MELIPRAMIN

Active material: Imipramine
When ATH: N06AA02
CCF: Antidepressant
ICD-10 codes (testimony): F31, F32, F33, F41.0, F41.2, F42, F98.0
When CSF: 02.02.01
Manufacturer: EGIS PHARMACEUTICALS Plc (Hungary)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Drop Brown color, čečeviceobraznye, with shiny surface, odorless or almost odorless.

Excipients: glycerol 85%, Titanium dioxide (E171), macrogol 35 000, dye (E172) (iron oxide red), gelatin, magnesium stearate, talc, sucrose, lactose monohydrate.

50 PC. – vials of dark glass (1) – packs cardboard.

Pharmacological action

Tricyclic antidepressants, dibenzoazepina derivative. Imipramine inhibits synaptic reverse takeover norarenalina and serotonin, released into the synaptic cleft, and thus facilitates noradrainergicescuu and serotoninergicescuu transfer nerve impulses. Imipramine also oppressing m-holinoretseptora and gistaminove n₂-receptors, therefore has antiholinergicakim and moderate sedative effects.

Antidepressant effect of the drug develops gradually. Optimal therapeutic effect may occur after 2-4 (perhaps, 6-8) weeks of treatment.

Pharmacokinetics

Absorption

After intake of imipramine is well absorbed from the digestive tract. Extensively metabolized in the “first pass” through the liver with the formation of dezipramina. Taking the drug with food does not affect absorption.

Distribution and metabolism

In Кажущийся_d imipramine is 10-20 l / kg.

Imipramine and desipramine have largely been associated with blood plasma proteins (imipramine 60-96%; desipramine 73-92%).

The main metabolite desipramine formed by demethylation has pharmacological activity and. Imipramine and dezipramina concentration in the blood plasma are characterized by considerable individual variability. After the introduction of the drug on 50 mg 3 times / day for 10 days C_ss imipramine in plasma is 33-85 ng / ml, desipramine – 43-109 ng / ml.

Deduction

Impramin return with urine (about 80%) and feces (about 20%) mainly in the form of inactive metabolites. With urine and feces is excreted 5-6% the dose imposed imipramina – in unmodified form or in the form of the active metabolita dezipramina. After a single injection of T_1/2 imipramine is about 19 no (9-28 no) .

Imipramine penetrates through the placental barrier, excreted in breast milk.

Pharmacokinetics in special clinical situations

As a result of decreased metabolism of drug concentration in the blood plasma is generally higher in elderly patients, than young.

After a single injection of the drug may have a significant increase in T_1/2 imipramine in elderly patients and in case of an overdose.

Testimony

-depression and depressive state of different etiology (endogenous, organic, psychogenic), accompanied by motor and ideatornoj block;

-panic disorder;

- Obsessive-compulsive disorders;

— enourez children aged 6 years (in cases, When excluded organic violations).

Dosage regimen

Daily dose and scheme of application set individually according to testimony and the severity of the disease. Adequate therapeutic effect can be achieved through 2-4 of the week (perhaps, through 6-8 weeks) after the start of therapy. Treatment should start with a low dose, You should gradually increase until reaching the minimum effective dose and. Increasing the dose to achieve an effective level of demands extra care at elderly patients, as well as in children and adolescents from 6 to 18 years.

Depression

Ambulatory patients aged 18 to 60 years: the initial dose – by 25 mg 1-3 times/day, followed by a gradual increase to 150- 200 mg/day by the end of the first week of treatment. The maintenance dose is, usually, 50-100 mg / day.

Stationary patients aged 18 to 60 years: in severe cases, starting dose is 75 mg/day, followed by an increase in 25 mg/day to achieve 200 mg / day, in exceptional cases up to 300 mg / day.

In older patients 60 or younger 18 years treatment should start with the smallest possible dose. Initial dose can be gradually increased to 50-75 mg / day. Optimal dose is recommended during 10 days and maintain this dose until the end of the treatment course.

