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REVERSIBLE MAO-A INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Moclobemide, a benzamide derivative, is a short acting reversible and selective inhibitor of monamine oxidase (MAO) type A (RIMA) . MAO-A preferentially deaminates adrenaline, noradrenaline and serotonin, whereas, MAO-B is more selective for 2-phenylethylamine and benzylamine.

Specific Substances

    A) BROFAROMINE
    1) 4-(7-Bromo-5-methoxy-2-benzofuranyl)piperidine
    2) Brofaromine hydrochloride
    3) CGP-113051 (brofaromine hydrochloride)
    4) Molecular Formula: C(14)H(16)BrNO(2)
    5) Molecular Weight: 310.2
    6) CAS 63638-91-5
    MOCLOBEMIDE
    1) 4-Chloro-N-(2-morpholinoethyl)benzamide
    2) Ro-11-1163
    3) Molecular Formula: C(13)H(17)CIN(2)O(2)
    4) Molecular Weight: 268.7
    5) CAS 71320-77-9
    TOLOXATONE
    1) 5-(Hydroxymethyl)-3-m-tolyl-2-oxazolidinone
    2) Molecular Formula: C(11)H(13)NO(3)
    3) Molecular Weight: 207.2
    4) CAS 29218-27-7

Available Forms Sources

    A) FORMS
    1) MOCLOBEMIDE: Moclobemide is currently not approved for use in the United States, but is available in Europe and Asia (Sweetman, 2004).
    2) BROFAROMINE: Is another RIMA (reversible inhibitor of monoamine oxidase A) which has been studied in the treatment of depression and in anxiety disorders (Sweetman, 2004). It is currently not approved for use in the United States.
    3) TOLOXATONE: Another RIMA that is used as an antidepressant (Sweetman, 2004). It has not been approved for use in the United States.
    B) USES
    1) Moclobemide is used in Europe and Asia for in the treatment of depression and social anxiety disorder (Sweetman, 2004).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Reversible monoamine oxidase inhibitors (MAOIs) are primarily used for the treatment of depression and social anxiety disorder. Moclobemide is currently not approved for use in the United States, but it is available in Europe and Asia.
    B) PHARMACOLOGY: These agents cause short-term, reversible inhibition of monoamine oxidase type A. The preferred substrates of MAO type A (MAO-A) include serotonin, epinephrine, norepinephrine, and metanephrine. Moclobemide inhibits deamination of these chemicals, increasing their concentration. MAO-A is present in the gastrointestinal tract where it decreases the bioavailability of biogenic amines, as well as the liver, pancreas, and monoaminergic neurons.
    C) TOXICOLOGY: When moclobemide is combined with other serotonergic agents (eg, venlafaxine, SSRIs, tricyclic antidepressants, MDMA), excessive stimulation of postsynaptic 5-HT1A and 5-HT2A receptors can cause severe serotonergic manifestations.
    D) EPIDEMIOLOGY: Moclobemide exposures are rare, and severe toxicity from moclobemide alone is unusual. Severe toxicity (serotonin syndrome, fatalities) has been reported after mixed overdose of moclobemide with other serotonergic agents (eg, SSRIs and tricyclic antidepressants).
    E) WITH THERAPEUTIC USE
    1) Dry mouth, headache, insomnia, dizziness, tremor, increased agitation or restlessness, nausea, gastrointestinal or epigastric pain, and constipation are frequently associated with therapeutic use.
    2) DRUG-DRUG OR DRUG-FOOD INTERACTIONS: In volunteer studies, moclobemide did not produce tyramine reactions. These reactions are theoretically possible if large doses of tyramine are ingested.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most cases involve only minimal effects or isolated gastrointestinal symptoms. CNS depression may occur and can be prolonged.
    2) SEVERE TOXICITY: Severe toxicity is very rare with isolated moclobemide ingestion. Most cases of severe toxicity occur when other serotonergic drugs are co-ingested. Severe effects may include agitation, coma, seizures, hypertension, hypotension, delirium, rigidity, severe hyperthermia, acidosis, rhabdomyolysis, renal failure, and rarely, disseminated intravascular coagulation. QT prolongation is reported but there are no reports of torsades de pointes. Most reported deaths are prehospital fatalities in which resuscitation was not attempted.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia has been reported as an early symptom of serotonin syndrome following mixed ingestions of moclobemide and other agents (therapeutic use or overdose).
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Mild alterations in blood pressure have been reported with therapeutic moclobemide use.
    B) WITH POISONING/EXPOSURE
    1) Mild hypertension, hypotension, and QT interval prolongation have been observed following moclobemide-alone overdoses.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headache, insomnia, dizziness, tremor, increased agitation, and restlessness are common following therapeutic moclobemide use. Less frequent CNS effects have included somnolence, sedation, increased anxiety, and weakness.
    2) Serotonin syndrome has been reported with moclobemide and coadministration of other antidepressants (eg, SSRIs, tricyclic antidepressants) or other drug therapies at therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Agitation, delirium, confusion, and restlessness are commonly reported in overdoses of moclobemide and concomitant drugs. These effects are reported less frequently or appear dose dependent in moclobemide-alone overdoses.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, gastrointestinal and epigastric pain, and constipation have occurred with therapeutic use. Diarrhea and vomiting have been reported less frequently.
    B) WITH POISONING/EXPOSURE
    1) Nausea and vomiting have developed following moclobemide overdose.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rash, pruritus, and urticaria have occurred infrequently with therapeutic moclobemide use.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Moclobemide plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect moclobemide.
    D) Asymptomatic patients do not require laboratory testing beyond the usual testing required for self-harm patients (electrolytes, serum acetaminophen and salicylate).
    E) Monitor electrolytes, CK, renal function, serum glucose, and ECG in patients with mild serotonin syndrome.
    F) Monitor liver enzymes, INR, and arterial or venous blood gases in patients with severe serotonin syndrome.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most patients will require no specific treatment. Agitation should be treated with benzodiazepines.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity is very rare with isolated moclobemide ingestion; most cases of severe toxicity will occur when other serotonergic drugs are co-ingested. Patients with severe agitation usually require heavy sedation (high doses of benzodiazepines) and endotracheal intubation. Hyperthermic patients should be sedated, paralyzed, and actively cooled. Patients with QT prolongation should be on a cardiac monitor and assure that serum magnesium and potassium concentrations are normalized. Torsade de Pointes should be treated with magnesium boluses and overdrive pacing. Serotonin syndrome should be treated with sedation. Cyproheptadine has been used successfully to treat serotonin syndrome associated with this overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: There is no role for prehospital decontamination because of the risk of CNS depression and subsequent aspiration.
    2) HOSPITAL: In general, decontamination is not indicated for this overdose, but may be considered for massive (more than 2 g) overdoses that present early. Activated charcoal could be considered if the patient is awake and cooperative and if the ingestion was relatively recent. There is no evidence for the use of whole bowel irrigation or multiple doses of charcoal.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (coma, respiratory depression, severe agitation).
    E) ANTIDOTE
    1) Cyproheptadine can be used for severe serotonin syndrome not responding to diazepine sedation. Initial dose is 12 mg orally, then 2 mg every 2 hours until improved; maintenance dose 8 mg every 6 hours (maximum 32 mg in 24 hours).
    F) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of value.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: There are no reports of significant toxicity from inadvertent single pill pediatric ingestions, so close home observation in these cases is reasonable. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with more than a single pill ingestions should be sent to a health care facility for observation and treatment.
    3) ADMISSION CRITERIA: Patients who develop symptoms should be admitted until symptoms resolve.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) While isolated ingestion of moclobemide is generally well tolerated, co-ingestion of other serotonergic medication increases the risk of severe toxicity.
    I) PHARMACOKINETICS
    1) Moclobemide is well-absorbed following ingestion. It is 50% protein bound. With therapeutic doses the serum half-life is approximately 1.5 hours, while the half-life in overdose is may be up to 10 hours. Metabolism is primarily hepatic and metabolites are excreted in the urine.
    J) DIFFERENTIAL DIAGNOSIS
    1) CNS infection, intracerebral hemorrhage, manic or psychotic episode due to psychiatric illness, sympathomimetic intoxication (eg, cocaine, methamphetamine), ethanol/diazepine/barbiturate, antipsychotic or clonidine withdrawal, hypoglycemia, hypoxia, serotonin syndrome from other agents.

