Brand name: Ludiomil
Maprotiline
Brand name: Ludiomil |
|
Antidepressant
Maprotiline has been shown to exhibit an antidepressant action. It strongly inhibits the uptake of noradrenaline in the brain and peripheral tissues, though it is notable in its lack of inhibition of serotonergic uptake. It has markedly less pronounced alpha adrenergic blocking activity than amitriptyline. A strong antihistaminic and a weaker anticholinergic action are seen in the pharmacological profile of maprotiline. Maprotiline also exerts a sedative effect on the anxiety component of depressive illness.
It is postulated that maprotiline exerts its antidepressant action by inhibition of presynaptic uptake of catecholamines, thereby increasing their concentration at the synaptic clefts of the brain. In single doses, the effect of maprotiline on the EEG revealed a rise in the alpha-wave density, a reduction of the alpha-wave frequency and an increase in the alpha-wave amplitude. However, as with other tricyclic antidepressants, maprotiline lowers the convulsive threshold.
In one as yet uncorroborated sleep study, it appears that maprotiline increases the REM phase of sleep in depressed patients, from its initially reduced base line, whereas imipramine reduced the REM phase of sleep.
Maprotiline is completely absorbed after oral administration in man. The binding to serum proteins was found to be 88%. The half-life of unchanged maprotiline, in man, is relatively long and ranged from 27.4 to 57.6 hours. The mean systemic clearance is 514 L/min.
Following repeated daily doses of maprotiline, a plasma steady state concentration was reached in the second week, with the majority of subjects receiving daily doses of 150 mg attaining steady state blood levels between 100 and 400 ng/mL. The same plasma levels are attained whether the daily dosage is given as a single dose of 150 mg, in 2 fractions of 75 mg or 3 fractions of 50 mg.
Maprotiline is metabolized by N-demethylation, deamination, aliphatic and aromatic hydroxylations and by formation of aromatic methoxy derivatives. Maprotiline is excreted primarily in the urine: within 21 days after single dosing, a total of 57% of the total dose is excreted in the urine, with about 30% biliary excretion. Only 2 to 4% of the dose is excreted unchanged in the urine. Ninety percent of the amount excreted in the urine consists of metabolites, 75% in the form of glucuronides.
Steady-state plasma concentrations at a given dose level are higher in elderly subjects (over 60 years) compared with younger patients. The half-life and renal excretion of maprotiline are not significantly affected by the presence of impaired renal function (creatinine clearance: 24 to 37 mL/min), provided that hepatic function is still normal. Urinary excretion of metabolites is reduced, although this reduction is offset by increased fecal elimination of metabolites through biliary excretion.
The drug treatment of endogenous depressive illness, including the depressed phase of manic-depressive illness (bipolar depression), psychotic depression (unipolar depression), and involutional melancholia. It might also be useful in selected patients suffering severe depressive neurosis.
Should not be used in patients with known or suspected convulsive disorders, since it is known to lower the seizure threshold (see Warnings).
Also contraindicated in patients with a history of hypersensitivity to the drug, and in those with existing severe hepatic or renal damage or a history of severe blood dyscrasias.
Patients with narrow angle glaucoma, or with urinary retention (i.e., due to prostatic disease) should not receive maprotiline because of its anticholinergic properties.
Maprotiline is contraindicated during the acute recovery phase following myocardial infarction in the presence of acute congestive heart failure, and in patients with conduction defects.
Maprotiline should not be given in conjunction with, or within 14 days of treatment with a MAO inhibitor. Combined therapy of this type could lead to the appearance of serious interactions such as hyperpyrexia, tremors, generalized clonic convulsions, delirium and possible death.
Maprotiline should not be employed, or should be withdrawn, in cases of acute poisoning with alcohol, hypnotics, analgesics or psychotropic drugs.
Children:
The drug is not recommended for
use in children.
Tricyclic and tetracyclic antidepressants, particularly in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of conduction time. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with these drugs. Therefore, extreme caution should be used when maprotiline is given to elderly patients, or those with known cardiovascular disease including those with a history of myocardial infarction, arrhythmias and/or ischemic heart disease. In such cases, treatment should be initiated at low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels of the drug. Monitoring of cardiac function and, if necessary, the ECG, are indicated in such patients.
