Carbamazepine
| 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 Main brand names, main trade names |
| 1.6 Main manufacturers, main 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 |
| 4.1.2 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 by route of exposure |
| 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 |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL 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 exposure |
| 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 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 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 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
CARBAMAZEPINE
International Programme on Chemical Safety
Poisons Information Monograph 100
Pharmaceutical
1. NAME
1.1 Substance
Carbamazepine
1.2 Group
Nervous system, antiepileptics, antiepileptics,
carboxamide derivatives.
1.3 Synonyms
G 32883
1.4 Identification numbers
1.4.1 CAS number
298-46-4
1.4.2 Other numbers
ATC code: NO3AF
1.5 Main brand names, main trade names
Biston, Calepsin, Convulsine, Epitol, Finlepsin,
Hermolepsin, Karbamazepine, Lexin, Mazepine, Neuritol,
Neurotol, Neurotop, Nordotol, Servimazepine, Sirtal,
Stazepine, Tegretal, Tegretol, Telesmin, Temporol, Teril,
Timonil, Trimonil Retard (Index Nominum, 1987).
1.6 Main manufacturers, main importers
Geigy (importer): Argentine, Australia, Belgium,
Canada, Denmark, France,
Italy, Netherlands, Norway,
Portugal, South Africa, Spain,
Switzerland, UK, USA.
Spofa: Prague, Czech Republic
Protea: Glebe, NSW 2037, Australia
Arzneitmittelwerk: 8122 Radebeul, Dresden,
Germany
Lääke: 20101 Abo, Finland
Fujinawa: Tokyo, Japan
ICN: Montreal, Quebec, Canada
Eczacoibasoi: Istanbul, Turkey
Farmos Group: 20101, Turku, Finland
Servipharm: 4002, Basel, Switzerland
Polfa: Warszawa, Poland
Orion: 00510, Helsinki, Finland
Taro: Haifa, Israel
Desitin: 2000 Hamburg, Germany
(Index Nominum, 1992/93; Reynolds, 1996)
2. SUMMARY
2.1 Main risks and target organs
The principle toxic effects of carbamazepine are
depression in level of consciousness, convulsions and ECG
changes.
2.2 Summary of clinical effects
Cardiovascular tachycardia, hypotension, conduction
disorders.
Respiratory: central respiratory depression.
Eyes: mydriasis, nystagmus.
Neurological: depressed level of consciousness, ataxia,
initial hyperreflexia followed by hyporeflexia,
ophisthotonus, agitation, disorientation, tremor, involuntary
movements, convulsions.
Gastrointestinal: nausea and vomiting
2.3 Diagnosis
The diagnosis should be considered in any patient with
access to carbamazepine who presents with a depressed level
of consciousness. The presence of seizure activity or ECG
changes makes the diagnosis more likely. The diagnosis is
confirmed in laboratory by measurement of toxic serum
carbamazepine levels.
2.4 First aid measures and management principles
Management is supportive. Particular attention is
directed towards maintenance of the airway and ventilation
and control of seizures. Other clinical features that may
require treatment include hypotension, hypothermia and
hyponatraemia.
The administration of oral activated charcoal to prevent
furhter absorption is indicated once the airway is secured.
Repeat doses of activated charcoal are effective in enhancing
elimination of carbamazepine.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic.
3.2 Chemical structure
Carbamazepine is an iminostilbene derivative that is
related chemically to the tricyclic antidepressants and is
structurally similar to phenytoin.
Chemical name: 5H-Dibenz[b,f]azepine-5-carboxamide;
5-carbamoyl-5H-dibenz[b,f]azepine
Molecular formula of carbamazepine: C15H12N2O.
Molecular weight: 236.26.
3.3 Physical properties
3.3.1 Colour
White to yellowish-white
3.3.2 State/form
Crystal
3.3.3 Description
Almost odourless, carbamazepine can either have
no taste or be slightly bitter. It is practically
insoluble in water and ether but soluble in acetone,
alcohol, carbon tetrachloride, chloroform,
dimethylformamide dioxane, and propylene glycol
Melting point: 190 to 193°C.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Storage conditions
Store in airtight containers, below 40°C and,
preferably, between 15 and 30°C, and away from light
(Budavari, 1996).
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
Carbamazepine has both antiepileptic and
psychotropic properties. Accepted indications
include:
Epilepsy: Generalized tonic-clonic (grand mal) and
partial (focal) seizures.
Pain syndromes: Trigeminal neuralgia and
glossopharyngeal neuralgia.
Manic depressive illness unresponsive to lithium.
