The preparation has a balanced spectrum of action: improves mood, eliminates anxiety and agitation, and psychomotor retardation. When masked depression medication can have a beneficial effect on the somatic symptoms. The mechanism of action equipoise steroid is associated with maprotiline pronounced inhibitory effect on the reuptake of noradrenaline presynaptic neurons of the cerebral cortex with very little inhibition of serotonin reuptake. Maprotiline has mild to moderate affinity for central alpha 1 adrenoretseptoram; has a significant inhibitory effect on the histamine H 1receptors and a moderate anticholinergic effects. Prolonged use Lyudiomila in the mechanism of action of the drug can also be set to change in the functional state of the neuroendocrine system (growth hormone, melatonin, endorfinergicheskaya system) and / or neurotransmitter systems (noradrenaline, serotonin gamma-aminobutyric acid).
After intravenous bolus injection Lyudiomila 50 mg maprotiline hydrochloride concentration in plasma is 48-150 nmol / l (13-47 ng / ml) is achieved within one hour after injection. Repeated application Lyudiomila orally or intravenously in a dose of 150 mg per day maprotiline equilibrium concentration achieved in the blood during the second week of treatment and 320-1270 nmol / l (100-400 ng / ml). The distribution coefficient distribution maprotiline between blood and plasma is 1.7. The mean value of the apparent distribution volume is 23-27 l / kg. Maprotiline Plasma protein binding is 88-90%, regardless of the age of the patient and the nature of the disease. Maprotiline concentrations in the cerebrospinal fluid is 2-13% of the serum concentration.Metabolism maprotiline hydrochloride is largely metabolized, only 2-4% of the dose is excreted in the urine in unchanged form. The main metabolite is pharmacologically active desmetilovy derivative. Other more minor metabolites are formed by hydroxylation and / or methoxylation; excreted in the urine as conjugates. Excretion half-life of maprotiline on average 43-45 hours. The mean total clearance value ranges from 510 to 570 ml / min. After the application of a single dose of excretion of the active substance takes place over 21 days: 2/3 of the dose is excreted in the urine (as unchanged or as conjugates) and about 1/3 – with the feces. Pharmacokinetics in specific patient groups In elderly patients (older than 60 s), as compared to younger patients, the application of the same dose Lyudiomila equilibrium concentration of active substance in the blood above the apparent half-life longer; therefore Lyudiomila daily dose should be reduced by a factor of 2. If the kidney function (creatinine clearance 24-37 ml / min) renal excretion and elimination half-life maprotiline vary slightly, provided that the liver function is normal. Renal excretion of metabolites is reduced, but this is offset by increased excretion of bile.
endogenous and involutional depression.
Psychogenic, reactive and neurotic depression, exhaustion depression.
The masked depression.
Menopausal (climacteric) depression.
- Other depressive mood disorders characterized by anxiety, dysphoria or irritability;
state of apathy (especially in the elderly);
psychosomatic and somatic symptoms in patients with depression and / or the presence of an alarm.
- Hypersensitivity to maprotiline or any other components of the drug; Cross hypersensitivity to tricyclic antidepressants;
- diseases accompanied by convulsive disorders or reduced seizure threshold (eg brain damage of varying aetiology, alcoholism);
- the acute phase of myocardial infarction and intracardiac conduction disorders;
- expressed human liver or kidney;
- angle-closure glaucoma or urinary retention outflow (eg due to prostatic disease);
- simultaneous treatment of MAO inhibitors;
- acute poisoning with alcohol, hypnotics, or psychotropic drugs.
The efficacy and safety Lyudiomila in children and adolescents (under 18 years) has not been established. Application Lyudiomila in this age group is not recommended.
