Anafranil SR - instructions for use, dose, side effects, contraindications

1 tablet of prolonged action, coated with a coating, contains: active substance - clomipramine hydrochloride 75 mg, and also auxiliary substances: calcium hydrophosphate dihydrate, 30% dispersion polyacrylate, calcium stearate, silicon dioxide colloidal anhydrous, hydroxypropyl cellulose, talc, titanium dioxide, polyoxyl 40 hydrogenated castor oil, iron oxide red.

Description:

Pink capsular biconvex tablets covered with a film sheath, with a risk on both sides. On one side it is squeezed out "With/G", on the other side "G/D".

Pharmacotherapeutic group:Antidepressant

ATX: & nbsp

Clomipramine

Pharmacodynamics:

Clomipramine is a tricyclic antidepressant, a norepinephrine reuptake inhibitor, and serotonin (a nonselective monoamine reuptake inhibitor).It is believed that the therapeutic effect of clomipramine is due to its ability to inhibit the reverse neuronal capture of noradrenaline (HA) and serotonin (5-HT) released into the synaptic cleft, the most important being the reuptake of serotonin reuptake. Clomipramine, in addition, has a wide range of other pharmacological actions: alpha-adrenoblocking, m-cholinoblock, blockade of H1-histamine and 5HT-serotonin receptors.

The drug affects the depressive syndrome in general, including such typical manifestations as psychomotor retardation, depressed 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 conditioned and not caused by somatic diseases, is probably related to the relief of nerve impulse transmission mediated by serotonin and norepinephrine.

Pharmacokinetics:Suction

Clomipramine is completely absorbed from the gastrointestinal tract (GIT).
Systemic bioavailability of unchanged clomipramine is about 50%.
This decrease in bioavailability is due to the effect of "first passage" through the liver with the formation of an active metabolite, N-desmethylclomipramine. After taking the drug at a dose of 75 mg, the maximum plasma concentration (C_max) was 32.55 ± 8.10 ng / ml at the time of reaching the maximum concentration (T_max) 9,00 ± 1,81 hours With a daily dose of 75 mg / day, the equilibrium concentration of clomipramine in the plasma is set in the range of 20 to 175 ng / ml. The equilibrium concentration of active metabolite N-desmethylclomipramine is 40-85% higher than the concentration of clomipramine.

Distribution

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

Metabolism

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

Excretion

After a single dose, about 2/3 of clomipramine is excreted as water-soluble conjugates with urine and about 1/3 with feces.Unchanged in the urine, about 2% of the dose of clomipramine and about 0.5% of desmethylclomipramine are excreted. The half-life from the plasma of dexmethylclomipramine averages 21 hours (range of vibrations from 12 to 36 hours), T1 / 2 desmethylclomipramine - an average of 36 hours.

Effect of food

Food does not have a serious effect on the pharmacokinetics of clomipramine a, there may be a slight slowing down of absorption while simultaneous application.

Pharmacokinetics in selected patient groups

In elderly patients due to reduced metabolic rate 8-hydroxyclomipromine or 8-hydroxy-M-desmethylclimipramine.
Clomipramine also hydroxylated at position 2; N-desmethyl clomine pramine can subsequently be demethylated to didesmethylcollipramine 2- and 8-hydroxymetabolites are excreted mainly in the form of glucuronides kidneys. Biotransformation of two active forms of the drug: clomipramine and N-desmethylclomipramine by forming 2- and 8-hydroxyclomipramine is catalyzed by the CYP2D6 isoenzyme.

Because the clomipramine is predominantly metabolized by cautery in the presence of isoenzymes CYP2D6, CYP3A4, CYP2S19 and CYP1A2,
a violation of liver function may affect the pharmacokinetics of the drug.
In patients with impaired liver function, the drug should be applied in a steady state.

Despite the fact that the influence of race on the pharmacokinetics of the drug has not been studied in depth, it is known that the metabolism of clomipramine depends on genetic factors that can lead to both 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.