(Reynolds, 1996)
4.2 Therapeutic dosage
4.2.1 Adults
The dose of carbamazepine should be adjusted
according to the needs of each patient. The
therapeutic plasma concentration is 4 to 12 mg/L (20
to 50 mmol/L). The total daily dose should preferably
be given as three or four divided doses.
Epilepsy: the initial oral dose is 200 mg twice a day,
increased by 200 mg at weekly intervals until the
patient responds. The maintenance dose is 800 mg to
1200 mg/day, maximum 1600 mg/day.
Neuralgia: the initial dose is 100 mg twice a day,
with an additional 200 mg every other day until pain
is relieved. The maintenance dose is 200-1200 mg
daily, maximum 1600 mg/day.
Psychosis: initial doses are 400-600 mg per day, to a
maximum of 1.6 g/day as needed and tolerated.
(Reynolds, 1996).
4.2.2 Children
The safety and efficacy of carbamazepine have
not been established in children less than
6-years-old. Some doctors give an initial dosage of
5 mg/kg daily, which may be increased to 10 to 20
mg/kg daily; the following doses can be used as
guidelines:
less than 1 year old: 100 to 200 mg/day
1 to 5 years old: 200 to 400 mg/day
5 to 10 years old: 400 to 600 mg/day
10 to 15 years old: 600 to 1000 mg/day
The dosage should not exceed 1 g/day (Reynolds, 1996)
4.3 Contraindications
Hypersensitivity to carbamazepine
Atrioventricular conduction defects (unless paced)
Aplastic anaemia
Acute intermittent porphyria
Caution should be exercised in administering carbamazepine to
patients with history of cardiac, hepatic, haematologic or
renal disease or with raised intraocular pressure.
Carbamazepine should not be given with monoamine oxidase
inhibitors or within two weeks of its cessation.
(Reynolds, 1996; Morant & Ruppaner, 1997).
5. ROUTES OF EXPOSURE
5.1 Oral
Carbamazepine is given orally in tablet or syrup form.
Carbamazepine intoxication occurs from ingestion.
5.2 Inhalation
Not relevant.
5.3 Dermal
Not relevant.
5.4 Eye
Not relevant.
5.5 Parenteral
No data available.
5.6 Other
Rectal.
6. KINETICS
6.1 Absorption by route of exposure
Absorption of carbamazepine from the gastrointestinal
tract is slow and erratic but almost complete. Oral
absorption is more rapid on a full stomach and slower from
tablets than from solution.
Peak plasma concentrations usually occur within 4 to 12 hours
of oral aministration. However, they may be delayed up to
24 hours after overdose.
6.2 Distribution by route of exposure
Carbamazepine is 76% bound to plasma proteins. It is
rapidly and uniformly distributed throughout the body.
Carbamazepine epoxide, the principal active metabolite, is
50% bound to plasma proteins (Rane et al., 1976). It is
probably subject to enterohepatic circulation (Laffey &
Guzzardi, 1983).
Carbamazepine crosses the blood-brain barrier and the
placenta, accumulates in fetal tissues, and is distributed
into breast milk at concentrations about 60% those of
maternal plasma. The drug has been detected in cerebrospinal
fluid in concentrations approximately 15% those of serum.
The volume of distribution is 0.79 to 1.4 L/kg increasing
after long-term treatment to 0.96 to 2.07 L/kg (Westenberg et
al., 1978).
6.3 Biological half-life by route of exposure
Carbamazepine induces its own metabolism, so that the
plasma half-life ranges from 18 to 60 hours following a
single dose, and from 10 to 35 hours during chronic therapy.
The half-life is shorter in children than in adults.
6.4 Metabolism
Carbamazepine can induce its own metabolism. It is
metabolized in the liver to an epoxide and several other
metabolites. A major metabolic pathway is oxidation by
microsomal enzymes to form carbamazepine 10, 11 epoxide. This
is an active compound and is almost completely metabolized to
an inactive metabolite, trans-10,11-dihydroxy-10,11-
dihydrocarbamazepine (trans-carbamazepine-diol), and excreted
in the urine mainly in an unconjugated form.
Carbamazepine is also inactivated by conjugation and
hydroxylation.
6.5 Elimination by route of exposure
Carbamazepine and its metabolites are excreted in the
urine. After oral administration, 72% of the dose is
excreted in the urine and 28% is eliminated in the faeces.
