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)