Universal reference book for medicines
Product name: Lyudomil ® (LUDIOMIL ® )

Active agent: maprotiline

Type: Antidepressant

Manufacturer: NOVARTIS PHARMA (Switzerland) produced by NOVARTIS Saglik Gida ve Tarim Urunlery Sanayi ve Ticaret (Turkey)
Composition, form of production and packaging
The tablets covered with a film cover of
light yellow color, round, slightly biconcave, with bevelled edges, on one side an engraving "CG", on another - "CO";
on the cross-section - the core of white color.
1 tab.

Maprotiline hydrochloride 10 mg

Excipients: lactose monohydrate 45 mg, corn pregelatinized corn starch 27 mg, calcium phosphate 10 mg, silicon dioxide colloidal anhydrous 5 mg, talc 2 mg, magnesium stearate 0.5 mg, stearic acid 0.5 mg.

Composition of the membrane: hypromellose 2.12 mg, talc 1.87 mg, titanium dioxide 0.39 mg, polysorbate 80 0.1 mg, iron oxide dye yellow 0.02 mg.

10 pieces.
- blisters (5) - packs of cardboard.
The tablets covered with a cover 1 tab.

maprotiline hydrochloride 25 mg

Excipients: silicon colloidal anhydrous, calcium phosphate, lactose monohydrate, magnesium stearate, stearic acid, hydroxypropyl cellulose, iron oxide yellow, iron oxide red, polysorbate 80, titanium oxide, talc, wheat starch.

10 pieces.
- blisters (3) - packs of cardboard.
The tablets covered with a cover 1 tab.

maprotiline hydrochloride 50 mg

Excipients: silicon colloidal anhydrous, calcium phosphate, lactose monohydrate, magnesium stearate, stearic acid, hydroxypropyl cellulose, iron oxide yellow, iron oxide red, polysorbate 80, titanium oxide, talc, wheat starch.

10 pieces.
- blisters (3) - packs of cardboard.
Concentrate for the preparation of solution for infusions is transparent, colorless.

1 ml of 1 amp.

Maprotiline methanesulfonate 5 mg 25 mg

Excipients: mannitol, methanesulfonic acid, water d / u.

5 ml - ampoules (10) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the print edition of 2007.

PHARMACHOLOGIC EFFECT

Tetracyclic antidepressant, but has a significant number of properties inherent in tricyclic antidepressants.
The drug has a well-balanced spectrum of action, improves mood, eliminates anxiety, agitation and psychomotor retardation. With masked depression, the drug can have a beneficial effect on physical complaints.
Maprotiline differs from tricyclic antidepressants in chemical structure and pharmacological properties.
Has a pronounced and selective inhibitory effect on norepinephrine reuptake by presynaptic neurons of the cerebral cortex, but has almost no inhibitory effect on re-uptake of serotonin. Maprotiline has a weak or moderately expressed affinity for the central? 1- adrenoreceptors; has a moderate anticholinergic effect and an inhibitory effect on histamine H 1 -receptors.
It is believed that changes in the functional state of the neuroendocrine system (growth hormone, melatonin, endorphinergic system) and / or the system of neurotransmitters (norepinephrine, serotonin, GABA) are also considered in the mechanism of action of the drug with its long-term use.

PHARMACOKINETICS

Suction

After a single tablet-coated tablet, Maprotiline hydrochloride is slowly but completely absorbed.
The average absolute bioavailability is 66-70%. After a single intake of the drug in a dose of 50 mg C max in the blood is 48-150 nmol / l (13-47 ng / ml) and is reached within 8 hours.
1 hour after IV bolus Ludomil in a dose of 50 mg, the concentration of the active substance in the blood is 54-182 nmol / l (17-57 ng / ml).