Only about 1 to 3% of the drug is excreted unchanged in the
urine.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Signs of toxicity appear at plasma
concentrations above the upper limit of the
therapeutic level (12 mg/L or 50 µmol/L) and are due
to the effects on the central nervous system (Salcman
& Pippenger, 1975), gastrointestinal irritation
(Lehrman & Bauman, 1981), arrhythmogenic properties
(Beerman et al., 1975) and its anti-diuretic action
(Stevens, 1977).
7.1.2 Pharmacodynamics
In cats, carbamazepine depresses thalamic
potential and bulbar and polysynaptic reflexes. Its
capacity to increase discharges of noradrenergic
neurones may contribute to its anti-epileptic actions
(Rall & Schleifer, 1985). Although the effects of
carbamazepine in animals and humans resemble those of
phenytoin, there are several important differences.
For example, carbamazepine is more effective than
phenytoin in reducing stimulus-induced discharges in
the amygdala of stimulated rats.
The mechanisms responsible for these effects are not
clearly understood. Carbamazepine seems to act by
reducing polysynaptic responses and blocking
post-tetanic potentiation (Drug Facts & Comparisons,
1985).
Its efficacy in neuralgia may result from the
reduction of excitatory synaptic transmission in the
spinal trigeminal nucleus because it increases the
latency of trigeminal neuronal response and decreases
the number of neuronal discharges. Carbamazepine
10,11-epoxide, the major metabolite of carbamazepine,
also has considerable activity against neuralgia.
The antidiuretic effects of carbamazepine are a
consequence of reduced plasma concentrations of
anti-diuretic hormone.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Of 22 adults requiring admission to
hospital following carbamazepine overdose,
the mean ingestion was 12 g (range 1.6 to 45
g). All survived. (Seymour, 1993).
7.2.1.2 Children
Children appear more likely to
suffer seizures and less likely to develop
electrocardiographic abnormalities (Bridge &
Norton, 1994).
7.2.2 Relevant animal data
In animals, the lethal concentrations (oral LD50) are:
Mice: 3750 mg/kg; Rats: 4025 mg/kg
(Budavari, 1996.
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
Carbamazepine in doses of 25, 75, and 250 mg was given
to Sprague-Dawley rats for two years. It caused a
dose-related increase in the incidence of hepatocellular
tumours in female rats and benign interstitial cell adenomas
in the testes of males. The significance of these findings
for humans is not known (PDR, 1988). There have been no
reports of tumorigenic effects in humans.
7.4 Teratogenicity
Carbamazepine is classified as category "C". That is to
say, studies in animals have revealed adverse effects on the
fetus but there are no controlled studies in women. Minor
malformations such as those seen with fetal hydantoin
syndrome have been observed with carbamazepine monotherapy.
However, carbamazepine has been recommended as the drug of
choice in women at risk of pregnancy who require
anticonvulsant therapy for the first time (Briggs et al.,
1986).
7.5 Mutagenicity
Bacterial and mammalian mutagenicity studies using
carbamazepine have shown no evidence of mutagenicity.
7.6 Interactions
Antibacterials
Co-administration of isoniazid or erythromycin can cause
significant increases in serum carbamazepine concentrations
and lead to toxicity (Valsalan & Cooper, 1982; Wright et al.,
1982; Wong et al., 1983; Mitsch, 1989).
Antidepressants
Co-adminstration of fluoxetine or fluvoxamine may result in
reduced serum carbamazepine concentrations (Pearson, 1990;
Fritz et al., 1991). Serotonin syndrome has been reported
with co-administration of carbamazepine and fluoxetine
(Brœsen & Kragh-Sœrensen, 1993). Severe neurotoxicity has
been associated with co-administration of carbamazepine and
lithium (Andrus, 1984; Chaudry & Waters, 1983).
Carbamazepine is chemically related to the tricyclic
antidepressants and should not be given to patients who are
sensitive to these drugs.
Antiepileptics
Phenytoin lowers serum carbamazepine by induction of
metabolism (Christiansen & Dam, 1973). Carbamazepine may in
turn lower serum phenytoin concentrations (Hansen et al.,
1971). Phenobarbitone reduces serum concentrations of
carbamazepine without loss of seizure control (Cereghino et
al., 1975).
Benzodiazepines
Long-term carbamazepine therapy may result in enhanced
metabolism of benzodiazepines due to enzyme induction
(Dhillon & Richens, 1981; Lai et al., 1978).
Calcium channel blockers
Verapamil and diltiazem can inhibit carbamazepine metabolism
to such an extent so as to result in clinical neurotoxicity
(Macphee et al., 1986; Brodie & Macphee, 1986).
