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
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   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
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   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
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults 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
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s) Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis Blood, plasma or serum Urine 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
   9.1 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 Central nervous system (CNS) Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal 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 Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
   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
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other

    International Programme on Chemical Safety
    Poisons Information Monograph  181

    This mongraph is harmonised with the Group monograph on
    Benzodiazepines (PIM G008).

    1.  NAME

        1.1  Substance


        1.2  Group

             ATC classification index

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

        1.3  Synonyms

             methyl diazepinone; diacepin;
             La III; Ro 5-2807;

        1.4  Identification numbers

             1.4.1  CAS number


             1.4.2  Other numbers

                    RTECS DF1575000

        1.5  Main brand names, main trade names

             Diazepam as the only active substance:
             Diazeplex, Diazepam, Relanium, Stesolid, Valium, Others.
             Combination products:
             Aneurol, Ansium, Calmaven, Diaceplex, Edym Sedante, Gobanal,
             Pacium, Pertranquil, Reladon, Tepazepam, Tropargal,

        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

        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.


        3.1  Origin of the substance

             A method for the synthesis of diazepam has been
             described(Sternbach et al, 1961). Benzoyl chloride reacts
             with p-chloroaniline to produce 2-amino-5-chlorobenzophenone.
             This is converted to the oxime with hydroxylamine. After
             cyclization with chloroacetyl chloride and ring enlargement
             with alkali treatment, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-
             benzodiazepin-2-one-4-oxide is reduced and methylatedto

        3.2  Chemical structure

             Chemical name
             Molecular formula C16H13ClN2O
              Molecular weight  284.76

        3.3  Physical properties

             3.3.1  Colour

                    White or yellow

             3.3.2  State/Form


             3.3.3  Description

                    Melting point 131.5 to 134.5 C.
                    Odourless, slightly bitter taste

                    The solubility of diazepam as per the British
                    Pharmacopoeia is very slightly soluble in water,
                    soluble in alcohol and freely soluble in chloroform
                    (Reynolds, 1993).
                    The solubility of diazepam as per the United States
                    Pharmacopeia is soluble 1 in 16 of ethyl alcohol, 1 in
                    2 of chloroform, and 1 in 39 of ether; practically
                    insoluble in water (Reynolds, 1993).
                    The pH is neutral.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    5 years (oral tablets)
                    3 years, (parenteral formulation)

             3.4.2  Storage conditions

                    Store in air-tight containers. Protect from
                    light (Reynolds, 1993).

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description


                    Seizures, status epilepticus
                    Symptoms of drug withdrawal associated with the
                    chronic abuse of ethanol, benzodiazepines,
                    barbiturates, and other CNS depressants.
                    Skeletal muscle spasticity and acute muscular spasms,
                    including tetanus and cerebral palsy.
                    Anxiety and/or desire for producing amnesia prior to
                    surgery, dental, and endoscopic procedures
                    Conscious sedation for short anesthesia, alone or in
                    combination with an opioid.

                    Continuous infusion for sedation or seizures in the
                    intensive care setting
                    Treatment of toxicity, based on the literature, can
                    CNS stimulants (e.g. cocaine, amphetamines)
                    Drug-induced seizures
                    -Sarin, VX, Soman, and potentially organophosphate
                    pesticides (in conjunction with atropine and oximes)
                    (Gupta, 1984; McDonough et al., 1989)
                    -Lindane (Griffith & Woolley, 1989)
                    -Chloroquine (Havens et al., 1988; Riou et al.,
                    -Physostigmine (Klemm, 1983)
                    -Pyrethroids (Gammon, 1982).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    mg to 30 mg daily, in 2 or 3 divided doses.
                    to 30 mg as a single dose.
                    Muscle spasm
                    to 15 mg daily in divided doses. In severe spasticity
                    associated with cerebral palsy, doses may be increased
                    gradually up to 60 mg daily
                    Premedication or sedation in surgery, dentistry to 20
                    mg as a single dose
                    Given as suppositories at the same doses used orally.
                    The oral solution can be administered rectally, and
                    has been used as treatment of seizures primarily in
                    children. The rectal solution is administered as a
                    single dose of 10 mg, followed by another dose 5
                    minutes later if there is no response in adults and
                    children more than 3 years of age.