With repeated use of Ljudomil inside or / in the dose of 150 mg / day C ss, maprotiline in the blood is reached in the second week of treatment and is 320-1270 nmol / l (100-400 ng / ml), regardless of whether the daily dose once or in 3 divided doses.
The values ​​of C ss are linear depending on the dose, although in some patients they vary considerably.
Distribution

The distribution coefficient of maprotiline between whole blood and plasma is 1.7.
The average value of the apparent V d is 23-27 l / kg. The binding of maprotiline to plasma proteins is 88-90%, regardless of the age of the patient and the nature of the disease. The concentration of maprotiline in the cerebrospinal fluid is 2-13% of the serum concentration.
Metabolism

Maprotiline hydrochloride is largely metabolized, only 2-4% of the accepted dose of the drug is excreted in the urine unchanged.

The main metabolite is the pharmacologically active desmethyl derivative.
Several hydroxylated and / or methoxylated metabolites are of little importance; they are excreted in the urine in the form of conjugates.
Excretion

T 1/2 of maprotiline averages 43-45 hours. The total clearance varies from 510 to 570 ml / min.
After taking a single dose of the drug, its elimination occurs within 21 days: 2/3 of the dose in the urine (unchanged or in the form of conjugates) and about 1/3 - with feces.
Pharmacokinetics in special clinical cases

When using the drug in the same dose in elderly patients (over 60 years of age), C ss of active substance in the blood is higher than in young patients;
apparent T 1/2 - longer; the daily dose of Ludomila therefore should be reduced by half. In case of impaired renal function (creatinine clearance values ​​of 24-37 ml / min), T 1/2 ofmaprotiline 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

- endogenous and involuntary depression;

- psychogenic, reactive and neurotic depression, depletion depression;

- somatogenic depression;

- masked depression;

- menopausal (menopausal) depression;

- other depressive mood disorders characterized by anxiety, dysphoria or irritability;
a state of apathy (especially in the elderly); psychosomatic or somatic complaints in patients with depression and / or with anxiety.
DOSING MODE

During treatment the patient should be under medical supervision.

The dosage regimen should be selected individually, changing it taking into account the patient's condition and its reaction to the drug.
For example, you can increase the evening dose, while reducing the daily dose, or you can assign the entire daily dose in the afternoon in 1 reception.
After a significant reduction in the severity of the symptoms is noted, an attempt may be made to reduce the dose of the drug.
However, if the deterioration of the patient's condition is noted again, the dose of the drug should be immediately increased to the initial level.
The goal of the treatment is to achieve a therapeutic effect by using the lowest effective dose of the drug.
This is especially important in adolescents and in elderly patients, which, in contrast to patients of intermediate age groups, are usually characterized by instability of the autonomic nervous system and a more pronounced reaction to the drug.
Tablets Ludomila should be swallowed whole and washed down with a sufficient amount of liquid.

Do not exceed the daily dose of 150 mg.

With moderate and moderate depression (especially in outpatients), Lyudomil is used at a dose of 25 mg 1-3 times / day or in a dose of 25-75 mg 1 time / day, depending on the severity of the symptoms and the patient's response to treatment.

With severe depression (especially in hospitalized patients), Lyudomil is used at a dose of 25 mg 3 times / day or at a dose of 75 mg 1 time / day.
If necessary, the daily dose of Ludomil can be gradually increased to a maximum value of 150 mg; this dose can be used in 1 or more receptions depending on the tolerability and the effect of the treatment.
The daily dose recommended for intravenous infusion is 25-100 mg.
For the preparation of the infusion solution, the contents of 1-2 ampoules (25-50 mg) are diluted with 250 ml of isotonic sodium chloride or glucose solution. Duration of infusion is 1.5-2 hours. In cases where a higher dose is required - 75-150 mg (3-6 ampoules), the volume of the solvent should be 500 ml, and the infusion time - 2-3 hours. Once a clear positive the dynamics of symptoms (usually within 1-2 weeks), it is necessary to switch to the appointment of the drug inside.
With other depressive mood disorders for children and adolescents, the recommended initial dose is 10 mg 3 times / day or 25 mg 1 time / day.
If necessary, the daily dose of Ludomil can be gradually, each time a small amount, increased to 25 mg 3 times / day or up to 75 mg 1 time / day (depending on the tolerance and the patient's response to treatment).
Since the clinical experience of using Ludomil in children is limited, the dosing regimen should be considered as an approximate recommendation.
Adolescents, if necessary, can be prescribed a drug at the same dose as adults.
Older patients generally recommend the use of smaller doses of Ludomila.
The initial dose is 10 mg 3 times / day or 25 mg 1 time / day. If necessary, the daily dose of the drug can be gradually, each time a small amount, increased to 75 mg (25 mg 3 times / day or 75 mg 1 time / day), depending on the tolerance and effect of treatment.
SIDE EFFECT