Range Of Toxicity

    A) TOXICITY: ADULTS: Individuals have survived doses of up to 20.5 g of moclobemide with minimal toxicity. Doses of approximately 2 g have resulted in few adverse effects in most cases. Ingestions of 3 to 4 g resulted in a slight increase in blood pressure and a mild decrease in consciousness. Ingestions 7 to 8 g have resulted in fatigue and agitation. Severe toxicity (eg, seizures, tachycardia, hyperthermia) developed in an adult who ingested 10 g. One woman died after ingesting 4.5 g of moclobemide. When combined with other serotonergic agents, even therapeutic doses of moclobemide can cause severe toxicity. CHILDREN: There are no reports of significant toxicity in pediatric patients.
    B) THERAPEUTIC DOSES: ADULT: 300 mg/day in 2 to 3 divided doses. May be increased up to 600 mg/day. CHILDREN: Not approved for pediatric use.

Clinical Effects

Summary Of Exposure

    A) USES: Reversible monoamine oxidase inhibitors (MAOIs) are primarily used for the treatment of depression and social anxiety disorder. Moclobemide is currently not approved for use in the United States, but it is available in Europe and Asia.
    B) PHARMACOLOGY: These agents cause short-term, reversible inhibition of monoamine oxidase type A. The preferred substrates of MAO type A (MAO-A) include serotonin, epinephrine, norepinephrine, and metanephrine. Moclobemide inhibits deamination of these chemicals, increasing their concentration. MAO-A is present in the gastrointestinal tract where it decreases the bioavailability of biogenic amines, as well as the liver, pancreas, and monoaminergic neurons.
    C) TOXICOLOGY: When moclobemide is combined with other serotonergic agents (eg, venlafaxine, SSRIs, tricyclic antidepressants, MDMA), excessive stimulation of postsynaptic 5-HT1A and 5-HT2A receptors can cause severe serotonergic manifestations.
    D) EPIDEMIOLOGY: Moclobemide exposures are rare, and severe toxicity from moclobemide alone is unusual. Severe toxicity (serotonin syndrome, fatalities) has been reported after mixed overdose of moclobemide with other serotonergic agents (eg, SSRIs and tricyclic antidepressants).
    E) WITH THERAPEUTIC USE
    1) Dry mouth, headache, insomnia, dizziness, tremor, increased agitation or restlessness, nausea, gastrointestinal or epigastric pain, and constipation are frequently associated with therapeutic use.
    2) DRUG-DRUG OR DRUG-FOOD INTERACTIONS: In volunteer studies, moclobemide did not produce tyramine reactions. These reactions are theoretically possible if large doses of tyramine are ingested.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Most cases involve only minimal effects or isolated gastrointestinal symptoms. CNS depression may occur and can be prolonged.
    2) SEVERE TOXICITY: Severe toxicity is very rare with isolated moclobemide ingestion. Most cases of severe toxicity occur when other serotonergic drugs are co-ingested. Severe effects may include agitation, coma, seizures, hypertension, hypotension, delirium, rigidity, severe hyperthermia, acidosis, rhabdomyolysis, renal failure, and rarely, disseminated intravascular coagulation. QT prolongation is reported but there are no reports of torsades de pointes. Most reported deaths are prehospital fatalities in which resuscitation was not attempted.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia has been reported as an early symptom of serotonin syndrome following mixed ingestions of moclobemide and other agents (therapeutic use or overdose).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA: Severe hyperthermia is common in patients who develop serotonin syndrome related to combination therapy or overdose with moclobemide and other serotonergic agents (Brodribb et al, 1994; Neuvonen et al, 1993; Spigset et al, 1993).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision has occurred in 1.8% to 5% of patients treated with moclobemide (Versiani et al, 1990; Stabl et al, 1989). However, this complication has been more frequent with tricyclic antidepressants (5% to 15% of patients) in controlled comparisons (Baumhackl et al, 1989; Stabl et al, 1989; Versiani et al, 1989).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild alterations in blood pressure have been reported with therapeutic moclobemide use.
    B) WITH POISONING/EXPOSURE
    1) Mild hypertension, hypotension, and QT interval prolongation have been observed following moclobemide-alone overdoses.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported infrequently with therapeutic moclobemide use (Prod Info Manerix(R), 2001).
    b) INCIDENCE
    1) In a review of prospective studies involving 13,741 patients treated with moclobemide, hypertension (0.11%) was rare. In another analysis of 11,569 patients, the reported incidence was 0.05%. In long-term studies, of those patients with preexisting hypertension, no significant increases in blood pressure above baseline were observed (Bonnet , 2003).
    c) TYRAMINE: Studies indicate that moclobemide produces minimal to no potentiation of the pressor effects of 50 to 100 mg of tyramine (unlike irreversible monoamine oxidase inhibitors) (Zimmer et al, 1990; Gieschke et al, 1988; Korn et al, 1988; Korn et al, 1986). However, "cheese reactions" (particularly headache) have been documented, rarely (Moll & Hetzel, 1990).
    2) WITH POISONING/EXPOSURE
    a) Hypertension has been reported infrequently following moclobemide-alone overdoses. In one study, a patient developed a systolic blood pressure of 170 mmHg following an ingestion of moclobemide 3000 mg, and another patient had a blood pressure reading of 150/110 mmHg after ingesting 8000 mg. Both recovered completely without intervention (Myrenfors et al, 1993a). In another study, a patient developed hypertension (blood pressure 150/100 mmHg) after ingesting more than 600 mg of moclobemide (Hetzel, 1992).
    B) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) In a clinical study (n=1922), tachycardia and palpitations were reported in 3.8% of patients taking moclobemide (Prod Info Manerix(R), 2001).
    2) WITH POISONING/EXPOSURE
    a) In a review of moclobemide-alone overdoses (n=33), 7 patients (21%) developed tachycardia (heart rate was not reported) (Isbister et al, 2003). A 34-year-old man had a pulse of 120 beats/min following an ingestion of moclobemide 7 to 8 g (Myrenfors et al, 1993).
    C) LOW BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) In a clinical study (n=1922), hypotension occurred in 3% of patients. Orthostatic hypotension (2.3%) was also reported , but at a lower incidence than the placebo group (3.3%) (Prod Info Manerix(R), 2001).
    b) INCIDENCE: In a review of prospective studies involving 13,741 patients, hypotension was reported in 0.04% of patients treated with moclobemide. In another long-term study (n=1120), no consistent alterations in supine or standing blood pressure were observed (Bonnet , 2003).
    2) WITH POISONING/EXPOSURE
    a) A 22-year-old woman ingested moclobemide 950 mg. Two hours later she was admitted to the hospital with disorientation, impaired reflexes, nausea, and drowsiness. Over the next 12 hours, she suffered moderate hypotension, with a nadir of 70/50 mmHg. Subsequently, her blood pressure normalized within 36 hours, and she recovered without incident (Heinze & Sanchez, 1986).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) The ECGs of patients presenting to a toxicology service with moclobemide overdose ingestions were reviewed (n=75). The QT and QTc intervals were compared with a cohort of patients (control group) who ingested benzodiazepines or acetaminophen (n=318). Prolongation of the QT and QTc intervals occurred in several patients following deliberate overdose ingestions of moclobemide. The median ingested moclobemide dose was 4.5 g (ranging from 0.6 to 18 g). The mean QT interval in the moclobemide group was 415 msec, as compared with 367 msec in the control group. The mean QTc interval in the moclobemide group was 459 msec, as compared with 426 msec in the control group. In 12 moclobemide overdose patients, the QTc interval was greater than 500 msec (ranging from 501 to 565 msec). Other than sinus tachycardia, the only cardiac dysrhythmias observed were first degree heart block (1 case with a QTc interval greater than 500 msec), left bundle-branch block, and a nonspecific intraventricular conduction defect (Downes et al, 2005).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Early symptoms of serotonin syndrome have included tachypnea and have been reported following mixed ingestions of moclobemide and other agents (eg, imipramine ) (Brodribb et al, 1994).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headache, insomnia, dizziness, tremor, increased agitation, and restlessness are common following therapeutic moclobemide use. Less frequent CNS effects have included somnolence, sedation, increased anxiety, and weakness.
    2) Serotonin syndrome has been reported with moclobemide and coadministration of other antidepressants (eg, SSRIs, tricyclic antidepressants) or other drug therapies at therapeutic doses.
    B) WITH POISONING/EXPOSURE
    1) Agitation, delirium, confusion, and restlessness are commonly reported in overdoses of moclobemide and concomitant drugs. These effects are reported less frequently or appear dose dependent in moclobemide-alone overdoses.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache (8%) was the most common CNS effect reported during clinical studies (n=1922) with moclobemide (Prod Info Manerix(R), 2001).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical studies (n=1922), dizziness (5.1%) was reported with moclobemide doses of 50 to 600 mg daily (Prod Info Manerix(R), 2001).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia (7.3%) was reported frequently during clinical trials (n=1922) with moclobemide (dose range 50 to 600 mg daily) (Prod Info Manerix(R), 2001).
    D) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Tremor (5%), increased agitation (4.5%), restlessness (4.1%), somnolence (3.7%), sedation (3%), increased anxiety (2.8%), and weakness (1.2%) were reported during clinical studies (n=1922) with moclobemide (Prod Info Manerix(R), 2001).
    2) WITH POISONING/EXPOSURE
    a) Agitation, delirium, confusion, and restlessness are commonly reported in overdoses of moclobemide and concomitant drugs (eg, clomipramine, benzodiazepines). Conversely, agitation was only reported in a patient taking 8000 mg of moclobemide alone (Myrenfors et al, 1993a).
