Included in the formulation
АТХ:N.06.A.A.21 Maprotiline
Pharmacodynamics:Tetracyclic antidepressant, showing the properties inherent in tricyclic antidepressants. Has a wide, well-balanced spectrum of antidepressant, anxiolytic and sedative action: improves mood, eliminates anxiety, agitation, psychomotor retardation, weakens the severity of somatic complaints with masked depression. The antidepressant effect is due to selective inhibition of the reverse neuronal seizure of norepinephrine with presynaptic endings. In this case, the reverse capture of serotonin is practically not inhibited. Has a moderate affinity to the central a1-adrenoceptors; has a significant inhibitory effect on histamine H1 receptors and moderate m-cholinoblocking action. With prolonged use changes the functional state of the neuroendocrine and / or neurotransmitter system.
Pharmacokinetics:When ingested slowly, but completely absorbed from the digestive tract. The average absolute bioavailability is 66-70%. Cmax in plasma is achieved after 8 hours. The distribution coefficient between whole blood and plasma is 1.7, the average value of the apparent Vd is 23-27 l / kg.Binding to plasma proteins - 88-89% (does not depend on the age of the patient and the nature of the disease). Concentration in the CSF is 2-13% of the serum concentration.
It is metabolized in the liver, only 2-4% of the accepted dose is excreted unchanged in the urine. The main metabolite is the pharmacologically active desmethyl derivative, the other metabolites are not significant and are excreted in the urine in the form of conjugates.
The half-life is 43-45 hours. The total clearance varies from 510 to 570 ml / min. After taking a single dose, its elimination is slow (within 21 days), 2/3 of the dose is excreted in the urine (mainly in the form of metabolites, 2-4% - unchanged), about 1/3 - with feces.
When administering maprotiline at the same dose, the Css value of the active substance in the blood and the apparent elimination half-life in elderly patients (over 60 years) is higher than in young patients, therefore, the daily dose of maprotiline should be reduced by half in elderly patients. If the renal function is impaired (creatinine clearance values of 24-37 ml / min), the half-life of maprotiline changes insignificantly (provided that the liver function is normal).Excretion of metabolites by the kidneys decreases, but this is compensated by an increase in excretion with bile.
Indications:Depression is endogenous, in t.ch. involutional, psychogenic, in t.ch. reactive and neurotic, depression depletion, somatogenic (organic and symptomatic), masked, menopause; other depressive mood disorders characterized by anxiety, dysphoria or irritability; a state of apathy (especially in the elderly); psychosomatic and somatic disorders caused by depression or fear.
V.F00-F09.F06 Other mental disorders due to damage and dysfunction of the brain or somatic disease
V.F00-F09.F06.3 Organic mood disorders [affective]
V.F30-F39.F31 Bipolar affective disorder
V.F30-F39.F32 Depressive episode
V.F30-F39.F33 Recurrent depressive disorder
V.F40-F48.F40 Phobic anxiety disorders
V.F40-F48.F41.2 Mixed anxiety and depressive disorder
V.F40-F48.F43 Reaction to severe stress and adaptation disorders
V.F40-F48.F45.3 Somatoform dysfunction of the autonomic nervous system
XIV.N80-N98.N95.1 Menopause and menopause in women
XVIII.R40-R46.R45.3 Demoralization and apathy
Contraindications:Hypersensitivity, cross-sensitivity to tricyclic antidepressants; epilepsy (including in the anamnesis), diseases accompanied by convulsive syndrome or reduced threshold of convulsive readiness (for example, damage to the brain of any etiology, alcoholism); acute stage of myocardial infarction, cardiac conduction abnormalities, marked violations of the liver or kidney function; angle-closure glaucoma; retention of urine outflow (eg, due to prostate disease); simultaneous treatment with MAO inhibitors, and also within 14 days after their cancellation; Acute poisoning with alcohol, sleeping pills or psychotropic drugs.
The efficacy and safety of the use of maprotiline in children and adolescents (under 18 years of age) has not been established. Its use in this age group is not recommended.
Carefully:Violations of urination, persistent constipation, increased intraocular pressure, manic-depressive psychosis, elderly age, cardiovascular diseases, including myocardial infarction, arrhythmia and / or ischemic heart disease, hyperthyroidism, thyroid hormone frequency of side effects from the heart), pregnancy, breast-feeding.
