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Moclobemide

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 ANALYSIS AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analysis
         8.1.1.2 Biomedical analysis
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analysis
         8.1.1.5 Other (unspecified) analysis
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analysis
         8.1.2.2 Biomedical analysis
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analysis
         8.1.2.5 Other (unspecified) analysis
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analysis
         8.1.3.2 Biomedical analysis
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analysis
         8.1.3.5 Other (unspecified) analysis
   8.2 Toxicological analysis 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 Test 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
         8.2.2.4 Advanced quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analysis
   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 analysis
      8.3.3 Haematological analysis
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analysis 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
         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
    MOCLOBEMIDE

    International Programme on Chemical Safety
    Poisons Information Monograph 151
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Moclobemide

        1.2  Group

             Psycholeptics (N06)/ Antidepressants (N06A)/
             Non-hydrazide MAO inhibitors (N06A G02)

        1.3  Synonyms

             RO 11-1163

        1.4  Identification numbers

             1.4.1  CAS number

                    71320-77-9

             1.4.2  Other numbers

                    No data available.

        1.5  Main brand names, main trade names

             Aurorix (Australia, Austria, Belgium, Germany,
             Netherlands, Norway, South Africa, Sweden, Switzerland);
             Manerix (Canada, Spain, UK);
             Moclamine (France);

        1.6  Main manufacturers, main importers

             Roche

    2.  SUMMARY

        2.1  Main risks and target organs

             Moclobemide is a short-acting, selective and reversible
             monoamine oxidase type A inhibitor (RIMA).
             It is generally well tolerated in overdose when taken
             alone.
    

             The serotonergic effects of moclobemide may be enhanced by
             combination with tricyclic antidepressants, other monoamine
             oxidase inhibitors, selective serotonin reuptake inhibitors
             (SSRIs), lithium or serotonergic substances. A life-
             threatening serotonin syndrome consisting of hyperthermia,
             tremor and convulsions can develop when moclobemide is
             ingested with these drugs.
             The concomitant consumption of large amounts of tyramine-rich
             foodstuff may result in a moderate increase of systolic blood
             pressure (cheese reaction).

        2.2  Summary of clinical effects

             Agitation, drowsiness, disorientation, slow-reacting
             pupils, myoclonic jerks in upper extremities; hypo or
             hypertension, tachycardia; nausea, vomiting, abdominal
             pain.

        2.3  Diagnosis

             Diagnosis of moclobemide poisoning is clinical and based
             on history of overdose and/or access to moclobemide and the
             presence of gastroenterological symptoms and minor
             neurological symptoms.
             Co-ingestion of tricyclic antidepressants and/or selective
             serotonin reuptake inhibitors should be suspected and the
             diagnosis of the serotonin syndrome should be considered in
             the presence of three or more of the following symptoms:
             behavioural change (confusion or hypomania), agitation,
             myoclonus, ocular clonus, hyperreflexia, sweating, shivering,
             tremor, diarrhoea, motor incoordination, muscle rigidity,
             fever. The differential diagnoses include neuroleptic
             malignant syndrome, acute poisoning with strychnine, acute
             sepsis, or severe metabolic disturbances.

        2.4  First aid measures and management principles

             Due to the potential for delayed toxicity, any patient
             with a history of acute moclobemide overdose, should be
             admitted for observation and remain for 24 hours, even in the
             absence of initial symptoms.
             Management of moclobemide overdose as a single agent consists
             primarily of observation and basic supportive care until
             symptoms resolve.
             Treatment of the serotonin syndrome may require aggressive
             supportive care including diazepam, mechanical ventilation,
             external cooling and if necessary, curarization. Although
             several deaths have been reported, the symptoms of the
             serotonin syndrome usually resolve over 1 to 2 days with
             supportive care.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Obtained by synthesis.

        3.2  Chemical structure

             Structural name: 4-Chloro-N (2-morpholinothyl)benzamide
    
             Molecular formula: C13H17O2N2Cl
    
             Molecular weight: 268.7

        3.3  Physical properties

             3.3.1  Colour

                    Whiteredish

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Weak odour
                    Solubility (g/100 mL) at 25 C:
                    Chloroform: 33.6
                    Methanol: 11.8
                    Water: 0.4
                    Artificial gastric fluid (pH 1.2): 2.6 at 37 C
                    Artificial intestinal fluid (pH 6.8): 0.3 at 37 C
                    pKa 6.2
                    Melting point: 138 C
                    (Roche lab., 1996)

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    3 years at 20 C

             3.4.2  Storage conditions

                    Keep at 20 C in polyethylene bottles or foil
                    packs.