Peculiarities of pharmacokinetics of the preparation Anafranil® CP in the form of tablets of prolonged action coated with a film membrane.

Delayed release of clomipramine in the use of the preparation Anafranil CP tablets of prolonged action coated with a film coat provides a smooth pharmacological profile of the drug by maintaining a therapeutic concentration in the blood plasma at the same level for more than 24 hours. The maximum concentration in the blood plasma is reached about 9 hours after the drug Anafranil ® SR. FROM_max after applying 75 mg of clomipramine in the form of prolonged-action tablets coated with a film coat is half as much as after application of 25 mg of clomipramine three times a day. At the same time, the exposure remains unchanged.

After repeated use of clomipramine in the form of sustained-release tablets coated with a film coat, achieved in the equilibrium state C_min and C_max remain within the therapeutic range. Tablets Anafranil® CP prolonged action, film-coated, and coated tablets Anafranil®, bioequivalent.

Indications:

Adults

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 psychopathy;

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

- Depressive mood disorders reactive, neurotic or psychopathic nature.

- Obsessive-compulsive syndromes.

- Phobias.

- Cataplexy accompanying narcolepsy.

Children and teens

- Obsessive-compulsive syndromes.

- At present, there is insufficient evidence of the efficacy and safety of the drug Anafranil® CP in children and adolescents in the treatment of depressive conditions of various etiologies, taking place with various symptoms, phobias and panic attacks, cataplexy, concomitant narcolepsy and chronic pain syndrome. Therefore, the drug Anafranil® SR in children and adolescents (0-17 years) is not recommended for these indications.

Contraindications:

- Hypersensitivity to clomipramine or any other components of the drug, 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 inhibitors monoamine oxidase (MAO) irreversible action, and also in the period less than 14 days before and after their application.

Contraindicated also the simultaneous use of selective MAO-A inhibitors of reversible action (such as moclobemide) and nonselective MAO inhibitors of reversible action (such as lipesolide).

- 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 an obstruction of an intestine.

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

Contraindicated the use of the drug Anafranil® in the form of long-acting tablets in the following groups of patients (due to the inability selection of initial dose):

- in children for all indications, except for obsessive-compulsive syndromes (in children from 5 years of age);

- in patients aged ≥65 years.

Carefully:

If you have any of the listed diseases before taking the drug, be sure to consult a doctor.

Caution should be used in the following groups of patients:

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

- in patients with epilepsy, as well as in the presence of other factors predisposing to the onset of convulsive syndrome, for example, with brain damage of various genesis, while using 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, and therefore should not exceed the recommended daily dose of the drug Anafranil®);

- in elderly patients under the age of 65 years (in patients over 65 years of age, the drug 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 elderly patients and patients forced to comply with bed rest;

- in patients with increased intraocular pressure, including patients with a 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 Anafranil® CP when pregnancy is limited. Since there are some reports of a possible association between tricyclic antidepressant use and fetal development disorders, the use of the drug in pregnancy should be avoided, unless 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, in newborns during the first few hours or days of life developed syndrome "cancellation", manifested aboutbreathing, fromirritability, intestinal colic, increased nervous excitability, increased or decreased blood pressure, tremor, spastic phenomena, or seizures. To avoid the development of this syndrome, the drug Anafranil® CP should be gradually canceled, at least 7 weeks before the expected delivery. Since the active substance of the drug penetrates into breast milk, either breastfeeding should be stopped or gradually abolish a drugAnafranil® FROMR.

Dosing and Administration:

Anafranil® CP in the form of sustained-release tablets coated with a film coat should be used only in patients who show a daily dose of clomipramine 75 mg, 150 mg, or 225 mg.
The drug can be taken regardless of food intake.
Tablets should be swallowed whole.
Before the start of therapy, hypokalemia should be eliminated. Dosage regimen preparation a is set individually, taking into account the patient's condition. The goal of the treatment is to achieve the optimal effect with the use of as much as possible painful doses of the drug and careful increase thereof.Special care should be taken with increasing doses in elderly patients and adolescents, who are generally more sensitive to Anafranil® CP than patients in other age groups.

