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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.

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    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
    


    See Also:
       Toxicological Abbreviations