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-morpholinoéthyl)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)