Data Sheet
Ludiomil
Maprotiline hydrochloride 25 mg and 75 mg film coated tablets
Presentation
Ludiomil® 25 mg are round, grey-orange tablets, diameter 6.1 mm, with slightly convex faces and slightly bevelled edges. The tablets are imprinted CG on one side and DP on the other. Each tablet contains 25mg maprotiline hydrochloride.
Ludiomil® 75 mg are round, brown-red tablets, diameter 8.1 mm, with slightly convex faces and slightly bevelled edges. The tablets are imprinted CG on one side and FS with score on the other side. Each tablet contains 75 mg maprotiline hydrochloride.
Uses
Actions
Maprotiline hydrochloride is a tetracyclic antidepressant, non-selective mono-amine reuptake inhibitor, which shares a number of basic therapeutic properties with the tricyclic antidepressants. It displays a well-balanced spectrum of action, brightening mood and alleviating anxiety, agitation and psychomotor retardation. In masked depression it can exert a favourable influence on somatic symptoms.
Maprotiline differs structurally and pharmacologically from the tricyclic antidepressants. It has a potent and selective inhibitory effect on noradrenaline re-uptake in the pre-synaptic neurons of cortical structures in the central nervous system but exerts hardly any inhibitory effect on serotonin re-uptake. Maprotiline shows weak to moderate affinity for central alpha1- adrenoceptors, marked inhibitory activity at histamine H1 receptors and a moderate anticholinergic effect.
Changes in functional responsiveness of the neuroendocrine system (growth hormone, melatonin, endorphinergic system) and/or neurotransmitters (noradrenaline, serotonin, GABA) during long-term treatment are also considered to be involved in the mechanism of action.
Pharmacokinetics
Absorption
Following single oral administration of film-coated tablets, maprotiline hydrochloride is slowly but completely absorbed. The mean absolute bioavailability is 66 to 70%. Within 8 hours of a single oral dose of 50 mg, peak blood concentrations of 48 to 150 nmol/L (13 to 47 ng/mL) are attained.
After repeated oral or intravenous administration of 150 mg Ludiomil daily, steady-state blood concentrations of 320 to 1270 nmol/L (100 to 400 ng/mL) are reached during the second week of treatment, whether the amount is given in a single dose or in three fractional doses. Steady-state levels of maprotiline are in linear proportion to the dose, although the concentrations vary greatly from one subject to another.
Distribution
The partition coefficient of maprotiline between blood and plasma is 1.7. The mean apparent distribution volume is 23 to 27 L/kg. Maprotiline is 88 to 90% bound to plasma proteins, independent of the patient's age or disease. Concentrations in cerebrospinal fluid are 2 to 13 % of serum concentrations.
Biotransformation
Maprotiline is primarily eliminated through metabolism; only 2 to 4 % of the dose is excreted unchanged in the urine. The principal route of metabolism is the formation of the pharmacologically active metabolite, desmethylmaprotiline. Primary elimination of maprotiline and desmethylmaprotiline is through hydroxylation and further conjugation of the metabolites and excretion in the urine. The hydroxylated metabolites, such as isomeric phenols, 2- and 3-hydroxymaprotiline and 2,3-dihydrodiol, represent only 4 to 8% of the dose excreted in human urine. The majority of the eliminated products are glucuronide conjugates of the primary metabolites (75%). The demethylation of maprotiline appears to be catalysed primarily by CYP2D6, with some contributions by CYP1A2.
Elimination
Maprotiline is eliminated from the blood with a mean half-life of 43 to 45 hours. Mean systemic clearance ranges between 510 and 570 mL/min.
Within 21 days, about two thirds of a single dose are excreted in urine, predominantly as free and conjugated metabolites, and about one third in the faeces.
Characteristics in patients
In elderly patients (aged over 60 years), steady-state concentrations are higher than in younger patients on the same dosage; the apparent elimination half-life is longer, and the daily dose should be halved (see Dosage and method of administration and Adverse effects). In renal impairment (creatinine clearance 24 to 37 mL/min), the elimination half-life and renal excretion of maprotiline are hardly affected, provided hepatic function is still normal. Renal excretion of metabolites is decreased, but this is compensated by increased elimination via the bile.
