Moclobemide

268.74

268.74

PJ0Y7AZB63

DTXSID9040554

Crystals from isopropanol

N06AG02|N - Nervous system

29349990

41.6

1.5

white

1.206±0.06 g/cm3(Predicted)

137 °C

447.7°C at 760 mmHg

DMSO: >20mg/mL

room temp

LD50 in rats (mg/kg): 707 orally (Burkard, Wyss)

10.6(ethanol-air)

10.6 (ethanol-air)

162.5 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|162.9 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]

Crystals from isopropanol; mp 208 /Hydrochloride/

Ⅲ

6.1(b)

3249

2

22-37/38-41-26/27/28

26-39-45-36/37/39-22

CV2462000

Xn,T+

P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P310, P312, P321, P330, P332+P313, P362, P403+P233, P405, P501

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

|Danger|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P340, P305+P351+P338, P310, P312, P321, P330, P332+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 47 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

LD50 (mouse) is 730mg/kg and LD50 (rat) is 1,300mg/kg. Signs of toxicity include hypertension, drowsiness, dizziness, confusion, tremors, headache, agitation, muscle rigidity and seizures. The effects of moclobemide alone in overdose are negligible, even with high volume ingestion. However, moclobemide overdose with a serotonergic agent (even in small, therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses.|IDENTIFICATION: Moclobemide is a monoamine oxidase inhibitor drug. Moclobemide is a white to red crystalline substance with a weak odor. It is soluble in chloroform, methanol and water. Indications: Accepted: Major mental depression and dysthymia. Investigational: Menopausal flushing, prophylactic treatment of migraine, smoking cessation and abstinence in heavy dependent smokers. HUMAN EXPOSURE: Main risks and target organs: Moclobemide is a short-acting, selective and reversible monoamine oxidase type A inhibitor (MAO-AI). It is generally well tolerated in overdose when taken alone. The serotonergic effects of moclobemide may be enhanced by combination with tricyclic antidepressants, other monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), lithium or serotonergic substances. A life-threatening serotonin syndrome consisting of hyperthermia, tremor and convulsions can develop when moclobemide is ingested with these drugs. The concomitant consumption of large amounts of tyramine-rich foodstuff may result in a moderate increase of systolic blood pressure (cheese reaction). Summary of clinical effects: Agitation, drowsiness, disorientation, slow-reacting pupils, myoclonic jerks in upper extremities; hypo or Hypertension, tachycardia; nausea, vomiting, abdominal pain. Contraindications: Absolute: Hypersensitivity to moclobemide, children less than 15 years old, breast feeding (in the absence of available data on potential toxic effects to suckling infants): less than 3 % of the administered dose of moclobemide is excreted in breast milk. Coadministration of sumatriptan: hypertensive crises, severe coronary vasoconstriction may occur. Co-administration of pethidine (meperidine), dextromethorphan: the serotonin syndrome may occur. Moclobemide is contraindicated in patients with acute confusional states and in those with pheochromocytoma. It should be avoided in excited or agitated patients and in those with severe hepatic impairment. Relative: Co-administration of drugs which increase the levels of monoamines such as serotonin and norepinephrine: tricyclic antidepressants, selective serotonin re-uptake inhibitor antidepressants: a serotonin syndrome may occur. Alcohol (as for other psychoactive drugs). Routes of exposure: Oral: Moclobemide is available as tablets, thus ingestion is the most common route of exposure. Kinetics: Absorption by route of exposure: Readily absorbed from the gastro-intestinal tract. Food delays absorption. Peak plasma concentration: 1 to 2 hours after ingestion. Oral bioavailability was reported as 60 % after a single dose and 80 % after repeated doses, due to an important and saturable hepatic first-pass effect. Distribution by route of exposure: Widely distributed throughout the body. Plasma protein binding is 50 %. After oral administration to 6 healthy subjects, the mean volume of distribution was about 1 L/kg. Biological half-life by route of exposure: After single oral doses, plasma half-life is 1 to 2 hours; with long term treatment, the half-life is reported to increase to 2 to 4 hours. Metabolism: Moclobemide undergoes extensive metabolism, mainly carbon and nitrogen oxidation in the liver, deamination and aromatic hydroxylation. Metabolites are inactive. Elimination and excretion: Metabolites of moclobemide and a small amount of unchanged drug (less than 1 %) are excreted in the urine; after an oral dose of radio-labelled moclobemide, 92% of the dose was excreted in the urine within 12 hours.Mode of action: Toxicodynamics: Moclobemide selectively and reversibly inhibits the activity of the intracellular enzyme monoamine oxidase A (MAO-A), thus preventing the normal metabolism of biogenic amines (noradrenaline, adrenaline, serotonin, dopamine). Mono amine oxidase inhibitors (MAOIs) exert their toxic effects by inhibiting the metabolism of sympathomimetic amines and serotonin, and by decreasing noradrenaline stores in post-ganglionic sympathetic neurons. They do not inhibit MAO synthesis. MAOIs also inhibit enzymes other than MAO, including dopamine-beta-oxidase, diamine-oxidase, amino-acid decarboxylase and choline dehydrogenase. Inhibition of these enzymes occurs only with very high doses of MAOIs and may be responsible for some of the toxic effects of MAOIs. Drugs that enhance serotonin release or reuptake (tricyclic antidepressants, selective serotonin reuptake inhibitors) may cause the serotonin syndrome when they are administered concurrently with the MAOIs, even at therapeutic doses. A toxic reaction to MAOIs may be caused by pressor amines such as tyramine, resulting in hypertensive crisis. When the protective role of intestinal and hepatic MAO is eliminated, increased absorption of tyramine from certain foods occurs and can cause a significant increase in blood pressure (cheese reaction) through the release of noradrenaline from pre-synaptic vesicles. Two isoforms of the MAO enzyme have been discovered: MAO-A and MAO-B. These isoforms differ in anatomical distribution and preferred substrates. The new MAOIs such as moclobemide are isoform selective and reversibly inhibit MAO-A. Thus having a lower potential for interactions than non selective MAOIs at therapeutic doses. Selectivity is lost in overdoses and in extreme situations such as high-dose combination therapies and mixed drug overdoses, and severe toxic reactions may occur. Pharmacodynamics: The MAOs are a group of enzymes that metabolize, and therefore inactivate endogenous pressor amines (such as norepinephrine, dopamine, serotonin) as well as ingested indogenous amines (such as tyramine). MAOIs inhibit the degradation of these amines by MAO. The increased availability of biogenic amines (such as norepinephrine and serotonin) is thought to be linked with the improvement in depression accounted for by MAIO treatment. Two isoforms of the MAO enzyme have been discovered: MAO-A and MAO-B, which differ in anatomical distribution and preferred substrates. The MAO type A enzymes preferentially metabolize serotonin and noradrenaline and are located primarily in the placenta, gut and liver. The MAO type B enzymes are predominant in brain, liver and platelets, and phenylethylamine, methylhistamine and tryptamine are their primary substrates. Both MAO-A and MAO-B metabolize tyramine. New MAOIs such as moclobemide, which are isoform selective and have reversible inhibition of the enzyme are called Reversible Inhibitors of MAO-A. The duration of MAO-A inhibition by moclobemide is shorter (16 to 24 hours) than the inhibition induced by conventional MAOIs (> 10 days). The interaction of the newer MAO-AI with hepatic cytochrome P450 appears to be much weaker than with the irreversible and nonspecific MAOIs. However, several studies in humans have suggested there is some involvement of cytochtome P450 in the metabolism of moclobemide, and also a weak inhibitory effect of moclobemide for its isoenzyme CYP2D6. The clinical relevance of this weak interaction is not clear and is probably of little consequence. Like tricyclic antidepressants, SSRIs and other MAOIs, moclobemide significantly reduces REM (rapid eye movement) sleep density, REM time and the REM percentage of total sleep time in patients with major depression. Interactions: Drug-food interactions: the dietary restrictions that need to be followed with irreversible MAOIs are less stringent with selective reversible inhibitors of monoamine oxidase type A such as moclobemide. However, the manufacturer of moclobemide recommends that since some patients may be more sensitive to tyramine, the consumption of large amounts of tyramine-rich foodstuffs should still be avoided; these foods include chocolate, aged cheeses, beer, chianti, vermouth, pickled fish and concentrated yeast extracts. Drug-drug interactions: Sympathomimetics and anorectic drugs should not be taken with moclobemide. Opioid analgesics: Central Nervous System (CNS) excitation or depression may occur. Drugs used in anesthesia: anesthesia may be performed 24 hours after discontinuation of moclobemide with little potential for significant interaction; when the washout period is not feasible, the use of meperidine and parenteral sympathomimetics should be avoided. Levodopa: a hypertensive crisis may be precipitated. Sumatriptan: the manufacturer recommends to not prescribe moclobemide concominantiantly with sumatriptan which is a selective agonist at serotonin type 1D receptors, because of possible hypertensive crises and severe coronary vasoconstriction, and advises a washout period of 24 hours after discontinuation of moclobemide; however a clinical study involving 103 episodes of migraine, did not show evidence of significant adverse effects. The metabolism of moclobemide is inhibited by cimetidine, leading to a prolonged half-life and increased