Panic disorder

Treatment should start with the smallest possible dose. Transient increase anxiety in the beginning of therapy can prevent or eliminate use of benzodiazepines, which can then be phased out as the symptoms of anxiety. Dose Melipramin^® You can gradually increase up to 75- 100 mg / day, in exceptional cases – to 200 mg / day. The minimum duration of treatment – 6 months. At the end of the course of treatment recommended the gradual elimination of the drug Melipramin^®.

Enuresis in children aged 6 years

The drug should be appointed only children older than 6 years and only for short-term adjuvant therapy enuresis, When excluded organic lesions. Recommended dose for children aged 6 to 8 years (weight 20-25 kg) – 25 mg / day; aged 9 to 12 years (weight – 20-35 kg) – 25-50 mg / day; the age 12 years (weight 35 kg) – 50-75 mg / day.

Doses, higher, than the recommended, justified only in the absence of a satisfactory response after 1 weeks of taking the drug in the smallest dose. Maximum daily dose for children – 2.5 mg / kg body weight. We recommend that you use the lowest dose of the above range of doses.

Daily dose preferably give for 1 admission after dinner or before bedtime. If incontinence occurs in the early night's sleep, It is recommended that you divide the daily dose on 2 admission (the first portion to give pm, and the second – before bedtime). Duration of treatment is at least 3 months. Supporting dose can be reduced depending on the clinical picture changes. At the end of the treatment course Melipramin^® should be lifted gradually.

Side effect

Some of the following side effects depend on the dose and disappear when lower doses or independently for continuing treatment. Some side effects are difficult to distinguish from the symptoms of depression (eg, fatiguability, sleep disorders, excitation, alarm, dry mouth).

Determination of the frequency of adverse reactions: often (≥ 10%), sometimes (>1% and < 10%), rarely (>0.001%-1%), rarely (< 0.001%).

Anticholinergic Effects: often – dry mouth, Sweating, constipation, ccomodation, reduced visual acuity, hot flushes; sometimes urination; rarely – midriaz, glaucoma, paralytic ileus.

From the central and peripheral nervous system: often-tremor; sometimes – fatigue, zevota, drowsiness, anxiety, reinforced alert, excitation, sleep disorders, nightmares, fluctuations from depression to gipomaniakal′nomu or maniakal′nomu as, delirium, confusion (especially in older patients and sufferers of Parkinson's disease), disorientation and hallucinations, decreased ability to concentrate, paresthesia, headache, dizziness; rarely – seizures, activation of psychotic symptoms, depersonalization; rarely – aggressiveness, EEG changes, myoclonus, weakness, extrapyramidal symptoms, ataxia, speech disorders, hyperpyrexia.

Cardio-vascular system: often – sinusova tachycardia and clinically insignificant ECG changes (zubza t and ST interval) in patients with a healthy heart, orthostatic hypotension; sometimes – Arrhythmia, breach of conduct (extension of the QRS complex, PR interval extension , bundle branch block), heartbeat; rarely – increased blood pressure, cardiac decompensation, causes peripheral blood vessels.

From the digestive system: sometimes – nausea, vomiting, food refusal, increase in liver transaminases; rarely – stomatitis, the defeat of language, gastrointestinal disorders, hepatitis with jaundice or without it.

Allergic reactions: sometimes – rash, hives; very rarely-angioneurotic edema (local or generalized), allergic alveolitis (pneumonitis) with or without Eosinophilia, systemic anaphylactic reactions (incl. hypotension).

Dermatological reactions: rarely – photosensitivity, petechiae, hair loss.

On the part of the endocrine system: rarely – breast enlargement, galactorrhea, violations of ADH secretion syndrome, increase or decrease the level of glucose in the blood, increase in size (edema) testicle.

Metabolism: often – weight gain; very rarely-reducing body weight.

From the hematopoietic system: rarely – eozinofilija, leukopenia, agranulocytosis, and thrombocytopenia Purpura.

Other: noise in ears, hypoproteinemia.