                    Severe anxiety or acute muscle spasm
                    Intravenous doses of 2 to 5 mg should be administered
                    at intervals of at least 10 min until the desired
                    effect is achieved.  The dose should be administered
                    at a rate of less than 5 mg per minute.
                    100 to 300 µg/kg intravenously (repeated every 1 to 4
                    Premedication or sedation in surgery, dentistry
                    2 to 10 mg intravenous doses, repeated at intervals of
                    at least 5 to 10 minutes, until adequate sedation
                    and/or anxiolysis is achieved.
                    Status epilepticus
                    5 to 10 mg intravenous doses. May be repeated every 5
                    to 10 minutes until termination of seizures. A maximum
                    dose of 40 to 60 mg is used. If this dose is
                    ineffective, other anticonvulsant drug therapy should
                    be instituted.
                    Continuous infusion for ICU patients
                    3 to 10 mg/kg over 24 hours.

             4.2.2  Children

                    40 to 200 µg/kg of bodyweight (Initial dose), which
                    can be repeated as tolerated up to 4 times daily.
                    40 to 200 µg/kg of bodyweight, which can be repeated
                    as tolerated up to 4 times daily.
                    Rectal solution
                    For the treatment of seizures, 5 mg (1 to 3 years of
                    age). May be repeated after 5 to 10 minutes.
                    Sedative or Muscle relaxant
                    200 µg/kg of bodyweight intravenously.

                    Status epilepticus
                    200 to 300 µg/kg of bodyweight intravenously. May
                    berepeated after 5 to 10 minutes if required.
                    (USPC, 1989; Reynolds, 1993)

    4.3  Contraindications

             The primary absolute contraindication is an allergy to
             diazepam or other benzodiazepines, or the constituents of the
             parenteral formulation.
             There are relative contraindications, which require more
             careful monitoring of patients after receiving diazepam, and
             stronger consideration of alternative drug therapy.  In these
             patients, the initial dose should be decreased:
             Chronic obstructive respiratory disease
             Neonates and infants up to 6 months of age
             Myasthenia gravis
             Close angle glaucoma
             Poisoning by other CNS depressants
             Breast feeding
             Geriatric patients
             Severe liver failure
             (USPC, 1989)


        5.1  Oral

             This is the most frequent route of diazepam
             administration for therapeutic use as well as accidental
             poisonings, intentional overdoses, and abuse.

        5.2  Inhalation

             The administration of diazepam solution into the lungs
             via an endotracheal tube has been demonstrated to produce
             therapeutic serum diazepam concentrations in animal

             Histologic examination of the lung demonstrated pneumonitis.
             These results suggest adequate absorption, however, the
             increased pulmonary toxicity indicates that this route should
             not be used in clinical practice (Rusli et al., 1987).

        5.3  Dermal

             Diazepam is absorbed through the skin, however, this
             route of administration is not used clinically (Hori,

        5.4  Eye

             No data available.

        5.5  Parenteral

             The preferred route of parenteral administration is
             intravenous.  Indications include severe anxiety, excitation,
             alcohol and drug withdrawal syndrome, and seizures. The
             intramuscular route of diazepam administration should be
             avoided because absorption is erratic, and may be
             significantly delayed. The benzodiazepine lorazepam is more
             consistently absorbed from muscle, and should be used if
             intramuscular administration is required (USPC 1989;
             Reynolds, 1993).
             The intraosseous infusion of diazepam has been described as
             efficacious in the critically ill child, however, this route
             of administration is not commonly used (McNamara et al.,
             Parenteral diazepam is irritating, and intravenous
             administration should be into a large peripheral vein.  The
             rate of administration should be no faster than 5 mg per
             minute, and be followed by a saline flush to decrease local
             venous irritation.
             Significant adverse effects of intravenous diazepam include
             coma, hypotension, bradycardia, and respiratory failure. Such
             effects usually occur in the setting of rapid administration,
             administration of excessive doses, or administration to high-
             risk patients (the elderly, infants, patients with chronic
             respiratory disease) (USPC 1989; Reynolds, 1993).

