Анафранил®

General characteristics. Structure:

Active agent - a klomipramina a hydrochloride of 25 mg, and also excipients: lactose, starch corn, silicon dioxide colloid anhydrous, stearic acid, talc, magnesium stearate, glycerin (85%), gidroksipropilmetiltsellyuloza, copolymer of vinylpyrrolidone/vinyl acetate, titanium dioxide, sucrose crystal, K30 polyvinylpirrolidone, disperse yellow 15093 анстед (ferrous oxide yellow [EEC 172] of 5% + titanium dioxide of 95% [EEC171]), polyethyleneglycol 8000 (macrogoal 8000), cellulose microcrystallic.

Description:
Tablets coated 25 mg: light yellow color, the round, biconvex tablets covered with a sugar cover. On one party "CG", on another - "FH" is marked by brown ink.

Pharmacological properties:

Pharmacodynamics. Anafranil is tricyclic antidepressant, inhibitor of the return capture of noradrenaline and serotonin (non-selective inhibitor of the return capture of monoamines). It is considered that medical action of Anafranil is carried out due to his ability to inhibit the return neyronalny capture of noradrenaline (ON) and serotonin (5-HT), released in a synaptic gap, and the most important is suppression of the return serotonin reuptake.
Anafranilu, besides, is inherent a wide range of other pharmacological actions: alfa1-adrenolytic, anticholinergic, antihistaminic and antiserotoninergichesky (blockade of 5-NT-retseptorov).
Anafranil affects a depressive syndrome in general, including its such typical manifestations as psychomotor block, oppressed mood and uneasiness.
The clinical effect is noted usually in 2-3 weeks of treatment.
Besides, Anafranil renders specific (different from its antidepressive effect) action at obsessivno-compulsive frustration.
Anafranil's action at the chronic pain syndromes both caused, and not caused by somatopathies is connected probably with relief of the transfer of nervous impulse mediated by serotonin and noradrenaline.

Pharmacokinetics.
Absorption
Klomipramin is completely soaked up from the digestive tract (DT). System bioavailability of not changed klomipramin makes about 50%. Such decrease in bioavailability is caused by effect of "the first passing" through a liver with formation of an active metabolite of N-desmetilklomipramina. Meal has no significant effect on bioavailability of a klomipramin. Perhaps only some delay of its absorption and, therefore, increase in time of achievement of the maximum concentration in a blood plasma (Cmax). Anafranil and Anafranil SR of a bioekvivalentna.
At administration of drug inside in a constant daily dose equilibrium concentration of a klomipramin in a blood plasma substantially vary at different patients. At daily administration of drug in a dose of 75 mg/days equilibrium concentration of a klomipramin in plasma is established in the range from 20 to 175 ng/ml. Values of equilibrium concentration of an active metabolite N-desmetilklomipramina are 40-85% higher, than concentration of a klomipramin.
Distribution
Communication of a klomipramin with proteins of a blood plasma makes 97.6%. The seeming volume of distribution makes about 12-17 l/kg of body weight. Concentration of a klomipramin in cerebrospinal fluid make about 2% of concentration it in a blood plasma. Klomipramin gets into maternal milk where is defined in the concentration close to concentration in a blood plasma.
Metabolism
Klomipramin is metabolized, mainly, by demethylation with formation of an active metabolite of N-desmetilklomipramina. In this reaction several isoforms of P450 cytochrome, but participate in the main CYP3A4, CYP2C19 and CYP1A2. Klomipramin and N-desmetilklomipramin are hydroxylated to a 8-gidroksiklomipromin or 8-hydroxy-N-desmetilklomipramina. Activity of 8 hydroxymetabolites of in vivo is not defined. Klomipramin is also hydroxylated in situation 2; N-desmetilklomipramin can demetilirovatsya further to a didesmetilklomipramin. 2-and 8 hydroxymetabolites are excreted preferential in the form of glucuronides with urine. Elimination of two active components - a klomipramin and N-desmetilklomipramina by education 2-and a 8-gidroksiklomipramina is catalyzed by CYP2D6.
Removal
After a single dose of Anafranil about 2/3 klomipramin are removed in the form of water-soluble conjugates with urine and about 1/3 - with a stake. In not changed view with urine about 2% of a dose of a klomipramin and about 0,5% of a desmetilklomipramin are removed. Plasma elimination half-life (T½) of a klomipramin averages 21 h (range of fluctuations from 12 to 36 h), T½ of a desmetilklomipramin is on average 36 h.
Pharmacokinetics at separate groups of patients
At patients of advanced age owing to decrease in intensity of metabolism of concentration of a klomipramin in plasma is higher, than at patients of younger age, regardless of the used Anafranil's dose. The abnormal liver functions and kidneys given about influence on pharmacokinetic parameters of a klomipramin are not received so far.

