Clomipramine - instructions for use, doses, side effects, contraindications

Active substanceClomipramineClomipramine

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Dosage form: & nbspsolution for intravenous and intramuscular administration

Composition:

Composition for 1 ml.

Active substance: clomipramine hydrochloride - 12.5 mg;

Excipients: glycerol (glycerol) in terms of 100% substance - 23.5 mg, water for injection - up to 1 ml.

Description:Colorless or slightly colored transparent liquid.

Pharmacotherapeutic group:Antidepressant

ATX: & nbsp

N.06.A.A.04 Clomipramine

Pharmacodynamics:

Clomipramine is a tricyclic antidepressant, a norepinephrine reuptake inhibitor, and serotonin (a nonselective monoamine reuptake inhibitor). It is believed that the effect of clomipramine is due to its ability to inhibit reverse neuronal seizure of norepinephrine (HA) and serotonin (5-HT), released into the synaptic cleft, the most important being the suppression of serotonin reuptake.

Clomipramine, in addition, has a wide range of other pharmacological actions: α₁_-adrenoblocker, m-holinoblocking, blockade H_i-gistamines and 5NT₂-serotonin receptors.

A drug Clomipramine acts on the depressive syndrome in general, including such typical manifestations as psychomotor inhibition, low mood and anxiety. The clinical effect is usually observed after 2-3 weeks of treatment.

Besides, clomipramine has a specific (different from its antidepressant effect) action in obsessive-compulsive disorders.

The effect of clomipramine in chronic pain syndromes, both caused and not caused by somatic diseases, is apparently associated with an improvement mediated by serotonin and norepinephrine of neuronal impulse transmission.

Pharmacokinetics:

Suction

With repeated intramuscular (IM) or intravenous (IV) administration of clomipramine at a dose of 50-150 mg / day, equilibrium concentration is achieved at the second week of treatment. The values of the equilibrium concentration of clomipramine range from less than 15 ng / ml to 447 ng / ml, and its pharmacologically active metabolite N-desmethylclomipramine - from less than 15 ng / ml to 669 ng / ml.

Distribution

The association of clomipramine with plasma proteins is 97.6%. Clomipramine is significantly distributed in the body, the apparent volume of distribution is about 12-17 l / kg body weight. The concentrations of clomipramine in the cerebrospinal fluid are about 2% of the its concentration in the blood plasma. Clomipramine penetrates into breast milk, where it is determined in a concentration close to the concentration in the blood plasma, and also penetrates through the placenta.

Metabolism

Clomipramine is metabolized mainly by demethylation to form an active metabolite N-desmethylclomipramine. Several cytochrome P450 isoforms participate in this reaction, but mostly CYP3A4, CYP2C19 and CYP1A2. Clomipramine and N-desmethylclomipramine are hydroxylated to 8-hydroxyclomipromine or 8-hydroxy-Ndesmethylclomipramine. Clomipramine also hydroxylated at position 2; N-desmethylclomipramine may further be demethylated to didesmetlclikipramine. 2- and 8-hydroxymetabolites are excreted mainly in the form of glucuronides by the kidneys. Biotransformation of two active forms of the drug: clomipramine and N- desmethylclomipramine by the formation of 2- and 8-hydroxyclomipramine is catalyzed by isoenzyme CYP2D6.

Excretion

After intramuscular and intravenous administration, the final half-life of clomipramine averages 25 hours (range from 20 to 40 hours) and 18 hours, respectively. About 2/3 of a single dose of clomipramine is excreted as water-soluble conjugates by the kidneys and about 1/3 of the dose is through the intestine. In unchanged form, about 2% of the dose of clomipramine and about 0.5% of desmethylclomipramine are excreted by the kidneys.

Pharmacokinetics in selected patient groups

Elderly patients

In elderly patients the clearance of clomipramine is lower than in younger patients. In this case, the therapeutic equilibrium concentration in patients of this category is achieved with the use of the drug in more low doses than in middle-aged patients. It should be used with caution in elderly patients.

The use of the drug in patients older than 65 years is contraindicated.

Patients with impaired renal function

At the moment there is no data describing the features of pharmacokinetics in patients with kidney disease. Although clomipramine is in the form of inactive metabolites, the accumulation of inactive metabolites can lead to a cumulation of the active substance and its active metabolite.Caution should be used in patients with impaired renal function of moderate and severe severity with control of their condition.

Patients with impaired hepatic function

Because the clomipramine predominantly metabolized in the liver in the presence of isoenzymes CYP2D6, CYP3A4, CYP2C19 and CYP1A2, a violation of liver function may affect the pharmacokinetics of the drug. In patients with impaired liver function, the drug should be used with caution.