        5.6  Other

             Administration of diazepam rectally as either
             suppositories or solution results in good absorption.  This
             route of administration is primarily used in convulsing
             children with no route of parenteral access.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Diazepam is absorbed rapidly following oral administration;
             with peak plasma concentrations generally being achieved
             within 1.0 hour (range 0.08 to 2.5 hours). (Greenblatt et
             al., 1988). The absorption rate is slowed by food and
             antacids.  Absorption is almost complete with
             close to 1.0. (Mandelli et al., 1978).
             Absorption is poor and erratic after intramuscular injection;
             plasma levels attained are equal to 60% of those reached
             after the same oral dose (Hillestad et al., 1974). The use of
             intramuscular diazepam has been described, however, this
             route should only be considered when other routes of
             administration or benzodiazepines are not available (USPC,
             1989; Reynolds, 1993; Vale & Scott, 1974).
             Blood concentrations of 400 ng/mL and 1,200 ng/mL were
             measured 15 minutes after intravenous bolus doses of 10 and
             20 mg, respectively (Hillestead et al., 1974).  Chronic
             administration of daily doses ranging from 2 mg to 30 mg
             result in plasma diazepam concentrations of 20 ng/mL to 1,010
             ng/mL, and concentrations of desmethyldiazepam, an active
             metabolite, of 55 ng/mL to 1,765 ng/mL (Reynolds,

        6.2  Distribution by route of exposure

             The volume of distribution has been calculated to range
             from 0.7 to 2.6 L/kg. (Mandelli et al, 1978; Baselt & Cravey,
             1989)  In human volunteers, the plasma protein binding of
             diazepam is greater than 95% (Klotz et al., 1976a; Mandelli
             et al., 1978). The concentration in the CSF appears to
             approximately correlate with the plasma free fraction (Kanto
             et al., 1975). Patients with low serum albumin concentrations
             may have greater CNS effects secondary to an increased free
             fraction of diazepam.
             Following intravenous administration, diazepam concentrations
             can be described by a 2 compartment kinetic model. An initial
             rapid decline in serum concentrations associated with
             distribution into tissue, is followed by a slower decline
             reflecting the terminal elimination half-life.

             Due to its high lipid solubility diazepam passes rapidly into
             the brain, and other well perfused organs, and is afterwards
             redistributed to muscle and adipose tissue.  Enterohepatic
             circulation is minimal.  Diazepam crosses the placental
             barrier to the fetus and is present in breast milk.

        6.3  Biological half-life by route of exposure

             The terminal elimination half-life of diazepam ranges
             from approximately 24 hours to more than two days.  With
             chronic dosing, steady state concentrations of diazepam are
             achieved between 5 days to 2 weeks.  The half-life is
             prolonged in the elderly and in patients with cirrhosis or
             hepatitis.  It is shortened in patients taking drugs which
             induce hepatic enzymes, included anticonvulsants.  The active
             metabolite desmethyldiazepam has a longer half-life than
             diazepam, and takes longer to reach steady state
             concentrations. (Klotz et al, 1976a; Mandelli et al, 1978;
             Klotz et al.,1975; Andreasen et al., 1976).

             A sample of 48 healthy male volunteers ranging in age from 18
             to 44 years demonstrated variable pharmacokinetic parameters.
             This demonstrates the need for further understanding of the
             variables which determine diazepam absorption, distribution,
             metabolism, and elimination (Greenblatt et al., 1989).