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Psychoanaleptic Antidepressant Monoamine oxidase inhibitor;
                    non-selective;
                    antidepressant

             4.1.2  Description

                    Accepted:
                    Major mental depression
                    Dysthymia.
                    Investigational:
                    Menopausal flushing (Menkes et al., 1994)
                    Prophylactic treatment of migraine (Meienberg &
                    Amsler, 1996)
                    Smoking cessation and abstinence in heavy dependent
                    smokers (Berlin et al., 1995).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Usual initial dosage is a total daily dose of
                    300 mg by mouth after food in 2 or 3 doses. This may
                    be increased to up to 600 mg daily according to
                    response (Reynolds, 1996).
                    Dosage should be reduced by one third or half the
                    normal dosage in patients with significant hepatic
                    impairment (Roche lab., 1996).

             4.2.2  Children

                    No data available

        4.3  Contraindications

             Absolute:
             Hypersensitivity to moclobemide.
             Children less than 15 years old.
             Breast feeding (in the absence of available data on potential
             toxic effects to suckling infants): less than 3 % of the
             administered dose of moclobemide is excreted in breast
             milk.
             Co-administration of sumatriptan: hypertensive crises, severe
             coronary vasoconstriction may occur.
             Co-administration of pethidine (meperidine),
             dextromethorphan: the serotonin syndrome may occur.
             (Roche lab., 1996)
    

             Moclobemide is contra-indicated in patients with acute
             confusional states and in those with phaeochromocytoma.
             It should be avoided in excited or agitated patients and in
             those with severe hepatic impairment.
             (Reynolds, 1996)
             Relative:
             Co-administration of drugs which increase the levels of
             monoamines such as serotonin and noradrenaline: tricyclic
             antidepressants, selective serotonin re-uptake inhibitor
             antidepressants: a serotonin syndrome may occur.
             Alcohol (as for other psychoactive drugs).
             Pregnancy (no data available)
             (Roche lab., 1996).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Moclobemide is available as tablets, thus ingestion is
             the most common route of exposure.

        5.2  Inhalation

             Not relevant

        5.3  Dermal

             Not relevant

        5.4  Eye

             Not relevant

        5.5  Parenteral

             No data available

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Readily absorbed from the gastro-intestinal tract.
             Food delays absorption (Fulton and Benfield, 1996).
             Peak plasma concentration: 1 to 2 hours after ingestion.
             Oral bioavailability was reported as 60 % after a single dose
             and 80 % after repeated doses, due to an important and
             saturable hepatic first-pass effect (Roche lab., 1996).

        6.2  Distribution by route of exposure

             Widely distributed throughout the body. Plasma protein
             binding is 50 %.
             After oral administration of 50 mg to 6 healthy subjects, the
             mean volume of distribution was about 1 L/kg (Raaflaub et
             al., 1984).
             The therapeutic levels range from 0.5 to 1.5 mg/L (Iwersen &
             Schmoldt, 1996).
             Less than 3 % of the administered dose is excreted in breast
             milk (Mayersohn & Guentert, 1995).

        6.3  Biological half-life by route of exposure

             After single oral doses, plasma half-life is 1 to 2
             hours; with long term treatment, the half-life is reported to
             increase to 2 to 4 hours (Iwersen & Schmoldt, 1996; Roche
             lab., 1996).

        6.4  Metabolism

             Moclobemide undergoes extensive metabolism, mainly
             carbon and nitrogen oxidation in the liver, deamination and
             aromatic hydroxylation. Metabolites are inactive (Mayersohn &
             Guentert, 1995).

