Melipramine - instructions for use, dose, side effects, contraindications

tablet shell: hypromellose 2.61 mg, magnesium stearate 0.24 mg, cosmetic reddish-brown dye (is a mixture: iron dye oxide red, iron oxide yellow oxide, iron oxide black oxide) 0.8 mg, dimethicone E-1049 39% 0 , 35 mg.

Description:

Red-brown round biconvex tablets coated with a film coating, with a matte surface, without or almost no odor.

Pharmacotherapeutic group:antidepressant

ATX: & nbsp

N.06.A.A.02 Imipramine

Pharmacodynamics:

Imipramine, a derivative of dibenzoazepine, is a tricyclic antidepressant. Imipramine inhibits the synaptic reuptake of norepinephrine and serotonin secreted by neuron stimulation, thereby facilitating noradrenergic and serotonergic impulse transmission. Imipramine It also blocks m-cholino- and H₁- histamine receptors, thus providing m-holin-blocking and moderate sedation.

The effects of the antidepressant develop gradually: the optimal therapeutic effect is achieved after 2-4 (possibly 6-8) weeks of treatment.

Pharmacokinetics:

Ingestion imipramine well absorbed from the gastrointestinal tract. Joint intake of food does not affect the absorption of imipramine.

The compound undergoes intensive metabolism in the "first pass" through the liver: its main pharmacologically active metabolite, desipramine (dimethyl-imipramine) is formed by demethylation. The concentration of imipramine and desipramine in the blood plasma is characterized by high individual variability. After 10 days of taking imipramine in a dose of 50 mg 3 times a day, the concentration in the plasma of imipramine in the equilibrium state is from 33 to 85 ng / ml, the concentration of desipramine is from 43 to 109 ng / ml. Due to reduced metabolism, plasma concentrations are usually higher in older patients compared to younger patients. The apparent volume of distribution of imipramine is 10-20 l / kg.

Both active compounds significantly bind to plasma proteins (imipramine by 60-96%, desipramine - by 73-92%).

Imipramine is excreted by the kidneys (about 80%) and feces (about 20%), mainly in the form of inactive metabolites. Excretion in the urine and feces of unchanged imipramine and its active metabolite desipramine is up to 5-6% of the dose. After taking one dose, the half-life of imipramine is about 19 hours and can vary from 9 to 28 hours, significantly increasing in the elderly and in case of an overdose.

Imipramine passes through the placental barrier and is excreted in breast milk.

Indications:

All forms of depression (with and without anxiety): major depression, depressive phase of bipolar disorder, atypical depression, depressive states.

Panic disorders.

Night incontinence in children (over 6 years of age, for short-term adjuvant therapy with the possibility of eliminating the organic cause).

Contraindications:

Hypersensitivity to any component of the drug or other tricyclic antidepressants from the dibenzoazepine group.

The use of MAO inhibitors (see.section "Interaction with other medicinal products").

Recently suffered myocardial infarction. Violation of intracardiac conduction. Violation of the heart rate.

Manic episodes.

Severe impairment of kidney and / or liver function.

Retention of urine.

Closed-angle glaucoma.

Age to 6 years in the treatment of bedwetting and up to 18 years in the treatment of depression and panic disorder (lack of sufficient clinical experience).

Pregnancy and lactation.

Galactose intolerance, congenital lactase insufficiency or malabsorption syndrome of glucose and galactose (tablets contain lactose monohydrate).

Pregnancy and lactation:

Since in certain cases, the possibility of the relationship between the use of tricyclic antidepressants and fetal development disorders has been established, the use of the drug in pregnancy is contraindicated.

Imipramine excreted in breast milk, respectively, the use of the drug during the lactation period is contraindicated.

Dosing and Administration:

The dose and frequency of reception are determined individually, depending on the nature and severity of the symptoms.As with other antidepressants, at least 2-4 weeks are required to achieve a therapeutic effect (possibly 6-8 weeks). Treatment should begin with low doses with a gradual increase in them to select the lowest effective maintenance dose. Dose titration before achieving efficacy requires extreme caution in the elderly and in patients younger than 18 years.

Depression

Out-patient patients aged 18-60 years:

The standard dose is 25 mg 1-3 times a day, the dose can be gradually increased to a daily dose of 150-200 mg by the end of the first week of therapy. The standard maintenance dose is 50-100 mg per day.

Hospital patients 18-60 years of age:

In a hospital in very severe cases, the initial dose is 75 mg per day, the dose may be increased by 25 mg per day to a daily dose of 200 mg (in exceptional cases, the daily dose may reach 300 mg).