When using Lyudiomila in therapeutic doses in patients without indication of seizure activity in the history of rarely observed seizures develop. In some cases, these patients had factors that contribute to the development of seizures (eg, the simultaneous use of drugs that reduce the seizure threshold). The risk of seizures may be increased when used together Lyudiomila with antipsychotics (eg phenothiazines, risperidone), while at the same time with a sharp lifting Lyudiomilom receiving benzodiazepines or in the case of a rapid increase in the recommended dose Lyudiomila. Although a clear causal link between the application and development of Lyudiomila seizure activity is not found to reduce the risk of seizures should be: start treatment with a small dose Lyudiomilom; maintain unchanged starting dose for 2 weeks; to carry out slow and gradually increase the dose; use the minimum effective dose of the drug for long-term maintenance therapy; carefully select the dosage of drugs that reduce the seizure threshold (eg, phenothiazines) or to avoid their simultaneous use with Lyudiomilom, avoid abrupt withdrawal of benzodiazepine or combined with Lyudiomilom.
When using tricyclic and tetracyclic antidepressants may develop arrhythmias, sinus tachycardia, and slowing of intracardiac conduction .
caution must be exercised in the appointment of tricyclic and tetracyclic antidepressants in elderly patients and patients with cardiovascular disease, including myocardial infarction, arrhythmias and / or ischemic heart disease. In this category of patients, particularly during long-term treatment with antidepressants, should be regular monitoring of cardiac function, including ECG. Patients with orthostatic hypotension should regularly measure blood pressure.
Use in pregnancy and lactation
is shown in experimental studies that Lyudiomil has no teratogenic or mutagenic effects; It does not cause disturbances in fertility, and no adverse effects on the fetus. However, the safety of the drug in human pregnancy has not yet been established. There are some reports of a possible association between the use Lyudiomila and undesirable effects on the human fetus. Do not use Lyudiomil during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus.
In order to prevent the development of the newborn symptoms such as shortness of breath, lethargy, irritability, tachycardia, marked reduction in blood pressure, cramps, nervous excitement and hypothermia, Lyudiomil should be discontinued for at least 7 weeks before the expected date of delivery (provided that the patient’s condition allows it).
maprotiline passes into breast milk. Lyudiomila Upon receiving a daily dose of 150 mg over 5 days maprotiline concentrations in human milk than in plasma concentration of 1.3-1.5 times. Although the development of these adverse events in infants when used in nursing mothers maprotiline No patients receiving treatment Lyudiomilom, or should renounce the use of the drug or stop breastfeeding.
Dosing and Administration
During treatment, patients should be under medical supervision.
Lyudiomil can be assigned intravenously in case of insufficient effect while taking the drug orally or in the case of refractory to oral therapy of depression.
Dosage should be adjusted individually, changing it in the condition of the patient and his reaction to the drug.
The drug is administered as an intravenous infusion.
The recommended daily dose is from 25 to 100 mg.
to prepare the infusion solution from 25 to 50 mg (contents of 1 to 2 ml vials -5-10 concentrate) is diluted with 250 ml of isotonic sodium chloride chloride or glucose. Infusion duration of 1.5 to 2 hours.
In cases where a higher dose of from 75 mg to 150 (the contents of vials 3 to 6), the amount of diluent should be 500 ml and the duration of infusion of 2 to 3 hours.
Once clear positive symptoms dynamics will be marked (usually within 1 to 2 weeks), proceed to the designation of the drug inside. Patients over 60 years of age usually recommended dose for initiation of therapy is 1 ampoule 25 mg, diluted with 250 ml of saline or glucose solution, introduced in an infusion over 1.5 to 2 hours. If necessary, depending on patient tolerability Lyudiomila and response to treatment, the daily dose can be gradually increased up to 2 or 3 vials (i.e., 50 or 75 mg), diluted from 250 mL to 500 fiz.rastvora or glucose solution, administered as infusion over 2 to 3 hours. Do not abruptly cancel the drug or reduce the dose drastically due to possible adverse reactions.
The observed adverse events were usually mild and transient, disappearing after stopping Lyudiomila or reducing its dose. They do not always correlate well with the concentration of the active substance in blood plasma or a dose of the drug. Often there are difficulties in the differential diagnosis of certain adverse events and symptoms of depression:. Fatigue, sleep disturbances, agitation, anxiety, constipation, dry mouth
With the development of serious adverse events, such as the central nervous system, Lyudiomil should be abolished.