        6.5  Elimination and excretion

             Systemic plasma clearance: 310 to 750 mL/min.
             Renal clearance: 1 to 5 mL/min
             Metabolites of moclobemide and a small amount of unchanged
             drug (less than 1 %) are excreted in the urine; after an oral
             dose of 50 mg radio-labelled moclobemide, 92 % of the dose
             was excreted in the urine within 12 hours (Roche lab.,
             1996).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Moclobemide selectively and reversibly inhibits
                    the activity of the intracellular enzyme monoamine
                    oxidase A (MAO-A), thus preventing the normal
                    metabolism of biogenic amines (noradrenaline,
                    adrenaline, serotonin, dopamine).
                    Mono amine oxidase inhibitors (MAOIs) exert their
                    toxic effects by inhibiting the metabolism of
                    sympathomimetic amines and serotonin, and by
                    decreasing noradrenaline stores in post-ganglionic
                    sympathetic neurons. They do not inhibit MAO
                    synthesis. MAOIs also inhibit enzymes other than MAO,

                    including dopamine-beta-oxidase, diamine-oxidase,
                    amino-acid decarboxylase and choline dehydrogenase.
                    Inhibition of these enzymes occurs only with very high
                    doses of MAOIs and may be responsible for some of the
                    toxic effects of MAOIs.
                    Drugs that enhance serotonin release or reuptake
                    (tricyclic antidepressants, selective serotonin
                    reuptake inhibitors) may cause the serotonin syndrome
                    when they are administered concurrently with the
                    MAOIs, even at therapeutic doses (Sternbach, 1991;
                    Livingston & Livingston, 1996).
                    A toxic reaction to MAOIs may be caused by pressor
                    amines such as tyramine, resulting in hypertensive
                    crisis. When the protective role of intestinal and
                    hepatic MAO is eliminated, increased absorption of
                    tyramine from certain foods occurs and can cause a
                    significant increase in blood pressure ("cheese
                    reaction") through the release of noradrenaline from
                    pre-synaptic vesicles (Mayersohn & Guentert,
                    1995).
                    Two isoforms of the MAO enzyme have been discovered:
                    MAO-A and MAO-B. These isoforms differ in anatomical
                    distribution and preferred substrates. The new MAOIs
                    such as moclobemide are isoform-selective and
                    reversibly inhibit MAO-A. Thus having a lower
                    potential for interactions than non selective MAOIs at
                    therapeutic doses. Selectivity is lost in overdoses
                    and in extreme situations such as high-dose
                    combination therapies and mixed drug overdoses, and
                    severe toxic reactions may occur (Mayersohn &
                    Guentert, 1995).

             7.1.2  Pharmacodynamics

                    The MAOs are a group of enzymes that
                    metabolise, and therefore inactivate endogenous
                    pressor amines (such as noradrenaline, adrenaline,
                    dopamine, serotonin) as well as ingested indogenous
                    amines (such as tyramine). MAOIs inhibit the
                    degradation of these amines by MAO. The increased
                    availability of biogenic amines (such as noradrenaline
                    and serotonin) is thought to be linked with the
                    improvement in depression accounted for by MAIO
                    treatment (Livingston & Livingston, 1996).
                    Two isoforms of the MAO enzyme have been discovered:
                    MAO-A and MAO-B, which differ in anatomical
                    distribution and preferred substrates. The MAO type A
                    enzymes preferentially metabolize serotonin and
                    noradrenaline and are located primarily in the
                    placenta, gut and liver. The MAO type B enzymes are
                    predominant in brain, liver and platelets, and
                    phenylethylamine, methylhistamine and tryptamine are
                    their primary substrates. Both MAO-A and MAO-B

                    metabolize tyramine (Mayersohn & Guentert, 1995).
                    New MAOIs such as moclobemide, which are isoform-
                    selective and have reversible inhibition of the enzyme
                    are called Reversible Inhibitors of MAO-A (RIMA). The
                    duration of MAO-A inhibition by moclobemide is shorter
                    (16 to 24 hours) than the inhibition induced by
                    conventional MAOIs (> 10 days) (Roche lab.,
                    1996).
                    The interaction of the newer RIMAs with hepatic
                    cytochrome P450 appears to be much weaker than with
                    the irreversible and nonspecific MAOIs. However,
                    several studies in humans have suggested there is some
                    involvement of cytochtome P450 in the metabolism of
                    moclobemide, and also a weak inhibitory effect of
                    moclobemide for its isoenzyme CYP2D6. The clinical
                    relevance of this weak interaction is not clear and is
                    probably of little consequence (Mayersohn & Guentert,
                    1995).
                    Like tricyclic antidepressants, SSRIs and other MAOIs,
                    moclobemide significantly reduces REM (rapid eye
                    movement) sleep density, REM time and the REM
                    percentage of total sleep time in patients with major
                    depression (Roche lab., 1996).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Myrenfors et al. (1993) reported a
                             case series of 8 pure moclobemide overdoses.
                             Patients ingesting up to 2 grams showed no
                             symptoms or mild gastro-intestinal
                             disturbances.
                             Ingestions of 3 to 4 grams were associated
                             with a slight increase in blood pressure, and
                             decrease in consciousness.
                             Fatigue, agitation, tachycardia, increased
                             blood pressure, and minimally reactive
                             mydriasis occurred with the ingestion of
                             moclobemide doses of 7 to 8 grams.
                             The ingestion of moclobemide with other drugs
                             produced a more varied and severe clinical
                             picture, even with moderate doses of
                             moclobemide.