Patients older than 60 years:

In these age groups, a marked response to the above doses may be noted, therefore, treatment should be started with the lowest possible doses. The initial dose may gradually increase to a total daily dose of 50-75 mg. It is recommended to reach the optimum dose within 10 days and maintain this dose throughout the treatment period.

Panic disorders

Since this group of patients has an increased incidence of drug side effects, treatment should begin with the lowest possible dose. The transient worsening of anxiety at the onset of antidepressant medication can be prevented or cured by benzodiazepines, the dose of which gradually decreases as the symptoms of anxiety improve. The dose of the drug Melipramin® can gradually increase to 75-100 mg per day (in exceptional cases up to 200 mg). The minimum duration of treatment is 6 months. Upon completion of treatment, it is recommended to cancel Melipramine® gradually.

Children:

The drug should be administered only to children over 6 years of age exclusively as a temporary adjuvant therapy for nocturnal enuresis with the exception of organic pathology.

Recommended doses are:

- 6-8 years (with a body weight of 20-25 kg): 25 mg / day;

- 9-12 years (with body weight 25-35 kg): 25-50 mg / day;

- over 12 years of age and body weight above 35 kg: 50-75 mg / day.

Exceeding the recommended doses is justified only in those cases when there is no satisfactory response to therapy after 1 week of treatment with the drug in lower doses.

The daily dose in children should not exceed 2.5 mg / kg of body weight.

It is recommended to use the lowest dose from the above range of doses.The daily dose is recommended to be taken only once after eating before going to bed. If nocturnal enuresis is noted in the early evening hours, it is recommended to divide the daily dose into two doses: one by day and one by night. Duration of treatment should not exceed 3 months. Depending on the changes in the clinical picture of the disease, the maintenance dose may be reduced. Upon completion of therapy, Melipramine® should be discontinued gradually.

Side effects:

The undesirable effects listed below are not necessarily observed in all patients. Some of the side effects depend on the dose, so they pass after a dose reduction or spontaneously as the treatment continues. A number of side effects are difficult to distinguish from symptoms of depression (eg, fatigue, sleep disorder, agitation, anxiety, dry mouth).

The use of imipramine should be temporarily discontinued with the development of severe neurological or psychiatric reactions.

Elderly patients are particularly susceptible to m-holinoblokiruyuschim, neurological, mental or cardiovascular effects. The ability to metabolize and eliminate the drug can be reduced, leading to a risk of increasing its concentrations in the plasma.

The undesirable effects observed with the use of the preparation of Melipramin® are classified according to the body systems and are listed below as very often (≥ 1/10), often (≥ 1/100 and <1/10); infrequently (≥ 1/1000 and <1/100); rarely (≥ 1/10000 and <1/1000); very rarely (<1/10000), the frequency is unknown (can not be determined from the available data).

In each of the frequency groups, the undesirable effects are given in order of decreasing severity.

Laboratory research: often - increased activity of transaminases.

From the cardiovascular system: very often - sinus tachycardia and ECG changes that have no clinical significance (changes in the T wave and segment ST) in patients with normal cardiac activity, orthostatic hypotension, hot flushes; often - arrhythmias, conduction disorders (expansion of the complex QRS and interval PR, blockade bundle His), a feeling of heartbeat; rarely - cardiac decompensation, increased blood pressure, peripheral vasospastic reactions.

On the part of the hematopoiesis system: rarely - agranulocytosis, leukopenia, thrombocytopenia and purpura, eosinophilia.

From the side of the central nervous system: very often - a tremor; often - paresthesia, headache, dizziness,delirious confusion (especially in elderly patients with Parkinson's disease), disorientation and hallucinations, transition from depression to hypomania or mania, agitation, anxiety, increased anxiety, fatigue, insomnia, sleep disorders, libido and potency disorders; infrequently - convulsions, activation of psychotic symptoms; rarely - extrapyramidal symptoms, ataxia, aggressiveness, myoclonus, speech disorders.

On the part of the organs of sight and hearing: very often - a violation of accommodation, blurred vision; rarely - glaucoma, mydriasis; unknown - ringing in the ears.

From the gastrointestinal tract: very often - constipation, dry mouth; often - vomiting, nausea; rarely - paralytic ileus, indigestion, stomatitis, language damage, hepatitis, not accompanied by jaundice.

From the urinary system: often - disorders of urination.

