive pupils three hours
             post-ingestion.  This treatment, however, has yet to be
             confirmed.  Naloxone has been reported to reverse the CNS
             depressant effects of valproic acid overdosage and
             theoretically it could also reverse the anti-epileptic
             effects of valproic acid, therefore naloxone should be used
             with caution (Ellenhorn & Barceloux, 1988; Physician's Desk
             Reference, 1990).

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1
    
             A 16-year-old epileptic female ingested 30 g of enteric
             coated sodium valproate tablets and 5 hours later appeared
             somnolent, though other physical examination findings appear
             to be within normal.  The serum valproate levels was 689.5
             mg/mL 6 hours after ingestion.  She was treated with gastric
             lavage and activated charcoal and awoke 12 hours post-
             ingestion (Ellenhorn & Barceloux, 1988).
    
             Case 2
    
             A 24-year-old female on 2.2 g/day of sodium valproate was
             stuporous, withdrawn and confused and suffered from visual
             hallucinations with a serum valproic acid level of 113 mg/mL.
             Dose was adjusted to 1.8 g/day and symptoms were resolved
             (Ellenhorn & Barceloux, 1988).
    
             Case 3
    
             A 15-year-old girl ingested an unknown amount of sodium
             valproate, became comatose and died of cardio-respiratory
             arrest at the 20th hour with a plasma level of 1,914 mg/L
             (Ellenhorn & Barceloux, 1988).
    
             Case 4
    
             One adult who ingested 36 g of valproic acid in addition to
             1 g of phenobarbital and 300 mg of phenytoin became deeply
             comatose 4 hours post-ingestion of the drugs.  The patient
             recovered following supporting therapy (McEvoy, 1991).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Drugs should not be used in patients with hepatic
             disease or significant hepatic dysfunction.  It should not be
             used in pregnant women.  It should be used with caution in
             children below 2 years old, patients with multiple anti-
             epileptic therapy, congenital metabolic disorders, and those
             with organic brain disease.

        12.2 Others

             No data available.

    13. REFERENCES

        Budavari S ed. (1989) The Merck index, an encyclopedia of
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,
        Merck and Co., Inc.
    
        Dupuis RL, Lichtman SIV, & Pollack GM (1990) Acute valproic
        overdose: Clinical course and pharmacokinetic disposition of
        valproic acid and metabolites. Drug Safety, 5(1) 65: 71.
    
        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis
        and treatment of human poisoning. New York, Elsevier Science
        Publishing Co, Inc, p 261-265.
    
        Gennaro AR ed. (1985) Remington's pharmaceutical sciences 17th ed.
        Easton, Pennsylvania, Mack Publishing Company, p 1082.
    
        Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New
        York, Pergamon Press, pp 450-453, 1714.
    
        Griffin JP ed.(1988) A Manual of Adverse Drug Interactions, 4th
        ed. (1988) Butterworth and Co (Publishers) Ltd, p 173.
    
        McEvoy GK ed. (1991)  American hospital formulary service, drug
        information. Bethesda, MD, American Society of Hospital
        Pharmacists, p 1147.
    
        Moffat AC ed.  (1986) Clarke's isolation and identification of
        drugs in pharmaceuticals, body fluids, and post-mortem material.
        2nd ed. London, The Pharmaceutical Press, p 1059.
    
        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 29th
        ed. London, The Pharmaceutical Press, p 413.
    
        Physician's Desk Reference (1990) 44th ed. Ordell NJ, Medical
        Economics.
    

        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th
        ed. London, The Pharmaceutical Press. pp 311-313.
    
        United States Pharmacopeia, 22nd rev. The National formulary 17th
        ed. (1990)  Rockville MD, United States Pharmacopeial Convention, 
        p 1400.

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author: Dr M Mercedes Maat
        National Poisons Control and Information Service
        University of the Philippines
        College of Medicine
        Philippine General Hospital
        Ermita
        Manila 1000
        Philippines
    
        Fax 63-2-50 10 78
    
        Date: December 1991
    
        Reviewer: Dr Tempowski, London Centre
    
        Date: February 1995
    
        Peer review:  Cardiff, United Kingdom, March 1995 (Drs Pronczuk,
        Hartigan-Go, Tempowski, & Ten Ham).
    
        Editor: Dr M. Ruse (October, 1997)