                    7.2.1.2  Children

                             No data available

             7.2.2  Relevant animal data

                    In mice: LD 50 (oral): 1141 mg/kg
                    LD 50 (intraperitoneal): 527 mg/kg
                    Symptomatology: sedation, muscle twitching,
                    respiratory depression, death.
    
                    In rats: LD 50 (oral): 4138 mg/kg
                    LD 50 (intraperitoneal): 678 mg/kg
                    Symptomatology: sedation, respiratory depression,
                    death.
    
                    In rabbits: LD 50 (oral): 800 mg/kg
                    Symptomatology: ataxia, decrease in motor activity,
                    respiratory depression, tremor, seizures, salivation,
                    death.
                    (Roche lab., 1996).

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             Animal studies: moclobemide was not carcinogenic in
             rats at doses ranging from 9 to 225 mg/kg/day orally for 2
             years. In mice given 10, 50 or 100 mg/kg/day orally over 80
             weeks, no carcinogenic effect was observed (Roche lab.,
             1996).

        7.4  Teratogenicity

             Animal studies:
             - doses up to 100 mg/kg/day did not affect fertility in
             rats.
             - in rabbits and rats oral doses of up to 100 and 200
             mg/kg/day respectively did not have embryotoxic or
             teratogenic effects
             (Roche lab., 1996).

        7.5  Mutagenicity

             In vitro and in vivo: moclobemide did not show
             mutagenicity (Roche lab., 1996).

        7.6  Interactions

             Drug-food interactions:
             the dietary restrictions that need to be followed with
             irreversible MAOIs are less stringent with selective
             reversible inhibitors of monoamine oxidase type A such as
             moclobemide. However, the manufacturer of moclobemide
             recommends that since some patients may be more sensitive to
             tyramine, the consumption of large amounts of tyramine-rich

             foodstuffs should still be avoided; these foods include
             chocolate, aged cheeses, beer, chianti, vermouth, pickled
             fish and concentrated yeast extracts (Reynolds, 1996; Roche
             lab., 1996).
    
             Drug-drug interactions:
             Sympathomimetics and anorectic drugs should not be taken with
             moclobemide.
             Opioid analgesics: Central Nervous System (CNS) excitation or
             depression may occur.
             Drugs used in anaesthesia: anaesthesia may be performed 24
             hours after discontinuation of moclobemide with little
             potential for significant interaction (Blom-Peters & Lamy,
             1993; Mac Farlane, 1994); when the washout period is not
             feasible, the use of pethidine and parenteral
             sympathomimetics should be avoided (Roche lab., 1996).
             Levodopa: a hypertensive crisis may be precipitated.
             Sumatriptan: the manufacturer recommends to not prescribe
             moclobemide concominantiantly with sumatriptan which is a
             selective agonist at serotonin type 1D receptors, because of
             possible hypertensive crises and severe coronary
             vasoconstriction, and advises a washout period of 24 hours
             after discontinuation of moclobemide; however a clinical
             study performed by Blier & Bergeron (1995) involving 103
             episodes of migraine, did not show evidence of significant
             adverse effects.
             The metabolism of moclobemide is inhibited by cimetidine,
             leading to a prolonged half-life and increased plasma
             concentrations (Livingston & Livingston, 1996); the
             manufacturer recommends that the dose of moclobemide be
             reduced to half strength in patients who are also given
             cimetidine.
             The co-administration of drugs that increase the levels of
             monoamines such as serotonin and noradrenaline, including
             tricyclic antidepressants (mainly clomipramine), selective
             serotonin re-uptake inhibitor antidepressants, and
             potentially other antidepressants may cause a serotonin
             syndrome (Spigset et al., 1993; Kuisma, 1995; Liebenberg et
             al., 1996).
             Lithium: according to Livingston & Livingston (1996), care
             should be taken when co-prescribing RIMAs with lithium, since
             it increases serotonin levels, although no interactions have
             been reported to date.
             Therapy with moclobemide should not be started until at least
             7 days following the discontinuation of tricyclic or
             serotonin reuptake inhibitor antidepressant treatment (2
             weeks in the case of paroxetine; 5 weeks in the case of
             fluoxetine) or for at least a week after stopping treatment
             with other monoamine oxidase inhibitors (Reynolds, 1996).
             Conversely, a washout period of 24 hours is advised when
             switching from moclobemide to other antidepressants (Lane &
             Fischler, 1995).
    