    E) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression and coma have been reported in cases of serotonin syndrome induced by a combination of moclobemide and other agents (eg, antidepressants, serotonergic drugs) (Brodribb et al, 1994; Neuvonen et al, 1993; Spigset et al, 1993).
    F) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have occurred following mixed overdoses of moclobemide and other drug therapies (eg, antidepressants) (Kuisma, 1995; Neuvonen et al, 1993; Spigset et al, 1993).
    G) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Serotonin syndrome has been reported rarely with moclobemide alone, but it has been reported in patients receiving therapeutic moclobemide and other drug therapies (eg, antidepressants, serotonergic agents) (Bonnet , 2003; Chan et al, 1998).
    b) CASE REPORT
    1) A 44-year-old man receiving moclobemide and alprazolam for 12 months for anxiety and depression developed serotonin syndrome. After 4 days of extreme heat (a likely contributing factor), the patient developed agitation, confusion, leadpipe rigidity, and tremulousness. He was intubated and was tachycardic and febrile. Creatinine rose to 30,130 Units(U)/L and peaked at 46,594 U/L. Treatment included diazepam and dantrolene (Butzkueven, 1997).
    2) Serotonin syndrome was reported in a 25-year-old woman after moclobemide (300 mg rapidly increased to 600 mg) was substituted for clomipramine (150 mg/day). The patient also received alprazolam 1.5 to 3 mg/day. Symptoms resolved after discontinuation of moclobemide. A drug interaction with clomipramine was suggested; serum clomipramine levels may have persisted after discontinuation due to clomipramine's half life of 22 to 84 hours (Dardennes et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Serotonin syndrome has been reported following intentional misuse of moclobemide and other antidepressant therapies, including SSRIs (eg, paroxetine, fluoxetine), tricyclic antidepressants (eg, clomipramine), and other serotonergic agonists(Isbister et al, 2003; Hernandez et al, 1995).
    CASE SERIES
    2) INCIDENCE: In a retrospective toxicity study of moclobemide (n=106), comparisons were made between poisoning by moclobemide alone (n=33; median ingested dose 6 g, range 0.9 to 18 g) and moclobemide with serotonergic coingestant (n=21). It was found that the effects of moclobemide alone in overdose are minor, even with massive ingestions; however, severe serotonin toxicity may occur following moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses). Serotonin toxicity occurred in 11 of 21 patients in the moclobemide with serotonergic coingestant group, and 6 patients had severe toxicity (temperature greater than 38.5 degrees C and muscle rigidity requiring intubation and paralysis). However, serotonin toxicity occurred in only 1 of 33 moclobemide-alone overdoses. One patient who ingested moclobemide 18 g developed hyperreflexia, tachycardia, and a temperature of 37.4 degrees C (Isbister et al, 2003).
    CASE REPORTS
    3) Severe serotonin syndrome was reported after a mixed overdose with paroxetine 600 mg and moclobemide (undetermined amount). Effects included diaphoresis, confusion, agitation, oculogyric crisis, decreased mental status (Glasgow coma scale 7), twitching, mydriasis, hyperreflexia, tachycardia, hypotension, trismus, fever, and respiratory failure (FitzSimmons & Metha, 1999).
    a) Following a mixed ingestion of moclobemide and paroxetine, an adult was found incoherent and shivering and later developed seizures. When the paramedics arrived, the patient was in full cardiac arrest and resuscitation efforts were unsuccessful (Singer & Jones, 1997).
    4) CASE REPORT: A 29-year-old man developed severe tremor, increased temperature (42 degrees C), nonreactive coma, and tonic-clonic seizures approximately 2 hours after ingesting benzodiazepines (clorazepate 450 mg), moclobemide 7.5 g, and clomipramine 1 g. Despite decontamination (gastric lavage within 1 hour of ingestion) and supportive intensive care measures, the patient had a fatal cardiopulmonary arrest approximately 3 hours after exposure (Ferrer-Dufol et al, 1998).
    5) CASE REPORT: Fatal serotonin syndrome developed in a 51-year-old woman after ingestion of moclobemide and fluvoxamine (Rogde et al, 1999).
    6) Five cases of fatal serotonin syndrome were reported in adults intentionally ingesting moclobemide 1000 to 1500 mg and clomipramine 225 to 500 mg (2 cases). In the moclobemide-citalopram group (3 cases), blood concentrations for moclobemide were 30 to 50 times higher and citalopram was about 5 times higher than therapeutic concentrations. Of the 4 patients with a recorded time of death, the range was 3 to 16 hours (Neuvonen et al, 1993).
    7) Fatal serotonin syndrome was reported in a mixed overdose ingestion which included moclobemide 6000 mg, clomipramine 300 mg, fluoxetine 340 mg, and clonazepam 12 mg. The patient developed classic signs of serotonin syndrome with severe hyperthermia and died from subsequent complications of disseminated intravascular coagulation and multiorgan failure (Power et al, 1995). Another case was reported in a woman following an ingestion of clomipramine (postmortem concentration was 1.8 mg/L; within therapeutic concentration) and moclobemide (postmortem concentration was 5 mg/L; therapeutic range is 1 to 3 mg/L) who was in cardiac arrest at the time of arrival to the emergency department. The patient died despite normal or near-normal drug levels (Kuisma, 1995).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, gastrointestinal and epigastric pain, and constipation have occurred with therapeutic use. Diarrhea and vomiting have been reported less frequently.
    B) WITH POISONING/EXPOSURE
    1) Nausea and vomiting have developed following moclobemide overdose.
    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL SYMPTOM
    1) WITH THERAPEUTIC USE
    a) In clinical studies, nausea (5.2% to 11%), constipation (3.9%), and gastrointestinal or epigastric discomfort (2.3%) were reported during therapeutic use (dose range 50 to 600 mg daily) of moclobemide (Prod Info Manerix(R), 2001; Tiller et al, 1995).
    b) Less frequent gastrointestinal effects with moclobemide therapy (dose range 50 to 600 mg/day) have included diarrhea (1.8%), abdominal fullness (1.6%), and vomiting (1.6%) (Prod Info Manerix(R), 2001).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have occurred following moclobemide overdose (Myrenfors et al, 1993a; Hetzel, 1992).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) In postmarketing surveillance, a low incidence (not defined) of increased liver enzymes with moclobemide use has been reported, with no associated clinical sequelae (Prod Info Manerix(R), 2001).
    2) CASE REPORT
    a) An 85-year-old woman developed cholestatic jaundice 7 days after starting moclobemide 100 mg 3 times daily. The patient had received prior therapy with fluoxetine for 5 months and was switched to moclobemide without a washout period. The patient's icteric status was accompanied by a 10-fold elevation in liver enzymes (liver function studies had been normal 3 months prior). Hematology and hepatitis screens were normal, and moclobemide was discontinued. The patient declined further diagnosis or treatment, and she died 12 days after the onset of jaundice. Autopsy revealed drug-induced intrahepatic cholestasis (Timmings & Lamont, 1996).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A fatal case of serotonin syndrome with severe hyperthermia, disseminated intravascular coagulation (DIC), and multiorgan failure was reported in a 40-year-old woman after ingestion of moclobemide 6000 mg, clomipramine 300 mg, fluoxetine 340 mg, and clonazepam 12 mg (Power et al, 1995). In another case, a 45-year-old woman was found comatose after ingesting moclobemide and clomipramine (dose undetermined), and she developed shock (blood pressure 50 mmHg), serotonin syndrome, rhabdomyolysis, and DIC. The patient did recover following prolonged intensive care support (intubated for 55 days), and sequelae consisted of peripheral sensory and motor neuropathy secondary to prolonged shock (Francois et al, 1997).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rash, pruritus, and urticaria have occurred infrequently with therapeutic moclobemide use.
    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Dry skin, rash, itching or pruritus, and urticaria have been reported in less than 1% of patients during clinical studies with moclobemide (Prod Info Manerix(R), 2001).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Hyperreflexia and clonus are common clinical features of serotonin syndrome, and they have developed following mixed ingestions of moclobemide and other drugs (eg, antidepressants) (Isbister et al, 2003; Myrenfors et al, 1993a).
    b) INCIDENCE: Hyperreflexia was reported in 15% of patients (n=33) following moclobemide-alone overdoses (Isbister et al, 2003).
    B) INCREASED MUSCLE TONE
    1) WITH POISONING/EXPOSURE
    a) Myoclonus and diffuse muscle rigidity are common clinical features related to serotonin syndrome, and they have developed following overdoses of moclobemide and concomitant drugs (eg, other antidepressants). In severe cases, rigidity of the jaw muscles has made airway management difficult (Kuisma, 1995; Brodribb et al, 1994; Spigset et al, 1993). Of note, clonus and rigidity were not reported in 33 patients with moclobemide-alone overdoses (Isbister et al, 2003).
    C) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis has been reported in patients who developed muscle rigidity and hyperthermia following overdose with moclobemide and concomitant drug therapies (Brodribb et al, 1994).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GALACTORRHEA NOT ASSOCIATED WITH CHILDBIRTH
    1) WITH THERAPEUTIC USE
    a) Moclobemide was associated with a significant increase in galactorrhea compared with SSRIs (adjusted rate ratio was 6.7 times higher). All cases occurred in women under age 50 (Dunn et al, 1998).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS71320-77-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Moclobemide plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect moclobemide.
    D) Asymptomatic patients do not require laboratory testing beyond the usual testing required for self-harm patients (electrolytes, serum acetaminophen and salicylate).
    E) Monitor electrolytes, CK, renal function, serum glucose, and ECG in patients with mild serotonin syndrome.
    F) Monitor liver enzymes, INR, and arterial or venous blood gases in patients with severe serotonin syndrome.

