Professional Drug Information > Manerex

Moclobemide (Systemic)

USAN:
Moclobemide

INN:
Moclobemide

BAN:
Moclobemide

VA CLASSIFICATION
Primary: CN602

Commonly used brand name(s): Manerix.

Another commonly used name is:
RO 11–1163 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

Category:


Antidepressant—

Indications

Accepted

Depression, mental (treatment)—Moclobemide is indicated for the relief of symptoms of depressive illness.^{01}


Pharmacology/Pharmacokinetics

Note: The pharmacokinetics of moclobemide are linear only up to 200 mg; at doses above that, non-linear pharmacokinetics are observed^{01}.


Physicochemical characteristics:

Chemical group—
    Benzamide derivative.
^{01}Molecular weight—
    268.74^{01}

pKa—
    approximately 6.2^{01}

Solubility
    Slightly soluble in water.^{01}

Partition coefficient
    Approximately 40 in a pH 7.4 octanol/ buffer solution^{01}.

Mechanism of action/Effect:

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 selectiveMAO 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).^{01} 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)^{01}. In contrast, some other MAO inhibitors (phenelzine, tranylcypromine) are non-selective, long-acting, and irreversible in their binding to MAO-A and MAO-B (See Antidepressants, Monoamine Oxidase (MAO) Inhibitor— Systemic).


Other actions/effects:

Monoamine oxidase inhibitors exhibit a hypotensive effect, which varies with the specific agent; the hypotensive mechanism of action may be due to chronic accumulation of the false neurotransmitter octopamine in adrenergic terminals.^{02}{03}

Monoamine oxidase inhibitors prevent the inactivation of tyramine by hepatic and gastrointestinal monoamine oxidase. Circulating tyramine releases norepinephrine from the sympathetic nerve terminals and produces a sudden increase in blood pressure.
^{04}
Absorption:

Well absorbed from the gastrointestinal tract ^{01}. The presence of food reduces the rate but not the extent of absorption^{01}. 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^{01}.

Distribution:

Small quantities of moclobemide are distributed into human breast milk.^{01}

Volume of distribution (Vol _D)—approximately 1.2 liter per kg (L/kg) ^{01}.

Protein binding:

Moderate (approximately 50%, mainly to albumin).^{01}

Biotransformation:

Extensively metabolized in the liver by oxidation.^{01}


Half-life:


Elimination:

1.5 hours (4 hours in cirrhotic patients)^{01}.


Time to peak concentration:

49 minutes (mean).^{01}

Peak serum concentration:

849 ng/mL (mean); 1607 ng/mL (cirrhotic patients).^{01}

Elimination:
    Renal, as metabolites.^{01} Less than 1% of an administered dose of moclobemide is eliminated unchanged^{01}.


Precautions to Consider

Carcinogenicity

Twenty-three cases of hepatocellular hyperplasia developed among 136 rats, with 7 occurring at doses of 45 mg of moclobemide per kg of body weight (mg/kg) per day and 15 occurring at 225 mg/kg per day given over 2 years.^{01} An increased incidence of alveolar foam cell aggregates occurred in male rats receiving 45 and 225 mg/kg doses of moclobemide per day and in female rats receiving 9, 45, and 225 mg/kg doses per day, and an increased incidence of small clusters of pigmented alveolar macrophages occurred in male rats receiving 225 mg/kg per day^{01}. No qualitative morphological differences between the alveolar macrophages of the treated and control rats were observed; however, the number and size of type II pneumocytes were increased in treated rats compared to controls.^{01}

Mutagenicity

Moclobemide did not exhibit mutagenicity in laboratory evaluations, including the Ames test and Micronucleus test (mouse bone marrow) and assays of Chinese hamster V79 cells, rat hepatocytes, or human lymphocytes.^{01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well controlled studies in pregnant women have not been done.