Maprotiline should be used with caution in hyperthyroid patients and in those on thyroid medication because of the possibility of cardiovascular toxicity. Potentiation of the cardiovascular effects of noradrenaline and adrenaline may occur. Maprotiline should be used with caution in patients receiving guanethidine or similar sympatholytic antihypertensive agents (bethanidine, reserpine, alpha-methyldopa, clonidine) since it may block the effects of these drugs with subsequent loss of blood pressure control.
Seizures have been reported in patients without a known history of seizures who were treated with maprotiline at therapeutic dose levels. However, in some of these patients other confounding factors such as concomitant medications known to lower seizure threshold were also present. The risk of seizures may be increased when maprotiline is taken concomitantly with phenothiazines, when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline, or when the recommended dosage of maprotiline is rapidly exceeded. While a cause-and-effect relationship has not been established, the risk of seizures may be reduced by: initiating therapy at a low dosage; maintaining the initial dosage for 2 weeks before raising it gradually in small increments (see Dosage) as required by the long half-life of maprotiline (average 51 hours); keeping the maintenance dosage at a minimally effective level (dosages below 200 mg/day); cautious alteration in or avoiding both the concomitant prescriptions of drugs that lower the seizure threshold, i.e., phenothiazines or rapid tapering of benzodiazepines.
Concurrent administration of ECT and maprotiline may be hazardous.
Because of its anticholinergic properties, maprotiline should be used with caution in patients with a history of increased intraocular pressure or history of urinary retention, particularly in the presence of prostatic hypertrophy.
Close supervision and careful adjustment of dosage is required when administering maprotiline with anticholinergic or sympathomimetic drugs because of the possibility of additive effects.
An activation of psychosis has occasionally been observed in schizophrenic patients administered tricyclic antidepressant drugs and must be considered as a possibility when administering maprotiline. Similarly, hypomanic or manic episodes in patients with cyclic disorders have been known to occur during treatment of a depressed phase with a tricyclic antidepressant. These 2 conditions, should they occur, may require a reduction in the dosage of maprotiline, discontinuation of the drug, and/or administration of an antipsychotic agent.
Pregnancy and Lactation:
As a general
rule, no drugs should be taken during the first 3 months of pregnancy, and the
benefits and risks of drug administration should be carefully considered
throughout the whole of pregnancy.
Safe use of maprotiline during pregnancy and lactation has not been established. Isolated cases suggesting a possible association between maprotiline and adverse effects on the fetus have been reported. Animal studies have shown neither teratogenic potential nor adverse effects on the embryo or fetus. It should therefore not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the benefits outweigh the possible hazards to the child or fetus.
Maprotiline passes into the breast
milk:
After repeated administration of 150 mg/day for 5 days,
concentrations of maprotiline in breast milk exceeded that in blood by a factor
of 1.3 to 1.5. Although reports thus far have shown no adverse effects on
nursing infants, maprotiline should be withdrawn or infants weaned in the case
of nursing women.
The possibility of suicide in seriously depressed patients is inherent in their illness and may persist until significant remission occurs. Therefore, patients must be carefully supervised during all phases of treatment with maprotiline and prescriptions should be written for the smallest amount consistent with good management.
Particularly in patients with heart diseases, as well as in elderly subjects, cardiac function should be monitored and ECG examinations performed during long-term treatment with high doses. Regular measurements of the blood pressure are called for in patients susceptible to postural hypotension.
Changes in WBC count have been reported with maprotiline in isolated cases and it is known that antidepressants may lead to changes in the blood picture. Periodic blood cell counts and monitoring for symptoms such as fever and sore throat are warranted particularly during the first few months of therapy with maprotiline. Periodic blood cell counts and liver function tests are recommended with prolonged therapy.
Tricyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in hospitalized patients. Therefore, since maprotiline has similar anticholinergic properties, appropriate measures should be taken if constipation occurs.
Occupational Hazards:
Since maprotiline
may produce sedation and decrease alertness, patients should be cautioned
against driving an automobile, operating heavy machinery or performing
potentially dangerous tasks that require mental alertness, judgement and
physical coordination.
