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Camazepam

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 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
   7.3 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
   8.6 References
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)



    Camazepam

    International Programme on Chemical Safety
    Poisons Information Monograph 283
    Pharmaceutical

    This monograph does not contain all of the sections completed. This
    mongraph is harmonised with the Group monograph on Benzodiazepines
    (PIM G008).

    1.  NAME

        1.1  Substance

             Camazepam

        1.2  Group

             ATC classification index

             Psycholeptics(N05)/  Anxiolytics (N05B)/
             Benzodiazepine derivatives (N05BA)

        1.3  Synonyms

             SB-5833

        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

             Central nervous system, causing depression of
             respiration and consciousness.

        2.2  Summary of clinical effects

             Central nervous system (CNS) depression and coma, or
             paradoxical excitation, but deaths are rare when
             benzodiazepines are taken alone. Deep coma and other
             manifestations of severe CNS depression are rare. Sedation,
             somnolence, diplopia, dysarthria, ataxia and intellectual
             impairment are the most common adverse effects of

             benzodiazepines. Overdose in adults frequently involves co-
             ingestion of other CNS depressants, which act synergistically
             to increase toxicity. Elderly and very young children are
             more susceptible to the CNS depressant action. Intravenous
             administration of even therapeutic doses of benzodiazepines
             may produce apnoea and hypotension.
             Dependence may develop with regular use of benzodiazepines,
             even in therapeutic doses for short periods. If
             benzodiazepines are discontinued abruptly after regular use,
             withdrawal symptoms may develop.  The amnesia produced by
             benzodiazepines can have medico-legal consequences.

        2.3  Diagnosis

             The clinical diagnosis is based upon the history of
             benzodiazepine overdose and the presence of the clinical
             signs of benzodiazepine intoxication.
             Benzodiazepines can be detected or measured in blood and
             urine using standard analytical methods. This information may
             confirm the diagnosis but is not useful in the clinical
             management of the patient.
             A clinical response to flumazenil, a specific benzodiazepine
             antagonist, also confirms the diagnosis of benzodiazepine
             overdose, but administration of this drug is rarely
             justified.

        2.4  First aid measures and management principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly involve co-
             ingestion of other CNS depressants and other drugs. Activated
             charcoal normally provides adequate gastrointestinal
             decontamination. Gastric lavage is not routinely indicated.
             Emesis is contraindicated. The use of flumazenil is reserved
             for cases with severe respiratory or cardiovascular
             complications and should not replace the basic management of
             the airway and respiration. The routine use of flumazenil is
             contraindicated because of potential complications, including
             seizures.  Renal and extracorporeal methods of enhanced
             elimination are not effective.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             Chemical name:
             Dimethylcarbamic acid 7-chloro-2,3-dihydro-1-methyl-2-oxo-5-
             phenyl-1H-1,4-benzodiazepin-3-yl ester;
    

             Alternatives
             7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-
             benzodiazepin-2-one dimethylcarbamate (ester);
    
             7-chloro-1,3-dihydro-3-(N,N-dimethylcarbamoyl)-1-methyl-5-
             phenyl-2H-1,4-benzodiazepin-2-one;
    
             Molecular formula: C19H18ClN3O3
    
             Molecular  weight: 371.82.

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Melting point: 173-174 degC. 
                    Soluble in alcohol; moderately soluble in water.

        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 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
        7.3  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
                             "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
             For toxicological analyses: whole blood 10 mL; urine 25 mL
             and gastric contents 25 mL.
    
             Biomedical analysis
             Blood gases, serum electrolytes, blood glucose and hepatic
             enzymes when necessary in severe cases.
    
             Toxicological analysis
             Qualitative testing for benzodiazepines is helpful to confirm
             their presence, but quantitative levels are not clinically
             useful. More advanced analyses are not necessary for the
             treatment of the poisoned patient due the lack of correlation
             between blood concentrations and clinical severity (Jatlow et
             al., 1979; MacCormick et al., 1985; Minder, 1989).
    