             Antipsychotics, benzodiazepines, nifedipine and
             hydrochlorothiazide may be coprescribed without major
             interaction (Livingston & Livingston, 1996).

        7.7  Main adverse effects

             They include sleep disturbances, dizziness, nausea, and
             headache.
             Confusional states, restlessness or agitation may occur.
             Mild elevations in liver enzyme values have been
             reported.
             Care is required in patients with thyrotoxicosis as
             moclobemide may theoretically precipitate a hypertensive
             reaction.
             Mental alertness may be impaired, patients under treatment
             should not drive or operate machinery (Reynolds, 1996).
             Manic episodes may be provoked in patients with bipolar
             disorders, moclobemide should be discontinued and
             antipsychotic therapy should be initiated (Reynolds, 1996;
             Roche lab., 1996).
             Less common adverse effects include:
             - hypertension, although the role of concomitant
             administration of clomipramine, buspirone, thyroxine in the
             case series reported by Coulter & Pillans (1995) may have
             contributed and cannot be disregarded,
             - alopecia (Sullivan & Mahmood, 1997),
             - a case of fatal intrahepatic cholestasis was described
             (Timmings & Lamont, 1996) in a 85 year-old woman after she
             was switched from fluoxetine to moclobemide without a washout
             period. The role of moclobemide in causing this adverse
             reaction is questionable and it is more likely that the
             hepatotoxic effect was associated with co-administration of
             both drugs,
             - a case of sexual hyperarousal in a female patient was
             reported by Lauerma (1995),
             - a toxic shock like-syndrome was described by O'Kane &
             Gottlieb (1996).

    8.  TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analysis

                    8.1.1.2  Biomedical analysis

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analysis

                    8.1.1.5  Other (unspecified) analysis

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analysis

                    8.1.2.2  Biomedical analysis

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analysis

                    8.1.2.5  Other (unspecified) analysis

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analysis

                    8.1.3.2  Biomedical analysis

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analysis

                    8.1.3.5  Other (unspecified) analysis

        8.2  Toxicological analysis 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  Test 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

                    8.2.2.4  Advanced quantitative method(s)

                    8.2.2.5  Other dedicated method(s)

             8.2.3  Interpretation of toxicological analysis

        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 analysis

             8.3.3  Haematological analysis

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analysis and
             toxicological investigations

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Patients may display minimal or no symptoms
                    following pure moclobemide overdose. However, the
                    ingestion of moclobemide may cause nausea, vomiting,
                    gastric pain; agitation, disorientation, drowsiness,
                    impaired reflexes, myoclonic jerks in upper
                    extremities, slow-reacting pupils; slight rise in
                    blood pressure or moderate hypotension and tachycardia
                    (Myrenfors et al., 1993; Iwersen & Schmoldt,
                    1996).
                    Co-ingestion of tricyclic antidepressants (primarily
                    clomipramine), opioids, or SSRIs can result in more
                    varied and severe symptoms appearing within 2 to 3
                    hours after ingestion, even with lower doses of
                    moclobemide. Symptoms include: both CNS depression
                    (confusion, drowsiness) and excitation (seizure),
                    tremor, mydriasis, hyperthermia with muscle rigidity,
                    hypertension and metabolic acidosis (Myrenfors et al.,
                    1993). Several fatal cases have been reported after a
                    combination of moclobemide with citalopram,
                    clomipramine and fluoxetine (Power et al., 1995;
                    Hernandez et al., 1995) and moclobemide with
                    citalopram and fluoxetine (Neuvonen et al.,
                    1993).