After achieving the therapeutic effect, it is necessary to provide maintenance therapy at the optimal dose 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. To reduce the risk of developing serotonergic toxicity and possible prolongation of the QT interval, do not exceed the recommended dose of the drug.

Caution should be used to increase the dose of Anafranil® CP in case of simultaneous use with other serotonergic drugs or drugs that extend the QT interval. It is necessary to avoid the abrupt withdrawal of the drug Anafranil® CP for long-term use should be done gradually, it is necessary to monitor the patient's condition after discontinuing therapy.

Depression, obsessive-compulsive syndromes and phobias

The initial dose of clomipramine is 50-75 mg per day (1 tablet of Anafranil® 25 mg, coated, 2-3 times a day or one prolonged-release tablet, film-coated once a day, preferably in the evening). Increase the dose should be consistently, 25 mg (1 tablet Anafranil® 25 mg, coated) per day every several days, depending on the tolerance of the drug to the patient, up to 100-150 mg during the first week of treatment. In severe cases, the daily dose can be increased to 250 mg. After achieving a significant improvement in the condition, you should bring the daily dose to the maintenance dose, which is 50 - 100 mg per day.

Children and teens

Obsessive-compulsive syndromes
The initial dose of clomipramine in this category of patients leaves 25 mg of the dasg, which is gradually increased during the first two weeks of use (the daily dose is divided into several doses) depending on the tolerance, up to a maximum daily dose of 3 mg / kg or 100 mg, depending on of what dose is less. Over the next few weeks, the daily dose is gradually increased to a maximum daily dose of 3 mg / kg or 200 mg, depending on which dose is less.

Side effects:

The observed undesirable effects are usually mild and transient, occur during the continuation of treatment or after a reduction 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 reactions from the nervous system or mental disorders, the drug should be canceled.

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

Disorders from the metabolism and power supply: very often - rise appetite; often - decreased appetite.

Disorders of the psyche: very 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 depression, insomnia, nightmares, delirium; infrequently - activation of psychotic symptoms.

Disorders from the nervous system: very 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.

Disorders from the heart: often - sinus tachycardia, palpitations, orthostatic hypotension, clinically insignificant changes on the ECG (eg, interval ST or T wave) in patients without a pathology of the heart; infrequently - arrhythmia, increased blood pressure; rarely - intracardiac conduction disorders (for example, expansion of the complex QRS, interval lengthening QT, interval changes PQ. blockade of the bundle of the bundle, a polymorphic ventricular tachycardia such as "pirouette" ("torsade des pointes"), especially in patients with hypokalemia).

Violations from the vessels: often - "tides".

Disturbances from the respiratory, thoracic and mediastinal systems: often - yawning; rarely - Allergic alveolitis (pneumonitis) with or without eosinophilia.

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

Disorders from the liver and bile ducts: very rare hepatitis with or without jaundice.

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

Disturbances from the musculoskeletal and connective tissue: often - muscle weakness.

Infringements from kidneys and urinary tract: very often disturbances of urination; rarely - retention of urine.

Violations from the genitals and breast cancer: very often - disorders of libido, erectile dysfunction; often - galactorrhea, an increase in the breast (breast) glands.

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

Immune system disorders: very rare - Anaphylactic and anaphylactoid reactions, including a decrease in blood pressure.

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

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

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

General disorders and disorders at the injection site: very often - fatigue; rarely - swelling (local or general), loss of hair, hyperpyrexia.

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

NI according to post-registration studies registered with the drug Anafranil in other dosage forms (frequency unknown, since data from AEs are reported voluntarily from a population of undetermined size).

Impaired nervous system: serotonin syndrome, extrapyramidal symptoms (including akathisia and tardive dyskinesia). Development of extrapyramidal symptoms, incl. tardive dyskinesia, possibly also with the use of the preparation Anafranil ® CP.

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: increased concentration of prolactin in the blood plasma.