Ethnic differences

Despite the fact that until now the influence of ethnic and racial affiliation on the pharmacokinetics of the drug has not been studied, it is known that the metabolism of clomipramine depends on genetic factors that can lead to a change in the metabolism of the active substance and its metabolite. Metabolism of clomipramine in representatives of the Caucasoid and Asian (in particular, representatives of Japanese and Chinese nationalities) races may vary.

Indications:

Treatment of depressive conditions of different etiology, taking place with different symptoms:

- endogenous, reactive, neurotic, organic, masked, involutional forms of depression;

- Depression in patients with schizophrenia and psychopathies;

- Depressive syndromes arising in old age, caused by chronic pain syndrome or chronic physical illnesses;

- Depressive mood disorders of reactive, neurotic or psychopathic nature.

Obsessive-compulsive syndromes.

Phobias.

Cataplexy accompanying narcolepsy.

Chronic pain syndrome.

Contraindications:

Hypersensitivity to clomipramine or any other components of the drug, a cross-sensitivity to tricyclic antidepressants from the dibenzazepine group.

Simultaneous use with antiarrhythmic drugs, which are potent inhibitors of the isoenzyme CYP2D6 (such as quinidine and propafenone).

The simultaneous use of selective and nonselective monoamine oxidase (MAO) inhibitors (MAO) irreversible, as well as a period of less than 14 days before and after their use. Contraindicated also the simultaneous use of selective MAO-A inhibitors of reversible action (such as moclobemide) and nonselective inhibitors of reversible MOA (such as linezolid).

Recently suffered myocardial infarction.

Congenital lengthening syndrome QT.

Acute intoxication with drugs that suppress the function of the central nervous system (for example, hypnotics, central analgesics, psychotropic drugs) or ethanol.

Acute retention of urine.

Hyperplasia of the prostate with a delay of urine.

Acute delirium.

Closed-angle glaucoma without treatment.

Stenosis of the pylorus of the stomach.

Paralytic ileus.

Do not recommend the use of the drug during pregnancy and during breastfeeding.

Age to 18 years.

Age over 65 years.

If you have one of the listed diseases (conditions), before taking the drug always consult a doctor.

Carefully:

Caution should be used in patients of the following groups:

- with diseases of the cardiovascular system (circulatory insufficiency, cardiac rhythm disturbances and intracardiac conduction (for example, atrioventricular blockade I-III degree);

- with epilepsy, as well as in the presence of other factors predisposing to the occurrence of convulsive syndrome, for example,with brain damage of various genesis, with the simultaneous use of neuroleptic drugs, during the period of alcohol withdrawal or withdrawal of drugs with anticonvulsant properties, for example, benzodiazepines (it is believed that the onset of seizures depends on the dose of the drug, therefore, do not exceed the recommended daily dose preparation Clomipramine);

- in elderly patients under the age of 65, the use of the drug in patients older than 65 years is contraindicated;

- in patients with impaired liver function;

- in patients with impaired renal function;

- in patients with tumors of the adrenal medulla (pheochromocytoma and neuroblastoma);

- in patients with hyperthyroidism or taking thyroid drugs;

- in patients with chronic constipation, especially in the elderly and patients forced to comply with bed rest;

- in patients with increased intraocular pressure, including patients with closed-angle glaucoma;

- in patients with a history of urinary retention (including due to prostatic hyperplasia);

- when used simultaneously with serotonergic drugs, such as selective serotonin reuptake inhibitors,serotonin reuptake inhibitors and norepinephrine, tricyclic antidepressants or lithium preparations.

Pregnancy and lactation:

Experience with the drug Clomipramine when pregnancy is limited. Since there are some reports of a possible association between the use of tricyclic antidepressants and fetal development disorders, the use of the drug should be avoided Clomipramine in pregnancy, except when the expected benefit to the mother clearly exceeds the potential risk to the fetus.

In cases where the mother took tricyclic antidepressants during pregnancy until the onset of labor, new withdrawal syndrome developed during the first few hours or days of life, manifested by shortness of breath, drowsiness, intestinal colic, increased nervous excitability, increased or decreased blood pressure (AD), tremor, spastic phenomena or seizures. To avoid the development of this syndrome, the drug Clomipramine should, if possible, be phased out at least 7 weeks before the expected delivery.

Since the active substance of the preparation Clomipramine penetrates into breast milk, you should either stop breastfeeding, or cancel the drug.

Dosing and Administration:

Before the start of therapy, hypokalemia should be eliminated.