Below are the side effects that develop both with the use of Lyudomil, and tricyclic antidepressants in general.

From the side of the central nervous system and peripheral nervous system.
Mental status: often - drowsiness, a sense of fatigue; sometimes - increased appetite, anxiety, sedation in the daytime, feelings of anxiety, feelings of tension, mania, hypomaniacal state, aggressiveness, memory disorders, sleep disorders, insomnia, nightmares, increased depression, impaired concentration; rarely - delirium, confusion, hallucinations (mainly in elderly patients), nervousness; in some cases - the activation of symptoms of psychosis, depersonalization. Neurological status: often - mild dizziness, headache, small-scale tremor, myoclonus; sometimes - dizziness, dysarthria, paresthesia (numbness, tingling sensation), muscle weakness; rarely - cramps, ataxia, akathisia; in some cases - changes in the electroencephalogram, dyskinesia, movement coordination disorders.
Effects due to anticholinergic activity: often - 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 (for example, changes in the ST interval or the T wave) in patients without deviations from the heart;
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 side of 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.
Dermatological reactions: sometimes - 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.
From the endocrine system and metabolism: sometimes - weight gain, libido and potency disorders;
in some cases - an increase in the mammary glands, galactorrhea, the syndrome of inadequate secretion of ADH.
From the respiratory system: in some cases - allergic alveolitis with or without eosinophilia, bronchospasm.

On the part of the hematopoiesis system: in some cases - leukopenia, agranulocytosis, eosinophilia, thrombocytopenia.

From the senses: in some cases - noise in the ears, a violation of taste, nasal congestion.

Other: The following symptoms sometimes occur after a sudden withdrawal or a rapid decrease in the dose: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety, increased depression or depressive mood disorders that have been treated.
The observed side effects are usually mild and transitory, disappear after stopping Ludomil intake or reducing its dose. They are not always clearly related to the level of the drug in the blood plasma or its dose. It is often difficult to distinguish certain side effects from complaints observed with depression, such as general weakness, sleep disorders, anxiety, anxiety, constipation or dry mouth.
Ludomil must be withdrawn if serious side effects develop, for example, from the nervous system.

The elderly are particularly sensitive to the anticholinergic effects of Ludomil, as well as to its effects on the nervous, cardiovascular and mental systems.
In elderly patients, the ability to metabolize and withdraw medications can be reduced, thereby increasing the risk of increasing blood levels of the drug, even when used in therapeutic doses.
CONTRAINDICATIONS

- diseases accompanied by convulsive syndrome or reduced threshold of convulsive readiness (for example, damage to the brain of any etiology, alcoholism);

- an angle-closure glaucoma;

- retention of urine outflow (eg, due to prostate disease);

- acute stage of myocardial infarction and intracardiac conduction disturbances;

- pronounced violations of the liver function;

- severe renal dysfunction;

- simultaneous treatment with MAO inhibitors;

- Acute poisoning with alcohol, sleeping pills or psychotropic drugs;

- hypersensitivity to the components of the drug;

- Cross-over hypersensitivity to tricyclic antidepressants.