The elderly It is particularly sensitive to anticholinergic effects Lyudiomila, as well as its effects on the central nervous and cardiovascular systems. In elderly patients with reduced ability to metabolize and derive drugs increases the risk of a significant increase in the concentration of the active substance in the blood plasma when using the drug at therapeutic doses.
The following are the adverse effects observed when used as Lyudiomila and tricyclic antidepressants listed in frequency since with the most frequent. The frequency of adverse reactions is estimated as follows: very common ( > 1/10); common ( > 1/100, <1/10); sometimes ( > 1 / 1,000, <1/100); rare ( > 1 / 10,000, <1 / 1,000); very rare (<1 / 10,000), including isolated reports. On the part of the central and peripheral nervous system : very often -sonlivost, dizziness, headache, tremor, myoclonus; often – sedation, loss of memory, impaired attention, paraesthesia, dysarthria; rarely – seizures, akathisia, ataxia;very rarely – dyskinesia, disorders of coordination, fainting, impaired sense of taste. Psychiatric disorders : often – worry, anxiety, agitation, manic disorders, libido, aggression, sleep disturbance, insomnia, nightmares, increased symptoms of depression, rarely – depression varying degrees of consciousness, delirious disorders, hallucinations (mainly in elderly patients), irritability; very rarely – activation of psychotic symptoms, depersonalisation. On the part of the cardiovascular system : often – sinus tachycardia, palpitations, orthostatic hypotension, flushing (feeling of heat); rarely – arrhythmias; very rarely – a violation of intracardiac conduction (eg, extension of the QRS complex, bundle branch block blockade, the PQ interval changes), increase the interval QT, ventricular tachycardia, ventricular fibrillation, torsades ventricular tachycardia (torsade de pointes), purpura. There have been reports of individual cases of ventricular tachycardia, ventricular fibrillation, torsades ventricular tachycardia (torsade de pointes) with a fatal outcome. On the part of the gastrointestinal tract : often – dry mouth; often -toshnota, vomiting, abdominal discomfort, constipation; rarely – diarrhea; very rarely – stomatitis, hepatitis, equipoise steroid accompanied or not by jaundice. For the skin : often – allergic dermatitis, rash, urticaria, photosensitivity, rash; very rarely – itching, cutaneous vasculitis, alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. On the part of the endocrine system and metabolism : often – increased appetite; sometimes – increase in body weight; very rarely – a syndrome of inappropriate secretion of antidiuretic hormone. The respiratory system, organs, thoracic and mediastinal disorders : very rarely – allergic alveolitis, with eosinophilia or without it, bronchospasm, nasal congestion.Hematopoietic system : rarely – leukopenia, agranulocytosis, eosinophilia , thrombocytopenia. From the senses : common – “blurred” vision, disturbances of accommodation; very rarely – ringing in the ears.On the part of the musculoskeletal system and connective tissue : often -Muscular weakness. On the part of the excretory and reproductive systems : common – urination disorders, erectile dysfunction; very rarely – urinary retention, hypertrophy of the breast, galactorrhoea. General disorders and administration site reactions : often – fatigue; often – fever; very rarely – edema (local or general). Laboratory and instrumental investigations : often – electrocardiographic abnormalities (eg, changes in ST segment and T wave); rarely – a marked increase in blood pressure, abnormalities of liver function tests; -Violation very rarely in the electroencephalogram. Other :. very rare – the fall caries After the sudden cancellation or rapid reduction of the dose of the drug sometimes experience the following symptoms: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety, increased depression or recurrence of depressive mood disorders.
So far, cases of overdose with parenteral use Lyudiomila not been reported.