When using maprotiline in therapeutic doses in patients without evidence of convulsive activity in an anamnesis, in rare cases development of seizures was observed. Patients with epilepsy should decrease the threshold of convulsive readiness or have convulsive disorders in an anamnesis with special care. To reduce the risk of seizures, treatment should be started with a small dose; keep the initial dose unchanged for 2 weeks, carry out a subsequent dose increase slowly and gradually, use the minimum effective dose for prolonged maintenance treatment; avoid simultaneous use of drugs that reduce the threshold of convulsive readiness (for example, phenothiazines) or, if such remedies are still used, with great care to change their dose; avoid rapid withdrawal of concomitantly used benzodiazepines.
Caution is required in the appointment of tetracyclic antidepressants to elderly patients and patients with cardiovascular diseases (including myocardial infarction in the anamnesis, arrhythmias and / or IHD) because of the risk of arrhythmia, sinus tachycardia and slowing of intracardiac conduction.These patients, especially with prolonged treatment with antidepressants, show regular monitoring of heart function, including ECG. Patients with orthostatic hypotension should regularly monitor blood pressure.
Pregnancy and lactation:In animal experiments, it had no teratogenic or mutagenic effect; did not cause violations of fertility or damage to the fetus. Safety of use in pregnant women has not yet been established.
The appointment to pregnant women is possible only if the intended benefit to the mother exceeds the potential risk for the fetus .. To prevent the development of the newborn symptoms such as dyspnea, lethargy, irritability, tachycardia, hypotension, convulsions, nervous excitement and hypothermia, maprotiline should be canceled at least 7 weeks before the expected day of childbirth (provided that the patient's condition allows it).
Penetrates into breast milk, the concentration in human milk can be 1.3-1.5 times higher than that in the blood. During lactation it is recommended to stop either taking maprotiline or breastfeeding.
Action category for the fetus by FDA - B.
Dosing and Administration:During treatment the patient should be under medical supervision. The goal of the treatment is to achieve a therapeutic effect by using the lowest effective dose of maprotiline, which is especially important in adolescents and elderly patients.
Inside. The dose is set individually and depends on the degree of depression and sensitivity to the drug. Usually the daily dose is 25-75 mg in 1-3 divided doses. To patients of advanced age - 10 mg 3 times / day; if necessary, the single dose is gradually increased to 25 mg. The maximum daily dose for outpatient treatment is 150 mg, for a stationary dose 225 mg. The initial dose is 25 mg, after 2 weeks the dose can be increased. With a reduction in depressive symptoms, a single dose can be gradually reduced.
Safety and effectiveness of application of maprotiline in children is not established. Dosing regimen should be considered as an approximate recommendation - the initial dose of 10 mg 3 r / day or 25 mg 1 p / day, the maximum daily dose of 75 mg once. Adolescents, if necessary, can be prescribed a drug at the same dose as adults.
Side effects:Undesirable phenomena are usually weakly expressed and transient, do not always correlate with the dose or concentration in the blood plasma,disappear after stopping the use of maprotiline.
From the central and peripheral nervous system: mental status - drowsiness, fatigue, anxiety, sedation in the daytime, feelings of anxiety, tension, mania, aggressiveness, memory impairment, sleep disorders, increased depression, impaired concentration; rarely - delirium, confusion, hallucinations (mainly in elderly patients), in some cases - activation of symptoms of psychosis, depersonalization.
Neurological status - dizziness, headache, small-scale tremor, myoclonus, dysarthria, paresthesia (numbness, tingling sensation), muscle weakness, rarely - convulsions, ataxia, akathisia; in some cases - changes in the EEG, dyskinesia, movement coordination disorders.
Effects due to anticholinergic activity: dry mouth; sometimes constipation, sweating, hot flashes, blurred vision, discomfort, accommodation, urination disorders; in some cases - stomatitis, dental caries.
From the cardiovascular system: sometimes sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant changes in the ECG (eg, changes in the ST interval or T wave) in patients without heart disease; rarely - arrhythmias, increased blood pressure; in some cases - violations of intracardiac conduction (for example, the expansion of the QRS complex, blockade of the bundle of the bundle, changes in the PQ interval), fainting.