PREGNANCY AND LACTATION

In animal experiments, it has been shown that Lyudomil does not have a teratogenic or mutagenic effect;
does not cause violations of fertility or damage to the fetus.However, the safety of the drug in humans in pregnancy is not yet established. There are isolated reports of the possible relationship between side effects on the human fetus and the reception of Ludomil. Ludomil should not be administered during pregnancy, except when the expected therapeutic effect on the mother clearly exceeds the risk to the fetus.
In order to prevent the development of symptoms such as shortness of breath, lethargy, irritability, tachycardia, hypotension, convulsions, nervous excitement and hypothermia in the newborn, Lydiomil should be discontinued at least 7 weeks before the expected day of labor (provided that the patient's condition allows it ).

Maprotiline penetrates into breast milk.
After taking Lyudomil in a daily dose of 150 mg for 5 days, the concentration of maprotiline in breast milk exceeds the concentration in the plasma by 1.3-1.5 times. Although published reports indicate that Ludomil does not lead to the development of side effects in newborns, during lactation should stop either taking the drug or breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

The drug is contraindicated in severe impairment of kidney function.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

The drug is contraindicated in severe violations of liver function.

APPLICATION FOR CHILDREN

Since the clinical experience of using Ludomil in children is limited, the dosing regimen should be considered as an approximate recommendation.
Adolescents, if necessary, can be prescribed a drug at the same dose as adults.
APPLICATION IN ELDERLY PATIENTS

Older patients generally recommend the use of smaller doses of Ludomila.
The initial dose is 10 mg 3 times / day or 25 mg 1 time / day. If necessary, the daily dose of the drug can be gradually, each time a small amount, increased to 75 mg (25 mg 3 times / day or 75 mg 1 time / day), depending on the tolerance and effect of treatment.
SPECIAL INSTRUCTIONS

Some rare reports on the development of seizures are known when using Lyudomil in therapeutic doses in patients who had no history of convulsions.
Sometimes in these cases there were factors (for example, simultaneous use of drugs that reduce the threshold of convulsive alertness), the effect of which could lead to the development of seizures. The risk of seizures may increase with concomitant use of phenothiazine derivatives, with the sudden withdrawal of concomitantly used doses of phosphodiester, or in the case of a rapid increase in the dose of Ludomila over the usually recommended. Although there was no clear causal relationship, it is nevertheless obvious that the risk of seizures can be reduced if the following recommendations are followed: start Ludomil treatment with a small dose; keep the initial dose unchanged for 2 weeks and then increase the dose slowly, in small "steps"; for long-term maintenance treatment use the lowest effective dose; avoid simultaneous use of drugs that reduce the threshold of convulsive readiness (for example, phenothiazines) or, if such remedies still apply, change their dose with great caution; avoid rapid withdrawal of concomitantly used benzodiazepines.
There are reports that tricyclic and tetracyclic antidepressants can cause arrhythmias, sinus tachycardia, and slowing of intracardiac conduction.
In this connection, care is required when assigning these drugs in elderly patients and in patients with cardiovascular disease, including myocardial infarction, arrhythmias and / or ischemic heart disease. These patients, especially during long-term treatment with antidepressants, shows regular monitoring of cardiac function, including ECG. Patients prone to orthostatic hypotension, BP should be measured regularly.
In patients with schizophrenia treated with tricyclic antidepressants, are sometimes observed exacerbation of psychotic symptoms; the risk of such complications should be taken into account when assigning Lyudiomila. Patients with cyclic affective disorders treated with tricyclic antidepressants during the depressive phase of the illness had taken place hypomanic or manic episodes. In such cases, it may be necessary to reduce the dose Lyudiomila, until canceled, and the appointment of an antipsychotic agent.
In severe depression is always an increased risk of suicidal acts, which may persist until remission. Posts known that in rare cases, the use of antidepressants can lead to increased suicidal tendencies. In one study in patients receiving prophylactic treatment Lyudiomilom about unipolar depression, it was identified strengthening the suicidal type behavior. As shown Lyudiomil comparable with other antidepressants such parameter as speed of death, occurs due to overdose. Therefore, at all stages of treatment requires careful monitoring of patients.
Tricyclic antidepressants in predisposed patients, and elderly patients can provoke the development of medicines (delirious) psychoses, especially at night; These effects usually disappear on their own within a few days after discontinuation of the drug.
To avoid sudden or abrupt cancellation Lyudiomila dose reduction, since it can lead to side effects.
Electroconvulsive therapy Lyudiomila application period should be implemented only with careful patient monitoring.
Although known only isolated reports of changes in leukocyte count in the peripheral blood during treatment Lyudiomilom nevertheless need periodic monitoring of this indicator and alert to symptoms such as fever and sore throat. Implementation of these recommendations is especially important 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 or urinary retention, especially in prostatic hypertrophy.
Tricyclic antidepressants may contribute to the development of paralytic ileus, mainly in elderly patients or patients in a hospital. Therefore, in case of constipation in patients required to take adequate measures.
Lyudiomil should be used with caution in patients with hyperthyroidism, as well as in those taking drugs thyroid hormones (may increase the frequency of side effects from the heart).
Prolonged treatment with antidepressants reported quickening of dental caries. In this regard, long-term therapy is recommended regular inspection of dental patient.
Due to the anticholinergic actions of tricyclic antidepressants may reduce lacrimation and relative increase in the amount of mucus in the tear fluid, which can cause damage to the corneal epithelium in patients using contact lenses.
Prior to the general or local anesthesia, the anesthesiologist should be warned that the patient takes Lyudiomil. Continued treatment Lyudiomilom is more secure than those disorders which may arise due to a sudden discontinuation of therapy before surgery.
Impact on the ability to drive vehicles and manage mechanisms