Indications
Depression
- Endogenous and late-onset (involutional) depression.
- Psychogenic, reactive, and neurotic depression, exhaustion depression.
- Somatogenic depression.
- Masked depression.
- Menopausal depression.
Other depressive mood disorders characterised by anxiety, dysphoria, or irritability; apathetic states (especially in the elderly); psychosomatic and somatic symptoms with underlying depression and/or anxiety.
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and
the International Statistical Classification of Diseases and Related Health
Problems (ICD-10) are standard classifications of mental disorders used by
mental health professionals and describe the above mentioned disorders as
follows:
Treatment of depressive episodes, recurrent depressive disorder or major
depression.
Dosage and Administration
During treatment with Ludiomil® the patient should be kept under medical surveillance.
The recommended dose range is between 75 and 150 mg daily. Depending on the severity of the symptoms, patient response and tolerance, the daily dose may start at 25 mg (one to three times daily) or 75 mg (once daily) then gradually titrated up to the effective dose. Daily doses above 150 mg are not recommended.
The dosage schedule should be determined individually and adapted to the patient's condition and response, e.g. by increasing the evening dose while lowering the doses given during the day or, alternatively, by administering only one daily dose. The aim is to achieve a therapeutic effect using the lowest possible doses, particularly in patients who are still growing or elderly patients with an unstable autonomic nervous system, since these patients are generally more likely to experience adverse events.
Ludiomil® tablets should be swallowed whole with sufficient liquid.
Elderly patients (more than 60 years of age):
In general, lower dosages are recommended. Initially, 10 mg 3 times daily or 25 mg once daily. If necessary, the daily dosage should be gradually increased in small increments up to 25 mg 3 times daily or 75 mg once daily, depending on tolerance and response.
Children and adolescents (less than 18 years of age):
The safety and efficacy of Ludiomil® in children and adolescents have not been established. Use in this age group is therefore not recommended.
Treatment discontinuation:
Abrupt withdrawal or abrupt dose reduction should be avoided because of possible adverse reactions.
Contraindications
- Hypersensitivity to maprotiline, any of the excipients, or cross-sensitivity to tricyclic antidepressants.
- Convulsive disorder or a lowered convulsion threshold (e.g. brain damage of varying aetiology, alcoholism).
- Acute stage of myocardial infarction and cardiac conduction defects.
- Severe hepatic or renal impairment.
- Narrow-angle glaucoma or urinary retention (e.g. due to prostatic disease).
- Concomitant treatment with a MAO inhibitor (see Interaction with other medicinal products and other forms of interaction).
- Acute poisoning with alcohol, hypnotics, or psychotropic agents (see Interaction with other medicinal products and other forms of interaction).
- Ludiomil is contraindicated for the treatment of depression in children and adolescents.
- Ludiomil is contraindicated for the treatment of nocturnal enuresis.
Warnings and Precautions
Antiarrhythmics
Antiarrhythmics that are potent inhibitors of CYP2D6, such as quinidine and propafenone, should not be used in combination with Ludiomil. The anticholinergic effects of quinidine may cause dose-related synergism with Ludiomil®.
Clinical Worsening and Suicide Risk:
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Symptons of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressivesness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a casual link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Ludiomil® should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Mania and Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with any antidepressant alone may increase the likelihood of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder. It should be noted that Ludiomil® is not approved for use in treating bipolar depression.
Information for Patients and Families
Patients and their families should be alerted about the need to monitor for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's doctor, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
The patient has the right to treatment meeting appropriate ethical and professional standards, and the patient needs to be fully informed with frank discussion of risk/benefit issues relating to the medicines efficacy and safety when used in the treatment regimen proposed.
Convulsions
There have been rare reports of convulsions occurring in patients without a history of convulsions who were treated with therapeutic doses of Ludiomil®. In some cases other confounding factors were present, such as concomitant medications known to lower the convulsion threshold. The risk of convulsions may be increased when antipsychotics (e.g. phenothiazines, risperidone) are given concomitantly (see Interaction with other medicinal products and other forms of interaction), when concomitant administration of benzodiazepines is interrupted abruptly, or when the recommended dosage of Ludiomil® is rapidly exceeded. While a causal relationship has not been established, the risk of convulsions may be reduced by: using low starting doses; maintaining the initial dosage for 2 weeks and then raising it gradually in small increments; keeping the maintenance dose at the minimum effective level; cautious adjustment or avoidance of comedication with medicinal products that lower the convulsion threshold (e.g. phenothiazines, risperidone), or rapid tapering of benzodiazepines.
