Action And Clinical Pharmacology: Moclobemide is a short-acting, reversible inhibitor of monoamine oxidase type A (RIMA). It is a benzamide derivative which inhibits the deamination of serotonin, noradrenaline and dopamine. This action leads to increased concentrations of these neurotransmitters, which may account for the antidepressant activity of moclobemide.
Monoamine oxidases are currently subclassified into 2 types, A and B, which differ in their substrate specificity. Moclobemide preferentially inhibits MAO-A; at a 300 mg dose, the inhibition of MAO-A is approximately 80%, while that of MAO-B is approximately 20 to 30%. The estimated MAO-A inhibition is short-lasting (maximum 24 hours) and reversible.
Pharmacokinetics: Volunteers: General: Following oral administration, moclobemide is 98% absorbed from the gastrointestinal tract. Due to hepatic first pass effect, absolute bioavailability is approximately 55% after single doses, but 90% after multiple doses. The apparent volume of distribution is approximately 1.2 L/kg, indicating extensive tissue distribution.
Moclobemide is extensively metabolized, 95% of the administered dose is excreted in the urine. The metabolites are pharmacologically inactive. Moclobemide is 50% bound to plasma proteins, mainly to albumin.
The presence of food reduces the rate, but not the extent of moclobemide absorption.
Single Dose: Following the administration of a 100 mg single oral dose of moclobemide to healthy subjects, peak plasma concentrations ranged from 488 ng/mL to 1 450 ng/mL (mean Cmax: 849 ng/mL) and were reached in 0.5 to 3.5 hours (mean Tmax: 49 min). The elimination half-life is 1.5 hours. Up to 200 mg, the pharmacokinetics of moclobemide are linear. At higher doses, nonlinear pharmacokinetics are observed. In a dose range of 400 mg to 1 200 mg, maximum plasma concentrations increased and clearance decreased in a non dose-proportional manner. With increasing doses, the elimination half-life also becomes prolonged.
Multiple Dose: During the second week of a 100 mg t.i.d. dosing regimen in healthy subjects, the steady-state trough concentrations of moclobemide ranged between 114 and 517 ng/mL. An increase in the dose to 150 mg t.i.d. resulted in a greater than proportional increase in moclobemide steady-state trough concentrations, namely to concentrations ranging between 346 and 1 828 ng/mL.
Patients: Hepatic Impairment, Single Dose: In patients with liver cirrhosis, the administration of a single 100 mg dose of moclobemide resulted in approximately a 3-fold increase in peak plasma concentrations (Cmax: 1 607 ng/mL) and elimination half-life (t1/2 Ã¡: 4.0 h), while clearance decreased about 4-fold (Cl: 337 mL/min).
Renal Impairment, Single Dose: In patients with renal insufficiency, the administration of a single 100 mg dose of moclobemide did not appreciably alter the pharmacokinetics of the drug, except for an increase in absorption time.
Elderly Patients, Single and Multiple Dose: Following a 100 mg t.i.d. dosing regimen in elderly subjects (65 to 77 years old), Cmax and AUC values were somewhat higher than in young subjects (21 to 34 years old), namely 1 498 vs 950 ng/mL and 5 571 vs 3 102 ng.h/mL, respectively. Clearance in the elderly was reduced (19.7 versus 32.3 L/h).
Slow Metabolisers: Approximately 2% of the caucasian population and 15% of the Asian population can be genetically phenotyped as slow metabolisers with respect to oxidative hepatic metabolism. It was found that the AUC measurement in slow metaboliser subjects was approximately 1.5 times greater than in extensive metaboliser subjects for the same dose of moclobemide. This increase is within the normal range of variation (up to 2-fold) typically seen in patients.
Indications And Clinical Uses: For the symptomatic relief of depressive illness.
Contra-Indications: In patients with a known hypersensitivity to the drug. As with any other exogenous compound the possibility of hypersensitivity reaction should be considered in susceptible patients. Moclobemide is also contraindicated in patients in an acute confusional state.
In a clinical study designed to test the interaction between moclobemide and a tricyclic antidepressant (clomipramine), severe adverse reactions emerged and the study was terminated. Data involving other tricyclic antidepressants are limited. Consequently, the concomitant use of moclobemide and tricyclic antidepressants is contraindicated.
Clinical data are not available on the concomitant use of moclobemide and selective serotonin reuptake inhibitors or conventional MAO inhibitors. Therefore, until such data become available, moclobemide should not be administered in combination with these agents.
There is no experience with the concomitant use of moclobemide and narcotics. However, death has occurred in patients receiving a conventional MAO inhibitor and meperidine given concomitantly. Therefore, moclobemide should not be used in combination with meperidine.
Children: As safety and effectiveness of moclobemide in children below the age of 18 have not been established, pediatric use is not recommended.
Precautions: General: The possibility of suicide in depressed patients is inherent in their illness and may persist until remission occurs. Therefore, patients must be carefully supervised during all phases of treatment with moclobemide. Prescriptions for potentially suicidal patients should be written for a limited supply only.