The dosage regimen and the way of using the drug (parenterally or orally) are set individually, taking into account the patient's condition. The goal of the treatment is to achieve the optimal effect when using the lowest possible doses of the drug and carefully increasing them. After achieving a therapeutic effect, it is necessary to conduct supporting therapy with the optimal dose of the drug in order to avoid the development of relapse. Patients with depression of recurrent course need long-term maintenance therapy. The duration and need for therapy should be periodically reviewed.

In order to reduce the risk of developing serotonergic toxicity and possible lengthening of the interval QT should not exceed the recommended dose of the drug. Care should be taken to increase the dose of the drug Clomipramine in the case of simultaneous use with other serotonergic drugs or drugs that extend the interval QT.

Avoid sudden discontinuation of drug therapy Clomipramine because of the possible development of withdrawal symptoms. Reduction of the dose after long-term use should be made gradually, monitoring of the patient's condition after discontinuation of therapy is necessary.

The use of the drug in patients under the age of 18 years is contraindicated.

Intramuscular injections

Begin the treatment with the introduction of 25-50 mg intramuscularly, then daily increase the dose by 25 mg to achieve a daily dose of 100-150 mg. After the improvement is noted, the number of injections gradually reduce, replacing them with maintenance therapy with oral forms of the drug.

Intravenous infusion

Treatment begins with an intravenous drip of 50-75 mg once a day. To prepare the infusion solution, use 250-500 ml of a 0.9% solution of sodium chloride or glucose solution; duration of infusion is 1.5-3 hours. During the infusion, careful monitoring of the patient is necessary in order to identify possible adverse reactions in a timely manner. Particular attention should be paid to the control of blood pressure in connection with the risk of developing orthostatic hypotension.When the patient's condition is clearly improved, the drug Clomipramine injected intravenously for 3-5 days. Then, to maintain the achieved effect, they switch to taking the drug inward in the form of tablets. As a rule, 2 tablets of 25 mg correspond to 1 ampule of the drug Clomipramine, containing 25 mg clomipramine hydrochloride. Gradual transition from infusion therapy to maintenance treatment with oral forms of the drug is possible with the replacement of infusion therapy with intramuscular injections followed by the transition to oral dosage forms.

Use in elderly patients

Due to the presence of a more pronounced therapeutic response in elderly patients than in patients of other age groups, special care should be taken in the treatment of patients in this category, and also with an increase in the dose of the drug Clomipramine.

Use in patients with impaired hepatic or renal function

Care should be taken when using the drug Clomipramine in patients with impaired liver or kidney function.

Side effects:

(Including adverse reactions described for tablets of the drug).

Most of the observed adverse events (AEs), as a rule, are mild and transient, resolved with continued therapy or with a decrease in the dose of the drug. They do not always correlate with the concentration of the active substance in the blood plasma or with the dose of the drug. Some undesirable phenomena, such as fatigue, sleep disturbances, agitation, anxiety, constipation, dry mouth, are often difficult to distinguish from manifestations of depression.

In case of serious adverse reactions from the nervous system or mental disorders, the drug Clomipramine should be canceled.

To estimate the frequency of development of AE, the following criteria were used (according to the classification of the World Health Organization (WHO)): very often - ≥1 / 10; often - ≥1 / 100 to <1/10; infrequently - ≥1 / 1000 to <1/100; rarely - ≥1 / 10000 to <1/1000; very rarely - <1/10000, including individual messages.

Disorders from the metabolism and nutrition: Often - increased appetite; often - decreased appetite.

Disorders of the psyche: Often - anxiety; often confusion, disorientation, hallucinations (especially in elderly patients and patients with Parkinson's disease), anxiety, agitation, sleep disorders, manic disorder, hypomanic conditions,aggressiveness, depersonalization, worsening of the course of depression, insomnia, nightmares, delirium; infrequently - activation of psychotic symptoms.

Impaired nervous system: Often - dizziness, tremor, headache, myoclonus, pathological drowsiness; often - speech disorders, paresthesia, increased muscle tone, dysgeusia, memory impairment, impaired concentration; infrequently - convulsions, ataxia; rarely - malignant neuroleptic syndrome.

Heart Disease: often - sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant changes on the electrocardiogram (ECG) (for example, the interval ST or T wave) in patients without a pathology of the heart; infrequently - arrhythmia, increased blood pressure; rarely - violations of intracardiac conduction (for example, expansion of the complex QRS, interval lengthening QT, interval changes PQ, blockade of the legs of the bundle of the Guiss, ventricular tachycardia of the type "pirouette" ("torsade de pointes"), especially in patients with hypokalemia).

Vascular disorders: often - "tides".