In case of overdose Lyudiomila taken inside, develop the same symptoms as in the case of an overdose of tricyclic anti-depressants. The main complications are disorders of the cardiovascular and neurological disorders. In children accidental introduction of the drug should be regarded as very serious and threatening to fatal accidents, regardless of the dose. Symptoms . Symptoms usually appear within 4 hours after administration Lyudiomila and reach a maximum after 24 hours of expression. Due to delayed absorption (anticholinergic effect), long half-life and recycling gepatoenteralnoy maprotiline, the risk to the patient’s life is maintained for 4-6 days. May experience the following symptoms. On the part of the central nervous system: drowsiness, stupor, coma, ataxia, restlessness, agitation, increased reflexes, muscle rigidity, horeoatetoidnye movements, convulsions. Cardio-vascular system: marked reduction of blood pressure, tachycardia, arrhythmia, disorders intracardiac conduction, shock, heart failure, ventricular tachycardia, ventricular fibrillation, torsades ventricular tachycardia (Torsade de Pointes); heart failure; In some cases, the symptoms of fatal accidents. In addition, there may be respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria. Treatment . There is no specific antidote, treatment is primarily symptomatic and supportive. Patients with suspected overdose Lyudiomila, particularly children, should be hospitalized and kept under close medical supervision at least 72 hours. It is necessary to carry out gastric lavage as soon as possible or, if the patient is conscious, induce vomiting. If the patient is unconscious, before gastric lavage should be carried out intubation of the trachea; vomiting in this case can not cause. These measures are recommended, if passed by the beginning of overdose of up to 12 hours and even more ,, since the anticholinergic effect of the drug may slow emptying from the stomach. To slow the absorption of maprotiline beneficial use of activated carbon. Symptomatic treatment is based on the use of modern methods of intensive care with close monitoring of heart functions, gas and electrolyte composition of the blood. If necessary, use of anticonvulsant therapy, mechanical ventilation, and other resuscitation techniques. Since the reports appeared that physostigmine may cause severe bradycardia, asystole and seizures, its use in cases of overdose Lyudiomila not recommended. Hemodialysis and peritoneal dialysis are not effective as maprotiline plasma concentrations are low.
Interaction with other drugs
When taken in combination with Lyudiomila SYP2D6 inhibitors in patients with extensive metabolizer phenotype dibrizohina may increase concentrations of maprotiline to 3.5 times (that is, the manifestation of poor metabolizer phenotype dibrizohina).
Concomitant use of Lyudiomila with monoamine oxidase inhibitors (MAOIs) such as moclobemide, which are potent inhibitors of CYP2D6 in vivo, is contraindicated. Lyudiomil should not be administered for at least 14 days after discontinuation of MAO inhibitors, due to the possible risk of drug interactions expressed, leading to the development of hyperpyrexia, tremor, generalized clonic convulsions, delirium deaths. Follow the same rule in the case when MAO inhibitors are assigned Lyudiomilom after previous treatment. Antiarrhythmic agents that are potent inhibitors of CYP2D6, for example, propafenone, quinidine, and should not be taken in combination with Lyudiomilom. Anticholinergic effects of quinidine may be a synergistic effect Lyudiomila, and its severity depends on the dose of these drugs. The combined use of Lyudiomila with sulfonylureas for oral or insulin may potentiate their hypoglycemic effect. In patients with diabetes needs to carry out regular monitoring of blood glucose levels in the early Lyudiomilom therapy, and at its end. The simultaneous use of Lyudiomila with antipsychotics (eg., Phenothiazines, risperidone) may increase maprotiline plasma concentrations decrease seizure threshold preparedness and the development of seizures. The combined use of Lyudiomila with the CYP2D6 inhibitor thioridazine may lead to severe arrhythmias. In a joint application Lyudiomila with antipsychotic drugs may require adjustment of doses of drugs. Some tricyclic antidepressants may increase the anticoagulant effect of coumarin derivatives, probably due to inhibition of their metabolism in the liver or reduce intestinal motility. No proof ability Lyudiomila inhibit the metabolism of anticoagulants , such as warfarin , the active S-enantiomer