Methods

    A) HPLC
    1) Plasma concentrations of moclobemide and its metabolites have been quantified by reverse phase high-performance liquid chromatography (HPLC). The limit of detection reported was 5.0 mcg/L (Isbister et al, 2003).
    B) POSTMORTEM ANALYSIS
    1) In one study, GC-MS and HPLC-PD methods were used to determine postmortem blood and urine levels of moclobemide. Biological tissue samples were also reported (Gaillard & Pepin, 1997).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop symptoms should be admitted until symptoms resolve.
    6.3.1.2) HOME CRITERIA/ORAL
    A) There are no reports of significant toxicity from inadvertent single pill pediatric ingestions, so close home observation in these cases is reasonable. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions or children with more than a single pill ingestions should be sent to a health care facility for observation and treatment.

Monitoring

    A) Monitor vital signs and mental status.
    B) Moclobemide plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect moclobemide.
    D) Asymptomatic patients do not require laboratory testing beyond the usual testing required for self-harm patients (electrolytes, serum acetaminophen and salicylate).
    E) Monitor electrolytes, CK, renal function, serum glucose, and ECG in patients with mild serotonin syndrome.
    F) Monitor liver enzymes, INR, and arterial or venous blood gases in patients with severe serotonin syndrome.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: There is no role for prehospital decontamination because of the risk of CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: In general, decontamination is not indicated for this overdose, but may be considered for massive (more than 2 g) overdoses that present early. Activated charcoal could be considered if the patient is awake and cooperative and if the ingestion was relatively recent. There is no evidence for the use of whole bowel irrigation or multiple doses of charcoal.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Moclobemide plasma concentrations are not clinically useful or readily availability.
    3) Screening urine toxicology immunoassays will not detect moclobemide.
    4) Asymptomatic patients do not require laboratory testing beyond the usual testing required for self-harm patients (electrolytes, serum acetaminophen and salicylate).
    5) Monitor electrolytes, CK, renal function, serum glucose, and ECG in patients with mild serotonin syndrome.
    6) Monitor liver enzymes, INR, and arterial or venous blood gases in patients with severe serotonin syndrome.
    B) PSYCHOMOTOR AGITATION
    1) Patients with severe agitation usually require heavy sedation (high doses of benzodiazepines) and endotracheal intubation.
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    C) BLOOD PRESSURE
    1) Alterations in blood pressure, both hypotension and hypertension, have been reported infrequently following overdose with moclobemide alone. Monitor blood pressure.
    D) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) SUMMARY: Hyperthermic patients should be sedated, paralyzed, and actively cooled.
    2) Control agitation (benzodiazepines) and muscle rigidity (neuromuscular blockade may be necessary). Initiate external cooling measures. Avoid phenothiazines. Early neuromuscular paralysis, intubation and ventilation in patients with a core temperature of greater than 39 C has been advocated by some authors (Henry, 1994).
    E) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    F) CYPROHEPTADINE
    1) Some of the manifestations of MAOI overdose, such as muscle hyperactivity, appear to be related to "serotonin syndrome". Both animal and human data have suggested that administration of serotonin antagonists might antagonize this effect.
    a) There are several reports of efficacy following exposure with reversible selective inhibitors of monoamine oxidase (RIMAs) and other antidepressant agents. In an 18-year-old female taking clomipramine and than changed to moclobemide without a washout period, symptoms of serotonin syndrome (i.e., increased irritability, twitching, agitation, myoclonus, hypertonicity) developed and were successfully treated with a total of 12 mg of cyproheptadine and was discharged. An elderly woman changed from fluoxetine to moclobemide was also treated successfully with cyproheptadine (total dose: 4 mg) after developing serotonin syndrome (Chan et al, 1998).
    b) OVERDOSE: Following an overdose of moclobemide (3 grams) and venlafaxine (2.6 grams) plus alcohol (undetermined amount), a 34-year-old male developed coma and serotonin syndrome and was intubated, provided supportive care, and treated with cyproheptadine (total 16 mg). The patient slowly regained consciousness two days after exposure (Roxanas & Machado, 1998).
    G) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    H) DANTROLENE
    1) There are a few case reports describing the use of dantrolene in patients with moclobemide induced serotonin syndrome. There is little data to support efficacy, and cyproheptadine is generally considered the drug of choice
    2) OVERDOSE: Following a mixed ingestion of 5000 mg moclobemide, 625 mg clomipramine, 20 mg flunitrazepam and one bottle of wine, a 24-year-old female developed hyperthermic crisis (body temperature 41.9 degrees Celsius and muscle rigidity) and was given dantrolene sodium at a dose of 1 mg/kg body weight followed by another dose 2.5 hours later for continued symptoms. Within 4.5 hours, the patient's temperature was down and muscle rigidity had decreased. The patient was extubated within 48 hours. A total of 3 doses of dantrolene were given. She was discharged on day 10, with some residual muscle pain and stiffness one month after exposure (Myrenfors et al, 1993a). Another patient with serotonin syndrome (thought to be induced by several days of extreme heat) was also treated with dantrolene following long-term (12 months) combination therapy with moclobemide and alprazolam (Butzkueven, 1997).