Disorders from the gastrointestinal tract: Often - nausea, dry mouth, constipation; often - vomiting, abdominal disorders, diarrhea.

Disorders from the liver and bile ducts: rarely - Hepatitis with or without jaundice.

Disturbances from the skin and subcutaneous tissues: Often - increased sweating; often - allergic dermatitis (rash, hives), photosensitization reactions, itching; rarely - purpura, alopecia.

Disorders from the kidneys and urinary tract: Often - violation of urination; rarely - retention of urine.

Violations of the genitals and breast: Often - Violation of libido, erectile dysfunction; often - galactorrhea, an increase in the dairy (breast) glands.

Disorders from the endocrine system: rarely - Syndrome of inadequate secretion of antidiuretic hormone.

Immune system disorders: rarely - systemic anaphylactic and anaphylactoid reactions, including a decrease in blood pressure.

Violations from the blood and lymphatic system: rarely - leukopenia, agranulocytosis, thrombocytopenia, eosinophilia.

Disorders from the side of the organ of vision: Often - violation of accommodation, blurred vision; often - mydriasis; rarely - glaucoma.

Hearing disorders and labyrinthine disturbances: often - noise in ears.

Disturbances from the respiratory system, organs of the thorax and mediastinum: often - yawn; rarely - Allergic alveolitis (pneumonitis) with / without eosinophilia.

Laboratory and instrumental data: Often - increase in body weight; often - increased activity of "liver" transaminases; rarely - changes on the electroencephalogram.

General disorders and reactions at the site of administration: Often - fatigue; rarely - Edema (local and general), increased body temperature, reactions at the injection site (thrombophlebitis, lymphangitis, burning sensation, allergic skin reactions).

NI according to post-registration research data registered with the drug in other dosage forms (frequency unknown, since information on AE data is reported voluntarily from a population of undetermined size):

Impaired nervous system: serotonin syndrome; extrapyramidal symptoms (including akathisia and tardive dyskinesia). Disturbances from the musculoskeletal and connective tissue: rhabdomyolysis (as a complication of malignant neuroleptic syndrome).

Violations of the genitals and breast: anejaculation, delay of ejaculation.

Laboratory and instrumental data: level up prolactin in the blood plasma.

The withdrawal syndrome: after sudden withdrawal or rapid reduction of the dose of Clomipramine, the following symptoms often occur: nausea, vomiting, abdominal pain, diarrhea, insomnia, headache, irritability, anxiety.

Fractures of bones

In patients aged> 50 years, receiving selective serotonin reuptake inhibitors and tricyclic antidepressants, there was an increased risk of fractures, the mechanism of occurrence of which is unknown.

Elderly patients

Elderly patients are particularly sensitive to the anticholinergic, neurological, psychiatric effects of the drug or its effect on the cardiovascular system. Metabolism and excretion of drugs in patients in this category can be slowed down,which can lead to an increase in the concentration of the drug in the blood plasma when applying therapeutic doses.

In patients older than 65 years, the use of the drug is contraindicated.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

On cases of drug overdose Clomipramine in the form of a solution for injection was not reported. Below you will find information about an overdose of the drug when taken orally.

Symptoms that develop with an overdose of the drug are similar to those described in an overdose of other tricyclic antidepressants. The main complications are heart disorders and neurological disorders. In children, the occasional intake of any dose of the drug inside should be regarded as a very serious and fatal event.

Symptoms

Symptoms usually appear within 4 hours after taking the drug and reach maximum severity after 24 hours. Due to delayed absorption (m-cholin-blocking action of the drug), prolonged half-life and hepatoenteric recycling of the active substance, the period of time during which the patient remains in the "risk zone" is 4-6 days.

The following symptoms may occur.

From the central nervous system: drowsiness, stupor, coma, ataxia, anxiety, agitation, revitalization of reflexes, rigidity of muscles, choreoathetoid movements, convulsions. In addition, there may be manifestations of serotonin syndrome (fever, myoclonus, delirium, coma).

From the cardiovascular system: decreased blood pressure, tachycardia, lengthening QTc, arrhythmias (including "torsade des pointes"), disturbances of intracardiac conduction, shock, heart failure; in very rare cases - cardiac arrest.

In addition, respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria, or anuria are possible.

Treatment

There is no specific antidote, treatment is, in the main, symptomatic and supportive. If you suspect a drug overdose Clomipramine, especially in children, the patient should be hospitalized and monitored carefully for a minimum of 72 hours. If the patient is conscious, promptly wash the stomach or induce vomiting.In connection with increased risk of seizures, the use of activated carbon is a more preferable treatment measure compared with gastric lavage. The use of activated carbon and gastric lavage are effective within 1 hour after taking the drug.