Indications to use:

Adults

- Treatment of the depressions of various etiology proceeding with various symptomatology:
- the endogenous, reactive, neurotic, organic, masked, involutional forms of a depression;
- a depression at patients with schizophrenia and psychopathies;
- the depressive syndromes arising at senile age, caused by a chronic pain syndrome or chronic somatopathies;
- depressive disturbances of mood of the reactive, neurotic or psychopathic nature.
- Obsessivno-kompulsivnye syndromes.
- Chronic pain syndrome.
- Phobias and panic attacks.
- The cataplexy accompanying a narcolepsy.

Children and teenagers
- Obsessivno-kompulsivnye syndromes.
- Night enuresis (only at patients 5 years and on condition of an exception of organic causes of illness are aged more senior).
Prior to therapy by Anafranil at night enuresis at children and teenagers it is necessary to estimate a ratio of potential advantage and risk for the patient. It is necessary to consider a possibility of performing alternative therapy.
Now the sufficient evidence of efficiency and safety of use of a klomipramin for children and teenagers at treatment of the depressions of various etiology proceeding with various symptomatology, phobias and the panic attacks, cataplexies, the accompanying narcolepsy and a chronic pain syndrome is not obtained. Therefore Anafranil's use for children and teenagers (0-17 years) at these indications is not recommended.

Route of administration and doses:

Before therapy it is necessary to eliminate a hypopotassemia (see the section "With Care").
The mode of dosing and route of administration of drug establish individually, taking into account a condition of the patient. The purpose of treatment consists in achievement of optimum effect at use of lower doses of drug and their careful increase. It is necessary to observe extra care at increase in doses at patients of advanced age and teenagers who in general are more sensitive to Anafranil, than patients of intermediate age groups.
Depression, obsessivno-compulsive syndromes and phobias
The initial daily dose makes 75 mg; appoint Anafranil 25 mg 2-3 times a day or Anafranilsr on 75 mg of 1 times a day (it is more preferable in the evening). Then within the first week of treatment the drug dose is gradually raised, for example, on 25 mg in each several days (depending on portability), to achievement of the daily dose making 100-150 mg. In hard cases the daily dose can be raised to maximum, making 250 mg. After improvement of a state will be reached, the patient is transferred to the maintenance dose of drug making 50-100 mg (2-4 tablets of Anafranil or 1 tablet of Anafranil of WEDNESDAY).
Panic attacks, agoraphobia
The initial dose of Anafranil makes 10 mg a day. Then, depending on Anafranil's portability, his dose is raised to achievement of desirable effect. The daily dose of Anafranil substantially varies and can make from 25 mg to 100 mg. If necessary increase in a dose to 150 mg a day is possible. It is recommended not to stop treatment within, at least, 6 months, slowly reducing a maintenance dose of drug during this time.
The cataplexy accompanying a narcolepsy
The daily dose of Anafranil makes 25-75 mg.
Chronic pain syndromes
The mode of dosing is set individually. The daily dose of Anafranil substantially varies and can make from 10 mg to 150 mg. At the same time it is necessary to consider the accompanying reception of analgetic means and a possibility of reduction of use of the last.
Patients of advanced age
The initial dose makes 10 mg a day. Then gradually, approximately within 10 days, the daily dose of drug is raised to optimum level which makes 30-50 mg.
Children and teenagers
Obsessivno-kompulsivnye syndromes
The initial dose makes 25 mg/days. Within the first 2 weeks a dose gradually increase, taking into account portability, to achievement of a daily dose either equal 100 mg, or calculated at the rate of 3 mg/kg - depending on what dose is less. Within the next several weeks either equal 200 mg, or calculated at the rate of 3 mg/kg - depending on what dose is less continue to raise a dose gradually to achievement of a daily dose.
Night enuresis
The initial daily dose of Anafranil for children at the age of 5-8 years makes 20-30 mg; for children at the age of 9-12 years - 25-50 mg; for children over 12 years - 25-75 mg. Use of higher doses is shown to those patients who completely have no clinical effect after 1 week of treatment. Usually all daily dose of drug is appointed in one step after a dinner, but when the involuntary urination is noted in early night hours, a part of a dose of Anafranil is appointed earlier - at 16 o'clock. After achievement of desirable effect treatment should be continued within 1-3 months, gradually reducing Anafranil's dose.