Moclobemide did not affect mating success, gestation length, or pregnancy outcome in rat studies (15, 40, or 100 mg/kg/day in males (36) for 70 days prior to and during mating; in females (36) for 14 days prior to mating continued until day 22 of lactation). However, doses of 100 mg/kg delayed pup weight development and reduced survival at lactation days 1 and 4 for the F-2 generation.^{01}

Moclobemide 15, 40, or 100 mg/kg/day from day 7 to day 19 of gestation caused dose-related retardation of maternal weight gain in 20 mated female rabbits; however, the reproductive process (mean number of corpora lutea and implantations) was not impaired in any dosage group.^{01}

Moclobemide should be given to pregnant women only if the physician believes the expected benefits outweigh the risks.^{01}

Breast-feeding

Small quantities of moclobemide are distributed into human breast milk.^{01}

Pediatrics

Appropriate studies have not been performed on the relationship of age to the effects of moclobemide in the pediatric population. Safety and efficacy have not been established in children up to 18 years of age.^{01}


Geriatrics


The maximum concentration and area under the concentration-time curve of moclobemide were somewhat higher in elderly subjects than in young subjects (1498 versus 950 ng/mL and 5571 versus 3102 ng.hour/mL, respectively); clearance was reduced (19.7 versus 32.3 L/hour).^{01} The potential for increased vascular accidents, increased sensitivity to hypotensive effects, and reduced metabolic capacity discourages the first-time use of monoamine (MAO) inhibitors in patients over 60 years of age. When an MAO inhibitor is prescribed for an elderly patient, the patient's history of depression, ability to comply with prescribing instructions, and any potential drug interactions must also be considered.


Pharmacogenetics

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.^{01}

Surgical

If anesthetics containing epinephrine are required in scheduled surgical procedures, moclobemide should be discontinued at least 2 days prior to anesthesia.^{01} In addition, the interaction of moclobemide with other sympathomimetic agents and meperidine must be considered in choosing medications that might be needed in surgical patients.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Alcohol ^{01}    (possible tyramine content in some alcoholic beverages, especially beer, wine, or ale; may induce hypertensive reactions^{01})


» Anesthetics, local, with epinephrine, or
» Anesthetics, spinal, with epinephrine    (concurrent use with moclobemide may cause severe hypertension due to sympathomimetic effects; moclobemide should be discontinued no less than 2 days before anesthesia^{01})


» Antidepressants, monoamine oxidase inhibitor, other, ^{01} or
» Antidepressants, tricyclic^{01}, or
» Selective serotonin reuptake inhibitors (SSRI)^{01}    (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, or sertraline] 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)

    (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 monoamine oxidase inhibitor [MAOI] [phenelzine, tranylcypromine] or SSRI. When switching patients from MAOI or serontonergic antidepressants to moclobemide, a wash-out period of 4 to 5 half-lives of the previously administered drug [and any active metabolites] should intervene. At least 5 weeks should elapse between withdrawal of fluoxetine and initiation of moclobemide^{01})


Antihypertensives^{01}    (moclobemide had inconsistent effects on the blood pressure of hypertensive patients during clinical trials; careful monitoring is important, especially during initial titration)


Antipsychotics ^{01}     (psychotic symptoms may be exaggerated if an antipsychotic agent and moclobemide are combined^{01})


» Cimetidine^{01}     (increased moclobemide plasma concentrations may occur; 50% reduction of moclobemide doses may be needed when coadministered with cimetidine^{01})


» Dextromethorphan ^{01}     (concurrent use with moclobemide may cause nausea, tremor, vertigo, or vomiting; cough and cold preparations should not be taken without consulting a physician so that non-dextromethorphan containing medications may be substituted^{01})


» Meperidine, and possibly other opioid (narcotic) analgesics ^{01}     (moclobemide has been shown to potentiate the effects of opiates. Co-administration of moclobemide with meperidine is contraindicated. Other opioid analgesics should be used with caution and a dose adjustment for these agents may be necessary ^{01})