Contraindications

-acute and subacute periods of myocardial infarction;

-serious violations of the intracardiac conduction (bundle-branch block, AV-blokada II degree);

-serious kidney and/or liver;

- Zakrыtougolynaya glaucoma;

— acute alcohol intoxication;

— acute intoxication hypnotics means, opioid analgesics and other medications, have a depressing effect on the central nervous system;

- Pregnancy;

- Lactation (breast-feeding);

- Simultaneous reception of MAO inhibitors and the period up to 14 days after their cancellation;

- Children up to age 6 years;

- Hypersensitivity to the drug;

-hypersensitivity to other tricyclic antidepressants from group dibenzoazepina.

FROM caution should designate product in chronic alcoholism, bipolar disorders (affective insanity), asthma, suppression of bone marrow hematopoiesis, angina, Arrhythmia, blockades of the heart, Heart Failure, after myocardial infarction, When feohromotsytome and nejroblastome (the risk of development gipertoniceski kriza), stroke, violation of GASTROINTESTINAL motor function (the risk of paralytic ileus), thyrotoxicosis, ocular hypertension, in light and moderate human liver and/or kidney disease, benign prostatic hyperplasia (with the delay of urine), Schizophrenia (possible activation of psychosis), epilepsy, and elderly patients.

Pregnancy and lactation

The drug is contraindicated during pregnancy and lactation.

Cautions

Therapeutic effect can occur no sooner than 2-4 weeks after initiation of treatment. As in the case of use of other antidepressants, late onset of therapeutic effect means, that patient to suicide propensity not eliminated immediately and the patient needs careful medical follow-up to significant improvement in his condition. The risk of suicidal actions at the beginning of treatment can be shown the combination of drugs from benzodiazepines or Neuroleptics.

Minimum duration of Administration dose – 6 months. Melipramin^® should be lifted gradually, because sudden cessation of its reception can cause withdrawal symptoms (nausea, Headache, general malaise, anxiety, alarm, sleep disorders, abnormal heart rhythm, extrapyramidal symptoms), especially in children. In patients with bipolar depression, imipramine can provoke compulsive or hypomanic State. The drug should not be taken during manic episodes.

Like other tricyclic antidepressants, Melipramin^® reduces threshold sudorojna preparedness. So epilepsy patients, as well as having the disease manifestations of spasmophilia and epilepsy, require careful medical follow-up and adequate anticonvulsant therapy .

Welcome Melipramina^® increases the risk of electroshock therapy, Therefore the drug is contraindicated during electroconvulsive therapy.

As a paradoxical reaction, in patients with panic disorder during the first days of reception tricyclic antidepressants may increase anxiety. Increased anxiety usually goes away on its own within 1-2 weeks, However, this manifestation can optionally remove appointment derived benzodiazepine.

In patients with schizophrenia in the initial period of treatment of tricyclic antidepressants may increase anxiety, anxiety and arousal.

Receiving imipramine should be suspended if you experience severe neurological or mental reactions.

Due to the effect of Melipramina application antiholinergicski^® requires careful medical supervision of patients with glaucoma, Prostate hypertrophy and heavy constipation, tk. the drug can enhance existing symptoms. Patients, using contact lenses, reduced production of tears and mucus ottorgaemoj accumulation can damage the corneal epithelium.

In CHD, violation of the liver and kidneys, as well as diabetes imipramine should be used with caution. Treatment of patients with tumors of the adrenal gland (feohromotsytoma, or nejroblastomoj) requires special care because. imipramine can provoke a hypertensive crisis. Treatment of patients with hyperthyroidism or thyroid medications using requires careful medical supervision because of the increased risk of side effects on the heart in these patients.

Due to a possible increased risk of arrhythmias and arterial hypotension during general anesthesia before surgery should notify anesthesiologist, that the patient takes imipramine.

With long-term use of imipramine noted higher incidence of caries. Regular consultations were therefore needed a dentist.