Maprotiline should be kept out of reach of children and, if possible, the drug should be dispensed in containers with child-resistant safety closures.
Drug Interactions:
Patients should be
warned that, while taking maprotiline, their responses to alcoholic beverages,
barbiturates, and other CNS depressants may be exaggerated.
Maprotiline may diminish or abolish the antihypertensive effects of adrenergic neuron blocking drugs, such as guanethidine, bethanidine, reserpine, clonidine and alpha-methyldopa. Therefore, patients requiring concomitant treatment for hypertension should be given antihypertensives of a different type (i.e., diuretics, vasodilators, or beta-blockers which do not undergo pronounced biotransformation).
The possibility of central sedative and depressant effects with clonidine and alpha-methyldopa, which may aggravate an already existing depressive state, prohibit their simultaneous use with tricyclic antidepressants even in the absence of negative interactions on the vascular system.
The plasma concentrations of maprotiline may be increased when the drug is administered concomitantly with beta-blockers subject to substantial biotransformation, such as propranolol. In such cases, plasma levels of maprotiline should be monitored and the dosage adapted accordingly.
Maprotiline may potentiate the cardiovascular effects of indirect and directly acting sympathomimetic drugs such as noradrenaline, adrenaline, and methylphenidate. Maprotiline may also potentiate the effects of anticholinergic drugs (atropine, biperiden) and levodopa. Therefore, close supervision and careful adjustment of dosage is required when administering maprotiline with anticholinergic or sympathomimetic drugs because of the possibility of additive effects.
Drugs that activate hepatic microsomal enzymes, such as barbiturates, phenytoin, oral contraceptives and carbamazepine, may accelerate the metabolism of maprotiline resulting in decreased antidepressant efficacy. If necessary, the dosage should be adapted accordingly.
Concomitant administration of phenytoin and maprotiline may increase serum phenytoin levels resulting in manifestation of the latter's side-effects. Adjustment of the phenytoin dosage may be necessary in such cases.
Concomitant treatment with maprotiline and major tranquilizers may result in increased plasma levels of maprotiline, a lowered convulsion threshold, and seizures.
The combination of maprotiline and benzodiazepines may cause increased sedation.
Although not reported for maprotiline, cimetidine has been shown to inhibit the metabolism of several tricyclic antidepressants resulting in increased plasma concentrations of the latter and an increase in unwanted effects (dryness of mouth, disturbed vision). Therefore, downward dosage adjustments may be required when given concomitantly with cimetidine, for both initiation and discontinuation of cimetidine therapy.
Maprotiline should not be administered for a period of at least 14 days after the discontinuation of treatment with MAO-inhibitors due to the potential for severe interactions (see Contraindications). The same caution should also be observed when administering an MAO-inhibitor after previous treatment with maprotiline.
Prior to elective surgery, maprotiline should be discontinued for as long as clinically feasible, since little is known about the interaction between maprotiline and general anesthetics.
Concurrent use of parenteral magnesium sulfate and maprotiline may result in serious potentiation of CNS depressant effects.
Adverse reactions with maprotiline have been mild and transient, usually disappearing with continued treatment or following a reduction in the dosage. Adverse reactions do not always correlate with plasma levels or dose. It is often difficult to differentiate certain unwanted effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation and dry mouth.
The most common adverse reactions reported with maprotiline are due to its anticholinergic, largely autonomic, effects which include: dry mouth, day sedation, vertigo, blurred vision, constipation, headache and nervousness. In the event of serious side-effects, such as those of a neurological or psychiatric nature, treatment should be discontinued.
Elderly patients are particularly sensitive to the adverse anticholinergic, neurologic, psychiatric, or cardiovascular reactions associated with the use of tricyclic antidepressants. The ability of elderly patients to metabolize and eliminate drugs may vary with subsequent risk of elevated plasma concentrations and adverse reactions at therapeutic dosages. Concomitant treatment with various medications in this age group increases the possibility of drug interactions.