» Sympathomimetics ^{01}     (an increase in systolic blood pressure [1.6 times higher] occurred following concurrent administration of moclobemide and phenylephrine. Patients should be advised to avoid concomitant use of cold, hay fever, or weight-reduction products which may contain amphetamine, ephedrine, or sympathomimetic amines^{01})


Tyramine- or other high pressor amine–containing foods and beverages, such as aged cheese; fava or broad bean pods; yeast/protein extracts; smoked or pickled meats, poultry, or fish; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; sauerkraut; any overripe fruit; beer; reduced-alcohol and alcohol-free beer and wine; red and white wines; sherry; and liqueurs    (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 restrictions 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^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Sensitivity to moclobemide^{01}
» Acute confusional state^{01}
Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment ^{01}     (moclobemide plasma concentrations may be significantly increased due to decreased metabolism and reduced elimination; dosage adjustments are recommended )


Hypertension    (hypotensive effects may be potentiated in hypertensive patients on multiple-drug therapy)


Pheochromocytoma or^{01}
Thyrotoxicosis ^{01}    (a hypertensive crisis may be precipitated)


Suicidal tendencies ^{01}     (suicidal tendencies may persist in all phases of treatment until remission of depression occurs)

^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure measurements ^{01}    (careful and frequent monitoring is recommended because of the variety of factors that may produce dangerous alterations in pressure during therapy )




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
^{01}Incidence more frequent
    
Headache (mild to moderate) or pressure in head^{01}

Incidence less frequent
    
Anxiety^{01}
    
blurred vision or other changes in vision^{01}
    
hypertension^{01} (high blood pressure)
    
hypotension or orthostatic hypotension^{01} ( dizziness, faintness, or lightheadedness, especially when getting up from a sitting or lying position)
    
increased agitation^{01} (anxiety; nervousness; restlessness; irritability)
    
nervousness^{01}
    
palpitations^{01} (pounding or irregular heartbeat)
    
restlessness^{01}
    
tachycardia^{01} (fast or racing heartbeat)
    
unusual tiredness or weakness^{01}

Incidence rare
    
Aggressive behavior^{01}
    
angina^{01} (chest pain)
    
apathy^{01} (loss of interest in self or surroundings)
    
bradycardia^{01} ( slow heartbeat)
    
confusion^{01}
    
conjunctivitis^{01} (itching, redness, and swelling of eye; feeling of something in the eye; increased sensitivity of eyes to light)
    
dysarthria^{01} (trouble in speaking)
    
dyspnea^{01} (troubled breathing)
    
dysuria^{01} (painful urination)
    
extrapyramidal effects (difficulty in speaking; loss of balance control; restlessness or desire to keep moving; twisting movements of body; uncontrolled movements, especially of face, neck, and back)
    
gastritis^{01} (stomach pain or burning)
    
gingivitis^{01} (bleeding gums)
    
hallucinations^{01} (seeing, hearing, or feeling things that are not there)
    
increased depression, or other mood or mental changes^{01}
    
malaise^{01} ( general feeling of illness)
    
memory problems^{01}
    
menstrual changes^{01} (irregular or prolonged periods)
    
migraine^{01} (severe headache)
    
polyuria^{01} (increase in urination)
    
paresthesias^{01} (burning, prickling, or tingling sensations)
    
skin rash, hives, or itching^{01}
    
stomatitis^{01} ( irritation or soreness of mouth)
    
tenesmus^{01} (pain or straining to pass urine or stool)
    
tinnitus^{01} ( ringing or noise in ears)
^{01}
Symptoms of hypertensive crisis
    
Bradycardia^{01} (slow heartbeat)
    
neck stiffness^{01}
    
occipital headache^{01} (severe throbbing headache which starts at the back of the head and radiates forward)
    
palpitations^{01} (pounding or irregular heartbeat)
    
tachycardia^{01} (fast or racing heartbeat)