Range Of Toxicity

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) In a retrospective toxicity study of moclobemide (n=106), comparisons, were made between moclobemide alone (n=33; median ingested dose of 6 grams, range 0.9 - 18 grams) and moclobemide with serotonergic coingestants (n=21) poisoning. In 5 patients with severe serotonin toxicity, toxicokinetics data were obtained. In 2 patients, the time peak plasma concentration (Tmax), was delayed occurring at 13 hours and 4.5 hours, respectively. In the patient with longer Tmax, the delayed peak corresponded with a delayed onset of serotonin toxicity and a generalized tonic clonic seizure 12 hours after ingestion. The peak plasma concentrations (Cmax) were 8, 25, 28, 30, and 50 mg/L following moclobemide 3, 2, 6, 9, and 12-gram doses, respectively. The coingested agents in these patients were venlafaxine, fluvoxamine, sertraline, amitriptyline, and citalopram (Isbister et al, 2003).
    2) CASE REPORT - A plasma concentration of 60.9 mg/L was reported within approximately 2 hours of an intentional ingestion of 3 grams of moclobemide. The patient was decontaminated, and within 12 hours the concentration was 4.6 mg/L. Only minor clinical symptoms were observed (Iwersen & Schmoldt, 1996).
    3) POSTMORTEM BLOOD LEVELS
    a) A plasma moclobemide concentration of 498 mcg/mL {or 498 mg/L} (approximately 64 to 1383-fold higher than therapeutic concentrations {0.36 to 7.76 mcg/mL}) was reported in a 47-year-old male found dead. Although prazepam and nordiazepam were detected in the blood, both agents were within normal therapeutic range and were determined to be noncontributory in this case. Other tissue concentrations are as follows:
    1) urine - 96.3 mcg/mL
    2) bile - 1193.3 mcg/mL
    3) liver - 883 mcg/g
    4) brain (cortex) - 1000 mcg/g
    b) Postmortem blood concentrations of 137 mg/L {or 137 mcg/mL} (therapeutic levels range from 0.36 to 3.00 mg/L) and liver concentrations of 432 mg/kg were reported in a previously suicidal, 48-year-old female found dead following an ingestion of an unknown amount of moclobemide (Camaris & Little, 1997).
    c) Postmortem moclobemide levels were approximately 49.9 mg/L {or 49.9 mcg/mL} in blood, 56.7 mg/kg in brain, 79.7 mg/kg in liver, and 81.4 mg/kg in kidney in a suicidal woman who had ingested an unknown amount of moclobemide and perazine (Musshoff et al, 1998).

Workplace Standards

    A) ACGIH TLV Values for CAS71320-77-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS71320-77-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS71320-77-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS71320-77-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Summary

    A) TOXICITY: ADULTS: Individuals have survived doses of up to 20.5 g of moclobemide with minimal toxicity. Doses of approximately 2 g have resulted in few adverse effects in most cases. Ingestions of 3 to 4 g resulted in a slight increase in blood pressure and a mild decrease in consciousness. Ingestions 7 to 8 g have resulted in fatigue and agitation. Severe toxicity (eg, seizures, tachycardia, hyperthermia) developed in an adult who ingested 10 g. One woman died after ingesting 4.5 g of moclobemide. When combined with other serotonergic agents, even therapeutic doses of moclobemide can cause severe toxicity. CHILDREN: There are no reports of significant toxicity in pediatric patients.
    B) THERAPEUTIC DOSES: ADULT: 300 mg/day in 2 to 3 divided doses. May be increased up to 600 mg/day. CHILDREN: Not approved for pediatric use.

Therapeutic Dose

    7.2.1) ADULT
    A) MOCLOBEMIDE
    1) ORAL - Initial therapy is 300 milligrams daily (given in two divided doses) and increased gradually to a maximum of 600 milligrams daily. Dosing should not be increased during the first week of therapy, because bioavailability has reportedly increased over the first week of therapy. Individual response may vary and dosing should be adjusted accordingly (Prod Info Manerix(R), 2001).
    B) TOLOXATONE
    1) ORAL - 200 milligrams three times daily (Sweetman, 2004).
    7.2.2) PEDIATRIC
    A) MOCLOBEMIDE
    1) Safety and effectiveness of moclobemide have not been established in children; pediatric use is not recommended (Prod Info Manerix(R), 2001).

Minimum Lethal Exposure

    A) Postmortem analysis (blood 15.5 mcg/mL, urine 323.7 mcg/mL) indicated that a 43-year-old woman died after ingesting 4.5 grams of moclobemide; no other substances were found during this analysis (Gaillard & Pepin, 1997). Of note, this dose is the lowest reported fatality due to moclobemide, individuals have previously developed only mild symptoms at this exposure (Myrenfors et al, 1993).

Maximum Tolerated Exposure

    A) SUMMARY
    1) In series of 15 patients, moclobemide is generally well tolerated in overdose unless mixed with other drugs. Patients ingesting up to 2 grams had no symptoms or only gastrointestinal complaints. Ingestions of 3 to 4 grams caused slight increases in blood pressure and depressed consciousness. Fatigue, agitation, tachycardia, increased blood pressure, and dilated, slow reacting pupils occurred with overdoses of 7 to 8 grams. Early gastric lavage however, was performed in this group. Mixed intoxications provided a more serious clinical picture, even with moderate doses of moclobemide. CNS depression and excitation (seizures) occurred along with tremor, mydriasis, hyperthermia, hypertension, and acidosis (Myrenfors et al, 1993).
    B) ADULTS
    1) In one reported case, a patient remained stuporous for over 36 hours following an overdose of 1,550 mg of moclobemide; organ toxicity was not reported (Prod Info Manerix(R), 2001).
    C) In over 40 reported cases of overdose, up to 20.5 grams (350 mg/kg) were ingested with no fatalities reported (Isbister et al, 2003; Tiller, 1993; Fulton & Benfield, 1996).
    D) CASE REPORT: A 39-year-old female ingested 10,000 milligrams moclobemide and developed seizures, tachycardia, and hyperthermia (42.7 degrees C) and recovered. Plasma moclobemide concentration was 36.5 mcg/mL 6 hours postingestion (Chen & Ruch, 1993).
    E) When combined with other serotonergic drugs (even at therapeutic doses), moclobemide overdoses (approximate doses in these cases ranged from 300 mg {therapeutic dose} to 7.5 g) or inadvertent combined ingestions can produce severe serotonin syndrome and fatalities in some cases (Isbister et al, 2003; Ferrer-Dufol et al, 1998; Kuisma, 1995).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Moclobemide is a short-acting, reversible inhibitor of monoamine oxidase type A (RIMA). Moclobemide is a benzmide derivative which inhibits the deamination of serotonin, noradrenaline and dopamine, which can lead to increased concentrations of these neurotransmitters and account for the antidepressant effect observed (Prod Info Manerix(R), 2001).
    B) Monoamine oxidases are subclassified as either type A or B, which differ in their substrate specificity. Moclobemide preferentially inhibits MAO-A. At 300-milligram doses, the inhibition of MAO-A is approximately 80%, while MAO-B is approximately 20% to 30%. Inhibition of MAO-A is considered short-term (lasting up to 24 hours) and reversible (Prod Info Manerix(R), 2001).