The following adverse reactions have been reported either with maprotiline or other similar tricyclic antidepressant drugs:
Neurological:
Occasional or frequent:
headache, dizziness, lightheadedness; rarely: incoordination, ataxia,
extrapyramidal symptoms (tremors, akathisia), myoclonus, seizures; isolated or
rarely: paresthesia (numbness, tingling), dysarthria, weakness, alterations in
EEG patterns; isolated cases of tinnitus and taste disturbances.
Behavioral:
Occasional or frequent:
fatigue, daytime sedation, drowsiness; rarely: insomnia, agitation, anxiety;
isolated cases: confusional states (especially in the elderly) with
hallucinations, disorientation, delusions, restlessness, nightmares, hypomania,
mania, exacerbation of psychosis, decrease in memory and feelings of unreality.
Autonomic:
Occasional or frequent: dry
mouth; rarely: sublingual adenitis; blurred vision, disturbances of
accommodation, mydriasis, constipation, paralytic ileus, urinary retention,
delayed micturition, dilation of the urinary tract; isolated cases: stomatitis.
Cardiovascular:
Occasional to rare:
orthostatic hypotension (primarily in the elderly or patients with a history of
cardiovascular disease), tachycardia, arrhythmia; isolated cases of
hypertension, heart block, syncope, atrial flutter, reversible T-wave changes,
Q-T prolongation and atypical ventricular tachycardia have been reported. The
following have been reported with tricyclic antidepressants: quinidine-like
effect and other reversible ECG changes, such as flattening or inversion of
T-waves, bundle branch block, depressed S-T segments, prolonged conduction time
and asystole, arrhythmias, heart block, fibrillation, myocardial infarction,
stroke and unexpected death in patients with cardiovascular disorders.
Respiratory tract:
Isolated cases:
allergic alveolitis with or without eosinophilia.
Hematologic:
Isolated instances of bone
marrow depression including agranulocytosis, eosinophilia, purpura and
thrombocytopenia have been reported and may occur as an idiosyncratic response.
Leukocyte and differential counts should be performed in any patient who
develops fever and sore throat during therapy; the drug should be discontinued
if there is evidence of pathological neutrophil depression.
Gastrointestinal:
Occasional: nausea or
vomiting; rarely: anorexia, epigastric distress, diarrhea, bitter taste,
abdominal cramps, black tongue, dysphagia, and increased salivation; rare to
occasional: constipation.
Endocrine:
Occasional: wight gain or
weight loss; isolated cases of gynecomastia in the male and breast enlargement
and galactorrhea in the female. Increased or decreased libido, impotence,
testicular swelling, and elevation or depression of blood sugar levels.
Allergic or toxic:
Occasional: skin rash,
petechiae, urticaria; isolated cases: itching, purpura, photosensitization
(avoid excessive exposure to sunlight); edema (general or of face and tongue),
drug fever, and cutaneous vasculitis.
Other:
Occasional to frequent: sweating;
rare: altered liver function, increased serum transaminases; isolated cases:
hepatitis with or without jaundice, flushing, urinary frequency, nasal
congestion and alopecia.
An increased incidence of dental caries has been reported in patients receiving long-term treatment with antidepressants. Regular dental inspections are therefore advisable during long-term therapy with maprotiline.
Symptoms:
The response of the patient to
toxic overdosage of maprotiline may vary in severity. Overdosage may result in
either a depressant or an excitant action on the CNS and give rise to severe
anticholinergic and cardiotoxic effects. Accidental ingestion in children of any
amount should be regarded as serious and potentially fatal.
Experience to date suggests that overdoses of maprotiline generally produce the same spectrum of toxicity as the tricyclic antidepressants. The first symptoms of intoxication arise after 1 to 2 hours after ingestion and may include motor unrest, muscular twitching and rigidity, tremor, ataxia, convulsions, hyperpyrexia, vertigo, mydriasis, vomiting, cyanosis, hypotension, shock, tachycardia, cardiac arrhythmias, impaired cardiac conduction, respiratory depression, and disturbances of consciousness up to deep coma. Initial hyperreflexia is subsequently followed by hyporeflexia.