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    No data available

             9.1.4  Eye contact

                    Not relevant

             9.1.5  Parenteral exposure

                    No data available

             9.1.6  Other

                    No data available

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    No data available

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    No data available

             9.2.4  Eye contact

                    Not relevant

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available

        9.3  Course, prognosis, cause of death

             Pure moclobemide overdoses usually have a fairly benign
             course.
             Several fatalities are reported in the literature, all
             involving a co-ingestion (Neuvonen et al., 1993; Power et
             al., 1995; Hernandez et al., 1995). The clinical course
             consisted of euphoria, agitation, then extreme tremor,

             followed by convulsions and hyperthermia. Death occured
             within 3 to 16 hours after ingestion, after intractable
             seizure and/or hyperthermia and its subsequent complications:
             disseminated intravascular coagulation and multiple organ
             failure.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Mild to moderate hypertension (Myrenfors et
                    al., 1993)
                    Moderate hypotension (Heinze & Sanchez, 1986)
                    Sinus tachycardia (Myrenfors et al., 1993)

             9.4.2  Respiratory

                    No data available.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system

                             Mild disorientation, agitation,
                             slurred speech, anxiety, dizziness; headache;
                             drowsiness, coma.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             Slow-reacting pupils, mydriasis
                             (Myrenfors et al., 1993).

                    9.4.3.4  Skeletal and smooth muscle

                             Myoclonic jerks in upper
                             extremities; muscle rigidity;
                             rhabdomyolysis.

             9.4.4  Gastrointestinal

                    Dry mouth; nausea, vomiting, gastric pain; diarrhoea.

             9.4.5  Hepatic

                    Mild increases in liver enzymes values.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Sweating

             9.4.9  Eye, ear, nose, throat: local effects

             9.4.10 Haematological

                    DIC has occurred in a fatal case.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Acidosis is expected in association
                             with coma and/or convulsions.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hyperkalemia

                    9.4.12.3 Others

                             Creatine phosphokinase may be
                             elevated in patients with muscular
                             hyperactivity or rigidity.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    No data available.

        9.5  Other

             Abuse potential does exist with MAOIs. Although there
             are currently no reported cases of dependence on the RIMAs,
             it is wise to be cautious when prescribing these drugs for
             individuals who have a substance misuse problem, including
             alcohol dependence, or for personality-disordered patients
             with poor impulse control (Livingston & Livingston,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1  General principles

             The primary management of isolated moclobemide overdose
             consists of the institution of careful observation of vital
             signs and neurological status and supportive care until signs
             and symptoms resolve. Intravenous access should be
             established as soon as practical.
             In more severe intoxications or where there are other
             substances ingested, more aggressive measures such as
             establishment of an airway, ventilation, administration of
             intravenous fluids, control of seizures, and control of
             hyperthermia may be necessary.

        10.2 Life supportive procedures and symptomatic/specific treatment

             In pure moclobemide overdose, intensive supportive care
             is rarely required. In severe cases or when a serotonin
             syndrome occurs, measures that may be required include:
             endotracheal intubation and assisted ventilation if coma is
             present, intravenous fluid resuscitation if hypotension is
             present, pharmacological control of seizures, and cooling if
             hyperthermia is present.

        10.3 Decontamination

             For doses of up to 2000 mg, gastrointestinal
             decontamination by administration of a single oral dose of
             activated charcoal should be considered. Gastric lavage
             followed by activated charcoal should be advocated in
             patients who have ingested higher doses and/or when there has
             been a co-ingestion.

        10.4 Enhanced elimination

             There are no effective methods known to enhance the
             elimination of moclobemide.