From the digestive system: sometimes - nausea, vomiting, discomfort in the abdomen; rarely - diarrhea, increased levels of hepatic enzymes (transaminase, alkaline phosphatase); in some cases - hepatitis with or without jaundice.
From the skin: allergic skin reactions (rash, urticaria), sometimes accompanied by fever; photosensitization; in some cases - itching, purpura, edema (local or general), cutaneous vasculitis, hair loss, alopecia, erythema multiforme, Stevens-Johnson syndrome.
From the endocrine system and metabolism: increased appetite, weight gain, libido and potency disorders; in some cases - gynecomastia, galactorrhea, syndrome of inadequate secretion of antidiuretic hormone.
From the respiratory system: Allergic alveolitis with or without eosinophilia, interstitial lung diseases, bronchospasm.
On the part of the hematopoiesis system: very rarely - leukopenia, agranulocytosis, eosinophilia, thrombocytopenia.
From the sense organs: often - "blurring" of vision, disruption of accommodation, in some cases - noise in the ears, a violation of taste, nasal congestion.
From the excretory and reproductive systems: often - urination disorders, erectile dysfunction, rarely - urinary retention.
Other: very rarely - falls, dental caries.
After a sudden cancellation or rapid dose reduction, nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety, increased depression or depressive mood disorders that are being treated rarely occur.
Overdose:The main complications of overdose are cardiac dysfunction and neurological disorders. In children, a random intake of the drug inside should be regarded as a very serious and fatal accident, regardless of the magnitude of the dose taken.
Symptoms of overdose develop after about 4 hours, peak within 24 hours, the risk to the patient's life persists for 4-6 days.
There may be the following symptoms: from the side of the central nervous system - drowsiness, stupor, coma, ataxia, anxiety, agitation, reflex reflexes, rigidity of muscles, choreoathetoid movements, convulsions; from the cardiovascular system - arterial hypotension, tachycardia, arrhythmias, intracardiac conduction disorders, shock, heart failure; in very rare cases - cardiac arrest. Also possible: respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria.
Treatment: symptomatic (there is no specific antidote). Patients with signs of overdose, especially children, should be hospitalized and under medical supervision for at least 72 hours. It should be as soon as possible to wash the stomach or, if the patient is conscious, cause vomiting. These measures are recommended to be carried out if from the beginning of an overdose it took up to 12 hours and even more, because The anticholinergic effect of the drug may slow its absorption.It is useful to use activated carbon to slow the absorption of maprotiline. Treatment is based on the use of modern intensive care with continuous monitoring of heart functions, gas composition and blood electrolytes. If necessary, use anticonvulsant therapy, mechanical ventilation and other methods of resuscitation. The introduction of physostigmine is not recommended due to an increased risk of bradycardia, asystole, the occurrence of seizures. Hemodialysis and peritoneal dialysis are not effective.
Interaction:Simultaneous use with MAO inhibitors is contraindicated. Maprotiline should not be prescribed for at least 14 days after the abolition of MAO inhibitors because of the possible risk of developing hyperpyrexia, tremor, generalized clonic seizures, fatal delirium. The same rule should be followed when prescribing MAO inhibitors after previous therapy with maprotiline.
Antiarrhythmic drugs (for example, quinidine and propafenone) should not be taken in combination with maprotiline. The anticholinergic effect of these drugs can be synergistic.
Joint use with sulfonylureas for oral or insulin use may potentiate their hypoglycemic effect (regular monitoring of glucose concentration in blood in patients with diabetes mellitus, both at the beginning of therapy with maprotilin, and at its end) is necessary.
Simultaneous use with antipsychotic agents (eg, phenothiazines, risperidone) can lead to an increase in the concentration of maprotiline in the plasma, lower the threshold of convulsive readiness and the development of seizures (dosage correction may be required). Co-administration with a CYP2D6 inhibitor thioridazine can lead to the development of severe arrhythmias.
Evidence of the ability of Maprotiline to inhibit the metabolism of anticoagulants (eg, warfarin, the active S-enantiomer of which is metabolized by CYP2C9), but it is recommended that the level of prothrombin in the plasma be carefully monitored with this combination.