If the patient is unconscious, before starting the gastric lavage, a tracheal intubation with a tube with a cuff should be performed to prevent aspiration; Vomiting in this case does not cause. These measures are recommended to be carried out even if 12 hours or more have passed since the overdose, since the m-cholinoblocking action of the drug Clomipramine can slow the emptying of the stomach. To reduce the absorption of the drug, it is useful to use activated carbon.

With the development of arterial hypotension and / or ventricular arrhythmia with the expansion of the complex QRS on an ECG of more than 100 ms for the purpose of treatment, a solution of sodium bicarbonate is added at a rate of 1 mmol / kg at one time or as a short-term infusion (5 minutes). The procedure can be repeated until the normalization of blood pressure and ECG parameters, under the control of the pH of the arterial blood, which should not exceed 7.55.Intravenous injection of lidocaine is also possible. Patients with bradycardia may use a temporary pacemaker. With the development of polymorphic ventricular tachycardia such as "pirouette" ("torsade des pointes") shows a single intravenous injection of 0.5 - 1.5 g of magnesium sulfate. With the development of seizures for the purpose of treatment should be an intravenous infusion of benzodiazepine. In case of coma and / or respiratory arrest, intubation of the trachea should be performed and artificial ventilation should be started. Apply hyperventilation for the purpose of correcting the pH of the blood should be only without the simultaneous use of bicarbonate (risk of severe alkalosis).

Since reports have appeared that physostigmine and pyridostigmine can cause severe bradycardia, asystole and seizures, use these drugs to treat an overdose with the drug Clomipramine Not recommended.

Hemodialysis and peritoneal dialysis are not effective, as clomipramine concentrations in the blood plasma are low.

Interaction:

Contraindicated drug interactions

MAO inhibitors (linezolid_the furazolidone and etc.). Do not use clomipramine for at least 2 weeks after the abolition of MAO inhibitors because of the risk of developing conditions such as hypertensive crisis, fever, and symptoms serotonin syndrome: myoclonus, agitation, convulsions, delirium and coma. The same rule should be followed if the MAO inhibitor is used after previous treatment with clomipramine. In either of these cases, initial doses of clomipramine or MAO inhibitors should be low, they should be increased gradually, under the constant control of the effects of the drug.

The existing experience shows that clomipramine can be appointed no earlier than 24 hours after the abolition of MAO-A inhibitors of reversible action, such as moclobemide. But if the MAO-A inhibitor of reversible action is applied after discontinuation of the drug Clomipramine, the duration of the break should be at least 2 weeks. Linezolid (which is a non-selective MAO inhibitor of reversible action) should not be used concomitantly with clomipramine.

Medications, not recommended for simultaneous use

Antiarrhythmic drugs (for example, quinidine and propafenone) should not be used simultaneously with tricyclic antidepressants, as they are potent inhibitors of the isoenzyme CYP2D6.

Diuretic preparations. Diuretic drugs can lead to hypokalemia, which, in turn, increases the risk of lengthening the interval QTc and development of arrhythmias "torsade des pointes"Correction of hypokalemia should be carried out before the beginning of therapy with the drug, it may be necessary to correct other disturbances of the water-electrolyte balance, for example, hypomagnesemia, before the drug therapy begins.

Selective serotonin reuptake inhibitors (such as fluoxetine, paroxetine or sertraline) inhibit the isoenzyme CYP2D6, other preparations of this group (for example, fluvoxamine) also inhibit isoenzymes CYP1A2, CYP2C19, which can lead to an increase in the concentration of clomipramine in the blood plasma and the development of the corresponding undesirable effects. A 4-fold increase in the equilibrium concentration of clomipramine was observed with simultaneous administration with fluvoxamine (concentration N-desmethylclomipramine decreased 2-fold).

With the simultaneous use of clomipramine with selective serotonin reuptake inhibitors or serotonin reuptake inhibitors and norepinephrine, tricyclic antidepressants and lithium preparations, the development of serotonin syndrome is possible. If fluoxetine is necessary, it is recommended to take a two-three-week break between the use of clomipramine and fluoxetine - to complete the use of fluoxetine 2-3 weeks before the start of clomipramine therapy or to begin fluoxetine therapy 2-3 weeks after the end of clomipramine treatment.

Simultaneous use of the drug Clomipramine with selective serotonin reuptake inhibitors may lead to increased exposure to the serotonin system.