Side effects may be more pronounced in elderly and young patients. Therefore, especially at the beginning of treatment, they should prescribe lower doses. Older patients are more susceptible to antiholinergicakim, Neurological, psychiatric and cardiovascular effects. Such patients can be lowered metabolism and excretion of drugs, that increases the risk of increasing their concentrations in blood plasma.

Imipramine calls fotosensibilizaciû, Therefore, during the course of treatment should avoid intense sun exposure.

Prone and/or elderly patients imipramine can cause malignant (deliriosny) psychotic syndrome, that goes for several days after discontinuation of the drug.

Patients are prohibited from drinking alcohol during treatment imipraminom.

Each Tablet, coated liner, It contains 116 Lactose mg. Therefore, the drug is not recommended to appoint patients with rare hereditary disorders of tolerance to galaktoze, hereditary deficiency of Sami or lactose glucose/Galactose malabsorption syndrome.

Tablet contains sucrose, Therefore, the drug is not recommended to give patients with rare hereditary fructose intolerance phenomena, glucose/Galactose malabsorption, as well as the lack of sucrase/izomal′tazy.

Prior to the start of treatment and regularly during treatment should monitor ad (especially in patients with labile blood circulation or arterial gipotenziei); liver function (especially if you have liver disease); cellular blood composition (immediately in case of fever or laryngitis, that may be signs of leukopenia and agranulocytosis, as well as at the beginning of treatment and regularly throughout the); ECG (in older patients and in cardiovascular diseases).

Effects on ability to drive vehicles and management mechanisms

At the beginning of treatment Melipraminom^® patient dolženotkazat′sâ from driving vehicles and from activities potentially hazardous activities, require high concentration and speed of psychomotor reactions. Subsequently, the degree of restriction is determined for each patient individually.

Overdose

Symptoms: System Vertigo, drowsiness, insomnia, hallucinations, confusion, stupor, coma, ataxia, anxiety, excitation, hyperreflexia, muscle stiffness, atetoidnye and horeoformnye movement, convulsions, gipotenziya, tachycardia, arrhythmia, violation of the institution, heart failure; In very rare cases – cardiac arrest, respiratory depression, cyanosis, shock, vomiting, fever, Sweating, midriaz, oliguria or anuria.

Children, compared with older, more susceptible to acute overdose, which should be considered dangerous and potentially lethal for them.

Treatment: imipramine overdose is suspected the patient should be hospitalized and left under close supervision for a period of not less than 72 no. No specific antidote, so shows a symptomatic and supportive therapy. Because malignant effect of the drug may delay the evacuation of stomach contents (on 12 h or more), should, as soon as possible, rinse the stomach or cause vomiting, If the patient is conscious, and activated carbon.

Requires constant monitoring of the cardiovascular system, gases and electrolytes blood. Symptomatic treatment, You can assign anticonvulsant therapy (eg, diazepam, phenytoin, phenobarbital, inhalation anesthetic + muscle relaxant), artificial respiration, temporary pacemaker, Enter plazmozameniteli, dopamine or dobutamine; in exceptional cases there may be a need for intensive care.

Hemodialysis and peritoneal dialysis are ineffective due to the low concentration of imipramine in plasma.

Since introduction fizostigmina calls expressed by bradycardia, asistoliû and epileptic seizures, It is not recommended as a treatment for an overdose Melipramina^®.

Drug Interactions

With a combination of Melipramina^® with MAO inhibitors manifested synergies action, as a result of which their peripheral noradrenergic effects overly amplified, While this may develop gipertoniceski kriza, giperpireksii, mioklonii, excitation, seizures, deliria, Coma. The combination of drugs contraindicated. Use of imipramine should begin no earlier than 3 weeks after the MAO inhibitors (with the exception of MAO inhibitor moclobemide reversible, After enough compliance interval 24 no). Interval 3 weeks between meals drugs should also comply with when transferring a patient with imipramine on MAO inhibitor. The appointment of a new medication or MAO inhibitor drug Melipramin^® you start with a low dose, which you can then gradually increase with careful observation of the clinical effects.