Concomitant electroconvulsive therapy should be carried out only under careful supervision.
Cardiac and vascular disorders
Tricyclic and tetracyclic antidepressants have been reported to produce cardiac arrhythmias, sinus tachycardia and prolongation of conduction time. Ventricular tachycardia, ventricular fibrillation, and Torsade de Pointes have very rarely been reported in patients treated with Ludiomil; some of these cases have been fatal. Caution is indicated in elderly patients and patients with cardiovascular disease, including a history of myocardial infarction, arrhythmias and/or ischaemic heart disease. Monitoring of cardiac function, including ECG, is indicated in such patients, especially during long-term treatment. Regular measurement of blood pressure is called for in patients susceptible to orthostatic hypotension.
Other psychiatric effects
Activation of psychosis has occasionally been observed in patients with schizophrenia receiving tricyclic antidepressants and must be considered a risk with Ludiomil®. Similarly, hypomanic or manic episodes have been reported in patients with bipolar disorders while under treatment with a tricyclic antidepressant during a depressive phase. In such cases it may be necessary to reduce the dosage of Ludiomil® or to withdraw it and administer an antipsychotic agent. Co-medication with antipsychotics (e.g. phenothiazines, risperidone) may result in increased plasma levels of maprotiline, a lowered convulsion threshold and convulsions (see Interaction with other medicinal product and other forms of interaction). Combination with the CYP2D6 inhibitor thioridazine may produce severe cardiac arrhythmia. Dose adjustment may therefore be necessary.
In predisposed and elderly patients, tricyclic antidepressants may provoke pharmacogenic (delirious) psychoses, especially at night; these disappear without treatment within a few days of withdrawal.
Hypoglycaemia
The possibility of hypoglycaemia should be considered in patients receiving Ludiomil concomitantly with oral sulfonylureas or insulin. Diabetic patients should closely monitor their blood glucose when treatment with Ludiomil® has been initiated or discontinued.
White blood cell count
Although changes in the white blood cell count have been reported with Ludiomil® only in isolated cases, periodic blood cell counts and monitoring for symptoms such as fever and sore throat are called for, particularly during the first few months of therapy. They are also recommended during prolonged therapy.
Anaesthesia
Before general or local anaesthesia, the anaesthetist should be informed that the patient has been receiving Ludiomil®. It is safer to continue treatment than to risk disruption due to discontinuation before surgery.
Specific treatment populations and long-term treatment
During long-term treatment it is advisable to monitor hepatic and renal function.
Caution is recommended in patients with a history of increased intraocular pressure, chronic severe constipation or a history of urinary retention, particularly in the presence of prostatic hypertrophy.
Tricyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in hospitalised patients. Appropriate measures should therefore be taken if constipation occurs.
Caution is recommended in hyperthyroid patients and patients on thyroid-hormone preparations (possible increase in unwanted cardiac effects).
An increase in dental caries has been reported in patients receiving long-term treatment with antidepressants. Regular dental checks are therefore advisable during long-term therapy.
Decreased lacrimation and relative accumulation of mucoid secretion associated with the anticholinergic properties of tricyclic antidepressants may cause damage to the corneal epithelium in patients who wear contact lenses.
Treatment discontinuation
Abrupt withdrawal or abrupt dose reduction should be avoided because of possible adverse reactions. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
Lactose
Ludiomil® tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Use during Pregnancy and Lactation
Pregnancy
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 Ludiomil® and adverse effects on the human foetus have been reported. Ludiomil® should not be administered during pregnancy unless the benefits clearly outweigh the risk to the foetus.
Ludiomil® 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 newborn.
Lactation
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 Ludiomil® should not breast-feed.