Possible drug interactions

Drug Interactions, enhancing the therapeutic effects of the drug Clomipramine

Simultaneous application with inhibitors of isoenzyme CYP2D6 can lead to an increase in the concentrations of both active components to threefold in persons with the phenotype of the rapid metabolizer of debrisoquine / sparteine.At the same time, in these patients, the metabolism decreases to a level characteristic for persons with the phenotype of a weak metabolizer.

It is assumed that the joint administration with isozyme inhibitors CYP1A2, CYP2C19 and CYP3A4 can lead to an increase in the concentration of clomipramine and a decrease in the concentration N-desmethylclomipramine, which generally does not affect the pharmacological parameters.

With the simultaneous use of the drug Clomipramine with an antifungal agent terbinafine (a potent inhibitor isoenzyme CYP2D6) in the form for oral administration, it is possible to increase the exposure and cumulation of clomipramine, as well as its N-detylated metabolite. When using clomipramine together with terbinafine, correction of the dose of clomipramine is required.

Simultaneous use with blocker H₂-cystamine receptors with cimetidine (which is an inhibitor of certain cytochrome P450 isoenzymes, including CYP2D6 and CYP3A4) can lead to an increase in plasma concentrations of tricyclic antidepressants, which requires a reduction in the dose of the latter.

There is no evidence to support the interaction between clomipramine (25 mg per day) and oral contraceptives (15 or 30 μg ethinyl estradiol per day) with constant intake of the latter.There is no evidence that estrogens are inhibitors of the isoenzyme CYP2D6, the main isoenzyme involved in the elimination of clomipramine, so there is no reason to expect their interaction. Although simultaneous use of the tricyclic antidepressant imipramine and estrogens in high doses (50 mcg per day), in some cases, the aggravation of side effects and the increased therapeutic effect of the antidepressant have been reported. It is not known whether these data are significant for the simultaneous use of clomipramine and estrogens in low doses. With the simultaneous use of tricyclic antidepressants and estrogens in high doses (50 μg per day), it is recommended to monitor the therapeutic effect of antidepressants, and, if necessary, adjust the dosage regimen.

Simultaneous use of neuroleptics (for example, phenothiazine derivatives) can lead to an increase in plasma concentrations of tricyclic antidepressants, a decrease in the convulsive threshold and the occurrence of seizures. Combination with thioridazine may lead to the development of severe cardiac rhythm disturbances.

Methylphenidate can help increase the concentration of tricyclic antidepressants in blood plasma, possibly due to the suppression of their metabolism. It may be necessary to reduce the dose of the latter.

With the simultaneous use of valproic acid and clomipramine, it is possible to inhibit the isoenzyme CYP2C and / or uridil diphosphate glucuronyltransferase, which may lead to an increase in the concentration of clomipramine and desmethylclomipramine in the blood plasma.

Drug Interactions, Therapeutic effects of Clomipramine

Simultaneous use of clomipramine with isozyme inducers CYP3A and CYP2C, such as rifampicin or anticonvulsant drugs (eg, barbiturates (phenobarbital), carbamazepine and phenytoin, which are inducers of cytochrome P450 isoenzymes, namely CYP3A4 CYP2C19), can lead to an acceleration of metabolism, a decrease in the concentration of clomipramine in the plasma and a decrease in the effectiveness of the drug Clomipramine.

Inductors of isoenzyme CYP1A2 (for example, nicotine / other components of cigarette smoke) reduce the concentrations of drugs having a tricyclic structure in the blood plasma.The equilibrium concentration of clomipramine in cigarette smoking patients is 2 times lower than that of non-smokers (concentration N-desmethylclomipramine did not change).

With the simultaneous use of ion-exchange resins (for example, colestyramine or colestipol), a decrease in the concentration of clomipramine serum is possible. It is recommended to apply clomipramine at least 2 hours before and 4-6 hours after the application of resins.

St. John's wort can lead to a decrease in plasma concentrations of clomipramine when used simultaneously.

Drug Interactions, not affecting the drug Clomipramine

Tricyclic antidepressants can potentiate the effect of drugs possessing m-cholinoblocking action (for example, phenothiazine derivatives, antiparkinsonian drugs, atropine, biperidene, H blockers₁ histamine receptors) on the organ of vision, central nervous system, intestine and bladder. In addition, with the simultaneous use of the above drugs, there is a risk of hyperthermia.

Clomipramine may reduce or completely eliminate the antihypertensive effects of guanethidine, betanidine, reserpine, clonidine and methyldopa.Therefore, in cases when simultaneous treatment with clomipramine requires the treatment of hypertension, other drugs should be used (eg, vasodilators or beta-blockers).