Features of use:

At Anafranil's use in the doses exceeding averages therapeutic or if concentration of a klomipramin in plasma exceeds average therapeutic, there is a risk of lengthening of a QTc-interval and developing of bidirectional spindle-shaped ventricular tachycardia ("torsade de points"). It is observed in case of joint reception with selective serotonin reuptake inhibitors or inhibitors of the return serotonin reuptake and noradrenaline. In this regard it is necessary to avoid the joint reception of a klomipramin and drugs causing its cumulation. It is also necessary to avoid joint reception with the drugs causing lengthening of a QTc-interval. It is established that the hypopotassemia is risk factor of lengthening of a QTc-interval and developing of bidirectional spindle-shaped ventricular tachycardia ("torsade de points"). Therefore, the hypopotassemia has to be eliminated prior to therapy by Anafranil. Because of risk of development of serotoninovy toxicity and lengthening of an interval of QTc it is necessary to adhere to the recommended doses and with care to raise a dose at joint appointment with the drugs extending QT interval, and serotonergic drugs. At simultaneous use of Anafranil with serotonergic drugs, such as, selective serotonin reuptake inhibitors, inhibitors of the return serotonin reuptake and noradrenaline, tricyclic antidepressants or drugs of lithium, development of a serotoninovy syndrome with such symptoms as fervescence, a myoclonus, agitation, spasms, a delirium and a coma is possible. In need of purpose of fluoxetine, it is recommended to do two - a three-week break between Anafranil's use and fluoxetine (see the section "Interaction with Other Medicines", serotonergic means). At many patients with panic frustration in an initiation of treatment by Anafranil uneasiness amplifies. Such paradoxical strengthening of uneasiness is most expressed in the first days of therapy and usually abates within two weeks.
At the patients with schizophrenia receiving tricyclic antidepressants activation of psychosis is sometimes noted.
At patients with diseases of a liver periodic control of activity of liver enzymes is recommended.
Anafranil, as well as other tricyclic antidepressants, appoint in combination with electroconvulsive therapy only on condition of careful medical observation. The risk of suicide actions which can remain up to achievement of reliable remission is inherent to the expressed depressions. At patients with a depression, both at adults, and at children, strengthening of a depression and/or suicide behavior or other psychiatric symptoms in independence of that can be observed, they receive therapy by antidepressants or not. Antidepressants increased risk of suicide thoughts and suicide behavior in short-term researches at children and teenagers with depressions and other psychiatric diseases.
All patients accepting Anafranil on any of indications should be inspected regarding deterioration in a clinical picture, suicide behavior and other psychiatric symptoms especially in an initial phase of therapy or at change of a dose of drug. At such patients it is necessary to consider the possibility of change of the mode of therapy, including possible drug withdrawal, especially, if such changes are brightly expressed, appeared suddenly or were not observed at the patient initially.
Families and trustees of patients (both children, and the adults) accepting antidepressants according to psychiatric or not psychiatric indications have to be warned about need to watch patients because of risk of emergence of other psychiatric symptoms including suicide behavior, and immediately to report about such symptoms to attending physicians.
At a recipe extract on Anafranil it is necessary to specify the minimum quantity of tablets to reduce risk of overdose. At the same time it is necessary to observe the adequate mode of therapy. Are available this, testimonial that against the background of Anafranil's reception the smaller number of lethal outcomes owing to overdose, than against the background of reception of other tricyclic antidepressants is noted.
Before carrying out the general or local anesthesia it is necessary to warn the anesthesiologist about what the patient accepts Anafranil.
It was reported about increase in frequency of development of caries of teeth at prolonged treatment by tricyclic antidepressants. Therefore in case of long therapy by Anafranil regular survey of the patient by the stomatologist is recommended.
Use of diuretics can lead to development of a hypopotassemia at which the risk of lengthening of a QTc-interval and developing of bidirectional spindle-shaped ventricular tachycardia ("torsade de points") increases. Prior to therapy by Anafranil correction of a hypopotassemia has to be carried out.
It is necessary to avoid sharp cancellation of Anafranil as it can lead to side reactions. If the decision to stop treatment is made, drug should be cancelled gradually, so quickly as far as it allows a clinical situation. At the same time it is necessary to consider that sharp drug withdrawal can be followed by development of certain symptoms.
Anafranil, tablets coated, contains lactose and sucrose. To patients with rare hereditary diseases, such as intolerance of a galactose and fructose, a heavy lactose intolerance, sucrose-izomaltaznaya insufficiency or malabsorption of glucose galactose, it is not necessary to take a pill of Anafranil, coated.

