Maprotiline Other names: Maprotiline hydrochloride

The risk of QTc prolongation and/or ventricular arrhythmias, including ventricular tachycardia and (e.g. Torsades de pointes (TdP) is increased with concomitant use of other medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics). Please check the data sheet of other medicines administered for information on their effects on the QTc interval. Caution is recommended while administering drug that prolong the QT interval, especially in patients with underlying risk factors.

Maprotiline is primarily metabolised by CYP2D6, and to some extent by CYP1A2. CYP2D6 has not been found to be inducible, but concomitant administration of substances known to induce CYP1A2 may increase the formation of desmethylmaprotiline and reduce the effectiveness of Ludiomil. The overall pharmacodynamic effect is not expected to be reduced, as this metabolite is active. However, induction of enzymes yet to be identified in the deactivation of maprotiline and desmethylmaprotiline (e.g. P450s, phase II enzymes) may accelerate the clearance of the active components and decrease the efficacy of Ludiomil. Adjustment of Ludiomil dosage may be necessary when administered concomitantly with substances that induce hepatic cytochrome P450s, particularly those typically involved in tricyclic antidepressant metabolism, such as CYP3A4, CYP2C19, and/or CYP1A2 (e.g. rifampicin, carbamazepine, phenobarbital, and phenytoin).

Patients taking maprotiline should be warned that their response to alcohol, barbiturates and other CNS depressants may be intensified.

Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin, possibly by inhibition of its metabolism in liver or decreased intestinal motility. There is no evidence of the ability of Ludiomil to inhibit the metabolism of anticoagulants such as warfarin (active S-enantiomer cleared by CYP2C9), but careful monitoring of plasma prothrombin is recommended for this class of substances.

Maprotiline may potentiate the effects of anticholinergic agents (e.g. phenothiazines, antiparkinson agents, atropine, biperiden, antihistamines) on the pupils, central nervous system (CNS), bowel and bladder.

Maprotiline may potentiate the cardiovascular effects of sympathomimetic agents such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine, as well as of decongestants and local anaesthetics (e.g. those used in dentistry). Close supervision (blood pressure, cardiac rhythm) and careful dosage adjustment are therefore required.

Concomitant administration of CYP2D6 inhibitors may lead to an increase in concentration of maprotiline, up to ~3.5-fold in patients with a debrisoquine extensive metaboliser phenotype, converting them to a poor-metaboliser phenotype.

Antiarrhythmics that are potent inhibitors of CYP2D6, such as quinidine and propafenone, should not be used in combination with maprotiline. The anticholinergic effects of quinidine may cause dose-related synergism with maprotiline.

Concomitant administration of terbinafine, an antifungal drug (a potent inhibitor of CYP2D6) may result in increased plasma levels of maprotiline. Dose adjustment of maprotiline may be necessary.

Selective serotonin reuptake inhibitors (SSRIs) that are inhibitors of CYP2D6, such as fluoxetine, fluvoxamine (also an inhibitor of CYP3A4, CYP2C19, CYP2C9, and CYP1A2), paroxetine, sertraline or citalopram, may result in highly increased plasma maprotiline concentrations, with corresponding side effects. Due to the long half-life of fluoxetine and fluvoxamine, this effect may be prolonged. Dose adjustment may therefore be necessary.

Although not reported with Ludiomil, co-administration with the histamine2 (H₂)-receptor antagonist cimetidine (an inhibitor of several P450 enzymes, including CYP2D6 and CYP3A4) 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 (dry mouth, disturbed vision). It may therefore be necessary to reduce the dosage of Ludiomil when given concomitantly with cimetidine.

Co-medication with oral sulfonylureas or insulin may potentiate the hypoglycaemic effect of antidiabetic agents. Diabetic patients should monitor their blood glucose when treatment with maprotiline has been initiated or discontinued.

Concomitant administration of beta blockers that are inhibitors of CYP2D6, such as propranolol, may cause an increase in plasma maprotiline concentrations. In such cases, monitoring of plasma levels and adjustment of the dosage is recommended.