Patients taking Lyudiomil should be warned that they may develop blurred vision, drowsiness and other CNS side effects, and that in such cases they should abandon a motor vehicle control, other mechanisms, as well as training in other potentially hazardous activities. Patients should also be warned about the fact that the use of alcohol or other means may be accompanied by strengthening of these side effects.
OVERDOSE

In case of overdose Lyudiomila develop the same symptoms and complaints, in the case of an overdose of tricyclic antidepressants. The main complications are violations on the part of the heart and neurological disorders. In children, accidental taking the drug inside should be regarded as very serious and threatening to fatal accidents, regardless of the size of the dose.
Complaints usually appear within 4 hours after administration Lyudiomila and reach a maximum after 24 hours of expression. Due to slow absorption (anticholinergic drug action), an extended half-life and gepatoenteralnoy recirculation maprotiline risk of life of the patient is maintained for 4-6 days.
May experience the following symptoms. CNS: drowsiness, stupor, coma, ataxia, restlessness, agitation, increased reflexes, muscle rigidity, horeoatetoidnye movements, convulsions. With the cardiovascular system: hypotension, tachycardia, arrhythmia, disorders of intracardiac conduction, shock, heart failure; in very rare cases - cardiac arrest. Furthermore, there may be respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria.
Treatment: the specific antidote does not exist, the treatment is mostly symptomatic and supportive. Patients who show signs of Lyudiomila overdose, especially children, should be hospitalized and kept under careful medical supervision for at least 72 hours.
It should be possible to carry out gastric lavage faster or if the patient is conscious, induce vomiting. If the patient is unconscious, before gastric lavage should be performed tracheal intubation; vomiting in this case can not cause. These measures are recommended, if passed by the beginning of overdose of up to 12 hours or even more, because anticholinergic effect of the drug can slow its absorption. To slow the absorption of maprotiline beneficial use of activated carbon.
Treatment is based on the use of modern methods of intensive care with continuous monitoring of cardiac function, gas composition, and blood electrolytes. If necessary apply anticonvulsant therapy, the ventilator and other resuscitation methods. Since then, as a message appeared that physostigmine may cause severe bradycardia, asystole and seizures, its use is not recommended Lyudiomila cases of overdose. Hemodialysis and peritoneal dialysis are not effective, because maprotiline plasma concentrations are low.
DRUG INTERACTION