plasma concentrations; the manufacturer recommends that the dose of moclobemide be reduced to half strength in patients who are also given cimetidine. The co-administration of drugs that increase the levels of monoamines such as serotonin and norepinephrine, including tricyclic antidepressants (mainly clomipramine), selective serotonin re-uptake inhibitor antidepressants, and potentially other antidepressants may cause a serotonin syndrome. Lithium: Care should be taken when co-prescribing MAO-AI with lithium, since it increases serotonin levels, although no interactions have been reported to date. Therapy with moclobemide should not be started until at least 7 days following the discontinuation of tricyclic or serotonin reuptake inhibitor antidepressant treatment (2 weeks in the case of paroxetine; 5 weeks in the case of fluoxetine) or for at least a week after stopping treatment with other monoamine oxidase inhibitors. Conversely, a washout period of 24 hours is advised when switching from moclobemide to other antidepressants. Antipsychotics, benzodiazepines, nifedipine and hydrochlorothiazide may be coprescribed without major interaction. Main adverse effects: They include sleep disturbances, dizziness, nausea, and headache. Confusional states, restlessness or agitation may occur. Mild elevations in liver enzyme values have been reported. Care is required in patients with thyrotoxicosis as moclobemide may theoretically precipitate a hypertensive reaction. Mental alertness may be impaired, patients under treatment should not drive or operate machinery. Manic episodes may be provoked in patients with bipolar disorders, moclobemide should be discontinued and antipsychotic therapy should be initiated. Less common adverse effects include: hypertension, although the role of concomitant administration of clomipramine, buspirone, and thyroxin in the case series reported may have contributed and cannot be disregarded, alopecia. Acute poisoning: Ingestion: Patients may display minimal or no symptoms following pure moclobemide overdose. However, the ingestion of moclobemide may cause nausea, vomiting, gastric pain; agitation, disorientation, drowsiness, impaired reflexes, myoclonic jerks in upper extremities, slow reacting pupils; slight rise in blood pressure or moderate hypotension and tachycardia. Co-ingestion of tricyclic antidepressants (primarily clomipramine), opioids, or selective serotonin reuptake inibitors can result in more varied and severe symptoms appearing within 2 to 3 hours after ingestion, even with lower doses of moclobemide. Symptoms include: both CNS depression (confusion, drowsiness) and excitation (seizure), tremor, mydriasis, hyperthermia with muscle rigidity, hypertension and metabolic acidosis. Several fatal cases have been reported after a combination of moclobemide with citalopram, clomipramine and fluoxetine and moclobemide with citalopram and fluoxetine. Course, prognosis, cause of death: Pure moclobemide overdoses usually have a fairly benign course. Several fatalities are reported in the literature, all involving a co-ingestion. The clinical course consisted of euphoria, agitation, then extreme tremor, followed by convulsions and hyperthermia. Death occurred within 3 to 16 hours after ingestion, after intractable seizure and/or hyperthermia and its subsequent complications: disseminated intravascular coagulation and multiple organ failure. Systematic description of clinical effects: Cardiovascular: Mild to moderate hypertension, moderate hypotension and sinus tachycardia. Neurological: Central nervous system: Mild disorientation, agitation, slurred speech, anxiety, dizziness; headache; drowsiness, coma. Autonomic nervous system: Slow-reacting pupils, mydriasis. Skeletal and smooth muscle: Myoclonic jerks in upper extremities; muscle rigidity; rhabdomyolysis. Gastrointestinal: Dry mouth; nausea, vomiting, gastric pain; diarrhea. Hepatic: Mild increases in liver enzymes values. Urinary: Renal Metabolic: Acid-base disturbances: Acidosis is expected in association with coma and/or convulsions. Fluid and electrolyte disturbances: Hyperkalemia. Others: Creatine phosphokinase may be elevated in patients with muscular hyperactivity or rigidity. ANIMAL STUDIES: In mice: (after oral and ip injection) Symptomatology: sedation, muscle twitching, respiratory depression, death. In rats: (after oral and ip injection) Symptomatology: sedation, respiratory depression, death. In rabbits (after oral and ip injection): Symptomatology: ataxia, decrease in motor activity, respiratory depression, tremor, seizures, salivation and death. Carcinogenicity: Animal studies: moclobemide was not carcinogenic in rats at oral doses for 2 years. In mice given the drug orally over 80 weeks, no carcinogenic effect was observed. Teratogenicity: Animal studies: doses up to 100 mg/kg/day did not affect fertility in rats. In rabbits and rats oral doses of up to 100 and 200 mg/kg/day respectively did not have embryotoxic or teratogenic effects. Mutagenicity: In vitro and in vivo: moclobemide did not show mutagenicity.