Maprotiline may diminish or abolish the antihypertensive effects of antiadrenergic agents such as guanethidine, bethanidine, reserpine, clonidine and alpha- methyldopa. Patients requiring comedication for hypertension should therefore be given antihypertensives of a different type (e.g. diuretics, vasodilators, or beta blockers that do not undergo pronounced biotransformation). Sudden withdrawal of maprotiline can also result in serious hypotension.

Co-medication with antipsychotics (e.g. phenothiazines, risperidone) may result in increased plasma levels of maprotiline, a lowered convulsion threshold and convulsions. Combination with the CYP2D6 inhibitor thioridazine may produce severe cardiac arrhythmia. Dose adjustment may therefore be necessary.

Co-medication with benzodiazepines may cause increased sedation.

Methylphenidate may increase plasma concentrations of tricyclic antidepressants and so intensify their effects. Dose adjustment may therefore be necessary.

Caution is recommended in patients with a history of increased intraocular pressure, phaeochromocytoma, chronic severe constipation or a history of urinary retention, particularly in the presence of prostatic hypertrophy.

Cyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in hospitalised patients. Appropriate measures should therefore be taken if constipation occurs.

In patients with a history of suicidal events, or those at high risk of suicide prior to commencement of therapy, the risk of suicidal ideation or suicide attempts is increased.

Caution is recommended in hyperthyroid patients and patients on thyroid-hormone preparations (possible increase in unwanted cardiac effects).

Smoking accelerates the metabolism of tricyclics (and thus of maprotiline) and reduces their concentrations in the blood.

Animal experiments showed no teratogenic or mutagenic effects and no evidence of impaired fertility or harm to the foetus. However, safe use during pregnancy has not been established. Isolated cases suggesting a possible association between maprotiline and adverse effects on the human foetus have been reported. Maprotiline should not be administered during pregnancy unless the benefits clearly outweigh the risk to the foetus.

Maprotiline should be given to pregnant women only if clearly needed.

Maprotiline should be withdrawn at least 7 weeks before the expected date of delivery, provided the clinical status of the patient permits, to prevent possible symptoms such as dyspnoea, lethargy, irritability, tachycardia, hypotonia, convulsions, jitter and hypothermia in the new-born.

Maprotiline passes into the breast milk. After oral administration of 150 mg daily for 5 days, concentrations in the breast milk exceed blood concentrations by a factor of 1.3 to 1.5. Although reports have shown no adverse effects on the infant, mothers receiving maprotiline should not breast-feed.

Fertility

No special recommendations.

Women of child-bearing potential

No special recommendations.

Patients receiving maprotiline should be warned that blurred vision, dizziness, somnolence and other CNS symptoms may occur, in which case they should not drive, operate machinery, or engage in other potentially dangerous activities. Patients should also be warned that consumption of alcohol or other medicinal products may potentiate these effects.

Adverse effects are usually mild and transient, disappearing with continued treatment or following a reduction in the dosage. They do not always correlate with plasma drug levels or with dose. It is often difficult to distinguish certain adverse effects from symptoms of depression such as fatigue, sleep disturbances, agitation, anxiety, constipation or dry mouth.

In the event of serious adverse reactions, e.g. of a neurological or psychiatric nature, maprotiline should be withdrawn.

Elderly patients are particularly sensitive to anticholinergic, neurological, psychiatric or cardiovascular effects. Their ability to metabolise and eliminate substances may be reduced, leading to risk of elevated plasma concentrations at therapeutic doses.

The following adverse effects have been reported either with maprotiline or with tricyclic antidepressants.

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100, <1/10) uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports, not known (frequency cannot be estimated from the available data).

Withdrawal symptoms

Although not indicative of addiction, the following symptoms occasionally occur after abrupt withdrawal or reduction of the dose: nausea, vomiting, abdominal pain, diarrhoea, insomnia, headache, nervousness, anxiety, worsening of underlying depression or recurrence of depressed mood.