        6.4  Metabolism

             Diazepam is primarily metabolized by hepatic enzymes,
             with very little unchanged drug eliminated in the urine.  The
             hepatic cytochrome enzyme isozyme responsible for S-
             mephenytoin hydroxylation polymorphism is most likely the
             hepatic enzyme species responsible for diazepam metabolism
             (Perucca et al., 1994)  Hepatic n-demthylation results in the
             formation of the active metabolite desmethyldiazepam (also
             known as nordiazepam). This metabolite is hydroxylated to
             form oxazepam, which is conjugated to oxazepam glucuronide. A
             minor active metabolite is temazepam.  The main active
             substances found in blood are diazepam and desmethyldiazepam,
             because oxazepam and temazepam are conjugated and excreted at
             almost the same rate as they are generated  (Greenblatt et
             al., 1988; Baselt & Cravey, 1989).

        6.5  Elimination and excretion

             A two-compartment open model is usually used to describe
             elimination kinetics of diazepam and plasma clearance of  26
             to 35 mL/min after a single intravenous dose has been
             reported (Klotz et al., 1975; Andreasen et al., 1976; Klotz
             et al., 1976a). Urinary excretion of diazepam is primarily in
             the form of sulphate and glucuronide conjugates, and accounts
             for the majority of the ingested dose (Mandelli et al., 1978;

             Baselt & Cravey, 1986; Gilman et al., 1990)  There is some
             evidence that the disposition of diazepam is slowed by
             chronic dosing and by plasma desmethyldiazepam levels (Klotz
             et al., 1976b).
             There is some evidence for species differences in biliary
             excretion.  However, studies by Klotz et al. (1975; 1976a,b)
             suggest that biliary excretion of diazepam is probably
             clinically unimportant in man.


        7.1  Mode of action

             7.1.1  Toxicodynamics

                    The toxic and therapeutic effects of diazepam
                    are a result of its effect on CNS GABA activity.  GABA
                    (gamma-aminobutyric acid) is an important inhibitory
                    neurotransmitter which mediates pre- and post-synaptic
                    inhibition in all regions of the central nervous
                    Diazepam and the other benzodiazepines appear to
                    either enhance or facilitate GABA activity by binding
                    to the benzodiazepine receptor, which is part of a
                    complex including an aminobutyric acid receptor, 
                    benzodiazepine receptor, and barbiturate receptor.
                    Binding at the complex results in increased CNS
                    inhibition by GABA.  The anticonvulsant and other
                    effects of diazepam are believed to be produced by a
                    similar mechanism, possibly involving various subtypes
                    of the receptor (Gilman et al., 1990).

             7.1.2  Pharmacodynamics

                    The pharmacodynamic effects of diazepam are
                    also produced primarily by its actions with the result
                    being enhancement of the inhibitory effects of GABA on
                    the CNS.  Two different zones have been described for
                    the benzodiazepine binding at receptor sites (Squires
                    et al., 1979) and they have been classified as type I
                    (chloride independent) and type II (chloride
                    dependent.  Type I receptor stimulation is believed to
                    be responsible for anxiolysis, and Type II receptors
                    responsible for sedation and ataxia  (Klepner et al.,
                    Skeletal muscle relaxation is most likely secondary to
                    the CNS effects of diazepam, and may also involve
                    inhibition of a presynaptic neural conduction at GABA
                    mediated sites in the spinal chord. It is unclear how

                    diazepam produces amnesia. Similar to other sedative
                    hypnotic drugs, preanesthetic doses of diazepam
                    produce anterograde amnesia in the presence of
                    therapeutic concentrations of diazepam, probably by
                    impairing the establishment of the memory trace in the
                    CNS (Gilman et al., 1990) It has been suggested that
                    diazepam may have some anticholinergic effects,
                    however, these are not clearly defined, and not
                    generally of clinical importance.  (Goodman & Gilman,
                    1986; USPC, 1989).  Grade IV come has, however, been
                    reversed by physostigmine in a case of severe
                    nitrazepam poisoning, confirmed by drug screening.
                    The serum nitrazepam concentration was 6 µmol/L
                    (Jacobsen & Kjeldsen, 1979).
                    Tolerance to its anticonvulsant effects of diazepam
                    generally develop within the first 6 to 12 months of
                    therapy, which result in loss of anticonvulsant
                    effects.  For this reason diazepam is not commonly
                    utilised for the chronic treatment of seizure