of which is metabolized by CYP2C9, but should carefully monitor the prothrombin levels in the plasma at said combination. Lyudiomil may potentiate the action of drugs having anticholinergic properties (for example, phenothiazines, antiparkinson drugs atropine, biperiden, antihistamines) on the pupil of the eye, central nervous system, the intestines and the bladder. Simultaneous use Lyudiomila with beta-blockers , which are inhibitors of CYP2D6, such as propranolol, may lead to increased plasma concentrations maprotiline. In such cases it is advisable to monitor drug levels in the plasma and to adjust the dose as necessary. Lyudiomil can reduce (or even completely block) antihypertensive effect of antiadrenergic drugs like quinidine, betanidin, reserpine, clonidine and alpha-methyldopa. Patients taking Lyudiomil, for the treatment of hypertension, should be applied to other classes of drugs (eg, diuretics, vasodilators, or beta-blockers), are not subject to pronounced biotransformation. The sudden cancellation Lyudiomila can lead to a marked reduction of blood pressure (BP). Lyudiomil may potentiate the cardiovascular effects of sympathomimetic agents such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine, a part of nose drops or a local anesthetic (eg, used in dentistry). In these situations require careful patient monitoring (control of blood pressure, heart rate) and the careful selection of drug dose. Patients taking Lyudiomil should be warned that their response to alcohol, barbiturates and other means, have a depressing effect on the central nervous system, may be more pronounced. The simultaneous use of Lyudiomila and benzodiazepines may lead to increased sedation. Methylphenidate may increase concentrations of tricyclic antidepressants in plasma and enhance their actions, and therefore it may be necessary to correct the dose.Concomitant use Lyudiomila with selective inhibitors of reverse neuronal serotonin reuptake that are inhibitors of CYP2D6, such as fluoxetine or fluvoxamine, which also inhibits CYP3A4, CYP2C19, CYP2C9 and CYP1A2, paroxetine, sertraline or citalopram, may lead to a significant increase in the blood concentration of maprotiline and corresponding to development of adverse events. Because of the long half-life of fluoxetine and fluvoxamine, this effect can be maintained for a long time. In such cases it may be necessary preparations dose adjustment. It was shown that an antagonist of the H 2 – histamine cimetidine receptors (an inhibitor of several P450 enzymes including CYP2D6 and CYP3A4) inhibits the metabolism of some tricyclic antidepressants, which leads to an increase in their concentration in the blood and increased frequency of adverse events ( dry mouth, blurred vision). Although there is no data on the interaction of cimetidine with Lyudiomilom, we can not exclude the possibility of reducing the dose Lyudiomila case of simultaneous application. Maprotiline is metabolized primarily by the enzyme CYP2D6, and to some extent of CYP1A2. Effect of induction with respect to CYP2D6 has not been identified. This joint appointment Lyudiomila with substances that induce CYP1A2, may lead to an increased formation desmetilmaprotilina. Reducing the clinical effect of the drug in this case is unlikely, as this is an active metabolite. However, induction of enzymes, whose role in the deactivation and maprotiline desmetilmaprotilina (eg., P450 system, phase II enzymes) is not defined, may increase the clearance of active substances and reduce the effectiveness Lyudiomila. When receiving Lyudiomila in combination with inducers of cytochrome P450 enzymes liver metabolizing especially tricyclic antidepressants such as CYP3A4, CYP2C19, and / or CYP1A2 (eg., Rifampicin, carbamazepine, phenytoin and phenobarbital), may require a dosage adjustment Lyudiomila.
standard classification of mental disorders – Diagnostic and Statistical Manual of DSM-IV mental illness and International Statistical Classification of Diseases ICD-10, define listed under “Indications” states as follows: depressive episode, recurrent depressive disorder or major depression.
Patients with schizophrenia during therapy with tricyclic antidepressants may increase psychotic symptoms; the risk of such complications should be taken into account when assigning Lyudiomila Patients with bipolar disorder cyclic therapy with tricyclic antidepressants during the depressive phase of the illness occurred hypomanic or manic episodes. In such cases it may be necessary to reduce the dose Lyudiomila, until canceled, and administering an antipsychotic agent.