Influence on ability to drive the car and to manage mechanisms
Patients who against the background of Anafranil's use have a drowsiness and other disturbances from TsNS (including a sight illegibility) should not drive the car, to manage mechanisms, and also to be engaged in other types of activity requiring special attention and bystry reaction.

Side effects:

The observed undesirable phenomena are usually poorly expressed also tranzitorna, pass in the course of continuation of treatment or after Anafranil dose decline. They not always correlate with concentration of active agent in a blood plasma or with a drug dose. Some undesirable phenomena, such as feeling of fatigue, sleep disorders, agitation, uneasiness, a lock, dryness in a mouth, it is often difficult to distinguish from displays of a depression.
In case of development of serious reactions from a nervous system or the mental status Anafranil has to be cancelled.
Elderly people are especially sensitive to Anafranil's action on a nervous system, cardiovascular system, to influence of drug on the mental status, and also to anticholinergic effect of Anafranil. Metabolism and removal of medicines at this age can be slowed down that leads to increase in concentration of drugs in a blood plasma when using therapeutic doses.
Undesirable reactions are listed on frequency, starting with the most frequent: arising "very often" - = 1/10, is "frequent" - =1/100-<1/10, "sometimes" - =1/1000-<1/100, is "rare" - =1/10000-<1/1000, is "very rare" - <1/10000, including separate cases.
From the central and peripheral nervous system. Mental status: very often - drowsiness, feeling of fatigue, concern, increase in appetite; often - confusion of consciousness, a disorientation, hallucinations (especially at patients of advanced age and at patients with Parkinson's disease), an alarming state, agitation, sleep disorders, a maniacal state, a hypomaniacal state, aggression, memory disturbances, depersonalization, strengthening of a depression, disturbance of concentration of attention, sleeplessness, nightmares, yawning; sometimes: activation of symptoms of psychosis.
Neurologic status: very often - dizziness, a tremor, a headache, a myoclonus; often - a delirium, disturbances of the speech, paresthesia, muscular weakness, increase in a tone of muscles; sometimes - spasms, an ataxy; very seldom - changes on the electroencephalogram, fervescence.
Anticholinergic effects: very often - dryness in a mouth, the increased perspiration, locks, accommodation disturbances, a sight illegibility ("a veil before eyes"), disturbances of an urination; often - inflows, a mydriasis; very seldom - glaucoma, an ischuria.
From cardiovascular system: often - sinus tachycardia, a heart consciousness, orthostatic hypotension, clinically insignificant changes on an ECG (for example, an interval of ST or a tooth of T) at patients without heart pathology; sometimes - arrhythmias, increase in the ABP; very seldom - disturbances of endocardiac conductivity (for example, expansion of the QRS complex, lengthening of an interval of QT, change of an interval of PQ, blockade of legs of a ventriculonector, bidirectional spindle-shaped ventricular tachycardia ("torsade de points"), especially at patients with a hypopotassemia).
From the digestive tract (DT): very often - nausea; often - vomiting, discomfort in a stomach, diarrhea, anorexia.
From a liver: often - increase in level of transaminases; very seldom - hepatitis with jaundice or without it.
Dermatological reactions: often - allergic skin reactions (rash, urticaria), a photosensitization, an itch; very seldom - hypostases (local or the general), a hair loss.
From endocrine system and a metabolism: very often - increase in body weight, disturbance of a libido and potentiality; often - a galactorrhoea, increase in mammary glands; very seldom - a syndrome of inadequate secretion of antidiuretic hormone.
Hypersensitivity reactions: very seldom - an allergic alveolitis (pneumonitis) with an eosinophilia or without it, system anaphylactic/anaphylactoid reactions, including hypotension.
From system of a hemopoiesis: very seldom - a leukopenia, an agranulocytosis, an eosinophilia, thrombocytopenia, a purpura.
From sense bodys: often - disturbances of flavoring feelings, a sonitus.
Withdrawal: after sudden cancellation or a bystry dose decline of Anafranil often there are following symptoms: nausea, vomiting, abdominal pains, diarrhea, sleeplessness, headache, irritability, uneasiness.