From the skin: very often - increased sweating; often - allergic skin reactions (skin rash, hives); rarely - swelling (local or generalized), photosensitivity, itching, petechiae, hair loss.

From the endocrine system: rarely - enlargement of mammary glands, galactorrhea, syndrome of inadequate secretion of antidiuretic hormone, increase or decrease in the concentration of glucose in the blood plasma.

Metabolism and nutrition disorders: very often - weight gain; often - anorexia; rarely - weight loss.

Other: rarely hyperpyrexia, weakness, systemic anaphylactic reactions, including lowering of arterial pressure, allergic alveolitis (pneumonitis) with or without eosinophilia. In people over 50 years of age who take antidepressants, the incidence of bone fractures increases.

In the treatment with imipramine and in the early stages after the withdrawal of the drug, there were cases of suicidal thoughts and suicidal behavior.

Overdose:

Symptoms

central nervous system: dizziness, lethargy, stupor, coma, ataxia, anxiety agitation, increased reflexes, rigidity of the musculature, athetoid and choreal movements, convulsions.

The cardiovascular system: lowering of arterial pressure, tachycardia, arrhythmia, conduction disorders, shock, heart failure, in very rare cases - cardiac arrest.

Other: depression of respiration; cyanosis, vomiting, fever, sweating, mydriasis, oliguria, or anuria.

Symptoms of overdose can occur within 4-6 days. Children, in comparison with adults, are more sensitive to acute overdose, which should be considered dangerous and potentially lethal for them.

Treatment

Patients with suspected overdose of imipramine should be hospitalized and observed in the hospital for at least 72 hours. There is no specific antidote, treatment is predominantly symptomatic and maintenance therapy. Since the m-cholinoblocking effect of the drug may delay the emptying of the stomach (by 12 or more hours), as soon as possible, establish a gastric tube or induce vomiting (if the patient is conscious) and enter Activated carbon. Continuous monitoring of cardiovascular activity, gas and electrolyte blood composition is required. As an symptomatic treatment, anticonvulsant therapy (IV) diazepam, phenobarbital, inhalation anesthetics and muscle relaxants), artificial ventilation, installation of a temporary pacemaker,the introduction of plasma-substituting fluids, dopamine or dobutamine intravenously drip, in exceptional cases cardiopulmonary resuscitation may be required. Hemodialysis or peritoneal dialysis is ineffective given the low plasma concentrations of imipramine. Due to the high volume of distribution, forced diuresis is also ineffective. Given reports that physostigmine can cause severe bradycardia, asystole and epileptic seizures, its use in an imipramine overdose is not recommended.

Interaction:

MAO inhibitors: combinations with MAO inhibitors should be avoided, since these two types of drugs have a synergistic effect and their peripheral noradrenergic effects can reach toxic levels (hypertensive crisis, hyperpyrexia, myoclonus, agitation, convulsions, delirium, coma). For safety reasons, imipramine should not be started earlier than 3 weeks after the end of therapy with MAO inhibitors (except for moclobemide, a reversible MAO inhibitor, which takes a break of 24 hours) .- A period without drug therapy of three weeks should also be observed when transferring the patient to imipramine on MAO inhibitors.Treatment with MAO inhibitors or imipramine should begin with small doses with a gradual increase in them with careful monitoring of clinical effects.

Inhibitors of microsomal liver enzymes: when combined with imipramine, inhibitors of isoenzyme 2D6 cytochrome P-450 can lead to a decrease in the metabolism of the drug and, thus, lead to an increase in the concentration of imipramine in the blood plasma. Inhibitors of this type include preparations that are not substrates of isoenzyme 2D6 cytochrome P-450 (cimetidine, methylphenidate), as well as drugs that are metabolized by this isoenzyme (that is, many other antidepressants, phenothiazines, antiarrhythmic drugs 1c of class (propafenone, flecainide)). All antidepressants related to selective serotonin reuptake inhibitors are inhibitors of isoenzyme 2D6 cytochrome P-450 of different power. Accordingly, caution is required when combining imipramine with these drugs, as well as when transferring a patient from antidepressants that are selective inhibitors of serotonin reuptake to imipramine (and vice versa), especially in cases with fluoxetine (given the long half-life of this drug). Tricyclic antidepressants can lead to an increase in plasma concentrations of antipsychotic drugs (competition at the level of hepatic enzymes).

Oral contraceptives, estrogens: a decrease in the effectiveness of antidepressants and the development of toxic effects of antidepressants are sporadically observed in women who jointly take oral contraceptives or estrogen preparations and tricyclic antidepressants. Thus, the joint use of these drugs requires caution, and with the development of toxic effects, the dose of one of the drugs should be reduced.