        10.5 Antidote treatment

             10.5.1 Adults

                    No data

             10.5.2 Children

                    No data

        10.6 Management discussion

             Although dantrolene has been used successfully by
             Myrenfors et al. (1993), its role in the management of the
             serotonin syndrome has yet to be defined.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Iwersen & Schmoldt (1996) described a 46-year-old
             female who ingested 3000 mg of moclobemide. Gastric lavage
             was performed and activated charcoal was administered two
             hours after ingestion. The patient was fully orientated. Her
             temperature was 37 C, blood pressure remained within a range
             of 110/70 to 143/81 mmHg during 24 hours following admission,
             and heart rate remained stable between 58 and 74 bpm. No
             abnormalities were observed during the period of continuous
             ECG monitoring. After 24 hours the patient was discharged. On
             admission, the plasma moclobemide was 60.9 mg/L, 12 hours
             later the concentration was 4.6 mg/L.
      
             Myrenfors et al. (1993) described a 24-year-old woman who
             ingested a combination of moclobemide (5000 mg) with
             clomipramine (625 mg), nitrazepam (20 mg) and one bottle of
             wine. Two hours later she was admitted to the emergency
             department with mild disorientation, nausea and drowsiness.
             Blood pressure was 90/60 mmHg, heart rate 145 bpm, and
             respiratory rate 21/minute. ECG showed sinus tachycardia. The
             stomach was emptied and activated charcoal was administered.
             15 minutes later she developed convulsions. She was intubated
             and mechanically ventilated and a continuous infusion of
             thiopentone (2 mg/kg) was given. The temperature was 38.7 C
             and mild metabolic acidosis was present. Three hours later
             the patient's temperature rose to 41.9 C and dantrolene
             sodium was given at a dose of 1 mg/kg body weight. Because of
             persisting fever and muscle rigidity, another dose was given
             2.5 hours later. Within 4.5 hours the temperature had
             declined to 37.9 C and the muscle rigidity was less
             pronounced. The patient was extubated 48 hours after
             admission, fully alert but complaining of muscular stiffness
             and pain, mainly in her legs. A third dose of dantrolene
             sodium was given. After developing pneumonia, the patient

             recovered uneventfully and was discharged on the 10th day.
             The muscle pain and stiffness were still present 1 month
             after the intoxication. Biological disturbances included:
             increased serum CPK, transient myoglobinuria and increased
             liver enzymes.
    
             Neuvonen et al. (1993) reported several fatalities after
             moclobemide-clomipramine overdoses. Two patients (male 23-
             year-old, female 19-year-old) ingested 1000 to 1500 mg of
             moclobemide and 225 to 500 mg of clomipramine in order to get
             "high". 2 to 3 hours later they were euphoric, but within the
             next 2 hours both had severe tremors, followed by convulsions
             and loss of consciousness. One patient also exhibited
             hyperthermia.  Both died 9 to 10 hours after taking the
             drugs. Blood concentrations of moclobemide and clomipramine
             at admission and at necropsy showed only moderate
             overdosage.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             No data

        12.2 Other

             No data

    13. REFERENCES

        Berlin I, Said S, Spreux-Varoquaux O, Launay JM, Olivares R,
        Millet V, Lecrubier Y & Puech AJ (1995) A reversible monoamine
        oxidase A inhibitor (moclobemide) facilitates smoking cessation
        and abstinence in heavy, dependent smokers. Clin Pharmacol Ther,
        58: 444-452
    
        Blier P & Bergeron R (1995) The safety of concomitant use of
        sumatriptan and antidepressant treatments. J Clin Psychopharmacol,
        15: 106-109
    
        Blom-Peters L & Lamy M (1993) Monoamine oxidase inhibitors and
        anaesthesia., 44, 2: 57-60
    
        Coulter DM & Pillans PI (1995) Hypertension with moclobemide.
        Lancet, 346: 1032
    
        Fulton B & Benfield P (1996) Moclobemide An update of its
        Pharmacological Properties and Therapeutic Use. Drug 53(3): 450-
        474
    
        Heinze G & Sanchez A (1986) Overdose with moclobemide. J Clin
        Psychiatry, 47: 438
    

        Hernandez AF, Montero MN, Pla A, & Enrique V (1995) Fatal
        Moclobemide overdose or death caused by serotonin syndrome?
        Journal of Forensic Sciences 40(1): 128-130.
    