7.7 Main adverse effects
The adverse effects that occur most frequently during
early treatment are dizziness, drowsiness, lightheadedness,
unsteadiness, ataxia, nystagmus, nausea, and vomiting. Their
severity and incidence may be minimised by starting therapy
with a low dose which is then gradually increased.
The most severe adverse reactions involve the haemopoietic
system, the skin, and the cardiovascular system. They
are:
Haemopoietic system
Leucocytosis, leucopenia, agranulocytosis, eosinophilia,
purpura, aplastic anaemia, and thrombocytopenia. These
reactions are rare but can be serious. Early detection of
haematological toxicity is very important because aplastic
anaemia and thrombocytopenia can be fatal.
Skin
Pruritic and erythematous rashes, urticaria, Stevens-Johnson
syndrome, exfoliative dermatitis, erythema multiforme or
erythema nodosum, photosensitivity reactions, alterations in
pigmentation, and aggravation of systemic lupus
erythematous.
Alopecia, diaphoresis, and toxic epidermal necrolysis may
also occur.
Cardiovascular system
Congestive heart failure, oedema, aggravation of
hypertension, hypotension, syncope and collapse, primary and
recurrent thrombophlebitis, aggravation of coronary artery
disease, arrhythmias and AV block, hyponatraemia and water
intoxication.
Other
Genitourinary, metabolic, hepatic, and other reactions are
rare. They include lymphadenopathy, urinary frequency, acute
urinary retention, albuminuria, glycosuria, elevated blood
urea nitrogen level, microscopic deposits in the urine,
impotence, cholestatic and hepatocellular jaundice, fever and
chills, myalgia and arthralgia, leg cramps, conjunctivitis,
and paraesthesiae.
(Reynolds, 1996)
8. TOXICOLOGICAL 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
Plasma carbamazepine concentration.
This should be repeated at regular intervals
until it is falling.
Serum electrolytes.
Renal function tests.
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
Arterial blood gases in the ventilated patient
or where pulmonary aspiration is suspected.
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
In general the peak plasma carbamazepine
concentration correlates well with the clinical
severity of the poisoning. The peak concentration may
be delayed up to 30 hours. A single plasma
carbamazepine concentration may not correlate very
well with the severity of intoxication.
Therapeutic plasma levels of carbamazepine are from 4
to 10 mg/L. Acute ingestion of greater than 10 mg/kg
can produce a plasma level above this range.
Ataxia and nystagmus may occur with levels greater
than 12 mg/L
In one series of adult admissions, a peak plasma
carbamazepine concentration above 170 mmol/L (40 mg/L)
was associate with an increased risk of serious
complications such as coma, seizures, respiratory
failure and cardiac conduction defects. In those
patients with a peak concentration less than 170
mcmol/L, only one was comatose and none had any of the
other severe symptoms (Hojer et al., 1993).
Peak plasma carbamazepine concentrations have been
reported as ranging from 13.5 to 57.7 mg/L (57 to 244
mmol/L) in symptomatic children (Macnab et al., 1993).
In ten severely poisoning children (coma, convulsions,
hypotension and respiratory depression), the mean
plasma carbamazepine concentration was 50 mg/L (213
mmol/L) with a range of from 333.7 to 80.9 mg/L (143
to 343 mmol/L) ( Tibbals, 1992).
8.4 Other biomedical (diagnostic) investigations and their
interpretation
A chest x-ray in indicated where there is coma or
convulsions have occurred to look for evidence of pulmonary
aspiration.
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
The first signs of acute intoxication begin 1
to 3 hours after an overdose but may be delayed;
presenting symptoms usually include disturbances of
the central nervous system, and cardiovascular and,
less frequently, anticholinergic signs and symptoms.
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
Not relevant.
9.1.4 Eye contact
Not relevant.
9.1.5 Parenteral exposure
No data available.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
Effects of chronic intoxication include:
dizziness, drowsiness, and disturbances of cerebellar
and oculomotor function (ataxia, nystagmus, and
diplopia), cardiac arrhythmias, congestive heart
failure (rarely), bone marrow failure including
aplastic anaemia, cholestatic and hepatocellular
jaundice, dermatological reactions,
tubulo-interstitial nephritis, water retention, and
hyponatraemia.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
Not relevant.
9.2.4 Eye contact
Not relevant.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Following overdose, peak plasma carbamazepine
concentrations and clinical effects are usually delayed by 4
to 8 hours and may be delayed up to 24 hours. The degree of
CNS depression is characteristically "cyclical" with sudden
improvements and deteriorations.