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

Fractures of bones

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 susceptible to the anticholinergic, neurological, psychiatric effects of the drug or its effect on the cardiovascular system.Metabolism and excretion of drugs in this category of patients 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, tell your doctor.

Overdose:Symptoms that develop with an overdose of Anafranil SR 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 (anticholinergic action of the drug), a prolonged half-life and hepatoenteric recycling of the active substance, a 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, increased reflexes, rigidity of muscles, choreoathetoid movements, convulsions. In addition, there may be manifestations of serotonin syndrome (fever, myoclonus, delirium, coma).

From the cardiovascular system: marked decrease in blood pressure, tachycardia, lengthening QT-Interval, arrhythmias (including "torsade de points") violations of intracardiac conduction, shock, heart failure, in very rare cases - cardiac arrest.
Besides, possible respiratory depression, cyanosis, vomiting, fever, mydriasis, sweating, oliguria or anuria.

Treatment

There is no specific antidote, treatment is, in the main, symptomatic and supportive. If you suspect an overdose of Anafranil, especially in children, the patient should be hospitalized and monitored carefully for at least 72 hours.
If the patient is conscious, promptly wash the stomach or induce vomiting.If the patient is unconscious, before starting the gastric lavage, intubation of the trachea should be performed using a tube with a cuff 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 anticholinergic action of Anafranil may slow down the emptying of the stomach. To reduce the absorption of the drug, it is useful to use activated carbon.

The treatment is based on the use of modern intensive care methods with the continuous monitoring of heart functions, gas composition and blood electrolytes, as well as the application of such urgent measures as necessary, such as anticonvulsant therapy, artificial lung ventilation and resuscitation methods. Since the reports that physostigmine can cause severe bradycardia, asystole and seizures have appeared, it is not recommended to use this drug to treat an overdose of Anafranil SR.
Hemodialysis and peritoneal dialysis are not effective, as clomipramine concentrations in the blood plasma are low.

Interaction:Farmakodinamichesky type of interaction

Blockers of adrenergic neuronal transmission.

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

Anticholinergics. Tricyclic antidepressants can potentiate the action of anticholinergics (eg, phenothiazines, antiparkinsonics, atropine, biperiden, antihistamines) on the organ of vision, the central nervous system, the intestine and the bladder.

Means that depress the central nervous system. Tricyclic antidepressants can enhance the effects of alcohol and other drugs that have a depressing effect on the central nervous system (eg, barbiturates, benzodiazepines, or anesthesia drugs).

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

Existing experience shows that Anafranil can be administered no earlier than 24 hours after canceling inhibitors of MAO-A reverse action, such as moclobemide. But, if the MAO-A inhibitor of reversible action is appointed after canceling Anafranil, the duration of the break should be at least 2 weeks.

Selective serotonin reuptake inhibitors.

The combined use of anaphranil with these agents may lead to an increased effect on the serotonin system.

Serotonergic agents. With simultaneous use of Anafranil with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants and lithium preparations, the development of serotonin syndrome with symptoms such as fever, myoclonus, agitation, convulsions, delirium and coma is possible.If it is necessary to prescribe fluoxetine, it is recommended to take a two-three-week break between the use of Anafranil and fluoxetine - to complete the use of fluoxetine 2-3 weeks before the initiation of Anaphranil therapy or to appoint fluoxetine 2-3 weeks after the end of Anafranil treatment.

Sympathomimetic drugs.

Anaphranil can increase the effect on the cardiovascular system of adrenaline, norepinephrine, isoprenaline, ephedrine and phenylephrine (even when these substances are part of local anesthetics).
Pharmacokinetic type of interaction

The active substance of the drug Anafranil - clomipramine - basically it is displayed in the form of metabololites. The main pathway of metabolism is demethylation to the active metabolite N-desmethylclomipramine, followed by hydroxylation and conjugation N-desmethylclomipramine with clomipramine. Several cytochrome P450 isoforms participate in the demethylation, mainly CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components is carried out by hydroxylation, which is catalyzed CYP2D6. Joint administration with isoform inhibitors 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 isoform inhibitors CYP1A2, CYP2C19 and CYP3A4 can lead to an increase in the concentration of clomipramine and a decrease in the concentration N-de-methyl-clomipramine.