        7.2  Toxicity

             7.2.1  Human data


                             There is no specific dose associated
                             with death.  In the few documented fatal
                             cases doses have not been known with
                             certainty and other factors complicated the
                             clinical presentation (Cardauns & Iffland,
                             1973).  In a survey of 914 benzodiazepine
                             related deaths in North America, only 2 cases
                             were associated with diazepam alone, in the
                             remainder other drugs were present which
                             either contributed to or caused death (Finkle
                             et al., 1979).  After the intentional
                             ingestion of doses of 450 to 500 mg, and 2000
                             mg in two cases, patients recovered without
                             specific therapy within 24 to 48 hours
                             (Greenblatt et al., 1978).
                             Toxicity associated with rapid intravenous
                             injection is not dose related, and may occur
                             at therapeutic doses.


                             As with adults, no specific diazepam
                             dose is associated with severe toxicity.  A
                             range of 4 to 5 mg/kg has been described as
                             producing clinical toxicity. (Arcas Cruz,
                             1985).  Cases involving the ingestion of 20
                             mg to 150 mg have resulted in complete
                             recovery (Clark, 1978).

                             The neonate is very sensitive to the effects
                             of benzodiazepine (Briggs et al.,

             7.2.2  Relevant animal data

                    LD50  (oral) rat  1200 mg/kg
                    LD50  (oral) dog  1000 mg/kg
                    LD50  (oral) mice 700  mg/kg
                    (Clarke, 1978)
                    Sub-chronic dosing
                    A number of repeated dose studies have been carried
                    out.  In general, toxic effects have not been
                    remarkable.  In a three-month study in rats and a six-
                    month study in dogs, some increase in liver size was
                    seen, together with an increase in blood cholesterol;
                    in the dogs an elevation of plasma alanine
                    aminotransferase activity was observed (Scrollini et
                    al., 1975).  The clinical significance of these data
                    is unclear.

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             While it was suggested that diazepam may be associated
             with increased frequency of tumours in some animal models,
             this has not been confirmed.  De la Iglesia et al. (1981)
             found no increase in tumour frequency after feeding diazepam,
             75 mg/kg/day, to rats and mice for 104 and 80 weeks,
             respectively. There is no evidence of carcinogencity in
             humans. (Reynolds, 1993)  A suggestion that benzodiazepine
             ingestion is associated with an increased risk of breast
             cancer has been disproved by additional studies (Kaufman,

        7.4  Teratogenicity

             There is a some evidence that diazepam and other
             benzodiazepines are teratogenic in humans, increasing the
             risk of congenital malformations when ingested by the mother
             during the first trimester of pregnancy (Reynolds, 1993;
             USPC, 1989; Briggs et al., 1986).

        7.5  Mutagenicity

             Diazepam has been reported to have mutagenic activity in
             the Salmonella typhimurium tester train TA100 in the Ames
             test (Batzinger et al., 1978), and to be genotoxic in a mouse
             bone marrow micronucleus test (Das & Kar, 1986).  Little or
             no effect was seen in an assay for chromosomal abberations,
             performed in Chinese hamster cells in vitro, by Matsuoka et