             TLC and EMIT: These provide data on the presence of
             benzodiazepines, their metabolites and possible associations
             with other drugs.
    

             GC or HPLC: These permit identification and quantification of
             the benzodiazepine which caused the poisoning and its
             metabolites in blood and urine.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The onset of impairment of consciousness is
                    relatively rapid in benzodiazepine poisoning.  Onset
                    is more rapid following larger doses and with agents
                    of shorter duration of action. The most common and
                    initial symptom is somnolence.  This may progress to
                    coma Grade I or Grade II (see below) following very
                    large ingestions.
    
                    Reed Classification of Coma (Reed et al., 1952)
    
                    Coma Grade I:   Depressed level of consciousness,
                                    response to  painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                                    intact
    
                    Coma Grade III: Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes absent. Vital
                                    signs intact
    
                    Coma Grade IV:  Coma grade III plus respiratory and
                                    circulatory collapse

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    Overdose by the intravenous route results in
                    symptoms similar to those associated with ingestion,
                    but they appear immediately after the infusion, and
                    the progression of central nervous system (CNS)
                    depression is more rapid. Acute intentional poisoning
                    by this route is uncommon and most cases are
                    iatrogenic. Rapid intravenous infusion may cause
                    hypotension, respiratory depression and
                    apnoea.

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxic effects associated with chronic exposure
                    are secondary to the presence of the drug and
                    metabolites and include depressed mental status,
                    ataxia, vertigo, dizziness, fatigue, impaired motor
                    co-ordination, confusion, disorientation and
                    anterograde amnesia. Paradoxical effects of
                    psychomotor excitation, delirium and aggressiveness
                    also occur. These chronic effects are more common in
                    the elderly, children and patients with renal or
                    hepatic disease.
    
                    Administration of therapeutic doses of benzodiazepines
                    for 6 weeks or longer can result in physical
                    dependence, characterized by a withdrawal syndrome
                    when the drug is discontinued. With larger doses, the
                    physical dependence develops more rapidly.

             9.2.2  Inhalation

                    No data.

             9.2.3  Skin exposure

                    No data.

             9.2.4  Eye contact

                    No data.

             9.2.5  Parenteral exposure

                    The chronic parenteral administration of
                    benzodiazepines may produce thrombophlebitis and
                    tissue irritation, in addition to the usual symptoms
                    (Greenblat & Koch-Weser, 1973).

             9.2.6  Other

                    No data.

        9.3  Course, prognosis, cause of death

             Benzodiazepines are relatively safe drugs even in
             overdose. The clinical course is determined by the
             progression of the neurological symptoms. Deep coma or other
             manifestations of severe central nervous system (CNS)
             depression are rare with benzodiazepines alone.  Concomitant
             ingestion of other CNS depressants may result in a more
             severe CNS depression of longer duration.
    
             The therapeutic index of the benzodiazepines is high and the
             mortality rate associated with poisoning due to
             benzodiazepines alone is very low. Complications in severe
             poisoning include respiratory depression and aspiration
             pneumonia. Death is due to respiratory arrest.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, bradycardia and tachycardia have
                    been reported with overdose (Greenblatt et al., 1977;
                    Meredith & Vale 1985). Hypotension is more frequent
                    when benzodiazepines are ingested in association with
                    other drugs (Hojer et al., 1989). Rapid intravenous
                    injection is also associated with hypotension.