Interaction with other medicines:

Pharmakodinamichesky type of interaction.
Blockers of adrenergic neyronalny transfer. Anafranil can reduce or completely eliminate anti-hypertensive action of a guanetidin, betanidin, Reserpinum, clonidine and alphamethyldopums. Therefore when along with Anafranil's reception treatment of arterial hypertension is required, it is necessary to apply medicines of other classes (for example, vazodilatator or beta adrenoblockers).
Anticholinergics. Tricyclic antidepressants can exponentiate action of anticholinergics (for example, fenotiazin, antiparkinsonichesky drugs, atropine, Biperidinum, antihistaminic drugs) on an organ of sight, TsNS, intestines and a bladder.
Means, the oppressing TsNS. Tricyclic antidepressants can strengthen effect of alcohol and other means having the oppressing influence on TsNS (for example, barbiturates, benzodiazepines or anesthetics).
MAO inhibitors. It is not necessary to appoint Anafranil within, at least, 2 weeks after cancellation of MAO inhibitors because of risk of development of such heavy symptoms and states as hypertensive crisis, fervescence, and also symptoms of a serotoninovy syndrome: myoclonus, agitation, spasms, delirium and coma. The same rule should follow if MAO inhibitor is appointed after the previous treatment by Anafranil. In any of these cases initial doses of Anafranil or MAO inhibitors have to be low, they should be raised gradually, under constant control of effects of drug.
The existing experience shows that Anafranil can be appointed not earlier than in 24 hours after cancellation of MAO-A inhibitors of reversible action, такихкак моклобемид. But, if MAO-A inhibitor of reversible action is appointed after Anafranil's cancellation, duration of a break has to make at least 2 weeks.
Selective serotonin reuptake inhibitors. Combined use of Anafranil with these means can lead to strengthening of action on serotoninovy system.
Serotonergic means. At simultaneous use of Anafranil with selective serotonin reuptake inhibitors or inhibitors of the return serotonin reuptake and noradrenaline, tricyclic antidepressants and drugs of lithium, development of a serotoninovy syndrome with such symptoms as fervescence, a myoclonus, agitation, spasms, a delirium and coma is possible. In need of purpose of fluoxetine, it is recommended to do two - a three-week break between Anafranil's use and fluoxetine - to finish use of fluoxetine in 2-3 weeks prior to therapy by Anafranil or to appoint fluoxetine in 2-3 weeks after the end of treatment Anafranily.
Sympathomimetic means. Anafranil can strengthen action on cardiovascular system of adrenaline, noradrenaline, izoprenalin, ephedrine and Phenylephrinum (including when these substances are a part of local anesthetics).