Severe intoxication is characterised by one or more of the
following features: coma, seizures, hypotension, or cardiac
conduction defects.
Moderate intoxication is characterized by a depression in the
level of consciousness not required intubation and without
other severe effects.
Minor intoxications may be asymptomatic or exhibit the
following features: minor drowsiness, nystagmus, ataxia or
dysarthria.
The prognosis for carbamazepine poisoning is usually good
even for severe cases provided that appropriate supportive
care is instituted in a timely fashion. Where death does
occur, it is not usually a direct result of carbamazepine
poisoning but secondary to being pulmonary aspiration of
gastric contents occuring during convulsions (Bates et al.,
1997).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
After acute ingestion, sinus tachycardia is
relatively common. Minor ECG abnormalities, including
prolongation of the PR, QRS and QT intervals, are less
common, do not correlate with serum carbamazepine
concentration and rarely result in clinically
significant dysrhythmias. Mild self-limiting
hypotension may be observed (Apfelbaum et al., 1995).
Minor ECG abnormalities may also occur in the context
of chronic carbamazepine therapy.
9.4.2 Respiratory
Severe acute intoxication leads to coma with
associated respiratory depression.
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
The most prominent feature of
carbamazepine toxicity is depression in the
level of consciousness. In one series, this
was observed in 100% of cases (Seymour,
1993). Fluctuation in the level of
consciousness with sudden deterioration or
improvement is said to be characteristic and
may reflect irregular absorption or
enterohepatic circulation of carbamazepine
(Durelli et al., 1989) Other observed
neurological features include paradoxical
seizures, mydriasis, abnormal muscle tone and
tendon reflexes, ataxia, nystagmus and
ophthalmoplegia (Seymour 1993).
Chronic carbamazepine intoxication can result
in headaches, diplopia and ataxia.
9.4.3.2 Peripheral nervous system
No significant effects.
9.4.3.3 Autonomic nervous system
Antimuscarinic effects especially
sinus tachycardia are frequently
observed.
9.4.3.4 Skeletal and smooth muscle
No significant effects.
9.4.4 Gastrointestinal
Nausea and vomiting are common features of
acute toxicity. Acute pancreatitis is described
following overdose (Tsao & Wright, 1993).
Chronic ingestion can cause dry mouth, gastric
distress, abdominal pain, nausea, vomiting, and
anorexia.
9.4.5 Hepatic
Transient hepatic dysfunction is described
following acute overdose (Seymour, 1993).
9.4.6 Urinary
9.4.6.1 Renal
Acute intoxication can cause urinary
retention.
9.4.6.2 Other
9.4.7 Endocrine and reproductive systems
High concentrations of carbamazepine can
stimulate vasopression secretion and lead to
hyponatraemia (Syndrome of inappropriate antidiuretic
hormone secretion - SIADH) (Gandelman, 1994).
9.4.8 Dermatological
No significant effects.
9.4.9 Eye, ear, nose, throat: local effects
No significant effects
9.4.10 Haematological
No significant effects with acute poisoning.
Dose-related leukopenia has been reported as a chronic
effect.
9.4.11 Immunological
No significant effects.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No significant effects.
9.4.12.2 Fluid and electrolyte disturbances
Hyponatraemia
9.4.12.3 Others
Hypothermia is reported after acute
overdose (Weaver et al., 1988).
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy: Carbamazepine is classified as
category "C". That is to say, studies in animals have
revealed adverse effects on the fetus but there are no
controlled studies in women. Minor malformations such
as those seen with fetal hydantoin syndrome have been
observed with carbamazepine monotherapy. However,
carbamazepine has been recommended as the drug of
choice in women at risk of pregnancy who require
anticonvulsant therapy for the first time (Briggs et
al, 1986).
Breast-feeding: Carbamazepine's safety when used
during lactation has not been established. The
concentration of carbamazepine in the milk is
approximately 60% of maternal plasma concentration.
Either breast-feeding or carbamazepine should be
discontinued, depending on the importance of the drug
for the woman (Reynolds, 1996).
Porphyria: A study in rats showed that carbamazepine
should be regarded as potentially hazardous in people
who have hereditary hepatic porphyria (Reynolds,1989).
9.5 Other
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
The management of carbamazepine toxicity is essentially
supportive. In severe cases, this may require endotracheal
intubation and ventilation.
10.2 Life supportive procedures and symptomatic/specific treatment
The major threat to life is from a decreased level of
consciousness and inadequate ventilation.