             9.4.2  Respiratory

                    Respiratory depression may occur in
                    benzodiazepine overdose and the severity depends on
                    dose ingested, amount absorbed, type of benzodiazepine
                    and co-ingestants. Respiratory depression requiring
                    ventilatory support has occurred in benzodiazepine
                    overdoses (Sullivan, 1989; Hojer et al.,1989). The
                    dose-response for respiratory depression varies
                    between individuals.  Respiratory depression or
                    respiratory arrest may rarely occur with therapeutic
                    doses. Benzodiazepines may affect the control of
                    ventilation during sleep and may worsen sleep apnoea
                    or other sleep-related breathing disorders, especially
                    in patients with chronic obstructive pulmonary disease
                    or cardiac failure (Guilleminault, 1990).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             CNS depression is less marked than
                             that produced by other CNS depressant agents
                             (Meredith & Vale, 1985). Even in large
                             overdoses, benzodiazepines usually produce
                             only mild symptoms and this distinguishes
                             them from other sedative-hypnotic agents.
                             Sedation, somnolence, weakness, diplopia,
                             dysarthria, ataxia and intellectual
                             impairment are the most common neurological
                             effects. The clinical effects of severe
                             poisoning are sleepiness, ataxia and coma
                             Grade I to Grade II (Reed). The presence of
                             more severe coma suggests the possibility of
                             co-ingested drugs. Certain of the newer
                             short-acting benzodiazepines (temazepam,
                             alprazolam and triazolam) have been
                             associated with several fatalities and it is
                             possible that they may have greater acute
                             toxicity (Forrest et al., 1986). The elderly
                             and very young children are more susceptible
                             to the CNS depressant action of
                             benzodiazepines.
                             The benzodiazepines may cause paradoxical CNS
                             effects, including excitement, delirium and
                             hallucinations. Triazolam has been reported
                             to produce delirium, toxic psychosis, memory
                             impairment and transient global amnesia
                             (Shader & Dimascio, 1970; Bixler et al,
                             1991). Flurazepam has been associated with
                             nightmares and hallucinations.
                             There are a few reports of extrapyramidal
                             symptoms and dyskinesias in patients taking
                             benzodiazepines (Kaplan & Murkafsky, 1978;
                             Sandyk, 1986).
                             The muscle relaxation caused by
                             benzodiazepines is of CNS origin and
                             manifests as dysarthria, incoordination and
                             difficulty standing and walking.

                    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

                    Oral benzodiazepine poisoning will produce
                    minimal effects on the gastrointestinal tract (GI)
                    tract but can occasionally cause nausea or vomiting
                    (Shader & Dimascio, 1970).

             9.4.5  Hepatic

                    A case of cholestatic jaundice due focal
                    hepatic necrosis was associated with the
                    administration of diazepam (Tedesco & Mills,
                    1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Vesical hypotonia and urinary
                             retention has been reported in association
                             with diazepam poisoning (Chadduck et al.,
                             1973).

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

                    Galactorrhoea with normal serum prolactin
                    concentrations has been noted in 4 women taking
                    benzodiazepines (Kleinberg et al., 1977).
                    Gynaecomastia has been reported in men taking high
                    doses of diazepam (Moerck & Majelung, 1979). Raised
                    serum concentrations of oestrodiol were observed in
                    men taking diazepam 10 to 20 mg daily for 2 weeks
                    (Arguelles & Rosner, 1975).

             9.4.8  Dermatological

                    Bullae have been reported following overdose
                    with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                    et al., 1990).
                    Allergic skin reactions were attributed to diazepam at
                    a rate of 0.4 per 1000 patients (Brigby,
                    1986).

             9.4.9  Eye, ear, nose, throat: local effects

                    Brown opacification of the lens occurred in 2
                    patients who used diazepam for several years (Pau
                    Braune, 1985).

             9.4.10 Haematological

                    No data.

             9.4.11 Immunological

                    Allergic reaction as above (see
                    9.4.8).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No direct disturbances have been
                             described.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    Hypersensitivity reactions including
                    anaphylaxis are very rare (Brigby, 1986). Reactions
                    have been attributed to the vehicle used for some
                    parenteral diazepam formulations (Huttel et al.,
                    1980). There is also a report of a type I
                    hypersensitivity reaction to a lipid emulsion of
                    diazepam (Deardon, 1987).

             9.4.14 Other clinical effects

                    Hypothermia was reported in 15% of cases in
                    one series. (Martin, 1985; Hojer et al.,
                    1989).