Pharmacokinetic type of interaction.
Active agent of drug Anafranil - кломипрамин - is generally removed in the form of metabolites. The main way of metabolism - demethylation to an active metabolite of N-desmetilklomipramina with the subsequent hydroxylation and conjugation of N-desmetilklomipramina with klomipraminy. In demethylation several isoforms of P450 cytochrome, participate in the main CYP3A4, CYP2C19 and CYP1A2. Elimination of both active components is carried out by a hydroxylation which is catalyzed by CYP2D6. Joint reception with inhibitors of the CYP2D6 isoform can lead to increase in concentration of both active components to triple size at persons with a phenotype of a bystry metabolizator of debrisoquine/sparteine. At the same time at these patients metabolism decreases to the level characteristic of persons with a phenotype of a weak metabolizator. It is supposed that joint reception with inhibitors of the CYP1A2, CYP2C19 and CYP3A4 isoforms can lead to increase in concentration of a klomipramin and decrease in concentration of N-dezmetilklomipramina.

MAO inhibitors (for example моклобемид) are contraindicated at reception of a klomipamin as in vivo they are strong CYP2D6 inhibitors.
Antiarrhytmic drugs (for example quinidine and пропафенон) should not be applied together with tricyclic antidepressants as they are strong CYP2D6 inhibitors.
Selective serotonin reuptake inhibitors (such as fluoxetine, пароксетин or sertraline) inhibit CYP2D6, other drugs of the specified group (for example флувоксамин) inhibit also CYP1A2, CYP2C19 that can lead to increase in concentration of a klomipramin in plasma and to development of the corresponding undesirable effects. 4-fold increase in equilibrium concentration of a klomipramin at joint reception with fluvoksaminy was observed (concentration of N-desmetilklomipramina decreased twice).
Combined use of neuroleptics (for example fenotiazina) can lead to increase in concentration in plasma of tricyclic antidepressants, to decrease in a convulsive threshold and developing of spasms. The combination with thioridazine can lead to development of heavy disturbances of a cordial rhythm.
Combined use with a blocker histamine (H2) - receptors Cimetidinum (which is inhibitor of some isoforms of P450 cytochrome, including CYP2D6 and CYP3A4) can lead to increase in concentration in plasma of tricyclic antidepressants in this connection the dose decline of the last is required.
There are no data confirming interaction between Anafranil (in a dose of 25 mg a day) and oral contraceptives (15 or 30 mkg of ethinylestradiol a day) at constant reception of the last. There are no data that estrogen is CYP2D6 inhibitors - the main enzyme participating in elimination of a klomipramin therefore there are no bases to expect them interaction. Though, at simultaneous use of tricyclic antidepressant of Imipraminum and estrogen in high doses (50 mkg a day), it was in certain cases reported about aggravation of side effects and strengthening of therapeutic effect of antidepressant. It is unknown whether these data are significant concerning simultaneous use of a klomipramin and estrogen in low doses. At combined use of tricyclic antidepressants and estrogen in high doses (50 mkg a day) monitoring of therapeutic effect of antidepressants, and, if necessary, correction of the mode of dosing is recommended.
Methylphenidate (Ritalinum) can promote increase in concentration of tricyclic antidepressants, perhaps, due to suppression of their metabolism. At combined use of the specified drugs increase in concentration of tricyclic antidepressants in a blood plasma is possible, at the same time can be required dose declines of the last.
Some tricyclic antidepressants can strengthen anti-coagulative effect of coumarins (for example, warfarin), perhaps, by inhibition of their metabolism (CYP2C9). There are no data proving ability of a klomipromin to inhibit metabolism of anticoagulants (warfarin). Nevertheless, when using this class of medicines monitoring of concentration of a prothrombin in plasma is recommended.
Joint reception of Anafranil with drugs - P450 cytochrome inductors, especially CYP3A4, CYP2C19 and/or CYP1A2 can lead to increase in metabolism and reduce Anafranil's efficiency.
Joint reception of Anafranil with drugs - the inductors CYP3A and CYP2C, such as rifampicin or anticonvulsant medicines (for example barbiturates, carbamazepine, phenobarbital and Phenytoinum), can lead to decrease in concentration of a klomipramin in plasma.
The known inductors CYP1A2 (for example nicotine / other components of cigarette smoke) reduce concentration of tricyclic antidepressants in a blood plasma. Equilibrium concentration of a klomipramin at the persons smoking cigarettes is twice lower that at non-smoking (concentration of N-desmetilklomipramina did not change).
Klomipramin, both in vivo, and in vitro (Ki=2.2 the microm), inhibits activity of CYP2D6 (sparteine oxidation). Thus, кломипрамин can increase concentration of at the same time used drugs which are metabolized mainly with participation of CYP2D6 at persons with a phenotype of a strong metabolizator.