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
    9) 67 FR 7164: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2002.
    10) 68 FR 42710: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2003.
    11) 69 FR 54144: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2004.
    12) AIHA: 2006 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook, American Industrial Hygiene Association, Fairfax, VA, 2006.
    13) American Conference of Governmental Industrial Hygienists : ACGIH 2010 Threshold Limit Values (TLVs(R)) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs(R)), American Conference of Governmental Industrial Hygienists, Cincinnati, OH, 2010.
    14) Appleton R: Lorazepam vs diazepam in the acute treatment of epileptic seizures and status epilepticus.. Dev Med Child Neuro 1995; 37:682-688.
    15) Baumhackl U, Biziere K, Fischbach R, et al: Efficacy and tolerability of moclobemide compared with imipramine in depressive disorder (DSM-III): an Austrian double-blind, multicentre study. Br J Psychiatry 1989; 155(suppl 6):78-83.
    16) Berlin I & Lecrubier Y: Food and drug interactions with monoamine oxidase inhibitors. How safe are the newer agents?. CNS Drugs 1996; 5:403-413.
    17) Berlin I, Zimmer R, Thiede HM, et al: Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase-A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects. Br J Clin Pharmacol 1990; 30:805-816.
    18) Bleumink GS, van Vliet ACM, van der Tholen A, et al: Fatal combination of moclobemide overdose and whisky. Netherlands J Med 2003; 61:88-90.
    19) Bonnet U: Moclobemide: Therapeutic use and clinical studies. CNS Drugs Rev 2003; 9:97-140.
    20) Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120.
    21) Brodribb TR, Downey M, & Gilbar PJ: Efficacy and adverse effects of moclobemide (letter). Lancet 1994; 343:475.
    22) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    23) Brown CV, Rhee P, Chan L, et al: Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?. J Trauma 2004; 56(6):1191-1196.
    24) Butzkueven H: A case of serotonin syndrome induced by moclobemide during an extreme heatwave. Aust NZ J Med 1997; 27:603-604.
    25) Camaris C & Little D: A fatality due to moclobemide. J Forensic Sci 1997; 42:954-955.
    26) Camp NE: Drug- and toxin-induced Rhabdomyolysis. J Emerg Nurs 2009; 35(5):481-482.
    27) Chan BSH, Graudins A, Whyte IM, et al: Serotonin syndrome resulting from drug interactions. MJA 1998; 169:523-525.
    28) Chen DT & Ruch R: Safety of moclobemide in clinical use. Clin Neuropharmacol 1993; 16:S63-S68.
    29) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    30) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    31) Claassen JAHR & Gelissen HPMM: The serotonin syndrome (letter). N Eng J Med 2005; 352(23):2455.
    32) Criddle LM: Rhabdomyolysis. Pathophysiology, recognition, and management. Crit Care Nurse 2003; 23(6):14-22, 24-26, 28.
    33) DFG: List of MAK and BAT Values 2002, Report No. 38, Deutsche Forschungsgemeinschaft, Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area, Wiley-VCH, Weinheim, Federal Republic of Germany, 2002.
    34) Dardennes RM, Even C, & Ballon N: Serotonin syndrome caused by a clomipramine-moclobemide interaction (letter). J Clin Psych 1998; 59:382-383.
    35) De Negri M & Baglietto MG: Treatment of status epilepticus in children. Paediatr Drugs 2001; 3(6):411-420.
    36) Downes MA, Whyte IM, & Isbister GK: QTc abnormalities in deliberate self-poisoning with moclobemide. Intern Med J 2005; 35:388-391.
    37) Dunn NR, Freemantle SN, & Pearce GL: Galactorrhoea with moclobemide (letter). Lancet 1998; 351:802.
    38) EPA: Search results for Toxic Substances Control Act (TSCA) Inventory Chemicals. US Environmental Protection Agency, Substance Registry System, U.S. EPA's Office of Pollution Prevention and Toxics. Washington, DC. 2005. Available from URL: http://www.epa.gov/srs/.
    39) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    40) Erdman AR & Dart RC: Rhabdomyolysis. In: Dart RC, Caravati EM, McGuigan MA, et al, eds. Medical Toxicology, 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2004, pp 123-127.
    41) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    42) Ferrer-Dufol A, Perez-Aradros C, & Murillo EC: Fatal serotonin syndrome caused by moclobemide-clomipramine overdose (letter). Clin Toxicol 1998; 36:31-32.
    43) FitzSimmons CR & Metha S: Serotonin syndrome caused by overdose with paroxetine and moclobemide. J Accid Emerg Med 1999; 16:293-295.
    44) Francois B, Marquet P, & Desachy A: Serotonin syndrome due to an overdose of moclobemide and clomipramine. Intens Care Med 1997; 23:122-124.
    45) Fulton B & Benfield P: Moclobemide. An update of its pharmacological properties and therapeutic use. Drugs 1996; 52:450-474.
    46) Gaillard Y & Pepin G: Moclobemide fatalities: report of two cases and analytical determinations by GC-MS and HPLC-PDA after solid phase extraction . Forensic Sci Internat 1997; 87:239-248.
    47) Giang DW & McBride MC : Lorazepam versus diazepam for the treatment of status epilepticus. Pediatr Neurol 1988; 4(6):358-361.
    48) Gieschke R, Schmid-Burgk W, & Amrein R: Interaction of moclobemide, a new reversible monoamine oxidase inhibitor, with oral tyramine. J Neural Transm 1988; 26(Suppl):97-104.
    49) Gillman PK: Ecstasy, serotonin syndrome and the treatment of hyperpyrexia (letter). MJA 1997; 167:109-111.
    50) Gillman PK: Successful treatment of serotonin syndrome with chlorpromazine (letter). MJA 1996; 165:345.
    51) Giroud C, Horisberger B, Eap C, et al: Death following acute poisoning by moclobemide. Forensic Sci Internat 2004; 140:101-107.
    52) Goldberg RJ & Huk M: Serotonin syndrome from trazodone and buspirone (letter). Psychosomatics 1992; 33:235-236.
    53) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    54) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    55) Graham PM: Successful treatment of the toxic serotonin syndrome with chlorpromazine (letter). Med J Australia 1997; 166:166-167.
    56) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    57) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    58) Heinze G & Sanchez A: Overdose with moclobemide. J Clin Psychiatry 1986; 47:438.
    59) Henry JA: Serotonin syndrome (letter). Lancet 1994; 343:607.
    60) Hernandez AF, Montero MN, & Pla A: Fatal moclobemide overdose or death caused by serotonin syndrome?. J Forensic Sci 1995; 40:128-130.
    61) Hetzel W: Safety of moclobemide taken in overdose for attempted suicide. Psychopharmacology 1992; 106(Suppl):S127-S129.
    62) Homsi E, Barreiro MF, Orlando JM, et al: Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19(2):283-288.
    63) Huerta-Alardin AL, Varon J, & Marik PE: Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005; 9(2):158-169.
    64) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide), 97, International Agency for Research on Cancer, Lyon, France, 2008.
    65) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxypropan-2-ol, 88, International Agency for Research on Cancer, Lyon, France, 2006.
    66) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Household Use of Solid Fuels and High-temperature Frying, 95, International Agency for Research on Cancer, Lyon, France, 2010a.
    67) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Smokeless Tobacco and Some Tobacco-specific N-Nitrosamines, 89, International Agency for Research on Cancer, Lyon, France, 2007.
    68) IARC Working Group on the Evaluation of Carcinogenic Risks to Humans : IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Some Non-heterocyclic Polycyclic Aromatic Hydrocarbons and Some Related Exposures, 92, International Agency for Research on Cancer, Lyon, France, 2010.
    69) IARC: List of all agents, mixtures and exposures evaluated to date - IARC Monographs: Overall Evaluations of Carcinogenicity to Humans, Volumes 1-88, 1972-PRESENT. World Health Organization, International Agency for Research on Cancer. Lyon, FranceAvailable from URL: http://monographs.iarc.fr/monoeval/crthall.html. As accessed Oct 07, 2004.
    70) International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans: list of classifications, volumes 1-116. International Agency for Research on Cancer (IARC). Lyon, France. 2016. Available from URL: http://monographs.iarc.fr/ENG/Classification/latest_classif.php. As accessed 2016-08-24.
    71) International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. Geneva, Switzerland. 2015. Available from URL: http://monographs.iarc.fr/ENG/Classification/. As accessed 2015-08-06.
    72) Isbister GK, Hackett LP, Dawson AH, et al: Moclobemide poisoning: toxicologic and occurrence of serotonin toxicity. Br J Clin Pharmacol 2003; 54:441-450.
    73) Iwersen S & Schmoldt A: Three suicide attempts with moclobemide. J Toxicol - Clin Toxicol 1996; 34:223.
    74) Kline SS, Mauro LS, & Scala-Barnett DM: Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharmac 1989; 8:510-514.
    75) Korn A, Da Prada M, Raffesberg W, et al: Effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine. J Cardiovasc Pharmacol 1988; 11:17-23.
    76) Korn A, Eichler HG, Fischbach R, et al: Moclobemide, a new reversible MAO inhibitor - interaction with tyramine and tricyclic antidepressants in healthy volunteers and depressive patients. Psychopharmacol 1986; 88:153-157.
    77) Kuisma MJ: Fatal serotonin syndrome with trismus (letter). Ann Emerg Med 1995; 26:108.
    78) Livingston MG & Livingston HM: Monoamine oxidase inhibitors. An update on drug interactions. Drug Safety 1996; 14:219-227.
    79) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    80) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    81) Mills KC: Serotonin syndrome: a clinical update. Med Toxicol 1997; 13:763-783.
    82) Mitchell WG: Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: etiology, outcome, and treatment. Epilepsia 1996; 37(S1):S74-S80.
    83) Moll E & Hetzel W: Moclobemide (Ro 11-1163) safety in depressed patients. Acta Psychiatr Scand 1990; 360(suppl):69-70.
    84) Musshoff F, Varchmin-Schultheiss K, & Madea B: Suicide with moclobemide and perazine. Int J Legal Med 1998; 196-198.
    85) Myrenfors PG, Eriksson T, & Sandstedt CS: Moclobemide overdose. J Int Med 1993; 233:113-115.
    86) Myrenfors PG, Eriksson T, Sandsted CS, et al: Moclobemide overdose. J Intern Med 1993a; 233(2):113-115.
    87) NFPA: Fire Protection Guide to Hazardous Materials, 13th ed., National Fire Protection Association, Quincy, MA, 2002.
    88) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 1, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2001.
    89) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 2, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2002.
    90) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 3, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2003.
    91) NRC: Acute Exposure Guideline Levels for Selected Airborne Chemicals - Volume 4, Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board on Environmental Studies and Toxicology, Commission of Life Sciences, National Research Council. National Academy Press, Washington, DC, 2004.