Lyudiomil not be administered for at least 14 days after the MAO inhibitors (expressed risk of drug interactions, leading to the development of hyperpyrexia, tremor, generalized clonic convulsions, delirium; lethal possible). Follow the same rule in a case when MAO inhibitors are assigned after previous therapy Lyudiomilom.
Lyudiomil can reduce (or even completely block) antihypertensive effects of drugs affecting the transmission adrenergic stimulation such as guanethidine, betanidin, reserpine, clonidine and alfametildopa. Therefore, in cases where simultaneously with reception Lyudiomila requires treatment of hypertension, it is necessary to apply another type of drugs (e.g., diuretics, vasodilators, beta blockers or without undergoing severe biotransformation). In addition, it should be borne in mind that the sudden cancellation Lyudiomila may cause severe hypotension.
Lyudiomil can potentiate the cardiovascular effects of sympathomimetic agents such as adrenaline (epinephrine), noradrenaline (norepinephrine), isoprenaline, ephedrine and phenylephrine, including and in cases where they are part of nose drops, or local anesthetics (such as used in dentistry). In these situations it requires careful monitoring of patients (control of blood pressure, heart rate), and careful selection of drug dose.
Lyudiomil may potentiate the action of drugs having anticholinergic properties (e.g., phenothiazines, antiparkinsonian drugs, atropine, biperiden, antihistamines) on the pupil of the eye, central nervous system, the intestines and the bladder.
Should not be administered in combination with Lyudiomil antiarrhythmic drugs such as quinidine. Anticholinergic effects of quinidine may act synergistically Lyudiomila and its severity depends on the doses of these drugs.
Simultaneous application Lyudiomila with major tranquilizers may lead to increased plasma concentrations maprotiline, lower seizure threshold and to the development of seizures. Combination preparation with thioridazine can lead to serious arrhythmias.
Medicaments activating microsomal liver enzymes (barbiturates, carbamazepine and oral contraceptives), maprotiline may enhance metabolism and, accordingly, reduce the effectiveness Lyudiomila. If necessary to revise the dose of these drugs. In addition, there may be a increase in the concentration of phenytoin or carbamazepine in serum and, accordingly, increased their inherent side effects. In the case of such drug combinations may be required to review drug doses.
Methylphenidate may increase concentrations of tricyclic antidepressants in plasma and enhance their actions.
If Lyudiomil used in conjunction with beta-blockers, characterized significant biotransformation (e.g., propranolol), maprotiline increase can be observed plasma concentration. When using this combination of drugs should regularly determine the plasma level of maprotiline and if necessary appropriately alter the dose Lyudiomila.
Lyudiomil may enhance the anticoagulant effect of coumarin derivatives by inhibiting their metabolism in the liver. In such cases, you should carefully monitor the amount of prothrombin time, and if necessary - to reduce the dose of anticoagulant.
Combined use Lyudiomila with sulfonylureas or insulin can potentiate their hypoglycemic action. In patients with diabetes requires regular monitoring of blood glucose levels in early Lyudiomilom therapy and after its completion.
The simultaneous use of fluoxetine or fluvoxamine can lead to a significant increase in blood levels of maprotiline and corresponding to development of side effects. Because of the long half-life of fluoxetine and fluvoxamine these side effects may persist for a long time.
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.
Simultaneous application Lyudiomila and benzodiazepines may result in increased sedation.
It is shown that cimetidine inhibits the metabolism of some tricyclic antidepressants, which leads to an increase in their concentration in the blood and increased frequency of adverse effects (dry mouth, blurred vision). Although a similar interaction with cimetidine Lyudiomilom not been reported, it is possible that in case of their simultaneous application may require dose reduction Lyudiomila.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
The drug should not be used after the expiration date.
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