In patients with thyrotoxicosis or pheochromocytoma, conventional MAO inhibitors may precipitate a hypersensitive reaction. Because there are no data available on the use of moclobemide in such patients, caution is advised when prescribing moclobemide to these subjects.
Occupational Hazards: Patients should be cautioned against driving an automobile or performing hazardous tasks until they are certain of the effect that moclobemide has on them.
Pregnancy: Safety of use in pregnancy has not been established. Therefore, moclobemide is not recommended in women who may be pregnant, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible risk to the fetus.
Lactation: Clinical data suggest that small quantities of moclobemide are excreted in human milk. Therefore, moclobemide is not recommended in nursing mothers unless the anticipated benefits outweigh the potential harm to the infant.
Hepatic Dysfunction: In patients with severe liver dysfunction, the daily dose of moclobemide should be substantially reduced to one-third or one-half of the standard dose (see Pharmacology, Pharmacokinetics).
Renal Dysfunction: Single dose pharmacokinetic data suggest that no dosage adjustment may be required in patients with impaired renal function (see Pharmacology, Pharmacokinetics). However, multiple dose studies with moclobemide have not been performed in patients with renal dysfunction, therefore, moclobemide should be used with caution in this patient population. In normal volunteers, the absolute bioavailability almost doubles following multiple dosing as compared to a single dose.
Drug Interactions: Cimetidine: Cimetidine doubles the AUC (area under the plasma concentration-time curve) of moclobemide and is expected to approximately double moclobemide steady-state concentrations.
In patients receiving moclobemide concomitantly with cimetidine, a 50% reduction in the dosage of moclobemide may be necessary.
Tyramine: During studies conducted at the maximum recommended moclobemide dose of 600 mg/day, the mean dose of tyramine required to produce a 30 mm Hg increase in systolic blood pressure was 148±50 mg (76 to 200 mg) when moclobemide was administered immediately after tyramine. The threshold dose of tyramine was reduced to 84±23 mg (54 to 112 mg) when the sequence of administration was reversed so that moclobemide was administered 1 hour before tyramine. These findings indicate that the potentiation of tyramine may be minimized by administering moclobemide after, instead of prior to, a tyramine-enriched meal. There is limited experience in patients who took moclobemide before meals. Most clinical trial protocols specified that the drug be taken immediately after meals. Therefore, patients should be instructed to take moclobemide immediately after meals.
Treatment with moclobemide does not necessitate special dietary restrictions. In clinical studies, it was demonstrated that up to 100 mg tyramine can be safely ingested during treatment with moclobemide 600 mg/day when moclobemide was given after meals. This amount of tyramine, 100 mg, corresponds to 1 000 to 2 000 g mild or 200 g strong cheese, or to 70 g Marmite yeast extract.
As a safety measure, patients should be urged to report immediately the abrupt occurrence of any of the following symptoms: occipital headache, palpitations, neck stiffness, tachycardia or bradycardia or other atypical or unusual symptoms not previously experienced.
Other Antidepressants: Concomitant Use: Clinical interaction studies between moclobemide and a tricyclic antidepressant (clomipramine) resulted in severe adverse reactions (see Contraindications). Data involving other tricyclic antidepressants are limited. Therefore, the concomitant use of moclobemide and tricyclic antidepressants is contraindicated.
Clinical data are not available on the concomitant use of moclobemide and selective serotonin reuptake inhibitors, or conventional MAO inhibitors. Therefore, until clinical data become available, moclobemide should not be administered in combination with these agents.
Sequential Use: Treatment with a tricyclic antidepressant may be initiated following the discontinuation of moclobemide with a short washout period of no less than 2 days.
When switching patients from serotonergic antidepressants to a conventional MAO inhibitor, it is standard practice to allow for a washout period equivalent to at least 4 to 5 half-lives of the previously administered drug or any active metabolites. This recommendation also applies to moclobemide.
Fluoxetine: An exception is fluoxetine; at least 5 weeks should elapse between its discontinuation and initiation of treatment with moclobemide.
Buspirone: To date, there is no experience regarding the coadministration of moclobemide and buspirone. Therefore, patients should be carefully monitored should concomitant administration be implemented.
Antipsychotics: In depressed patients with schizophrenic or schizoaffective disorder, psychotic symptoms may be exacerbated during treatment with moclobemide. There is little experience regarding the concomitant use of moclobemide and antipsychotic drugs. Therefore, patients should be carefully monitored should concomitant treatment be undertaken.
Alcohol: Excessive alcohol consumption should be avoided. Alcohol interaction studies were performed at blood alcohol concentrations of 0.05%. However, no studies were conducted at blood alcohol concentrations recognized as legally intoxicating.
Anesthetic Agents: While specific data on the use of moclobemide in patients undergoing anesthesia are not available, based on its reversible action and short elimination half-life (see Pharmacology), moclobemide should be discontinued no less than 2 days before the administration of anesthetic agents, especially spinal or local anesthetic agents that contain epinephrine.
