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Moclobemide
(MoclamineŽ)
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moclobemide research Moclobemide is a short-acting, reversible inhibitor of
monoamine oxidase (MAO). It is a benzamide derivative which inhibits the
deamination of serotonin, norepinephrine and dopamine. This action leads to
increased concentrations of these neurotransmitters, which may account for the
antidepressant activity of moclobemide.
MAOs 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.
Drug Interactions:
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.
Cimetidine:
In a drug interaction study, the concomitant administration of cimetidine and
moclobemide led to the doubling of the area under the plasma concentration-time
curve of moclobemide. Cimetidine therapy is expected to approximately double
moclobemide steady-state concentrations.
Pharmacokinetics:
Volunteers:
General:
Following oral administration, moclobemide was 98% absorbed from the
gastrointestinal tract. Due to hepatic first pass effect, absolute
bioavailability was approximately 55% after single doses, but 90% after multiple
doses. The apparent volume of distribution was approximately 1.2 L/kg,
indicating extensive tissue distribution.
Moclobemide was extensively metabolized, 95% of the
administered dose was excreted in the urine. The metabolites were
pharmacologically inactive. Moclobemide was 50% bound to plasma proteins, mainly
to albumin.
The presence of food reduced 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 1450 ng/mL
(mean C(max): 849 ng/mL) and were reached in 0.5 to 3.5 hours (mean t(max): 49
min). The elimination half-life was 1.5 hours. Up to 200 mg, the
pharmacokinetics of moclobemide were linear. At higher doses, non-linear
pharmacokinetics were observed. In a dose range of 400 mg to 1200 mg, maximum
plasma concentrations increased and clearance decreased in a non
dose-proportional manner. With increasing doses, the elimination half-life also
became 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 ng/mL
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 ng/mL and 1828 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 three-fold increase in peak plasma
concentrations (C(max): 1607 ng/mL), and elimination half-life (t(1/2): 4 hr),
while clearance decreased about 4 fold (CI 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), C(max) and AUC values were somewhat higher than in young subjects (21 to
34 years old), namely 1498 versus 950 ng/mL and 5571 versus 3102 ng h/mL,
respectively. Clearance in the elderly was reduced (19.7 versus 32.3 L/h).
For the symptomatic relief of depressive illness.
In patients with a known hypersensitivity to the drug.
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 is 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 other available MAO
inhibitors. Therefore, until such data becomes 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
nonreversible, nonselective MAO inhibitor and meperidine given concomitantly.
Therefore, moclobemide should not be used in combination with meperidine.
Children:
As the safety and effectiveness of moclobemide in children below the age of 18
have not been established, pediatric use is not recommended.
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 in
potentially suicidal patients should be written for a limited supply only.
Depressed patients in whom agitation is the predominant
clinical symptom should not be treated with moclobemide.
In patients with thyrotoxicosis or pheochromocytoma,
conventional MAO inhibitors may precipitate a hypertensive 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 suggests 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).
Renal Dysfunction:
Single dose pharmacokinetic data suggest that no dosage adjustment may be
required in patients with impaired renal function (see Pharmacology). 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 (see Pharmacology).
In patients treated with cimetidine, it is recommended
that moclobemide be initiated at the lowest recommended dose, i.e., 100 to 200
mg/day.
In patients treated with moclobemide, a 50% reduction in
the dosage of moclobemide may be necessary before commencing cimetidine
treatment.
Tyramine:
In a limited number of clinical pharmacology trials, the blood pressure increase
observed during administration of moclobemide together with tyramine-enriched
food was less than what would be expected after the administration of currently
marketed MAO inhibitors.
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 (see Pharmacology).
Treatment with moclobemide does not necessitate the
special dietary restrictions required for other available MAO inhibitors.
However, until further studies are carried out, patients should be advised to
avoid the consumption of excessive amounts of aged or overripe cheese and yeast
extracts.
As an added 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. Hypertensive
patients should be cautioned to avoid excessive consumption of foods that are
high in tyramine content.
Other Antidepressants:
Concomitant Use:
Clinical studies between moclobemide and a tricyclic antidepressant (clomipramine)
resulted in severe adverse reactions (see Contraindications). Data involving
other tricyclic antidepressants is 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 re-uptake inhibitors, or other available 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 co-administration 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 0.5%. However, no studies were
conducted at blood alcohol concentrations recognized as legally intoxicating.
Anesthetic Agents:
It is accepted medical practice to discontinue treatment with conventional MAO
inhibitors 10 to 14 days before the administration of anesthetic agents,
especially spinal or local anesthetic agents that contain epinephrine. While
specific data on the use of moclobemide in patients undergoing anesthesia are
not available, based on the reversible action and short elimination half-life of
'Manerix' (see Pharmacology) this period may be shortened to no less than 2
days.
Sympathomimetics:
Following multiple oral doses of moclobemide (200 mg t.i.d.), a phenylephrine-induced
increase in systolic blood pressure was potentiated after i.v. administration.
Patients should be advised to avoid the concomitant use of all 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.
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.
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 with 1550 mg moclobemide.
All abnormal laboratory values and vital signs returned to within normal range 1
to 5 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.
Note:
Moclobemide should always be taken after meals in order to minimize tyramine
potentiation and the possibility of a hypertensive reaction (see Pharmacology
and Drug Interactions).
Usual Adult Dosage:
The administration of moclobemide should be initiated at 300 mg daily dose
(usually administered in 3 divided doses), and increased gradually 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.
Individual response may allow a reduction of the daily
dose to 150 mg or an increase to a maximum of 600 mg/day, depending on the
severity of the depression. In clinical trials, the majority of patients
responded to doses of 450 mg or less.
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 Pharmacology).
In patients treated with cimetidine, it is recommended
that moclobemide be initiated at the lowest recommended dose, i.e., 100 to 200
mg/day.
In patients treated with moclobemide, a 50% reduction in
the dosage of moclobemide may be necessary before commencing cimetidine
treatment.
100 mg:
Each orange, single-scored, biconvex, film-coated tablet imprinted "ROCHE
100" on one side, and single scored on the other, contains: Moclobemide 100
mg. Nonmedicinal ingredients: Cornstarch, ethylcellulose, lactose, magnesium
stearate, methylhydroxypropyl cellulose, povidone, red iron oxide, sodium starch
glycolate, talc, titanium dioxide and yellow iron oxide. Gluten-free, parabens-free,
sucrose-free, sulfites-free and tartrazine-free. Bottles of 100.
150 mg:
Each pale yellow, single-scored, biconvex, film-coated tablet imprinted
"ROCHE 150" on one side, single scored on the other, contains:
Moclobemide 150 mg. Nonmedicinal ingredients: Same as 100 mg tablet plus
polyethylene glycol. Gluten-free, parabens-free, sucrose-free, sulfites-free and
tartrazine-free. Bottles of 100.
Store at 15 to 30°C.
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