        Iwersen S & Schmoldt A (1996) Three suicide attempts with
        moclobemide. Clin Toxicol, 34: 223-225
    
        Kuisma MJ (1995) Fatal serotonin syndrome with trismus. Ann Emerg
        Med, 26, 1: 108
    
        Lane R & Fischler B (1995) The serotonin syndrome: co-
        administration, discontinuation and washout periods for the
        selective serotonin reuptake inhibitors (SSRIs). J Serotonin
        Research, 3: 171-180
    
        Lauerma H (1995) A case of moclobemide-induced hyperorgasmia. Int
        Clin Psychopharmacol, 10, 2: 123-124
    
        Liebenberg R, Berk M & Winkler G (1996) Serotonergic syndrome
        after concomitant use of moclobemide and fluoxetine. Human
        Psychopharmacol: Clin and Experiment, 11: 146-147
    
        Livingston M & Livingston H (1996) Monoamine oxidase inhibitors.
        An update on drug interactions. Drug Safety, 14, 4: 219-227
    
        Mac Farlane (1994) Anaesthesia and the new generation monoamine
        oxidase inhibitors. Anaesthesia, 49, 7: 597-599
    
        Mayersohn M & Guentert TW (1995) Clinical pharmacokinetics of the
        monoamine oxidase-A inhibitor moclobemide. Clin Pharmacokinet, 29,
        5: 292-332
    
        Meienberg O & Amsler F (1996) Moclobemide in the prophylactic
        treatment of migraine. A retrospective analysis of 44 case. Eur
        Neurol, 36: 109-110
    
        Menkes DB, Thomas MC & Phipps RF (1994) Moclobemide for menopausal
        flushing. Lancet, 344, 8923: 691-692
    
        Myrenfors PG, Eriksson T, Sansdtedt CS & Sjoberg G (1993)
        Moclobemide overdose. J Intern Med, 233: 113-115
    
        Neuvonen P, Pohjola-Sintonen S, Tacke U & Vuori E (1993) Five
        fatal cases of serotonin syndrome after moclobemide-citalopram or
        moclobemide-clomipramine overdoses. Lancet, 342: 1419
    
        O'Kane GM & Gottlieb T (1996) Severe adverse reaction to
        moclobemide. Lancet, 347: 1329-1330
    
        Power BM, Pinder M, Hackett LP & Ilett KF (1995) Fatal serotonin
        syndrome following a combined overdose of moclobemide,
        clomipramine and fluoxetine. Anaesth Intens Care, 23: 499-502
    

        Raaflaub J, Haefelfinger P & Trautman KH (1984) Single-dose
        pharmacokinetics of the MAO-inhibitor moclobemide in man. Arzneim
        Forsch, 34: 80-82
    
        Reynolds JEF ed (1996) Martindale: the extra pharmacopoeia, 31st
        ed. London, The Pharmaceutical Press
    
        Roche laboratoires: Moclamine. Manufacturer information. 92521
        Neuilly sur Seine France, 1996
    
        Spigset O, Mjorndal T & Lovheim O (1993) Serotonin syndrome caused
        by a moclobemide-clomipramine interaction. Br Med J, 306, 6872:
        248
    
        Sternbach H (1991) The serotonin syndrome. Am J Psychiatry, 148:
        705-713
    
        Sullivan G & Mahmood A (1997) Hair loss associated with
        moclobemide use. Human Psychopharmacol: Clin and Experiment, 12:
        81-82
    
        Timmings P & Lamont D (1996) Intrahepatic cholestasis associated
        with moclobemide leading to death. Lancet, 347: 762-763

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

        Author: MO Rambourg Schepens
        Centre Anti-Poisons de Champagne Ardenne
        Centre Hospitalier Universitaire
        F- 51092 Reims cedex France
    
        Telephone 33 326 862 686
        Fax 33 326 865 548
        E-mail: marie-odile.rambourg@wanadoo.fr
    
        Reviewer: WA Watson 
        Emergency Medicine. Truman Medical Center.
        2301 Holmes Street. Kansas City, MO, USA
    
        E-mail: wawatson@CCTR.UMKC.EDU
    
        Date: June 1997
    
        Peer review: Oslo (2 July, 1997) Members of group: Marie-Odile
        Rambourg, Bill Watson, Rob Dowsett, Barbara Groszek, Michael
        Ruse
    
        Editor: Dr. M. Ruse (August, 1997)
    


    See Also:
       Toxicological Abbreviations