One case of acute intoxication with 5 g of maprotiline in a 58 year old woman has been reported, in which full recovery occurred. Other cases of recorded clinical recovery have been reported in the dose range of 1.6 to 2 g. A 22 year old woman, however, died from cardiac arrest 5 days after ingestion of 3 g of the drug. Fatal outcomes have also been reported in combined intoxication with tricyclic antidepressants, sedatives or hypnotics in the maprotiline dose range of 2 to 10 g.
Treatment:
There is no specific antidote
and treatment is essentially symptomatic and supportive. Cardiac arrhythmias and
CNS involvement pose the greatest threat and may occur suddenly even when
initial symptoms appear to be mild. Therefore, patients who may have ingested an
overdosage of maprotiline, particularly children, should be hospitalized and
kept under close surveillance.
The stomach should be emptied as quickly as possible by gastric lavage or, if the patient is alert, by induced emesis. It may be helpful to leave the tube in the stomach, with irrigation (with an electrolyte balanced fluid) and continual aspiration of stomach contents possibly promoting more rapid elimination of the drug from the body. If the patient is not alert, a cuffed endotracheal tube should be inserted before lavage is performed and emesis should not be induced. These measures are recommended up to 12 hours or even more after the overdose since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce absorption of maprotiline. The value of dialysis is doubtful due to the extensive plasma protein binding of maprotiline.
Treatment should be designed to insure maintenance of the vital functions. An open airway should be maintained in comatose patients and assisted ventilation instituted, if necessary, but respiratory stimulants should not be used. Hyperpyrexia should be controlled by external measures, such as ice packs and cooling sponge baths. Acidosis may be treated by cautious administration of sodium bicarbonate. Adequate renal function should be maintained. In the event of hypotension and circulatory collapse, administer a plasma expander.
External stimulation should be minimized to reduce the tendency to convulsions. If convulsions occur, anticonvulsants (preferably intravenous diazepam) should be administered. Barbiturates may intensify respiratory depression, particularly in children, and aggravate hypotension and coma. Paraldehyde may be used in some children to counteract muscular hypertonus and convulsions with less likelihood of causing respiratory depression. If the patient fails to respond rapidly to anticonvulsants, artificial ventialtion should be instituted. Prompt control of convulsions is essential since they aggravate hypoxia and acidosis and may thereby precipitate cardiac arrhythmias and arrest.
ECG monitoring in an intensive care unit is recommended in all patients, particularly in the presence of ECG abnormalities, and should be maintained for several days after the cardiac rhythm has returned to normal. Unexpected deaths attributed to cardiac arrhythmias have been reported several days following an apparent recovery from tricyclic antidepressant overdose. Correction of hypoxia, if present, may be beneficial. Correction of metabolic acidosis and low potassium concentrations by means of bicarbonate i.v. and potassium substitution may also be effective for treatment of arrhythmias. If bradyarrhythmia or AV-block occur, consider temporary insertion of a cardiac pacemaker. Because of its effect on cardiac conduction, digitalis should be used only with caution. If rapid digitalization is required for the treatment of congestive heart failure, special care should be exercised in using the drug.
Shock should be treated with supportive measures, such as intravenous fluids, oxygen and corticosteroids, as indicated. Hypotension usually responds to elevation of the foot of the bed. Pressor agents (but not epinephrine) should be given cautiously, if indicated. In the event of reduced myocardial function, consider recourse to treatment with dopamine or dobutamine by i.v. drip.
Physostigmine i.v. has been used in the treatment of tricyclic-induced anticholinergic toxicity. Its use is controversial and should be reserved for life-threatening situations. Physostigmine is not innocuous and carries the risk of inducing seizures, bronchospasm, hypertension and severe arrhythmias. It should not be used routinely or to reverse coma. However, it may be indicated in the treatment of seizures or combative hallucinations. It should not be used in patients who are acidemic or who have cardiac conduction defects.
Adults:
A test dose of 0.5 mg i.v. is
given initially. Give 1 to 2 mg slowly i.v. (over 2 minutes). If no clinical
changes or cholinergic signs occur within 15 or 30 minutes, an additional 1 to 2
mg may be cautiously administered. Repeat doses of 1 to 2 mg i.v. every 30
minutes up to 2 hours.