Contraindications:

Hypersensitivity to a klomipramin or any other ingredients of drug, cross hypersensitivity to tricyclic antidepressants from group of dibenzazepine.
Simultaneous use of inhibitors of a monoaminooxidase (MAO), and also the period less than 14 days before their use. Also simultaneous use of the MAO-A selection inhibitors of reversible action, such as моклобемид is contraindicated.
Recently postponed myocardial infarction.
Inborn syndrome of lengthening of a QT interval.
Do not recommend to use drug at pregnancy and during breastfeeding (see the section "With Care").
Ppenapat do not recommend to apply at children under 5 years (see the section "With Care").

With care
It is known that at the patients with cyclic affective frustration accepting tricyclic antidepressants in the period of a depressive phase maniacal or hypomaniacal states can develop. In such cases there can be a need for a dose decline of Anafranil or for his cancellation and purpose of antipsychotic therapy. After stopping of the specified states if there are indications, treatment by Anafranil in low doses can be resumed.
At predisposed patients and patients of advanced age tricyclic antidepressants can provoke development of medicinal delirious psychoses, preferential at night. After drug withdrawal the specified frustration take place within several days.
With extra care patients should appoint Anafranil with cardiovascular diseases, first of all, with cardiovascular insufficiency, disturbances of endocardiac conductivity (for example, an atrioventricular block of the I-III degree) or arrhythmias. At such patients as well as at patients of advanced age, it is necessary to control indicators of cardiac performance and an ECG regularly.
Before therapy by Anafranil it is recommended to measure the ABP as at patients with orthostatic hypotension or lability of cardiovascular system sharp decrease in the ABP can be noted.
It is known that tricyclic antidepressants reduce a threshold of convulsive readiness therefore Anafranil has to be applied with extra care at patients with epilepsy, and also in the presence of other factors contributing to emergence of a convulsive syndrome, for example, injuries of a brain of various etiology, simultaneous use of neuroleptics, during refusal of alcohol or cancellation of the drugs having anticonvulsant properties (for example, benzodiazepines). It is considered that developing of spasms against the background of Anafranil's use depends on a drug dose. In this regard it is not necessary to exceed the recommended daily dose of Anafranil.
As drug has anticholinergic properties, it should be used with extra care at patients in whose anamnesis there are data on the increased intraocular pressure, closed-angle glaucoma or an ischuria (for example, owing to prostate diseases).
Owing to the anticholinergic action inherent to tricyclic antidepressants, decrease in a slezootdeleniye and accumulation of a mucous secret is possible that can lead to damage of an epithelium of a cornea at the patients using contact lenses.
Care is necessary at treatment by tricyclic antidepressants of patients with a heavy liver failure, and also at patients with tumors of a medulla of adrenal glands (for example, a pheochromocytoma, a neuroblastoma) as in this case these drugs can provoke development of hypertensive crisis.
It is necessary to be careful at treatment of the patients suffering from a hyperthyroidism, or receiving drugs of hormones of a thyroid gland which can have cardiotoxic effect.
Care when using Anafranil's at patients with chronic locks is necessary. Tricyclic antidepressants can cause paralytic intestinal impassability, is preferential at patients of advanced age or at the patients forced to observe a bed rest.
Though about changes of level of leukocytes during treatment by Anafranil it was reported only in some cases, the periodic research of composition of peripheral blood and attention to such symptoms as fever and a pharyngalgia, especially in the first months of therapy is recommended or at prolonged use of drug.