Moclobemide has been shown to potentiate the effects of opiates. Co-administration of moclobemide with meperidine is contraindicated /SRP:due to the risk of serotonin syndrome/. Other opioid analgesics should be used with caution and a dose adjustment for these agents may be necessary.|Increased moclobemide plasma concentrations may occur; 50% reduction of moclobemide doses may be needed when coadministered with cimetidine.|Concomitant use of moclobemide and a tricyclic antidepressant (TCA) is contraindicated. Treatment with a TCA may be initiated following discontinuation of moclobemide and a wash-out period of no less than 2 days. Moclobemide should not be administered in combination with a conventional monamine oxidase inhibitor (MAOI) (phenelzine, tranylcypromine) or a selective serotonin reuptake inhibitor (SSRI). When switching patients from MAOI or serotonergic antidepressants to moclobemide, a wash-out period of 4 to 5 half-lives of the previous administrated drug (and any active metabolites) should intervene. At least 5 weeks should elapse between withdrawal of fluoxetine and initiation of moclobemide.|A potentially lethal hyperserotonergic state known as the serotonin syndrome may occur as the result of combining serotonergic agents (such as amitriptyline, clomipramine, doxepin, or imipramine, fluvoxamine, fluoxetine, paroxetine, sertraline /SRP: and meperidine) with monoamine oxidase inhibitors. The syndrome may be manifested by mental status changes (confusion, hypomania), restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever.|For more Interactions (Complete) data for MOCLOBEMIDE (11 total), please visit the HSDB record page.