Note: Patients should be instructed to report immediately any combination of the above symptoms.^{01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dryness of mouth^{01}
    
nausea^{01}
    
tremor^{01} (trembling or shaking of arms or legs)

Incidence less frequent or rare
    
Abdominal or stomach pain or discomfort^{01}
    
constipation^{01}
    
change in your sense of taste^{01}
    
dizziness
    
drowsiness^{01}
    
diarrhea^{01}
    
heartburn or indigestion^{01}
    
hot flushes^{01} (feeling of warmth of the face, neck, arms, and occasionally upper chest)
    
increased or decreased appetite^{01}
    
increased sweating^{01}
    
insomnia^{01} (trouble sleeping )
    
joint or muscle pain^{01}
    
nightmares^{01}
    
vomiting^{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Agitation
    
amnesia (loss of memory)
    
decreased reflexes
    
disorientation ( confusion)
    
extreme drowsiness
    
hypertension (high blood pressure)
    
nausea
    
seizures
    
slurred speech
    
vomiting
^{01}
Note: One patient was stuporous for 36 hours following an overdose of moclobemide 1550 mg. Vital signs and laboratory values returned to normal range 1 to 5 days later. No organ toxicity occurred.^{01}



Treatment of overdose


To decrease absorption:
Induction of vomiting or gastric lavage with protected airway followed by instillation of activated charcoal in early overdose^{01}



Monitoring:
Monitor closely for signs of potentially fatal serotonergic syndrome, which has been reported after overdose of moclobemide with other antidepressants^{01}.



Supportive care:
There is no known specific antidote to moclobemide. Treatment is generally symptomatic and supportive. Maintain fluid control.^{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Moclobemide (Systemic)..

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to moclobemide





Breast-feeding—Moclobemide is distributed into breast milk.





Use in the elderly—Elderly patients may have a greater incidence or severity of side effects. Dizziness or lightheadedness may be especially likely to occur in elderly patients.

Surgical
If anesthetic agents containing epinephrine are required, administration of moclobemide should be discontinued no less than 2 days before surgery.
Other medications, especially cimetidine, dextromethorphan, meperidine (and possibly other narcotic [opioid] analgesics), other monoamine oxidase inhibitors, sympathomimetics, selective serotonin uptake inhibitors, or tricyclic antidepressants.
Other medical problems, especially acute confusional states, hepatic function impairment, hypertension, pheochromocytoma, or thyrotoxicosis.

Proper use of this medication
» Lag time between initiation of moclobemide and therapeutic response

» Taking exactly as directed by physician

» Importance of not taking more medication than the amount prescribed

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Avoiding alcoholic beverages, over-the-counter cold, cough, hay fever, or weight-reduction medicines, and other medications, unless prescribed

» Checking with physician if symptoms of hypertensive crisis develop

» Checking with physician before discontinuing medication; gradual reduction may be needed to prevent withdrawal effects

» Dizziness may occur; caution when getting up suddenly from a lying or sitting position

» Drowsiness or blurred vision may occur; caution when driving or doing things requiring alertness or clear vision

» Caution if any kind of surgery is required


Side/adverse effects
Signs of potential side effects, especially symptoms of hypertensive crisis; mild to moderate headache or pressure in head; anxiety; blurred vision or other visual changes; hypertension; hypotension or orthostatic hypotension; increased agitation; nervousness; palpitations; restlessness; tachycardia; unusual tiredness or weakness; aggressive behavior; angina; apathy; bradycardia; confusion; conjunctivitis; dysarthria; dyspnea; dysuria; extrapyramidal effects; gastritis; gingivitis; hallucinations; increased depression or other mood and mental changes; malaise; memory problems; menstrual changes; migraine; polyuria; paresthesias; skin rash, hives, or itching; stomatitis; tenesmus; and tinnitus