In severe depression an increased risk of suicidal action can continue until the occurrence of significant remission. In patients with depression, both adults and children, there may be increased depression and / or suicidal behavior or other psychopathological symptoms, regardless of whether they receive treatment with antidepressants or not. In short-term studies in children and adolescents with depression and other mental disorders it is shown that antidepressants increased the risk of suicidal thoughts and suicidal behavior. In rare cases, antidepressants may condition worsening suicidal ideation (tendencies).
In one study in patients receiving prophylactic treatment Lyudiomilom about unipolar depression, were identified strengthening of suicidal behavior. The frequency of death due to overdose during treatment Lyudiomilom comparable with other antidepressants. Therefore, at all stages of treatment requires careful monitoring of patients. All patients taking Lyudiomil according to any of the testimony should be evaluated for clinical worsening, suicidal behavior and other psychiatric symptoms, especially in the initial phase of therapy or when changing dose. These patients should be considered the possibility of changing treatment regimen, including the possible removal Lyudiomila, particularly if such changes are pronounced appeared suddenly and were not observed in the patient before administration of the substance.
The goal of treatment is to achieve a therapeutic effect by using the minimum effective dose, especially in patients ( older than 18 years) with non-completion of the process of growth or the elderly, who are usually inherent instability of the autonomic nervous system, and which is generally higher likelihood of adverse events.
in order to reduce the risk of overdose in the recipe should specify the minimum number of Lyudiomila necessary to comply adequate regimen. Maprotiline as tricyclic antidepressants may provoke the development of drugs (delirious) psychoses, in predisposed patients and elderly patients, particularly at night. Psychosis usually cropped own a few days after discontinuation of the drug.
Avoid sudden cancellation or drastic reduction of the dose Lyudiomila, as this may lead to undesirable reactions. The drug should be withdrawn gradually, as soon as the clinical situation allows. It should be borne in mind that abrupt withdrawal of the drug may be associated with the development of certain symptoms.
Electroconvulsive therapy in the period of application Lyudiomila must be carried out with careful monitoring of the patient.
Although known only isolated reports of changes of leukocytes in peripheral blood during treatment Lyudiomilom, none However, the need for periodic monitoring of this indicator and alert to symptoms such as fever and sore throat. Implementation of these recommendations is especially true in the first months of treatment and long-term therapy Lyudiomilom. During long-term therapy Lyudiomilom recommended to regularly monitor liver function and kidney.
Lyudiomil should be used with caution in patients with a history of references to increased intraocular pressure, severe chronic constipation or urinary retention outflows, especially in prostatic hypertrophy.Since maprotiline exhibits some properties inherent tricyclic antidepressants, should take into account that tricyclic antidepressants may contribute to the development of paralytic ileus, particularly in elderly patients or in patients who are in hospital. Therefore, in the event of constipation in patients required to take adequate measures. The therapy Lyudiomilom not be excluded characteristic tricyclic anti depressants anticholinergic effects: decreased lacrimation, and the relative increase in the amount of mucus in the tear fluid which may cause damage to the corneal epithelium in patients who use contact lenses.
Lyudiomil should be used with caution in patients with hyperthyroidism, as well as those who are taking drugs of thyroid hormones (may increase the frequency of adverse reactions on the part of the heart).
long-term treatment with antidepressants reported a higher incidence of dental caries. In this regard, long-term therapy is recommended systematic inspections dentist.
Anesthesiologist should be warned before carrying general or local anesthesia that the patient receives equipoise steroid. Continued treatment Lyudiomilom seems safer than those violations that may occur due to the sudden withdrawal of the drug prior to surgery. Families and caregivers of patients (both children and adults) receiving antidepressant drugs for various indications, should be alerted about the need to monitor the patients due to the risk of other psychiatric symptoms, including suicidal behavior, and immediately report such symptoms to physicians. anaboliset steroidit mista