LD50 Rat oral 707 mg/kg

Approximately 50% (primarily to albumin)

Small quantities of moclobemide are distributed into human breast milk.|The concentrations of moclobemide and /3-keto-meclobemide/ (Ro-12-8095) in milk were highest at 3 hr after moclobemide administration and the drug and metabolite were not detectable after 12 hr.

/Toxicological/ results obtained /post-mortem from a 41-yr-old Caucasian male, with a history of depression and suicide attempts showed/ blood and urine /levels/, respectively, were as follows: Ro 12-5637 (moclobemide N'-oxide) not detected and 424 ug/mL; Ro 12-8095 (3-keto-moclobemide) 2.26 ug/mL and 49.7 ug/mL; moclobemide 5.62 ug/mL and 204 ug/mL;|Autopsy findings /for a young man was found shivering and incoherent at home/ were unremarkable, but toxicology testing revealed the following: moclobemide (subclavian blood, 18.5 mg/L; liver, 28.5 mg/kg; gastric contents, 77 mg/69 g) and paroxetine (subclavian blood, 1.58 mg/L; liver, 15.3 mg/kg; gastric contents, 0.7 mg/69 g).

For the treatment of major depressive disorder and bipolar disorder.

Moclobemide is indicated for the relief of symptoms of depressive illness. /Included in US product labeling/|Antidepressants appear to be useful in the treatment of pain disorders.|EXPTL Therapy: This randomized, prospective, double-blind study evaluated the efficacy and tolerability of moclobemide, a reversible, selective inhibitor of monoamine oxidase-A, in reducing the frequency and severity of hot flashes. Thirty postmenopausal women were enrolled, and 28 were allocated to 5 weeks of treatment with moclobemide 150 mg (group 1, n = 10), moclobemide 300 mg (group 2, n = 11), or placebo (group 3, n = 9). Data on hot flashes were recorded in a daily diary. Mean reductions in the hot flash severity score were 24.4% in the placebo group, 69.8% in group 1, and 35.0% in group 2.|EXPTL Therapy: In a double-blind placebo controlled study, 12 male outpatients suffering from psychogenic erectile dysfunction without any other psychiatric disorder were investigated. Based on comprehensive diagnosis before the beginning of the study, organic factors relevant for sexual function were excluded. The treatment period was 8 weeks. Half the patients received 450 mg moclobemide during the first week, and 600 mg afterwards; the others received placebo. Apart from assessment of erectile function by means of the Clinical Global Impression (CGI) scale, nocturnal erections were measured under polysomnographic control at baseline and at the end of the treatment period. The evaluation of the CGI scale revealed a clearly stronger improvement under moclobemide compared to placebo during the study period. The therapeutic efficacy found on the subjective level had no clear correlate on the neurophysiological level. No alterations of nocturnal erectile parameters were obvious under treatment; neither were clinically relevant alterations found regarding sleep EEG parameters. The medication was well tolerated without serious adverse events. The findings support the hypothesis that moclobemide has a specific effect on /psychogenic/ erectile dysfunction.|Moclobemide represents a new class of drug, the so-called RIMA compounds--reversible inhibitors of MAO-A. Unlike classical monoamine oxidase (MAO) inhibitors, moclobemide is devoid of hepatotoxicity and has only a slight potentiating effect on the hypertensive action of tyramine; treatment does not require a tyramine-restricted diet. Studies comparing moclobemide with tricyclic antidepressants (TCAs) indicate that moclobemide is significantly better tolerated than TCAs and slightly less well tolerated than placebo.

Safety aspects were compared in 2203 patients given moclobemide and 1214 who received other antidepressants or placebo. A total of 2294 adverse events were reported by patients on moclobemide, mainly subjective symptoms (28.6%). Adverse events such as dry mouth, tremor, sweating, dizziness and constipation occurred much more frequently among 681 patients treated with various tricyclic antidepressants than in the 694 moclobemide patients with whom they were compared.|Because moclobemide is partially metabolized by the polymorphic isozymes CYP2C19 and CYP2D6, plasma concentrations of this medication may be affected in patients with genetically or drug-induced poor metabolism. Approximately 2% of whites and 15% of Asians can be genetically phenotyped as slow metabolizers with respect to oxidative hepatic metabolism. In slow metabolizer subjects, the area under the concentration-time curve (AUC) was found to be 1.5 times greater than in extensive metabolizer subjects for the same dose of moclobemide. This increase is within the normal range of variation (up to two-fold) typically seen in patients.|Concurrent consumption of tyramine-rich food with irreversible monoamine inhibitors may cause sudden and severe hypertensive reactions; since moclobemide is a reversible inhibitor of MAO-A (RIMA), dietary restriction may not be necessary; consumption of up to 100 mg of tyramine with 600 mg of moclobemide per day is not expected to cause problems; potential hypertensive reactions may be minimized if moclobemide is taken after meals.|Moclobemide had inconsistent effects on the blood pressure of hypertensive patients during clinical trials; careful monitoring is important, especially during initial titration.|For more Drug Warnings (Complete) data for MOCLOBEMIDE (12 total), please visit the HSDB record page.

A selective, reversible inhibitor of monoamine oxidase (MAO) which increases the. Besides its presence in sympathetic nerves, there is an abundant evidence that MAO-A is localized in noradrenergic neurons in the locus coeruleus and MAO-B is closely associated with serotonergic neurons of the raphe nucleus.

Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. (See all compounds classified as Antidepressive Agents.)|A chemically heterogeneous group of drugs that have in common the ability to block oxidative deamination of naturally occurring monoamines. (From Gilman, et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p414) (See all compounds classified as Monoamine Oxidase Inhibitors.)