When combined with Melipraminom^® izofermenta inhibitors of CYP2D6 metabolism slowed imipramina, that could lead to an increase in its concentration in the blood plasma. To inhibitors of this type are also medicinal substances, which are not substrates CYP2D (cimetidine or methylphenidate), but the metaboliziruûŝiesâ enzyme, eg, many other antidepressants, fenotiazinы, class I antiarrhythmics (C) (propafenone, flekainid). All antidepressants a class of selective serotonin reuptake inhibitors, to varying degrees, are inhibitors of CYP2D6. Therefore, caution should be used in combination with these drugs imipramine, as well as when transferring a patient with antidepressant class of selective serotonin reuptake inhibitors on imipramine (and vice versa), especially in the case of the use of fluoxetine because of its long T_1/2. Tricyclic antidepressants can increase the concentration of antipsychotics in plasma due to competition at the level of the liver enzymes.

In some cases, women, using oral contraceptives or oestrogen hormone drugs concurrently with tricyclic antidepressants, reduction of antidepressive action and the development of toxic effects of antidepressants. Therefore there is a need for caution in combination these tools, dose of either drug should be reduced by the emergence of toxic effects.

Hepatic enzyme inducers (incl. ethanol, nicotine, meprobamate, barbiturates, antiepileptics) increase metabolism slowed imipramina, reduce its concentration in the plasma and reduce antidepressant effect.

Anticholinergic drugs (eg, fenotiazinы, antiparkinsonian agents, antihistamines, atropyn, biperidin) reinforce the anticholinergic side effects (eg, paralytic ileus) When coupled with imipraminom. The combination of the patient's condition requires careful monitoring and careful selection of doses.

Imipramine in combination with drugs, have a depressing effect on the central nervous system (eg, opioid analgesics, ʙenzodiazepinami, barbiturates and general anesthesia), with ethanol significantly amplifies the main and side effects of these drugs.

Antipsychotic drugs can increase concentrations of tricyclic antidepressants in plasma and their main and side effects. In these combinations may require lower doses of the drug. Together with the application tioridazinom may develop severe arrhythmia.

Thyroid hormone drugs may increase antidepressant effect imipramina and its adverse effects on the heart. Therefore, when the combination of special care is required.

Adrenergic neuron blockers: imipramine may reduce the antihypertensive effects of adrenergic neuron blocker used together (guanethidine, ʙetanidina, reserpine, clonidine and alpha-methyldopa). Therefore, patients, requiring concomitant antihypertensive therapy, You should assign antihypertensives of other classes (eg, diuretics, vasodilators or beta-adrenoblokatora).

Imipramine strengthens cardiovascular effects simpatomimetikov (mainly epinephrine, norepinephrine, isoprenaline, ephedrine, phenylephrine).

Imipramine weakens protivosudorozhny effect fenitoina.

In order to avoid violations of conduction and arrhythmias tricyclic antidepressants should not be used in combination with antiarrhythmic drugs hinidinopodobnymi.

Tricyclic antidepressants inhibit the metabolism of oral anticoagulants and extend their T_1/2. This increases the risk of bleeding, Therefore, when such a combination recommended careful metabolic control and monitoring of prothrombin plasma level.

In appointing Melipramina^® patients, receiving hypoglycemic drugs, should be considered, that imipramine with long-term use may change the content of glucose in the blood. Therefore, we recommend that you control the content of glucose in the blood at the beginning and end of treatment, and also if you change the dosage.

When combined with alpha-adrainostimulatorami for intranasal or for use in ophthalmology (with significant systemic vsasavanii) can increase their sossoudossouerveshchee effect.

In the face of treatment Melipraminom^® m-holinoblokatora and antipsychotic medications (neuroleptics) increase the risk of developing giperpirexii (especially in hot weather).

The joint appointment Melipramina^® with other gematotoksičnymi drugs may increase gematotoksicnosti.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

List B. The drug should be kept out of the reach of children at a temperature from 15° to 25° c. Shelf life – 3 year.