Effects on ability to drive and use machines
Patients receiving Ludiomil® should be warned that blurred vision, dizziness, somnolence and other CNS symptoms (see Adverse Effects) 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
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, Ludiomil 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 (see Dosage and method of administration and Pharmacokinetic properties).
The following adverse effects have been reported either with Ludiomil or with tricyclic antidepressants.
Table 1
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.
| Infections and infestations | |
| Very rare: | Dental caries. |
| Blood and lymphatic system disorders | |
| Very rare: | Leukopenia, agranulocytosis, eosinophilia, thrombocytopenia. |
| Endocrine disorders | |
| Very rare: | Inappropriate anti-diuretic hormone secretion . |
| Metabolism and nutrition disorders | |
| Common: | Increased appetite. |
| Psychiatric disorders | |
| Common: | Restlessness, anxiety, agitation, mania, hypomania, libido disorder, aggression, sleep disorder, insomnia, nightmare, depression. |
| Rare: | Delirium, confusion, hallucination (particularly in geriatric patients), nervousness. |
| Very rare: | Activation of psychotic symptoms, depersonalisation. |
| Nervous system disorders | |
| Very common: | Somnolence, dizziness, headache, tremor, myoclonus. |
| Common: | Sedation, memory impairment, disturbances in attention, paraesthesia, dysarthria. |
| Rare: | Convulsion, akathisia, ataxia. |
| Very rare: | Dyskinesia, coordination abnormal, syncope, dysgeusia. |
| Eye disorders | |
| Common: | Blurred vision, disorders of visual accommodation. |
| Ear and labyrinth disorders | |
| Very rare: | Tinnitus. |
| Cardiac disorders | |
| Common: | Sinus tachycardia, palpitations. |
| Rare: | Arrhythmia. |
| Very rare: | Conduction disorder (e.g. widening of QRS complex, bundle-branch block, PQ changes), QT interval prolongation, ventricular tachycardia, ventricular fibrillation, torsade de pointes. |
| Vascular disorders | |
| Common: | Hot flush, orthostatic hypotension. |
| Very rare: | Purpura. |
| Respiratory, thoracic and mediastinal disorders | |
| Very rare: | Alveolitis allergic (with or without eosinophilia), bronchospasm, nasal congestion. |
| Gastro-intestinal disorders | |
| Very common: | Dry mouth. |
| Common: | Nausea, vomiting, abdominal disorders, constipation. |
| Rare: | Diarrhoea. |
| Very rare: | Stomatitis. |
| Hepato-biliary disorders | |
| Very rare: | Hepatitis (with or without jaundice) |
| Skin and subcutaneous tissue disorders | |
| Common: | Dermatitis allergic, rash, urticaria, photosensitivity reaction, hyperhidrosis. |
| Very rare: | Pruritus, cutaneous vasculitis, alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. |
| Musculoskeletal, connective tissue and bone disorders | |
| Common: | Muscle weakness. |
| Renal and urinary disorders | |
| Common: | Micturition disorder. |
| Very rare: | Urinary retention. |
| Reproductive system and breast disorders | |
| Common: | Erectile dysfunction. |
| Very rare: | Hypertrophy breast, galactorrhoea. |
| General disorders and administration site conditions | |
| Very common: | Fatigue. |
| Common: | Pyrexia. |
| Very rare: | Oedema (local or generalised). |
| Investigations | |
| Common: | Weight increased, electrocardiogram abnormalities (e.g. ST and T wave changes) |
| Rare | Blood pressure increase, liver function test abnormal. |
| Very rare: | Electroencephalogram abnormal. |
| Injury, poisoning and procedural complications | |
| Very rare: | Fall. |
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.
Interactions
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.
MAO inhibitors
Monoamine oxidase (MAO) inhibitors that are potent CYP2D6 inhibitors in vivo, such as moclobemide, are contraindicated for co-administration with Ludiomil®. Ludiomil® must not be given for at least 14 days after discontinuation of treatment with MAO inhibitors to avoid the risk of severe interactions such as hyperpyrexia, tremor, generalised clonic convulsions, delirium, and possible death. The same applies when giving an MAO inhibitor after previous treatment with Ludiomil®.