Well absorbed from the gastrointestinal tract (> 95%). The presence of food reduces the rate but not the extent of absorption. Hepatic first-pass metabolism reduces bioavailability to about 56% following administration of one dose, but increases to 90% with steady-state dosing as a result of saturation of the first pass effect. Peak plasma concentrations are reached within 0.3 - 1 hours following oral administration with a terminal half-life of 1.6h.|Moclobemide is almost completely renally excreted.|1-1.5 L/Kg|Clearance of 30-78 L/h, mainly excreted in urine.|Moclobemide is readily absorbed (>95%) through the gastrointestinal tract. Within 1 to 2 hours of oral use, a peak plasma level of about 1 ug/mL is reached. It is protein bound to the extent of 50%.|Small quantities of moclobemide are distributed into human breast milk.|Well absorbed from the gastrointestinal tract. The presence of food reduces the rate but not the extent of absorption. Absolute bioavailability ranges from approximately 55% following administration of single doses of moclobemide to 90% following multiple dosing, due to the hepatic first pass effect.|Elimination: Renal, as metabolites. Less than 1% of an administered dose of moclobemide is eliminated unchanged.|The excretion of moclobemide and its major metabolites in human breast milk was studied in 6 lactating women (aged 24-36 yr) who received a single dose of 300 mg moclobemide in oral tablet form. Moclobemide and /3-keto-meclobemide/ (Ro-12-8095) were measured in milk and plasma samples. /Moclobemide-N'-oxide/ (Ro-12-5637) was only detected in plasma. The concentrations of moclobemide and Ro-12-8095 in milk were highest at 3 hr after moclobemide administration and the drug and metabolite were not detectable after 12 hr. The percentages of the dose excreted as moclobemide and Ro-12-8095 were 0.057+/-0.02% and 0.031+/-0.011%, respectively.

Moclobemide is almost completely metabolized in the liver by Cytochrome P450 2C19 and 2D6. Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of CYP1A2, CYP2C19, and CYP2D6.|The role of mephenytoin oxidation polymorphism in the metabolism of moclobemide was studied in 15 healthy subjects (ages 23-27 yr), including 7 poor metabolizers and 8 extensive metabolizers of S-mephenytoin, who received a single dose of 300 mg moclobemide and multiple doses of 600 mg/day moclobemide. Poor metabolizers of S-mephenytoin had lower moclobemide clearance (median single dose 16.1 vs 43.2 L/hr) and longer half-life (median single dose 4 vs 1.8 hr) compared with extensive metabolizers. Plasma levels of a metabolite formed by C-hydroxylation were lower in poor metabolizers. Moclobemide thus partially underwent oxidative metabolism via polymorphic CYP2C19. Changes in metabolic indexes were compatible with reversible inhibition of oxidation by way of CYP2C19, CYP2D6, and CYP1A2. It was concluded that there is a cosegregation between moclobemide clearance and mephenytoin oxidation polymorphism.|Moclobemide appears to be eliminated (after first-pass hepatic metabolism) by first-order kinetics, resulting in urinary excretion of the monoamine metabolites homovanillic acid (HAV), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenyl glycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA).

1-2 hours (4 hours in cirrhotic patients); metabolites are renally excreted|Elimination: 1.5 hours (4 hours in cirrhotic patients).

The mechanism of action of moclobemide involves the selective, reversible inhibition of MAO-A. This inhibition leads to a decrease in the metabolism and destruction of monoamines in the neurotransmitters. This results in an increase in the monoamines, relieving depressive symptoms.|The exact mechanism of antidepressant effect is unknown; however, it is established that the activity of the enzyme monoamine oxidase (MAO) is inhibited. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters, such as norepinephrine and dopamine. Moclobemide, as a selective MAO inhibitor, preferentially inhibits monoamine oxidase-A (MAO-A) and, to a lesser extent, monoamine oxidase-B (MAO-B) (approximately 80% inhibition of MAO-A and 20% to 30% inhibition of MAO-B, 300 mg). Reduced MAO activity results in an increased concentration of serotonin and catecholamine neurotransmitters in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. This increased availability of one or more monoamines has been thought to be the basis for the antidepressant activity of MAO inhibitors. MAO-A inhibition by moclobemide is short-acting (maximum 24 hours) and reversible (transient binding to MAO-A). In contrast, some other MAO inhibitors (phenelzine, tranylcypromine) are non-selective, long-acting, and irreversible in their binding to MAO-A and MAO-B.