Maprotiline can potentiate the effect of drugs with anticholinergic action (eg, phenothiazines, antiparkinsonics, atropine, biperiden, antihistamines) on the pupil of the eye, the central nervous system, the intestine and the bladder.
Simultaneous use with beta-blockers, which are inhibitors of CYP2D6 (such as propranolol), can lead to an increase in the concentration of maprotiline in the plasma (should monitor its plasma level and, if necessary, adjust the dose). Maprotiline can reduce (or even completely block) the antihypertensive effect of drugs with adrenoblocking properties (such as quinidine, betanidine, reserpine, clonidine and alpha-methyldopa). Patients receiving maprotiline, antihypertensives of other classes should be used (for example, diuretics, vasodilators or beta-blockers that do not undergo significant biotransformation). A sudden reversal of maprotiline can lead to a marked decrease in blood pressure.
Maprotiline can potentiate the cardiovascular effects of sympathomimetic drugs (such as epinephrine, norepinephrine, isoprenaline, ephedrine and phenylephrine), included in the composition of nasal drops or local anesthetics (for example, used in dentistry). It requires monitoring the patient (control of blood pressure, heart rate) and careful selection of the dose of drugs.
Patients receiving maprotiline, should be warned that their reaction to alcohol, barbiturates and other drugs that exert a depressing effect on the central nervous system may be more pronounced.
Simultaneous use with benzodiazepines can lead to increased sedation.
Simultaneous use with SSRIs, which are inhibitors of CYP2D6, such as fluoxetine, fluvoxamine (inhibits also CYP3A4, CYP2C19, CYP2C9 and CYP1A2), paroxetine, sertraline or citalopram, can lead to a significant increase in the concentration of maprotiline in the blood and the development of undesirable phenomena. You may need to adjust the dose of drugs.
Admission in combination with inducers of cytochrome P 450 enzymes (rifampicin, carbamazepine, phenobarbital and phenytoin) may require correction of the dose of maprotiline.
Special instructions:When appointing patients with schizophrenia should take into account the risk of exacerbation of psychotic symptoms. In severe depression, the risk of suicidal actions is always increased, which can persist until the onset of remission, so careful monitoring of patients is necessary at all stages of treatment. All patients taking maprotiline for any of the indications, should be examined for deterioration of the clinical picture, suicidal behavior and other psychopathological symptoms, especially in the initial phase of therapy or when changing the dose of maprotiline. Such patients should consider the possibility of changing the regimen of therapy, up to the withdrawal of maprotiline, especially if such changes are pronounced, appeared suddenly or were not observed in the patient prior to his appointment.
In order to reduce the risk of overdose, the prescription should specify the minimum amount of maprotiline necessary to adhere to an adequate regimen of therapy. Maprotiline can provoke the development of medicinal (delirious) psychoses in predisposed patients and in elderly patients, especially at night. Psychoses usually stop on their own several days after the withdrawal of maprotiline.
It should avoid sudden discontinuation of taking maprotiline or a sharp decrease in its dose. this can lead to the development of the "withdrawal" syndrome.
Periodic monitoring of the number of leukocytes in peripheral blood and alertness to symptoms such as fever and sore throat are necessary.The implementation of these recommendations is especially important in the first months of treatment and with prolonged therapy with maprotiline. During long-term therapy it is recommended to regularly monitor the indicators of liver and kidney function.
Because the maprotiline shows some properties inherent in tricyclic antidepressants, it should be borne in mind that the latter can contribute to the development of paralytic intestinal obstruction, mainly in elderly patients or in patients in hospital. Therefore, in case of constipation, the patient should take appropriate measures.
Due to the anticholinergic effect of Maprotiline, tearing can be reduced and the relative amount of mucus in the tear fluid can be increased, which can damage the corneal epithelium in patients using contact lenses.
Before conducting general or local anesthesia, an anesthesiologist should be warned that the patient is taking maprotiline. The continuation of treatment seems safer to them in comparison with those violations that may arise due to a sudden abolition before the operation.
Impact on the ability to drive vehicles and manage mechanisms
Patients receiving maprotiline, it should be warned that they may develop "clouding" of vision, drowsiness and other violations of the CNS and that in such cases they should abandon the management of the vehicle, other mechanisms, as well as from engaging in other potentially hazardous activities.