As the CNS effects of physostigmine wear off rapidly, it is important to monitor the patient continuously.
Physostigmine is the only drug of this class that may be used. Neostigmine should not be used as it does not have any cholinergic effects.
If symptoms of cholinergic toxicity develop, physostigmine should be discontinued.
Deaths by deliberate or accidental overdosage have occurred with the use of tricyclic and tetracyclic antidepressants. Since the propensity for suicide is high in depressed patients, a suicide attempt by other means may occur during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be considered.
Patients should be kept under medical surveillance during treatment with maprotiline.
The dosage of maprotiline should be individualized according to the requirements of each patient. Treatment should be initiated at the lowest recommended dose and increased gradually, noting carefully the clinical response and any evidence of intolerance. It should be kept in mind that a lag in therapeutic response usually occurs at the onset of therapy, lasting from several days to a few weeks. Increasing the dosage does not normally shorten this latent period and may increase the incidence of side effects.
Initial Dosage:
Adults:
The
recommended initial dosage is 75 mg daily in 2 or 3 divided doses. Because of
the long half-life of maprotiline this dosage should usually be maintained for 2
weeks. It may then be increased gradually in increments of 25 mg as required and
tolerated, preferably by adding to the late afternoon or bedtime dose. The
maximum recommended dose in outpatients is 150 mg daily, although doses up to
200 mg may be required in some patients. In the treatment of severely depressed
hospitalized patients, a higher initial dose of 100 mg daily in 2 or 3 divided
doses may be indicated. The usual optimal dose in these patients is 150 mg
daily, but some patients may require up to 225 mg in divided doses. When these
higher doses are used, it is essential to exclude a history of convulsive
disorders.
Elderly and Debilitated Patients:
In
general, lower dosages are recommended for these patients, and doses should only
be increased in gradual increments. This approach is particularly important in
elderly patients, since these individuals generally show a more marked response
to maprotiline than patients in younger age groups. Initially, 10 mg 3 times
daily is suggested, with very gradual increments, depending on tolerance and
response, up to 75 mg daily in divided doses. A maintenance dose of 50 to 75 mg
daily is usually satisfactory. Blood pressure and cardiac rhythm should be
checked frequently, particularly in patients who have unstable cardiovascular
function.
Maintenance Dosage:
Dosage during
maintenance therapy should be kept at the lowest effective level. Medication
should be continued for the expected duration of the depressive episode in order
to minimize the possibility of relapse following clinical improvement.
When a maintenance dosage has been established as described above, maprotiline may be administered in a single daily dose at bedtime, provided such a dosage regimen is well tolerated. However, if the total daily dose exceeds 150 mg, it should be administered in divided doses.
10 mg:
Each cream colored, round,
film-coated, slightly biconvex tablet, engraved CIBA on one side and
identification code CO engraved on the other contains: Maprotiline HCl 10 mg.
Also contains lactose. Energy: 1.1 kJ (0.26 kcal).
25 mg:
Each orange, round, film-coated,
slightly biconvex tablet, engraved CIBA on one side and identification code DP
engraved on the other contains: Maprotiline HCl 25 mg. Also contains lactose and
tartrazine. Energy: 0.91 kJ (0.21 kcal).
50 mg:
Each dark orange, round,
film-coated, slightly biconvex tablet, engraved CIBA on one side and
identification code ER engraved on the other contains: Maprotiline HCl 50 mg.
Also contains lactose. Energy: 0.92 kJ (0.22 kcal).
75 mg:
Each red-orange, round,
film-coated, slightly biconvex tablet, engraved CIBA on one side and
identification code FS engraved on each side of the score line contains:
Maprotiline HCl 75 mg. Also contains lactose. Energy: 1.3 kJ (0.32 kcal).
Bisulfite-free, gluten-free, parabens-free and sodium-free. Bottles of 100 and 500.
The research information is available separately on Internet Mental Health.
Note: This information is from a Canadian monograph. There can be differences in indications, dosage forms and warnings for this drug in other countries.
Internet Mental Health (www.mentalhealth.com) copyright ) 1995-2003 by Phillip W. Long, M.D.