Tricyclic antidepressants can enhance the effects of ethanol and other agents that have a depressing effect on the central nervous system (eg, barbiturates, benzodiazepines, or anesthesia products).

Clomipramine can enhance the action of epinephrine on the cardiovascular system, norepinephrine, isoprenaline, ephedrine and phenylephrine (even when these substances are part of local anesthetics).

Some tricyclic antidepressants may enhance the anticoagulant effect of coumarin derivatives (for example, warfarin), possibly by inhibiting their metabolism (isoenzyme CYP2C9). There is no evidence to demonstrate the ability of clomipramine to inhibit the metabolism of anticoagulants (warfarin). However, when using this class of drugs, it is recommended to monitor the concentration of prothrombin in the blood plasma.

Besides, clomipramine is an in vitro and in vivo inhibitor of isoenzyme activity CYP2D6 (oxidation of sparteine). In this way, clomipramine can increase concentrations of concomitantly used drugs, metabolized mainly with the participation of isoenzyme CYP2D6.

Incompatibility: drug solution Clomipramine with a solution of diclofenac.

Special instructions:

In the case of severe depression, there is a risk of suicidal attempts, which can persist until a reliable remission is achieved. In patients with depression, both in adults and in children, there may be an increase in depression and / or suicidal behavior or other symptoms, regardless of whether they receive antidepressant therapy or not. Antidepressants increased the risk of suicidal thoughts and suicidal behavior in short-term studies in children, adolescents and adult patients under the age of 25 with depression and other mental illnesses.

All patients taking the drug Clomipramine on any of the indications, should be examined for deterioration of the clinical picture, suicidal behavior and other mental disorders, especially in the initial phase of therapy or when changing the dose of the drug.Such patients should evaluate the need for a change in the treatment regimen, including the possibility of drug withdrawal, especially if the symptoms are pronounced, suddenly or not observed in the patient initially. Families and caregivers of patients (both children and adults) who take antidepressant medications for psychiatric and nonpsychiatric indications should be warned about the need to monitor patients for other psychiatric symptoms, including suicidal behavior, and immediately report such symptoms the attending physician.

There is evidence that when an overdose of the drug Clomipramine Lethal outcomes are less common than with an overdose of other tricyclic antidepressants.

Many patients with panic disorders may experience increased anxiety at the onset of treatment. This paradoxical increase in anxiety is most pronounced in the first days of therapy and usually subsides for two weeks.

In patients with schizophrenia receiving tricyclic antidepressants, sometimes the activation of psychosis is noted.

It is known that in patients with bipolar affective disorder, taking tricyclic antidepressants, during the depressive phase, manic or hypomanic conditions may develop. In such cases, it may be necessary to reduce the dose of the drug Clomipramine or its cancellation and administration of antipsychotic therapy. After stopping these conditions, if necessary, drug treatment Clomipramine can be resumed in low doses.

In predisposed and elderly patients, tricyclic antidepressants can provoke the development of medicinal delirious psychoses, mainly at night. After the drug is discontinued, the symptomatology disappears within a few days.

Serotonin syndrome

In view of the risk of developing serotonergic toxicity, the recommended dosing regimen should be followed.

With the simultaneous use of the drug Clomipramine with serotonergic drugs, such as selective serotonin reuptake inhibitors, serotonin reuptake inhibitors and norepinephrine, tricyclic antidepressants or lithium preparations,possibly the development of serotonin syndrome, manifested by hyperthermia, myoclonus, agitation, convulsions, delirium, coma. When the need for fluoxetine, it is recommended to take a break from two to three weeks before and after using fluoxetine.

Diseases of the cardiovascular system

With extreme caution, use the drug Clomipramine in patients with diseases of the cardiovascular system, primarily with circulatory insufficiency, conduction disorders (for example, atrioventricular blockade I-III degree) and arrhythmias.

These patients need to regularly monitor cardiac performance and ECG. When using the drug Clomipramine in doses exceeding therapeutic, or in the event that the concentration of clomipramine in the blood plasma exceeds therapeutic, there is a risk of lengthening QTc and the occurrence of ventricular tachycardia such as "pirouette" ("torsade des pointes") This is observed in the case of simultaneous administration with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors.In this regard, it is necessary to avoid the simultaneous use of clomipramine and drugs that cause its cumulation. It is also necessary to avoid simultaneous use with drugs that cause lengthening of the interval QTc. It has been established that hypokalemia is a risk factor for lengthening the interval QTc and the occurrence of ventricular tachycardia such as "pirouette" ("torsade des pointes") In connection with the foregoing, hypokalemia should be eliminated before starting therapy with the drug Clomipramine.