The patient should be immediately assessed for adequacy of
airway, breathing and circulation, and level of
consciousness. The airway should be secured by endotracheal
intubation if necessary. Supplemental oxygen should be
provided. Intravenous access should be established. Vital
signs, level of consciousness and cardiac rhythm should be
carefully monitored.
Seizures, hypotension, hyponatraemia, hypothermia should be
managed according to standard guidelines.
10.3 Decontamination
Administer oral or nasogastric activated charcoal as
soon as possible once the airway is deemed adequate or
secured.
10.4 Enhanced elimination
Repeat-dose activated charcoal is the method of choice
to enhance elimination of carbamazepine. A dose of 25 to 50 g
of activated charcoal should be adminstered by nasogastric
tube every 3 to 4 hours until clinical improvement occurs.
Although charcoal haemoperfusion has been used to enhance the
elimination of carbamazepine, repeat-dose actived charcoal
appears to be at least as effective and is a much less
invasive therapy (Vale, 1992). It is important to note that,
although repeat dose activated charcoal has been should to
significantly enhance the elimination of carbamazepine, this
has not been shown to associated with a more rapid clinical
recovery (Wason et al., 1992)
10.5 Antidote treatment
10.5.1 Adults
There is no antidote.
10.5.2 Children
There is no antidote.
10.6 Management discussion
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A 23-year-old woman with epilepsy developed superficial
coma, tachycardia, hypothermia, irregular respiration and
dilated pupils after she ingested 16,000 mg carbamazepine.
Gastric lavage was performed. However, 45 hours after she
was admitted to hospital, her coma deepened and her
respiration became more irregular. Delayed absorption of
carbamazepine from the gut, with an increase in serum
carbamazepine concentration, probably accounts for these
findings. Following treatment with activated charcoal,
sodium sulphate, forced diuresis (with sorbitol and
mannitol), and metoclopramide, she recovered 100 hours after
hospital admission (De Zeeuw et al., 1979).
A 21-year-old man developed coma, respiratory depression,
increased central venous pressure, hypotension and nodal
tachycardia after he ingested 40 000 mg carbamazepine, with
an unknown amount of lithium citrate. Gastric lavage was
successful and he was given IV fluids, diazepam, and
phenobarbital. Forty-five hours after ingestion, he
developed fixed mydriasis and hypotonia. He was treated with
corticosteroids, diuretics, and hyperventilation, and 16
hours later his pupils reacted increasingly to light. He was
extubated 24 hours later, and 2 days later he was conscious
(Wernberg et al., 1982).
A 23-month-old healthy boy (13.5 kg body weight) developed an
unsteady gait after he ingested 2000 mg carbamazepine (148
mg/kg) and was admitted to hospital 3 hours later. His vital
signs were normal but he was lethargic and ataxic and his
pupils were moderately dilated. He was given ipecac syrup
but when he vomited, his vomitus did not contain pill
fragments. He was then given activated charcoal and
magnesium sulphate. He went into a deep coma 9 hours
post-ingestion. Fifteen hours after ingestion his vital
signs were: blood pressure, 110/76 mmHg; pulse, 108 bpm;
respiration, 24/minute; and temperature 36.4°C. He was given
multiple doses of activated charcoal and sodium sulphate.
Twenty-six hours after ingestion he had 3 episodes of
tonic-clonic generalized seizures that were treated with
diazepam 5 mg intravenous (IV). The patient recovered
completely in a few days, and there were no sequelae six
months later (Deng et al., 1986).
A 41-year-old woman was given erythromycin stearate (500 mg
every 6 hours) while she was being treated with carbamazepine
and phenobarbital (100 mg, 4 times a day). This combination
caused carbamazepine toxicity, with inappropriate ADH
secretion, dizziness, nystagmus, and ataxia. One week after
receiving erythromycin, her blood levels increased from 13.3
mg/L to 28.2 mg/L. Twenty-four hours after all medication
was stopped, her carbamazepine levels fell to 5.9 mg/L.
Carbamazepine and phenobarbital were then resumed, and her
carbamazepine levels rose to 10.8 mg/L after 24 hours and to
11.3 mg/L after three weeks (Carranco et al., 1985).
A 22-year-old healthy male ingested an overdose of
carbamazepine. He had an initial period of restlessness and
aggression. He then became stuporous and was admitted to
hospital in a coma. His vital signs were normal. Gastric
lavage was performed and he was given 30 g sodium sulphate
and a suspension of 50 g activated charcoal. Haemoperfusion
was performed for 4 hours, reducing the half-life and
successfully enhancing the elimination of carbamazepine
(Groot et al., 1984).