    92) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,3-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    93) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2,4-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    94) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Butylene Oxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648083cdbb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    95) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,2-Dibromoethane (Proposed). United States Environmental Protection Agency. Washington, DC. 2007g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802796db&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    96) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 1,3,5-Trimethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d68a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    97) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for 2-Ethylhexyl Chloroformate (Proposed). United States Environmental Protection Agency. Washington, DC. 2007b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037904e&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    98) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Acrylonitrile (Proposed). United States Environmental Protection Agency. Washington, DC. 2007c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648028e6a3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    99) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Adamsite (Proposed). United States Environmental Protection Agency. Washington, DC. 2007h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    100) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Agent BZ (3-quinuclidinyl benzilate) (Proposed). United States Environmental Protection Agency. Washington, DC. 2007f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ad507&disposition=attachment&contentType=pdf. As accessed 2010-08-18.
    101) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Allyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039d9ee&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    102) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    103) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Arsenic Trioxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480220305&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    104) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Automotive Gasoline Unleaded (Proposed). United States Environmental Protection Agency. Washington, DC. 2009a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cc17&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    105) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Biphenyl (Proposed). United States Environmental Protection Agency. Washington, DC. 2005j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1b7&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    106) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bis-Chloromethyl Ether (BCME) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648022db11&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    107) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Boron Tribromide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae1d3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    108) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromine Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2007d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648039732a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    109) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Bromoacetone (Proposed). United States Environmental Protection Agency. Washington, DC. 2008e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187bf&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    110) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Calcium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    111) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803ae328&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    112) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Carbonyl Sulfide (Proposed). United States Environmental Protection Agency. Washington, DC. 2007e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648037ff26&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    113) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Chlorobenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064803a52bb&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    114) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Cyanogen (Proposed). United States Environmental Protection Agency. Washington, DC. 2008f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809187fe&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    115) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Dimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbf3&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    116) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Diphenylchloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    117) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091884e&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    118) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyl Phosphorodichloridate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480920347&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    119) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethylbenzene (Proposed). United States Environmental Protection Agency. Washington, DC. 2008g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809203e7&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    120) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ethyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    121) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Germane (Proposed). United States Environmental Protection Agency. Washington, DC. 2008j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963906&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    122) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Hexafluoropropylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064801ea1f5&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    123) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Ketene (Proposed). United States Environmental Protection Agency. Washington, DC. 2007. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ee7c&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    124) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Aluminum Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    125) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Magnesium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    126) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Malathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2009k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064809639df&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    127) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Mercury Vapor (Proposed). United States Environmental Protection Agency. Washington, DC. 2009b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a087&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    128) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Isothiocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a03&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    129) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963a57&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    130) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyl tertiary-butyl ether (Proposed). United States Environmental Protection Agency. Washington, DC. 2007a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064802a4985&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    131) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methylchlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5f4&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    132) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    133) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Methyldichlorosilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2005a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c646&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    134) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN1 CAS Reg. No. 538-07-8) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006a. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    135) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN2 CAS Reg. No. 51-75-2) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006b. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    136) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Mustard (HN3 CAS Reg. No. 555-77-1) (Proposed). United States Environmental Protection Agency. Washington, DC. 2006c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6cb&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    137) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Tetroxide (Proposed). United States Environmental Protection Agency. Washington, DC. 2008n. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648091855b&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    138) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Nitrogen Trifluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009l. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e0c&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    139) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Parathion (Proposed). United States Environmental Protection Agency. Washington, DC. 2008o. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480963e32&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    140) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perchloryl Fluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e268&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    141) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Perfluoroisobutylene (Proposed). United States Environmental Protection Agency. Washington, DC. 2009d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26a&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    142) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008p. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dd58&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    143) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2006d. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020cc0c&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    144) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phenyldichloroarsine (Proposed). United States Environmental Protection Agency. Washington, DC. 2007k. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020fd29&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    145) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phorate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008q. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096dcc8&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    146) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene (Draft-Revised). United States Environmental Protection Agency. Washington, DC. 2009e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a8a08a&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    147) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Phosgene Oxime (Proposed). United States Environmental Protection Agency. Washington, DC. 2009f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e26d&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    148) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    149) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Potassium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005c. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    150) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Propargyl Alcohol (Proposed). United States Environmental Protection Agency. Washington, DC. 2006e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec91&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    151) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Selenium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec55&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    152) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Silane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006g. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d523&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    153) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Cyanide (Proposed). United States Environmental Protection Agency. Washington, DC. 2009h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7cbb9&disposition=attachment&contentType=pdf. As accessed 2010-08-15.