             9.4.15 Special risks

                    Pregnancy
                    Passage of benzodiazepines across the placenta depends
                    on the degree of protein binding in mother and fetus,
                    which is influenced by factors such as stage of
                    pregnancy and plasma concentrations of free fatty
                    acids in mother and fetus (Lee et al., 1982). Adverse
                    effects may persist in the neonate for several days
                    after birth because of immature drug metabolising
                    enzymes. Competition between diazepam and bilirubin
                    for protein binding sites could result in
                    hyperbilirubinemia in the neonate (Notarianni,
                    1990).

                    The abuse of benzodiazepines by pregnant women can
                    cause withdrawal syndrome in the neonate. The
                    administration of benzodiazepines during childbirth
                    can produce hypotonia, hyporeflexia, hypothermia and
                    respiratory depression in the newborn.
                    Benzodiazepines have been used in pregnant patients
                    and early reports associated diazepam and
                    chlordiazepoxide with some fetal malformations, but
                    these were not supported by later studies (Laegreid et
                    al., 1987; McElhatton, 1994).
    
                    Breast feeding
                    Benzodiazepines are excreted in breast milk in
                    significant amounts and may result in lethargy and
                    poor feeding in neonates.  Benzodiazepines should be
                    avoided in nursing mothers (Brodie, 1981; Reynolds,
                    1996).

        9.5  Other

             Dependence and withdrawal
             Benzodiazepines have a significant potential for abuse and
             can cause physical and psychological dependence. Abrupt
             cessation after prolonged use causes a withdrawal syndrome
             (Ashton, 1989). The mechanism of dependence is probably
             related to functional deficiency of GABA activity.
             Withdrawal symptoms include anxiety, insomnia, headache,
             dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
             weakness, perspiration, irritability, hypersensitivity to
             visual and auditory stimuli, palpitations, tachycardia and
             postural hypotension. In severe and rare cases of withdrawal
             from high doses, patients may develop affective disorders or
             motor dysfunction: seizures, psychosis, agitation, confusion,
             and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
             Reynolds, 1996).
             The time of onset of the withdrawal syndrome depends on the
             half-life of the drug and its active metabolites; the
             symptoms occur earlier and may be more severe with short-
             acting benzodiazepines. Others risk factors for withdrawal
             syndrome include prolonged use of the drug, higher dosage and
             abrupt cessation of the drug.
    
             Abuse
             Benzodiazepines, particularly temazepam, have been abused
             both orally and intravenously (Stark et al., 1987; Woods,
             1987; Funderburk et al, 1988)
    
             Criminal uses
             The amnesic effects of benzodiazepines have been used for
             criminal purposes with medicolegal consequences (Ferner,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. It should be remembered that
             benzodiazepine ingestions by adults commonly include other
             drugs and other CNS depressants. Activated charcoal normally
             provides adequate gastrointestinal decontamination. Gastric
             lavage is not routinely indicated. Emesis is contraindicated.
             The use of flumazenil is reserved for cases with severe
             respiratory or cardiovascular complications and should not
             replace the basic management of the airway and respiration.
             Renal and extracorporeal elimination methods are not
             effective.

        10.2 Life supportive procedures and symptomatic/specific treatment

             The patient should be evaluated to determine adequacy
             of airway, breathing and circulation. Continue clinical
             observation until evidence of toxicity has resolved.
             Intravenous access should be available for administration of
             fluid. Endotracheal intubation, assisted ventilation and
             supplemental oxygen may be required on rare occasions, more
             commonly when benzodiazepines are ingested in large amounts
             or with other CNS depressants.

        10.3 Decontamination

             Gastric lavage is not routinely indicated following
             benzodiazepine overdose. Emesis is contraindicated because of
             the potential for CNS depression. Activated charcoal can be
             given orally.

        10.4 Enhanced elimination

             Methods of enhancing elimination are not indicated.