With symptomatic and supportive treatment in a hospital, moclobemide overdose patients ... appeared to recover usually within 24 hours and, in two cases, within 5 to 7 days. Seizures may require diazepam, thiopental, and mechanical ventilation. Dantrolene may be useful for hyperthermia. Blood pressure must be monitored in all moclobemide overdose patients.|Monitoring: Monitor closely for signs of potentially fatal serotonergic syndrome, which has been reported after overdose of moclobemide with other antidepressants. /SRP: Serotonin syndrome/|Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|For more Antidote and Emergency Treatment (Complete) data for MOCLOBEMIDE (9 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Patients ingesting up to 2000 mg of moclobemide have shown only mild gastrointestinal symptoms or no symptoms at all. At 3000 to 4000 mg, depressed consciousness and a slight increase in blood pressure have been observed. At 7000 to 8000 mg, patients show fatigue, agitation, tachycardia, increased blood pressure, and dilated slow-reacting pupils. Both central nervous system depression and excitation (Seizures) have been observed. Tremor, mydriasis, hyperthermia, hypertension, and acidosis may be seen. There may be an additive effect with tricyclic antidepressants. In massive overdoses (>2000 to 6000 mg), seizures, hyperthermia, muscle rigidity, and pain, together with rhabdomyolysis, resemble classical MAOI intoxication as well as the unusual neuroleptic malignant syndrome.|/CASE REPORTS/ A 41-yr-old Caucasian male, with a history of depression and suicide attempts, was found deceased at home. Multiple containers of medication, the MAO-inhibitor moclobemide (Aurorix), the SSRI citalopram (Cipramil), and the benzodiazepine lormetazepam (Noctamid) as active substance, as well as a bottle of whiskey were present at the scene. The autopsy findings were unremarkable, but systematic toxicological analysis (EMIT, radioimmunoassay, high-performance liquid chromatography-diode-array detection [HPLC-DAD], gas chromatography-nitrogen-phosphorus detection, and gas chromatography-mass spectrometry) revealed the following: ethanol (0.23 g/L blood, 0.67 g/L urine), lormetazepam (1.65 ug/mL urine), cotinine (0.63 ug/mL blood, 5.08 ug/mL urine), caffeine (1.20 ug/mL urine), moclobemide (and metabolites), and citalopram (and metabolite). There upon, we developed a new liquid chromatographic separation with optimized DAD, preceded by an automated solid-phase extraction, for the quantitation of the previously mentioned antidepressive drugs. The results obtained for blood and urine, respectively, were as follows: Ro 12-5637 (moclobemide N'-oxide) not detected and 424 ug/mL; Ro 12-8095 (3-keto-moclobemide) 2.26 ug/mL and 49.7 ug/mL; moclobemide 5.62 ug/mL and 204 ug/mL; desmethylcitalopram 0.42 ug/mL and 1.22 ug/mL; and citalopram 4.47 ug/mL and 19.7 ug/mL. The cause of death was attributed to the synergistic toxicity of moclobemide and citalopram, both antidepressants, which, by intentional or accidental combined ingestion, can produce a potentially lethal hyperserotoninergic state. Based on the history of the case and pharmacology of the drugs involved, the forensic pathologists ruled that the cause of death was multiple drug intoxication, resulting in a fatal "serotonin syndrome," and that the manner of death was suicide.|/CASE REPORTS/ The cases of 5 patients (ages 19-41 yr) who developed fatal serotonin syndrome following overdoses of 1000-1500 mg moclobemide (Aurorix) and 225-500 mg clomipramine hydrochloride (Anafranil Retard) or moclobemide and citalopram hydrobromide (Cipramil) are described. The patients were initially euphoric, but then developed tremor, followed by convulsions and loss of consciousness. The patients died 3-16 hr after ingesting the drugs. Blood levels for the drugs at admission and at necropsy are reported.

Apo Moclobemide

Not commercially available in US.|Canada: 150 mg (Rx); Manerix (scored, film-coated; cornstarch, ethylcellulose, iron oxide, lactose, magnesium sterate, methylhydroxypropyl cellulose, polyethylene glycol, povidone, sodiumstarch glycolate, talc, titanium dioxide). 300 mg (Rx); Manerix (scored, film-coated; cornstarch, ethylcellulose, lactose, magnesium sterate, methylhydroxypropyl cellulose, polyethylene glycol, povidone, sodiumstarch glycolate, talc, titanium dioxide).|Trade Name: Auroxix