Inducers of microsomal liver enzymes (alcohol, nicotine, meprobamate, barbiturates, antiepileptic drugs, etc.) increase the metabolism of imipramine and reduce its concentration in the blood plasma and antidepressant effects.

Preparations with m-cholinoblocking properties (for example, phenothiazines, drugs for the treatment of parkinsonism, blockers H₁-gistaminovyh receptors, atropine, biperidine) when combined with imipramine are characterized by an increase in antimuscarinic effects and side effects (eg, paralytic ileus). Combination therapy with these drugs requires careful monitoring of the patient and careful selection of doses.

Preparations depressing the central nervous system: a combination of imipramine with drugs that cause depression of the central nervous system (eg, narcotic analgesics, benzodiazepines, barbiturates, drugs for general anesthesia) and alcohol leads to - a marked increase in the effects and side effects of these drugs.

Antipsychotics can increase the concentration in the blood plasma of tricyclic antidepressants, thus increasing the side effects. A dose reduction may be required. Combined use with thioridazine can cause severe arrhythmia.

Preparations of thyroid hormones may increase the antidepressant effect of imipramine, as well as its side effect on the heart, so their joint application requires special care.

Sympatholytics: imipramine can lead to a decrease in the antihypertensive effect of the joint adrenergic neuron blockers (guanethidine, betanidine, reserpine, clonidine, methyldopa).Thus, in patients requiring the joint use of drugs for the treatment of hypertension, it is necessary to use antihypertensive drugs of a different type (for example, diuretics, vasodilators or βadrenoblockers).

Sympathomimetics: cardiovascular effects of sympathomimetics (mainly epinephrine, norepinephrine, isoprenaline, ephedrine, phenylephrine) are increased by imipramine.

Phenytoin: imipramine leads to a decrease in the anticonvulsant effect of phenytoin.

Quinidine: in order to avoid the risk of conduction disorders and arrhythmias, tricyclic antidepressants should not be used in combination with antiarrhythmic drugs of Class 1a.

Indirect anticoagulants: Tricyclic antidepressants inhibit the metabolism of indirect anticoagulants and increase their half-life. This leads to an increased risk of bleeding, so careful medical supervision and monitoring of prothrombin content is recommended.

Hypoglycemic drugs: the concentration of glucose in blood plasma in the treatment with imipramine can change, therefore, at the beginning of treatment, at the end of it, as well as when changing the dose, it is recommended to control the concentration of glucose in the blood.

Special instructions:

Suicide / suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicidal events). This risk persists until a marked remission occurs. Since improvements may not occur within the first few weeks of treatment or more, careful monitoring of the patient is required until such an improvement is achieved. According to general clinical experience, the risk of suicide can be increased in the early stages of recovery. The incidence of suicide is increased in children and young people under 24 years of age.

Other mental states in which Melipramin® is prescribed may also be associated with an increased risk of suicidal events. In addition, these conditions can accompany a major depressive disorder. Therefore, in the treatment of patients with other mental disorders, the same precautions are required as in the treatment of patients with major depressive disorder.

Patients with a history of suicidal events or patients with significant suicidal ideation prior to initiating therapy are at increased risk of suicidal ideation or suicide attempts, and therefore require careful follow-up during therapy.A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with mental disorders revealed an increased risk of suicidal behavior with antidepressants compared with placebo.

Drug therapy should be accompanied by careful monitoring of patients, in particular high-risk patients, especially in the early stages of treatment and after a dose change. Patients (and caregivers) should be warned about the need to observe any clinical impairment, suicidal behavior or thoughts and unusual behavioral changes and seek immediate medical attention if these symptoms are present. The therapeutic effect can be expected not earlier than 2-4 weeks of treatment. As with the use of other antidepressants, the later onset of a therapeutic effect means that the patient's suicidal tendencies will not be eliminated immediately, so the patient needs careful medical supervision until significant improvements are achieved.

Therapy with a maintenance dose should last at least 6 months.Imipramine therapy should be phased out gradually, as abrupt discontinuation may cause withdrawal symptoms (nausea, headache, fatigue, anxiety, anxiety, sleep disorders, arrhythmia, extrapyramidal symptoms).

In the case of bipolar depression imipramine can promote mania. The drug should not be used during manic episodes.

Like other tricyclic antidepressants, imipramine reduces convulsive threshold, therefore, patients with epilepsy and spasmophilia or epilepsy in a history require careful medical supervision and adequate anticonvulsant therapy.