Use at pregnancy and in the period of a lactation
Experience of use of Anafranil at pregnancy is limited. As there are separate messages on possible communication between reception of tricyclic antidepressants and disturbances of fetation, it is necessary to avoid Anafranil's use at pregnancy unless the expected advantage for mother undoubtedly exceeds potential risk for a fruit.
When mother accepted tricyclic antidepressants during pregnancy up to approach of childbirth, at newborns within the first several hours or days of life the withdrawal shown by the asthma, drowsiness, intestinal gripes increased by nervous irritability, the expressed increase or the expressed decrease in the ABP, a tremor, the spastic phenomena or spasms developed. In order to avoid development of this syndrome, Anafranil it is necessary to cancel, whenever possible, gradually, at least, in 7 weeks prior to the expected childbirth.
As active agent of drug gets into breast milk, it is necessary or to stop breastfeeding, or gradually to cancel Anafranil.

Use for children
Experience of use of Anafranil for children under 5 years is not available.

Overdose:

The symptoms developing at Anafranil's overdose are similar to those which are described at overdose of other tricyclic antidepressants. The main complications are disturbances from heart and neurologic frustration.
At children accidental reception of any dose of drug inside has to be regarded as very serious and threatening with a lethal outcome event.
Symptoms
Symptoms usually appear within 4 hours after administration of drug and reach the maximum expressiveness after 24 hours. Owing to the slowed-down absorption (anticholinergic effect of drug), a long elimination half-life and gepatoenteralny recirculation of active agent, the span during which the patient remains in "a risk zone" makes 4-6 days.
The following symptoms can be observed. From the central nervous system: drowsiness, stupor, coma, ataxy, concern, agitation, strengthening of reflexes, muscle tension, choreoathetoid movements, spasms. Besides, manifestations of a serogoninovy syndrome (fervescence, a myoclonus, a delirium, a coma) can be observed. From cardiovascular system: the expressed decrease in the ABP, tachycardia, lengthening of a QTc-interval, arrhythmia (including "torsade de points") disturbances of endocardiac conductivity, shock, heart failure; seldom or never - a cardiac standstill. Besides, respiratory depression, cyanosis, vomiting, fever, a mydriasis, perspiration, an oliguria or an anury are possible.
Treatment
The specific antidote does not exist, treatment is, generally symptomatic and supporting. At suspicion on Anafranil's overdose, especially at children, the patient should be hospitalized and to observe attentively during at least 72 h. If the patient in consciousness, it is necessary to carry out as soon as possible a gastric lavage or to cause vomiting. If the unconscious patient, before a gastric lavage it is necessary to carry out for prevention of aspiration a trachea intubation by means of a tube with a cuff; vomiting is not caused in this case. The specified events are recommended to be held even if from the moment of overdose there passed 12 hours or more as anticholinergic action of Anafranil can slow down gastric emptying. For reduction of absorption of drug use of absorbent carbon is useful.
Treatment is based on use of modern methods of an intensive care with continuous monitoring of functions of heart, gas structure and electrolytes of blood, and also on use in need of such urgent measures as anticonvulsant therapy, artificial ventilation of the lungs and methods of resuscitation. Since there were messages that physostigmine can cause the expressed bradycardia, an asystolia and spasms, it is not recommended to use this drug for treatment of overdose of Anafranil. The hemodialysis and peritoneal dialysis are not effective as concentration of a klomipramin in a blood plasma low.

Storage conditions:

In the dry place at a temperature not above 25 °C. Drug should be stored in the place, unavailable to children. Period of validity of 5 years. Drug should not be used after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets coated 25 mg on 10 pieces in the blister. 2 or 3 blisters together with the application instruction in a cardboard pack.