A 45-year-old epileptic woman who had been receiving
long-term therapy with carbamazepine, valproic acid, and
phenytoin, ingested a carbamazepine overdose. When she
arrived at hospital, she was stuporous and had motor
restlessness. Her heart rate was 90 bpm, blood pressure
140/80 mmHg, and temperature 35.0°C. Eight hours later she
was in a coma, her blood pressure was 90/50 mmHg, and her
temperature 34.3°C. Gastric lavage was performed and she was
given activated charcoal and sodium sulphate. Haemoperfusion
for 4 hours, slowly decreased the plasma concentration of
carbamazepine. Her condition steadily improved (Groot et al.,
1984).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Therapy with carbamazepine should begin at low doses
and be increased gradually until the patient responds.
Special care should be taken when carbamazepine is
administered in addition to other anticonvulsant therapy, or
when the patient requires other medications because drug
interactions can occur.
12.2 Other
No data available.
13. REFERENCES
Abrantes J & Marques Penha J (1986). Therapeutic arsenal in
clinical toxicology, Emergência Médica, II (6): 9-17 (in
Portuguese).
Andrus PF (1984) Lithium and carbamazepine. J Clin Psychiatry
45:525
Bates N, Edwards N, Roper J & Volans G (eds) (1997) Paediatric
Toxicology. Handbook of Poisoning in Children. Macmillan
Reference Ltd., London, U.K.
Beerman B, Edhag O, Vallin H (1975). Advanced heart block
aggravated by carbamazepine, Br Heart J 37: 668.
Borges A (1986). The use of ipecac syrup and activated charcoal
in toxicology, Emergência Médica, II (6): 4-7 (in Portuguese).
Briggs GG, Freeman RM & Yaffe SJ (1986). Drugs in Pregnancy and
Lactation. 2nd Ed Williams & Wilkins, Baltimore, Maryland.
Brodie MJ & Macphee GJA (1986) Carbamazepine neurotoxicity
precipitated by diltiazem. Brit Med J 292:1170-1.
Brœsen K & Kragh-Sœrensen P (1993) Concomitant intake of
nortriptyline and carbamazepine. Ther Drug Monit 15:258-60.
Budavari S (ed) (1996) The Merck Index. An encyclopedia of
chemicals, drugs and biologicals. 12th Ed. Merck & Co. Inc.
Whitehouse Station, New Jersey.
Carranco E, Kareus J, Shenley C et al. (1985). Carbamazepine
toxicity induced by concurrent erythromycin therapy. Arch Neurol.
42: 187 - 188.
Cereghino JJ et al. (1975) The efficacy of carbamazepine
combination in epilepsy. Clin Pharmacol Ther 18:733-41.
Chaudry RP & Waters BGH (1983) Lithium and carbamazepine
interaction: possible neurotoxicity. J Clin Psychiatry 44:30.
De Zeeuw RA, Westenberg HGM, Klein E van der, Gimbrere JSF
(1979). An unusual case of Carbamazepine Poisoning with a
near-fatal relapse after two days. Clinical Toxicology l4:
263-269.
Deng JF, Shipe Jr JR, Donowitz L & Spyker DA (1986).
Carbamazepine Toxicity: Comparison of measurement of drug levels
by HPLC and Emit and Model of carbamazepine Kinetics. Journal of
Toxicology and Clinical Toxicology 24: 281- 294.
Dhillon S & Richens A (1981) Pharmacokinetics of diazepam in
epileptic patients and normal volunteers following intravenous
administration. Brit J Clin Pharmacol 12:841-4.
Drug Facts and Comparisons (1985). Philadelphia, JB Lippincott
Company.
Durelli L, Massazza V & Cavallo R (1989) Carbamazepine toxicity
and poisoning. Incidence, clinical features and managment. Med
Toxicol Adv Drug Experience 4:95-107.
Fritz J et al. (1991) Interaction between carbamazepine and
fluvoxamine. Acta Psychiatr Scand 84:583-4.
Gandelman MS (1994) Review of carbamazepine-induced
hyponatraemia. Prog Neuropsychopharmacol Biol Psychiatry
18:211-33.
Groot G, Heijst ANP & Maes RAA (1984). Charcoal Haemoperfusion in
the treatment of two cases of acute carbamazepine poisoning.
Journal of Toxicology and Clinical Toxicology 22: 349-362.
Hansen JM et al. (1971) Carbamazepine-induced acceleration of
diphenylhydantoin and warfarin metabolism in man. Clin Pharmacol
Ther 12:539-43.