General Dosing Information
As with other antidepressants, there may be a lag time between initiation of moclobemide and therapeutic response.^{01}

In normal volunteers, the absolute bioavailability almost doubles following multiple doses compared with single dosing.^{01}

Potentially suicidal patients should not have access to large quantities of this medication since depressed patients, particularly those who use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs.^{01}

Diet/Nutrition
Moclobemide should always be taken after meals. Potentiation of a tyramine reaction may be minimized by taking moclobemide immediately after meals.^{01}

Excessive alcohol consumption should be avoided during moclobemide therapy.^{01}

Consumption of tyramine-rich food with irreversible monoamine oxidase inhibitors may cause sudden and severe hypertensive reactions. Since moclobemide is a reversible inhibitor of MAO-A (RIMA), dietary restrictions are not considered necessary. Consumption of up to 100 mg of tyramine with 600 mg of moclobemide a day is not expected to cause problems. Examples of foods that can be safely eaten include up to 7.5 times the normal serving of aged or overripe cheese; e.g., up to 2 kg (4.4 pounds) of mild cheese, up to 200 grams (7 ounces) of strong cheese, and up to 70 grams (2.5 ounces) of Marmite yeast extract may be consumed safely^{01}.

(Examples of foods and beverages containing tyramine or other high pressor amines include aged cheese; fava or broad bean pods; yeast/protein extracts; fermented foods; canned, aged or processed [smoked, pickled] meats, poultry, or fish; sauerkraut; raisins; canned figs; licorice; monosodium glutamate; soy sauce; beer; wine [especially Chianti and sherry]; and liqueurs. Other foods, such as yogurt, sour cream, cottage cheese, American cheese, mild Swiss cheese, chocolate, or coffee [containing caffeine] are considered safe to be consumed in low amounts [no more than 2 ounces daily] during therapy with an irreversible monoamine oxidase inhibitor.)^{02}


Oral Dosage Forms

MOCLOBEMIDE TABLETS

Usual Adult Dose
Depression, mental (treatment)
Oral, 150 mg two times a day.^{01} The dose may be increased as needed and tolerated to a maximum of 600 mg a day. The initial daily dose of 300 mg should not be increased until after the first week of therapy in order to minimize side effects.^{01}{01}


Note: In patients with severe hepatic impairment, the daily dose of moclobemide should be reduced to one-third to one-half of the standard dose.^{01}


Usual adult prescribing limits
600 mg daily .
^{01}
Usual Pediatric Dose
Safety and efficacy have not been established.^{01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


150 mg (Rx) [Manerix (scored, film-coated) (cornstarch, ethylcellulose, iron oxide, lactose, magnesium stearate, methylhydroxypropyl cellulose, polyethylene glycol, povidone, sodiumstarch glycolate, talc, titanium dioxide )]^{01}


300 mg (Rx) [Manerix (scored, film-coated) (cornstarch, ethylcellulose, lactose, magnesium stearate, methylhydroxypropyl cellulose, polyethylene glycol, povidone, sodiumstarch glycolate, talc, titanium dioxide)]^{01}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F).^{01}

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Additional information:
Antidepressants, including moclobemide, should be withdrawn gradually to reduce the risk of withdrawal symptoms.

Developed: 05/17/2000

References

1. Product Information: Manerix®, moclobemide tablets. Hoffmann-La Roche Limited, Mississauga, Ontario, Canada, (PI revised 2/1998) reviewed 4/2000.
   

2. DiPiro JT, Talbert RL, Yee GC et al (eds): Pharmacotherapy: A Pathophysiologic Approach. Appleton & Lange, Stamford, CN, 1997, pp 1404–1405.
   

3. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 192. Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 165, 419, 422-6.
   

4. Walker JJ. How to improve patient compliance with MAOIs. [In: J Clin Psychiatry 1984; 45: 78.] Reactions 1984 Aug 25.
   

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