    154) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sodium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    155) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Strontium Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005f. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    156) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Sulfuryl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2006h. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020ec7a&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    157) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tear Gas (Proposed). United States Environmental Protection Agency. Washington, DC. 2008s. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e551&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    158) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tellurium Hexafluoride (Proposed). United States Environmental Protection Agency. Washington, DC. 2009i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7e2a1&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    159) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tert-Octyl Mercaptan (Proposed). United States Environmental Protection Agency. Washington, DC. 2008r. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5c7&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    160) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Tetramethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-17.
    161) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethoxysilane (Proposed). United States Environmental Protection Agency. Washington, DC. 2006i. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d632&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    162) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethyl Phosphite (Proposed). United States Environmental Protection Agency. Washington, DC. 2009j. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=0900006480a7d608&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    163) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Trimethylacetyl Chloride (Proposed). United States Environmental Protection Agency. Washington, DC. 2008t. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648096e5cc&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    164) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for Zinc Phosphide (Proposed). United States Environmental Protection Agency. Washington, DC. 2005e. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020c5ed&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    165) National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances: Acute Exposure Guideline Levels (AEGLs) for n-Butyl Isocyanate (Proposed). United States Environmental Protection Agency. Washington, DC. 2008m. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=09000064808f9591&disposition=attachment&contentType=pdf. As accessed 2010-08-12.
    166) National Institute for Occupational Safety and Health: NIOSH Pocket Guide to Chemical Hazards, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Cincinnati, OH, 2007.
    167) National Research Council : Acute exposure guideline levels for selected airborne chemicals, 5, National Academies Press, Washington, DC, 2007.
    168) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 6, National Academies Press, Washington, DC, 2008.
    169) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 7, National Academies Press, Washington, DC, 2009.
    170) National Research Council: Acute exposure guideline levels for selected airborne chemicals, 8, National Academies Press, Washington, DC, 2010.
    171) Neuvonen P, Pohjola-Sintonen S, Tacke U, et al: Five cases of serotonin syndrome after moclobemide-citalopram or moclobemide clomipramine overdoses (letter). Lancet 1993; 342:1419.
    172) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    173) Polderman KH: Acute renal failure and rhabdomyolysis. Int J Artif Organs 2004; 27(12):1030-1033.
    174) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    175) Power BM, Pinder M, & Hackett LP: Fatal serotonin syndrome following a combined overdose of moclobemide, clomipramine, and fluoxetine. Anaesth Intens Care 1995; 23:499-502.
    176) Product Information: ATIVAN(R) injection, lorazepam injection. Baxter Healthcare Corporation, Deerfield, IL, 2003.
    177) Product Information: Manerix(R), Moclobemide. Hoffmann-La Roche Limited, Mississauga, Ontario, Canada, 2001.
    178) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    179) Qureshi A, Wassmer E, Davies P, et al: Comparative audit of intravenous lorazepam and diazepam in the emergency treatment of convulsive status epilepticus in children. Seizure 2002; 11(3):141-144.
    180) Raaflaub J, Haefelfinger P, & Trautmann KH: Single-dose pharmacokinetics of the MAO-inhibitor moclobemide in man. Arzneim-Forsch 1984; 34:80-82.
    181) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    182) Rogde S, Hilberg T, & Teige B: Fatal combined intoxication with new antidepressants. Human cases and an experimental study of postmortem moclobemide redistribution. Forensic Sci Int 1999; 100:109-116.
    183) Roxanas MG & Machado JFD: Serotonin syndrome in combined moclobemide and venlafaxine ingestion (letter). MJA 1998; 168:523-524.
    184) S Sweetman: Martindale: The Complete Drug Reference. Pharmaceutical Press. London, UK (Internet Version). Edition expires 2004; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    185) Singer PP & Jones GR: An uncommon fatality due to moclobemide and paroxetine. J Analyt Toxicol 1997; 21:518-520.
    186) Spigset O, Mjorndal T, & Lovheim O: Serotonin syndrome caused by a moclobemide-clomipramine interaction. Br Med J 1993; 306:248.
    187) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2010; 14(2):162-168.
    188) Stabl M, Biziere K, Schmid-Burgk W, et al: Moclobemide vs tricyclic antidepressants and vs placebo in depressive states. J Neural Transm 1989; 28(suppl):77-89.
    189) Sternbach H: The serotonin syndrome. Am J Psychiatr 1991; 148:705-713.
    190) Tiller JWG, Johnson GFS, & Burrows GD: Moclobemide for depression: An Australian psychiatric practice study. J Clin Psychopharmacol 1995; 15(suppl 2):31S-34S.
    191) Tiller JWG: Clinical overview on moclobemide. Prog Neuro-Psychopharmacol Biol Psychiatr 1993; 17:703-712.
    192) Timmings P & Lamont D: Intrahepatic cholestasis associated with moclobemide leading to death. Lancet 1996; 347:762-763.
    193) U.S. Department of Energy, Office of Emergency Management: Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 26 for chemicals of concern. U.S. Department of Energy, Office of Emergency Management. Washington, DC. 2010. Available from URL: http://www.hss.doe.gov/HealthSafety/WSHP/Chem_Safety/teel.html. As accessed 2011-06-27.
    194) U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project : 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Washington, DC. 2005. Available from URL: http://ntp.niehs.nih.gov/INDEXA5E1.HTM?objectid=32BA9724-F1F6-975E-7FCE50709CB4C932. As accessed 2011-06-27.
    195) U.S. Environmental Protection Agency: Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Environmental Protection Agency's (EPA) Resource Conservation and Recovery Act (RCRA); List of hazardous substances and reportable quantities 2010b; 40CFR(261.33, e-f):77-.
    196) U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Washington, DC. 2011. Available from URL: http://cfpub.epa.gov/ncea/iris/index.cfm?fuseaction=iris.showSubstanceList&list_type=date. As accessed 2011-06-21.
    197) U.S. Environmental Protection Agency: List of Radionuclides. U.S. Environmental Protection Agency. Washington, DC. 2010a. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    198) U.S. Environmental Protection Agency: List of hazardous substances and reportable quantities. U.S. Environmental Protection Agency. Washington, DC. 2010. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-sec302-4.pdf. As accessed 2011-06-17.
    199) U.S. Environmental Protection Agency: The list of extremely hazardous substances and their threshold planning quantities (CAS Number Order). U.S. Environmental Protection Agency. Washington, DC. 2010c. Available from URL: http://www.gpo.gov/fdsys/pkg/CFR-2010-title40-vol27/pdf/CFR-2010-title40-vol27-part355.pdf. As accessed 2011-06-17.
    200) U.S. Occupational Safety and Health Administration: Part 1910 - Occupational safety and health standards (continued) Occupational Safety, and Health Administration's (OSHA) list of highly hazardous chemicals, toxics and reactives. Subpart Z - toxic and hazardous substances. CFR 2010 2010; Vol6(SEC1910):7-.
    201) U.S. Occupational Safety, and Health Administration (OSHA): Process safety management of highly hazardous chemicals. 29 CFR 2010 2010; 29(1910.119):348-.
    202) United States Environmental Protection Agency Office of Pollution Prevention and Toxics: Acute Exposure Guideline Levels (AEGLs) for Vinyl Acetate (Proposed). United States Environmental Protection Agency. Washington, DC. 2006. Available from URL: http://www.regulations.gov/search/Regs/contentStreamer?objectId=090000648020d6af&disposition=attachment&contentType=pdf. As accessed 2010-08-16.
    203) Vanholder R, Sever MS, Erek E, et al: Rhabdomyolysis. J Am Soc Nephrol 2000; 11(8):1553-1561.
    204) Versiani M, Nardi AE, Figueira ILV, et al: Tolerability of moclobemide, a new reversible inhibitor of monoamine oxidase-A, compared with other antidepressants and placebo. Acta Pschiatr Scand 1990; 360(suppl):24-28.
    205) Versiani M, Oggero U, Alterwain P, et al: A double-blind comparative trial of moclobemide vs imipramine and placebo in major depressive episodes. Br J Psychiat 1989; 155(suppl 6):72-77.
    206) Walter LA & Catenacci MH: Rhabdomyolysis. Hosp Physician 2008; 44(1):25-31.
    207) Wheless JW : Treatment of status epilepticus in children. Pediatr Ann 2004; 33(6):376-383.
    208) Zimmer R, Puech AJ, Philipp F, et al: Interaction between orally administered tyramine and moclobemide. Acta Psychiat Scan 1990; 360(suppl):78-80.