MAO inhibitors (for example moclobemide) are contraindicated in taking clomipamine, since in vivo they are potent inhibitors CYP2D6.

Antiarrhythmic drugs (for example quinidine and propafenone) should not be used in conjunction with tricyclic antidepressants, since they are potent inhibitors CYP2D6.

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

- Joint use of neuroleptics (eg phenothiazines) 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.

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

- There is no evidence to support the interaction between anaphranil (at a dose of 25 mg per day) and oral contraceptives (15 or 30 μg ethinylestradiol per day) with constant intake of the latter. There is no evidence that estrogens are
inhibitors CYP2D6 - mainstream enzyme, of the participating at elimination of clomipramine, so there is no reason expect their interaction. Although, with simultaneous application of tricyclic antidepressant imipramine and estrogens in high doses (50 mcg / day), in some cases it has been reported that the side effects are aggravated and the therapeutic effect of the antidepressant is increased. It is not known whether these data are significant for the simultaneous use of clomipramine and estrogens in low doses. When combined use of tricyclic antidepressants and estrogens in high doses (50 mcg per day), monitoring of the therapeutic effect
antidepressants, and, if necessary, correction of the dosing regimen.

Methylphenidate (Ritalin) can help increase the concentration of tricyclic antidepressants, possibly by suppressing their metabolism. With the joint use of these drugs may increase the concentration of tricyclic antidepressants in blood plasma, while it may be necessary to reduce the dose of the latter.

Some tricyclic antidepressants can enhance the anticoagulant effect of coumarins (for example, warfarin), possibly by inhibiting their metabolism (CYP2C9). There is no evidence to prove the ability of clomipromine
inhibit the metabolism of anticoagulants (warfarin). Nevertheless, when using this class of drugs, it is recommended to monitor the concentration of prothrombin in the plasma.

Joint reception of Anafranil with drugs - inducers of cytochrome P450, especially CYP3A4, CYP2C19 and / or CYP1A2 can lead to increased metabolism and reduce the effectiveness of Anafranil.

Joint reception Anafranil with drugs - inducers CYP3A and CYP2C, such as rifampicin or anticonvulsant drugs (eg, barbiturates, carbamazepine, phenobarbital and phenytoin), can lead to a decrease in the concentration of clomipramine in plasma.

Known inductors CYP1A2 (e.g., nicotine and other components of cigarette smoke) reduce the concentration of tricyclic antidepressants in blood plasma.
The equilibrium concentration of clomipramine in cigarette smokers is 2 times lower than that of non-smokers (concentration N-desmethylclomipramine did not change).

Clomipramine, as in vivo, and in vitro (Ki= 2.2 microM), inhibits activity CYP2D6 (oxidation of sparteine). In this way, clomipramine can increase concentrations of concomitantly used drugs, metabolized mainly with participation CYP2D6, in individuals with a phenotype of a strong metabolizer.

Special instructions:

When Anaphranil is used in doses exceeding the average therapeutic dose, or if the clomipramine concentration in the plasma exceeds the average therapeutic level, there is a risk of lengthening QTc-interval and occurrence of bidirectional spindle-shaped ventricular tachycardia ("torsade de points") This is observed in the case of co-administration with selective serotonin reuptake inhibitors or serotonin and noradrenaline reuptake inhibitors.Therefore, it is necessary to avoid the simultaneous administration of clomipramine and the drugs that cause its cumulation, and it is also necessary to avoid joint intake with drugs that cause lengthening QT-Interval. It has been established that hypokalemia is a risk factor for lengthening QT-interval and occurrence of bidirectional spindle-shaped ventricular tachycardia ("torsade de pointsTherefore, hypokalemia should be eliminated before therapy with Anafranil.
Because of the risk of developing serotonin toxicity and lengthening the interval QT should be
adhere to the recommended dosage and carefully increase the dose in a joint appointment with drugs that extend the interval QT, and serotonergic drugs.