Serotonin syndrome may occur with the use of drugs that inhibit the reuptake of serotonin (tricyclic and tetracyclic antidepressants, serotonin reuptake inhibitors, etc.), or blocking the metabolism of serotonin / (MAO inhibitors). Serotonin syndrome can develop with their combination or in combination with other drugs that enhance the action of serotonin (L-tryptophan, pentazocine, meperidine, bromocriptine, dextromethorphan, etc.).Because of the risk of developing serotonin syndrome, caution is required when combining imipramine with such drugs, and when transferring a patient from antidepressants that are selective inhibitors of serotonin reuptake to imipramine (or vice versa), especially in cases of fluoxetine (given the long half-life of this drug). Serotonin syndrome, comprising three groups of symptoms - motor, autonomic, and mental disorders - develops within a few hours or days after the commencement of treatment serotoninomimeticheskim agent or increasing its dosage. Treatment includes the abolition of serotonergic drugs and the implementation of symptomatic measures.

Melipramine® increases the risk associated with carrying out electroconvulsive therapy, so the use of the drug in electroconvulsive therapy is not recommended.

In the form of a paradoxical reaction in patients with panic disorders, increased anxiety in the first few days of therapy. The increase in anxiety usually passes spontaneously within 1-2 weeks, benzodiazepine derivatives can be used for its treatment if necessary.

In patients with psychosis at the beginning of therapy with tricyclic antidepressants, anxiety, anxiety, and agitation may increase.

Due to the m-cholinoblock effect, the use of imipramine requires careful medical observation with glaucoma, prostatic hyperplasia and severe constipation, since treatment can lead to increased severity of these symptoms.

Patients who use contact lenses, a decrease in the production of tear fluid and the accumulation of mucous discharge can lead to damage to the epithelium of the cornea.

Imipramine should be used with caution with ischemic heart disease, impaired liver and kidney function and diabetes mellitus (changes in blood glucose concentration).

Patient treatment with tumors of the adrenal glands (pheochromocytoma or neuroblastoma) requires extreme caution, since imipramine can provoke the development of hypertensive crisis.

Patient Therapy with hyperthyroidism and patients using thyroid hormone preparations, requires careful medical observation, taking into account the increased risk of cardiovascular adverse reactions in these patients.

Given the increased risk of arrhythmia and lowering blood pressure in general anesthesia, the anesthesiologist should be informed before the operation that the patient is taking imipramine.

In a number of cases, the treatment with imipramine reported the development of eosinophilia, leukopenia, agranulocytosis, thrombocytopenia and purpura, therefore regular monitoring of blood test parameters is required.

With prolonged therapy with antidepressants, there is an increase in frequency caries of teeth, therefore regular dental examinations are required.

Side effects may be more severe in elderly and young patients, therefore, especially at the beginning of treatment, lower doses are required.

Imipramine causes photosensitivityTherefore, during treatment, exposure to intense sunlight should be avoided.

In patients with predisposition and / or elderly patients, imipramine can cause m-holinoblokiruyuschy (delirious) syndrome, which is stopped within a few days after drug discontinuation.

Melipramine® tablets coated with a film coating contain lactose monohydrate.

When using imipramine, it is forbidden to drink alcoholic beverages.

Before the start of treatment and regularly during the treatment it is recommended to control the following indicators:

- ablood pressure (especially in patients with unstable blood circulation or arterial hypotension);

- fliver function (especially in patients with liver disease);

- Pperipheral blood users (immediately with an increase in temperature or laryngitis, as they may be a sign of leukopenia and agranulocytosis, in other cases before the start of therapy and regularly during therapy);

- ECG (in elderly patients and patients with heart disease).

Effect on the ability to drive transp. cf. and fur:

The use of the preparation of Melipramin® leads to an increased risk of accidents, so at the beginning of therapy, driving and working with machinery should be prohibited. Later, the degree and duration of these restrictions are determined by the doctor individually.

Form release / dosage:

Film-coated tablets, 25 mg.

Packaging:

For 50 tablets in a bottle of brown glass.

1 bottle with instructions for use in a cardboard box.

Storage conditions:Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001750

Date of registration:02.07.2012

Date of cancellation:2017-07-02

The owner of the registration certificate:EGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Manufacturer: & nbsp

EGIS PHARMACEUTICALS, Plc Hungary

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp12.10.2015

Illustrated instructions

Instructions

Melipramine® (Melipramin®)