        10.5 Antidote treatment

             10.5.1 Adults

                    Flumazenil, a specific benzodiazepine
                    antagonist at central GABA-ergic receptors is
                    available. Although it effectively reverses the CNS
                    effects of benzodiazepine overdose, its use in
                    clinical practice is rarely indicated.
                    Use of Flumazenil is specifically contraindicated when
                    there is history of co-ingestion of tricyclic

             antidepressants or other drugs capable of producing seizures
             (including aminophylline and cocaine), benzodiazepine
             dependence, or in patients taking benzodiazepines as an
             anticonvulsant agent. In such situations, administration of
             Flumazenil may precipitate seizures (Lopez, 1990; Mordel et
             al., 1992).
                    Adverse effects associated with Flumazenil include
                    hypertension, tachycardia, anxiety, nausea, vomiting
                    and benzodiazepine withdrawal syndrome.
                    The initial intravenous dose of 0.3 to 1.0 mg may be
                    followed by further doses if necessary. The absence of
                    clinical response to 2 mg of flumazenil within 5 to 10
                    minutes indicates that benzodiazepine poisoning is not
                    the major cause of CNS depression or coma.
                    The patient regains consciousness within 15 to 30
                    seconds after injection of flumazenil, but since it is
                    metabolised more rapidly than the benzodiazepines,
                    recurrence of toxicity and CNS depression can occur
                    and the patient should be carefully monitored after
                    initial response to flumazenil therapy.  If toxicity
                    recurs, further bolus doses may be administered or an
                    infusion commenced at a dose of 0.3 to 1.0 mg/hour
                    (Meredith et al., 1993).

             10.5.2 Children

                    The initial intravenous dose of 0.1 mg should
                    be repeated each minute until the child is awake.
                    Continuous intravenous infusion should be administered
                    at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                    1993).

        10.6 Management discussion

             Most benzodiazepine poisonings require only clinical
             observation and supportive care. Flumazenil is the specific
             antagonist of the effects of benzodiazepines, but the routine
             use for the treatment of benzodiazepine overdosage is not
             recommended. The use of Flumazenil should only be considered
             where severe CNS depression is observed. This situation
             rarely occurs, except in cases of mixed ingestion. The
             administration of flumazenil may improve respiratory and
             cardiovascular function enough to decrease the need for
             intubation and mechanical ventilation, but should never
             replace basic management principles.
             Flumazenil is an imidazobenzodiazepine and has been shown to
             reverse the sedative, anti-convulsant and muscle-relaxant
             effects of benzodiazepines. In controlled clinical trials,
             flumazenil significantly antagonizes benzodiazepine-induced
             coma arising from anaesthesia or acute overdose. However, the
             use of flumazenil has not been shown to reduce mortality or
             sequelae in such cases.

             The administration of flumazenil is more effective in
             reversing the effects of benzodiazepines when they are the
             only drugs producing CNS toxicity. Flumazenil does not
             reverse the CNS depressant effects of non-benzodiazepine
             drugs, including alcohol. The diagnostic use of flumazenil in
             patients presenting with coma of unknown origin can be
             justified by its high therapeutic index and the fact that
             this may limit the use of other diagnostic procedures (CT
             scan, lumbar puncture, etc).
             Flumazenil is a relatively expensive drug and this may also
             influence its use, especially in areas with limited
             resources.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

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

        Author:           Dr Ligia Fruchtengarten
                          Poison Control Centre of Sao Paulo  -  Brazil
                          Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          FAX / Phone:   55  11  2755311
                          E-mail:   lfruchtengarten@originet.com.br
    
        Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                          Coperpas 12
                          Centro de Controle de Intoxicaçoes de Sao Paulo
                          Av Francisco de Paula Quintanilha Ribeiro, 860
                          04330 - 020   Sao Paulo  -  SP  -  Brazil.
    
        Date:             July 1997
    
        Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                          September 1997.
                          R. Ferner, L. Murray (Chairperson), M-O.
                          Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                          Nolf, A.Borges.
    
        Review 1998:      Lindsay Murray
                          Queen Elizabeth II Medical Centre
                          Perth, Western Australia.
    
        Editor:           Dr M.Ruse, April 1998