Antiarrhythmics
Antiarrhythmics that are potent inhibitors of CYP2D6, such as quinidine and propafenone, should not be used in combination with Ludiomil®. The anticholinergic effects of quinidine may cause dose-related synergism with Ludiomil®.
Antidiabetic agents
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 Ludiomil® has been initiated or discontinued.
Antipsychotics
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.
Anticoagulants
Some tricyclic antidepressants may potentiate the anticoagulant effect of coumarin, possibly by inhibition of its metabolism 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.
Anticholinergic agents
Ludiomil® 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.
Antihypertensive agents
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.
Ludiomil® 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 Ludiomil® can also result in serious hypotension.
Sympathomimetic agents
Ludiomil® may potentiate the cardiovascular effects of sympathomimetic agents such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine, as well as of nasal drops and local anaesthetics (e.g. those used in dentistry). Close supervision (blood pressure, cardiac rhythm) and careful dosage adjustment are therefore required.
Central nervous system depressants
Patients taking Ludiomil® should be warned that their response to alcohol, barbiturates and other CNS depressants may be intensified.
Benzodiazepines
Co-medication with benzodiazepines may cause increased sedation.
Methylphenidate
Methylphenidate may increase plasma concentrations of tricyclic antidepressants and so intensify their effects. Dose adjustment may therefore be necessary.
SSRIs
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.
H2-receptor antagonists
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.
Effect of cytochrome P450 inducers on maprotiline metabolism
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. 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).
Overdosage
Symptoms
The signs and symptoms of overdose with Ludiomil are similar to those reported with tricyclic antidepressants. Cardiac abnormalities and neurological disturbances are the main complications. In children accidental ingestion of any amount should be regarded as serious and potentially fatal.
Symptoms generally appear within 4 hours of ingestion and reach maximum severity at 24 hours. Due to delayed absorption (anticholinergic effect), long half-life, and enterohepatic recycling, the patient may remain at risk for up to 4 to 6 days.
The following signs and symptoms occur.
Central nervous system: somnolence, stupor, coma, ataxia, restlessness, agitation, enhanced reflexes, muscular rigidity and choreo-athetotic movements, convulsions.
Cardiovascular system: hypotension, tachycardia, arrhythmias, conduction disorders, shock, heart failure; ventricular tachycardia, ventricular fibrillation, Torsade de Pointes, cardiac arrest, some of which have been fatal.
In addition, respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, and oliguria or anuria may occur.
Treatment
There is no specific antidote and treatment is essentially symptomatic and supportive.
Patients, particularly children, who may have ingested an overdose of Ludiomil should be hospitalised and kept under close surveillance for at least 72 hours.
The stomach should be emptied as quickly as possible by lavage, or induced emesis if the patient is alert. If the patient is not alert, the airway should be secured with a cuffed endotracheal tube before beginning lavage, and emesis should not be induced. These measures are recommended for up to 12 hours or even longer after the overdose, since the anticholinergic effect of the drug may delay gastric emptying. Administration of activated charcoal may help to reduce drug absorption.
Symptomatic treatment is based on modern methods of intensive care with continuous monitoring of cardiac function, blood gases and electrolytes, and possible need for emergency measures, such as anticonvulsive therapy, artificial respiration, and resuscitation. Physostigmine has been reported to cause severe bradycardia, asystole and convulsions, and its use is therefore not recommended in cases of overdosage with Ludiomil®. Haemodialysis and peritoneal dialysis are ineffective because of the low plasma concentrations of maprotiline.
Pharmaceutical Precautions
Store in a cool dry place.
Medicines Classification
Prescription Medicine
Package Quantities
25 mg: Blister pack of 100 tablets
75 mg: Blister pack of 30 tablets.
Further Information
Ludiomil® tablets also contain Silica, Calcium phosphate, Lactose, Magnesium stearate, Stearic acid, Hydroxypropyl methylcellulose, Yellow iron oxide (E 172), Polysorbate 80, Titanium dioxide (E 171), Talc; Maize starch, Red iron oxide (E 172)
Name and Address
AFT Pharmaceuticals Ltd
9 Anzac Street (Level 2)
Takapuna
Auckland
Email:customer.service@aftpharm.com
Date of Preparation
8 August 2008