Sympathomimetics: Following multiple oral doses of moclobemide (total dose: 600 mg/day), a phenylephrine-induced increase in systolic blood pressure was potentiated (1.6 times) after i.v. administration. Patients should be advised to avoid the concomitant use of sympathomimetic amines (e.g., amphetamine and ephedrine like compounds contained in many proprietary cold, hay fever or weight-reducing preparations), until further studies have been conducted.
Dextromethorphan: In isolated cases, the coadministration of moclobemide and dextromethorphan resulted in adverse events, including vertigo, tremor, nausea and vomiting. Since cough and cold medicines may contain dextromethorphan, they should not be taken without prior consultation with the physician, such that nondextromethorphan containing alternatives may be given.
Antihypertensive Agents: Clinical trials with moclobemide have shown inconsistent effects on the blood pressure of hypertensive patients. Therefore, careful monitoring is recommended during initial treatment.
Adverse Reactions: Table I lists the adverse events reported during clinical trials in which 1 922 patients were treated with 50 to 600 mg/day moclobemide for depressive illness. Limited experience in 60 patients treated with 601 to 750 mg/day of moclobemide suggests that the incidence of adverse reactions may increase at higher doses.
Central and Peripheral Nervous System: migraine, extrapyramidal effects, tinnitus, paresthesia, dysarthria.
Gastrointestinal: heartburn, gastritis, meteorism, indigestion.
Cardiovascular: hypertension, bradycardia, extrasystoles, angina/chest pain, phlebitic symptoms.
Dermatological/Mucocutaneous: exanthema/rash, allergic skin reaction, itching, gingivitis, stomatitis, dry skin, conjunctivitis.
Genitourinary: disturbances of micturition (dysuria, polyuria, tenesmus) metrorrhagia, prolonged menstruation.
Miscellaneous: general malaise, skeletal/muscular pain, altered taste sensations, hot flushes/cold sensation, photopsia, dyspnea.
Laboratory Abnormalities: Laboratory examinations were performed in a total of 1 401 patients during clinical trials with moclobemide. Reductions were observed in leukocyte, AST and ALT values, however, these reductions were not considered clinically relevant. No other laboratory abnormalities were noted.
Symptoms And Treatment Of Overdose: Symptoms: Signs and symptoms of overdosage with moclobemide include nausea, drowsiness, mild disorientation, slurred speech, amnesia and reduced reflexes. One patient remained stuporous for 36 hours following an overdose of 1 550 mg moclobemide. All abnormal laboratory values and vital signs returned to within normal range one to five days after overdosage. No organ toxicity was reported.
Treatment: The treatment of overdosage should consist of general supportive measures. Gastric lavage or induction of emesis, activated charcoal and fluid control may be of benefit.
Dosage And Administration: Note: Moclobemide should always be taken after meals (see Precautions, Drug Interactions).
Usual Adult Dosage: The administration of moclobemide should be initiated at 300 mg daily (in 2 to 3 divided doses), and increased gradually to a maximum of 600 mg/day if needed, noting carefully the clinical response and any evidence of intolerance. As with other antidepressants, it should be kept in mind that there may be a lag time in therapeutic response. There is no evidence that increasing the dosage rapidly shortens this latent period and may, in fact, increase the incidence of side effects.
Liver Dysfunction: In patients with severe liver dysfunction, the daily dose of moclobemide should be reduced to one-third or one-half of the standard dose.
Renal Dysfunction: Single dose pharmacokinetic data suggest that no dosage adjustment may be required in patients with impaired renal function. However, multiple dose studies with moclobemide have not been performed in patients with renal dysfunction, therefore, moclobemide should be used with caution in this patient population. In normal volunteers, the absolute bioavailability almost doubles following multiple dosing as compared to a single dose.
Geriatrics: No dosage adjustments are necessary in elderly patients.
Cimetidine: Cimetidine doubles the AUC (area under the plasma concentration-time curve) of moclobemide and is expected to approximately double moclobemide steady-state concentrations (see Precautions, Drug Interactions).
In patients receiving moclobemide concomitantly with cimetidine, a 50% reduction in the dosage of moclobemide may be necessary.
Availability And Storage: 100 mg: Each orange, oval, biconvex, film-coated tablet, scored on one side and engraved APO over 100 on the other, contains: moclobemide 100 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, dextrates, hydroxypropyl methylcellulose, magnesium stearate, polydextrose, polyethylene glycol (carbowax), red ferric oxide, titanium dioxide and yellow ferric oxide. Bottles of 100 and 500.
150 mg: Each pale yellow, oval, biconvex, film-coated tablet, scored on one side and engraved APO over 150 on the other, contains: moclobemide 150 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, dextrates, hydroxypropyl methylcellulose, magnesium stearate, polydextrose, polyethylene glycol (carbowax), titanium dioxide and yellow ferric oxide. Bottles 100 and 500.
Store at room temperature 15 to 30°C.
APO®-MOCLOBEMIDE Apotex Moclobemide Antidepressant