Hojer J, Malmlund HO & Berg A (1993) Clinical features in 28
consecutive cases of laboratory confirmed massive poisoning with
carbamazepine alone. J Toxicol Clin Toxicol 31:449-58.
Index Nominum (1992/93). Repertoire des Substances
médicamenteuses, Zurich, Centre Scientifique de la Société Suisse
de Pharmacie.
Laffey SH & Guzzardi LJ (1983). "Phenytoin and other
anticonvulsants" in Haddad LM & Winchester JF ed. Clinical
Management of Poisoning and Drug Overdose. USA, Saunders Co.
Lai AA et al. (1978) Time course of interaction between
carbamazepine and clonazepam in normal man. Clin Pharmacol Ther
24:316-23.
Lehrman SN, Bauman ML (198l). Carbamazepine overdose. Am J Dis
Child 135: 768.
London, Pharmaceutical Press, 368-372.
Macnab WJ et al. (1993) Carbamazepine poisoning in children.
Pediatr Emerg Care 9:195-8.
Macphee GJA et al. (1986) Verapamil potentiates carbamazepine
neurotoxicity: a clinically important inhibitory interaction.
Lancet i:700-3.
Mitsch RA (1989) Carbamazepine toxicity precipitated by
intravenous erythromycin. Drug Intell Clin Pharm 23:878-9.
Morant J & Ruppaner H (1997) Compendium Suisse des Médicaments,
18eme ed, Documed, Bâle, CH.
PDR - Physicians' Desk Reference (1988), USA Medical Economics
Company.
Pearson HJ (1990) Interaction of fluoxetine with carbamazepine. J
Clin Psychiatry 51:126.
Rall TW & Schleifer LS (1985). Drugs effective in the therapy of
the Epilepsies - Iminostilbenes, in: Goodman and Gilman's The
Pharmacological Basis of Therapeutics. New York, MacMillan
Publishing Co., Inc.
Rane A, Hojer B, Wilson JT (1976). Kinetics of carbamazepine and
its 10,11-epoxide metabolite in children. Clin Pharmacol Ther 19:
276-283.
Reynolds JEF (ed) (1996) Martindale, The Extra Pharmacopoeia,
31st edition
Rosa FW (1991). Spina bifida in infants of women treated with
carbamazepine during pregnancy. New Engl. J Med. 324:
674 - 677.
Salcman M, Pippenger CE (1975). Acute carbamazepine
encephalopathy. J Am Med Assoc 231: 915.
Stevens WP (1977). Water intoxication due to carbamazepine, Br
Med J 1: 754.
Tibbals J (1992) Acute toxic reation to carbamazepine: clinical
effects and serum concentrations. J Pediatr 121:295-9.
Tsao CY & Wright FS (1993) Acute chemical pancreatitis associated
with carbamazepine intoxication. Epilepsia 34:174-6.
Valsalan VC & Cooper GL (1982) Carbamazepine intoxication caused
by interaction with isoniazid. Br Med J 285:261-2.
Weaver DF, Camfield P & Frazer A (1988) Massive carbamazepine
overdose: clinical and pharmacologic observation in five episodes.
Neurology 38:755-9.
Wernberg M, Peterson TK & Kristensar HK (1982). Carbamazepine
poisoning. Ugeskt Laeg l43: 619-620 (in German).
Westenberg HGM, Klein E van der, Oei TT, Zeeuw RA de (1978).
Kinetics of carbamazepine and carbamazepine epoxide determined by
use of plasma and saliva. Clin Pharmacol Ther 23: 320-328.
Wong YY et al. (1983) Effect of erythomycin on carbamazepine
kinetics. Clin Pharmacol Ther 33:460-4.
Wright JM et al. (1982) Isoniazid-induced carbamazepine toxicity
and vice versa. N Engl J Med 307:1325-7.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Authors: Arlinda Borges, J. Bivar Abrantes, J. Marques Penha,
P. Paiva Parada, M. Teresa Teixeira, Teresa M. Pinto
Centro de Informaçao Antivenénos
Instituto Nacional de Emergencia Médica
Rua Infante D Pedro, 8
1700 Lisbon
Portugal
Tel: 7930503
Fax: 7937124
Telex: 13304 SNALP P
Date: February 1988
Reviewer: Dr J. Pronczuk
CIAT, 7° piso
Hospital de Clinicas
Av. Italia s/n
Montevideo
Uruguay
Date: July 1988
Peer
review: Adelaide, Australia, April 1991
Update: Dr R. Fernando, June 1993
Update/edit: Dr M.O. Rambourg-Schepens & Dr L. Murray
Date: November 1999