        7.6  Interactions

             Synergistic effects of CNS depression is observed when
             diazepam is ingested together with ethanol and other CNS
             depressant drugs. CNS depressant co-ingestants are very
             common, and virtually always present if coma greater than
             Grade II is present (Jatlow et al., 1979).
             Metabolic interactions
             Diazepam does not induce or inhibit hepatic enzyme activity,
             and does not alter the metabolism of other agents.  There is
             also no evidence of autoinduction or inhibition which would
             significantly alter its own metabolism with chronic therapy
             (Reynolds, 1993).  There is a report suggesting that diazepam
             therapy may alter digoxin serum concentrations (Reynolds,
             As diazepam is primarily dependent on hepatic metabolism for
             elimination, numerous agents which either induce or inhibit
             hepatic cytochrome P450 pathways or conjugation can alter the
             rate of diazepam metabolism.  With many interactions it is
             not clear whether the interaction is maintained with chronic
             therapy.  These interactions would be expected to be most
             significant with chronic diazepam therapy, and their clinical
             significance is variable.  The following lists includes most
             of the reported interactions (however, the possibility of
             interactions between diazepam and any substance known to
             alter hepatic metabolism should be considered).
             Agents inhibiting diazepam metabolism:
             Oral contraceptives

             Agents inducing diazepam metabolism:
             Cigarette smoking
             (Gilman et al., 1990; Plon & Gottschalk, 1988; Reynolds,
             1993; USPC, 1989; Lemberger et al., 1988; Perucca et al.,
             1994; Okiyama et al., 1987).
             Dynamic interaction
             The major dynamic interactions with diazepam involve the
             synergistic increase in CNS depression (including central
             respiratory depression and hemodynamic depression) associated
             with other CNS depressant agents, including ethanol, non-
             benzodiazepine sedative hypnotics, barbiturates, drugs with
             CNS anticholinergic effects such as the antihistamines and
             tricyclic antidepressants, and opioids.  These interactions
             increase synergistically the CNS depression, respiratory
             depression, and hemodynamic depression produced by each agent
             Diazepam can decrease the efficacy of L-dopa used for the
             treatment of Parkinsonism.  The effect is reversible
             (Reynolds, 1993).
             The anticonvulsant action of diazepam antagonizes the pro-
             convulsant activity of certain agents, including cocaine and

        7.7  Main adverse effects

             The primary adverse effects are secondary to the
             pharmacologic action of enhanced CNS GABA activity. Cognitive
             and psychomotor abilities may be impaired at therapeutic
             doses.  Additional adverse effects include dizziness and
             prolonged reaction time, motor incoordination, ataxia, mental
             confusion, dysarthria, anterograde amnesia, somnolence,
             vertigo, and fatigue. Dysarthria and dystonia occur much less

             Paradoxical reactions of CNS hyperactivity occur rarely and
             manifest primarily as aggressive behaviour, irritability, and
             anxiety. Intravenous injection can produce local phlebitis
             and thrombophlebitis.  Intra-articular injection may produce
             arterial necrosis.  Diazepam and other benzodiazepines can
             cause physical and psychological dependence when administered
             at high doses for prolonged periods of time (Hollister et
             al., 1961; 1963; 1981; Hollister, 1988).
             A withdrawal syndrome has been described after continuous
             ingestion of 30 to 45 mg per day of diazepam for
             approximately 6 weeks or longer.  Symptoms are generally
             minimal initially, and increase in severity over the first 5
             to 9 days after diazepam ingestion is stopped. (Pevnick et
             al., 1978).
             The clinical manifestations of the withdrawal syndrome are
             similar to those associated with withdrawal of other sedative
             hypnotic and CNS depressants drugs. The long half-life and
             presence of active metabolites result in delayed onset of
             symptoms. The symptoms include anxiety, insomnia,
             irritability, confusion, anorexia, nausea and vomiting,
             tremors, hypotension, hyperthermia, and muscular spasm.
             Severe withdrawal symptoms include seizures and death. The
             treatment to prevent withdrawal and minimize any symptoms is
             to slowly reduce the dose of diazepam over 2 to 4