With simultaneous application Anafranil with serotonergic drugs such as selective serotonin reuptake inhibitors, serotonin reuptake inhibitors and noradrenaline, tricyclic antidepressants or lithium drugs may develop serotonin syndrome with symptoms such as fever, myoclonus, agitation, convulsions, delirium and coma. If it is necessary to administer fluoxetine, it is recommended to take a two-three-week break between the use of anaphranil and fluoxetine (see section "Interaction with other drugs", serotonergic drugs).
In many patients with panic disorders at the beginning of treatment Anafranil increases anxiety. 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.

In patients with liver disease, periodic monitoring of hepatic enzyme activity is recommended.

Anaphranil, as well as other tricyclic antidepressants, is prescribed in combination with electroconvulsive therapy only under the condition of careful medical supervision.
Depression is characterized by the risk of suicidal actions, which can persist until a reliable remission is achieved. In patients with depression, both in adults and in children, depression and / or suicidal behavior or other psychiatric symptoms may increase, 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 and adolescents with depression and other psychiatric illnesses.

All patients taking Anafranil for any of the indications should be examined for worsening clinical picture, suicidal behavior and other psychiatric symptoms, especially in the initial phase of therapy or when changing the dose of the drug. Such patients should consider the possibility of changing the regimen of therapy, including the possible withdrawal of the drug, especially if such changes are pronounced, suddenly or not observed in the patient initially.

Families and guardians of patients (both children and adults) who take antidepressants for psychiatric or nonpsychiatric indications,should be warned about the need to observe patients because of the risk of other psychiatric symptoms, including suicidal behavior, and immediately report such symptoms to the treating physicians.

When prescribing for Anafranil, the minimum number of tablets should be indicated to reduce the risk of overdose. In this case, an adequate treatment regimen should be observed. There is evidence suggesting that with the use of Anafranil, there are fewer deaths due to an overdose than with the use of other tricyclic antidepressants.

Before conducting general or local anesthesia, an anesthesiologist should be warned that the patient is taking Anafranil.

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 Anafranil recommended regular examination of the patient by the dentist.

The use of diuretics can lead to the development of hypokalemia, which increases the risk of lengthening QT-interval and occurrence of bidirectional spindle-shaped ventricular tachycardia ("torsade de points").Prior to the initiation of therapy, anaphrenil should be corrected for hypokalemia.

It is necessary to avoid the abrupt withdrawal of Anafranil, since this can lead to adverse reactions. If a decision is made to discontinue treatment, the drug should be withdrawn gradually, as quickly as the clinical situation permits. It should be taken into account that the abrupt withdrawal of the drug may be accompanied by the development of certain symptoms.

Anafranil, coated tablets, contains lactose and sucrose. Patients with rare hereditary diseases, such as intolerance to galactose and fructose, severe lactase deficiency, sucrose-isomaltase deficiency or malabsorption of glucose-galactose, do not take tablet coated Anafranil tablets.

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

If there is drowsiness, blurred vision and other abnormalities from the side of the CNS (violation of attention, confusion, disorientation, aggravation of depression, delirium, etc.), patients should refuse to manage motor vehicles and work with mechanisms, and also from performing other types of activities,requiring increased attention and quick response.

Form release / dosage:

The coated tablets are 25 mg.

Packaging:The tablets covered with a cover of 25 mg on 10 pieces. in the blister pack. 2 or 3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.
The drug should be stored 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:LS-001129

Date of registration:01.08.2011 / 08.04.2016

Expiration Date:Unlimited

The owner of the registration certificate:Novartis Pharma, LLC Novartis Pharma, LLC Russia

Manufacturer: & nbsp

NOVARTIS FARMA, S.p.A. Italy

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp30.03.2018

Illustrated instructions

Instructions

Anafranil® SR (Anafranil SR)