Because of the risk of lengthening the interval QTc and the development of serotonin syndrome should adhere to the recommended dosage and with caution increase the dose with simultaneous use with drugs that extend the interval QT, and serotonergic drugs.

Before starting therapy with the drug Clomipramine it is recommended to measure BP, because in patients with orthostatic hypotension or lability of the cardiovascular system, a sharp decrease in blood pressure can occur.

Elderly patients should monitor cardiac function and ECG.

Convulsions

It is known that tricyclic antidepressants reduce the threshold of convulsive readiness, therefore, the drug Clomipramine should be used with extreme caution in patients with epilepsy, as well as in the presence of other factors predisposing to the occurrence of convulsive syndrome, for example, brain damage of various etiologies, simultaneous use of neuroleptic drugs, during alcohol withdrawal or withdrawal of drugs with anticonvulsant properties (for example, benzodiazepines). It is believed that the onset of seizures on the background of the drug Clomipramine depends on the dose of the drug. In this regard, do not exceed the recommended daily dose of the drug Clomipramine. Just like other tricyclic antidepressants, the drug Clomipramine apply in combination with electroconvulsive therapy only under the condition of careful medical supervision.

M-holinoblokiruyuschee action

Because the drug has m-cholin-blocking properties, it should be used with extreme caution in patients who have a history of increased intraocular pressure, angle-closure glaucoma, or urinary retention (for example, due to prostate disease).It is also possible to reduce tear and accumulation of mucous secretions, which can lead to damage to the corneal epithelium in patients using contact lenses.

Anaphylactic reactions

In connection with the emergence of reports on the development of anaphylactic shock in the use of clomipramine, strict monitoring of the condition of patients receiving the drug Clomipramine intravenously.

It is necessary to use with caution tricyclic antidepressants in patients with severe liver diseases and in the treatment of patients with tumors of the adrenal medulla (for example, pheochromocytoma, neuroblastoma) because of the risk of hypertensive crisis. In patients with liver diseases, periodic laboratory monitoring of the activity of "liver" enzymes is recommended, in patients with renal pathology - renal function indicators.

Caution should be exercised in patients with hyperthyroidism, or receiving thyroid hormone medications; possibly the appearance of cardiotoxic action.

Caution is necessary when using the drug Clomipramine in patients with chronic constipation.Tricyclic antidepressants can cause paralytic intestinal obstruction, especially in elderly patients and patients who are obliged to comply with bed rest.

Although changes in the content of leukocytes during the period of treatment with the drug Clomipramine reported only in selected cases, it is recommended to periodically examine the composition of peripheral blood and attention to symptoms such as fever and sore throat, especially in the first months of therapy or with prolonged use of the drug.

Before conducting general or local anesthesia, an anesthetist should be warned that the patient is taking the drug Clomipramine. An increase in the incidence of dental caries during long-term treatment with tricyclic antidepressants has been reported. Therefore, in the case of prolonged therapy with the drug Clomipramine a regular examination of the patient by a dentist is recommended.

It should be borne in mind that ethanol can enhance the undesirable effects of the drug on the central nervous system, such as blurred vision, drowsiness, etc.

Do not abruptly discontinue the drug Clomipramine because of the risk of developing the "cancellation" syndrome.If a decision is made to discontinue treatment, the drug should be withdrawn gradually, as quickly as possible allows the clinical situation, but it should be borne in mind that the abrupt withdrawal of the drug may be accompanied by the development of certain symptoms.

Data on the effect of prolonged drug treatment Clomipramine on the growth, development, cognitive functions and behavior of children and adolescents under the age of 18 do not.

Effect on the ability to drive transp. cf. and fur:When there is a background against the use of the drug Clomipramine drowsiness, blurred vision and other abnormalities of the central nervous system (attention disturbance, confusion, disorientation, depression aggravation, delirium, etc.), patients should refuse to manage vehicles and mechanisms, as well as from performing other activities requiring increased attention and quick response.

Form release / dosage:Solution for intravenous and intramuscular injection, 12.5 mg / ml.

Packaging:

2 ml per ampoules of neutral glass class D. 5 ampoules per circuit cell packaging made of polyvinyl chloride or polyethylene terephthalate film.

For 1, 2 or 5 contour squares with instructions for use in a pack of cardboard.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

5 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004429

Date of registration:24.08.2017

Expiration Date:24.08.2022

The owner of the registration certificate:FARMZASCHITA NPC, FSUE FARMZASCHITA NPC, FSUE Russia

Manufacturer: & nbsp

FARMZASCHITA NPC, FSUE Russia

Illustrated instructions

Instructions

Clomipramine (Clomipramine)