        8.1  Material sampling plan
             8.1.1  Sampling and specimen collection
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses
             8.1.2  Storage of laboratory samples and specimens
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses
             8.1.3  Transport of laboratory samples and specimens
            Toxicological analyses
            Biomedical analyses
            Arterial blood gas analysis
            Haematological analyses
            Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation
             8.2.1  Tests on toxic ingredient(s) of material
            Simple Qualitative Test(s)
            Advanced Qualitative Confirmation Test(s)
            Simple Quantitative Method(s)
            Advanced Quantitative Method(s)
             8.2.2  Tests for biological specimens
            Simple Qualitative Test(s)
            Advanced Qualitative Confirmation Test(s)
            Simple Quantitative Method(s)
            Advanced Quantitative Method(s)
            Other Dedicated Method(s)
             8.2.3  Interpretation of toxicological analyses
        8.3  Biomedical investigations and their interpretation
             8.3.1  Biochemical analysis
            Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"
            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

        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


        9.1  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
                    Coma Grade II:  Depressed level of consciousness, no
                                    response to painful stimuli
                                    Deep tendon reflexes and vital signs
                    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

             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

            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
                             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.

            Peripheral nervous system

            Autonomic nervous system

            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,

             9.4.6  Urinary


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


             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,

             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

           Acid-base disturbances

                             No direct disturbances have been

           Fluid and electrolyte disturbances

                             No direct disturbances have been


             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.,

             9.4.15 Special risks

                    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,

                    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,

        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.
             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,

        9.6  Summary


        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

        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

        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.,
                    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.,

        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


        11.1 Case reports from literature

             A  61 year old women ingested between 450 and 500 mg of
             diazepam approximately 8 hours before presentation.  She had
             been treated with imipramine for depression, though there was
             no evidence of coingestion of imipramine.  She did not
             respond to the administration of naloxone or 50% Dextrose in
             water intravenously, and responded only to noxious physical
             stimuli. Her blood pressure was 110/80 mmHg, heart rate was
             75 to 80 per minute, and respiratory rate was 20 per min.
             Arterial blood gases were normal, as were other laboratory
             tests.  She was observed, and other than a mild episode of
             hypotension which resolved without treatment, her recovery
             was uneventful.  She was fully alert and responsive 1 day
             after admission (Greenblatt et al., 1978).
             A 28 year old man ingested 2,000 mg diazepam approximately 10
             hours before presentation.  He had a blood pressure of 110/60
             mmHg, heart rate of 68 per minute, and spontaneous
             respirations of 16 per minute.  He was responsive to verbal
             stimuli, and oriented to person, place and time.  He was
             observed, and fully alert 2 days after admission (Greenblatt
             et al., 1978).
             A healthy young male known to use diazepam was admitted two
             hours after ingestion of 1 gram of diazepam.  Upon admission
             he felt tired, otherwise the clinical examination and
             standard laboratory evaluation was normal.  The serum
             diazepam concentration was 18.6 µmol/L.  The patient
             recovered uneventfully (Jacobsen et al., 1979).

    12. Additional information

        12.1 Specific preventive measures

             Not relevant.

        12.2 Other

             Not relevant.


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        Author           Dr Pere Munne
                         Urgencias (Toxicologia)
                         Hospital Clinic Emergency Department
                         170 Villarroel Street
                         08036 Barcelona
                         Tel: 34-3-4546000
                         Fax: 34-3-4546691
                         Date: April 1990
        Peer Review:     Strasbourg, France, April 1990
                         Adelaide, Australia, April 1991
                         Dr. Wm Watson, August, 1996
                         INTOX - 9, Cardiff, Wales, September, 1996

        This monograph has been harmonised with the Group Monograph (G008)
        on Benzodiazepines:
        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

    See Also:
       Toxicological Abbreviations
       Diazepam (IARC Summary & Evaluation, Volume 66, 1996)