Azaleprol® (Azaleprol®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceClozapineClozapine
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  • Azaleprol®
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    LEKHIM, AO     Ukraine
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    ORGANICS, JSC     Russia
  • Clozapine
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    MOSCOW ENDOCRINE FACTORY, FSUE     Russia
  • Clozasten®
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    VALENTA PHARM, PAO     Russia
  • Leponeks®
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    Novartis Pharma AG     Switzerland
    • Dosage form: & nbsppills
    Composition:

    1 tablet contains:

    active substance: clozapine 25 mg or 100 mg;

    Excipients: lactose monohydrate 67 mg or 110 mg, potato starch 5 mg or 32.5 mg, magnesium stearate 1 mg or 2.5 mg, povidone-25 2 mg or 5 mg.

    Description:

    Tablets are light yellow or light yellow with a greenish tint of color, round, flat-cylindrical in shape.

    Pills with a dosage of 25 mg with bevel, tablets with a dosage of 100 mg with risk and chamfer.

    Marble is allowed on the surface of the tablets.

    Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)
    ATX: & nbsp

    N.05.A.H.02   Clozapine

    Pharmacodynamics:

    Clozapine - an atypical neuroleptic, has an antipsychotic and sedative effect, without causing any significant extrapyramidal reactions and virtually no effect on the level of prolactin in the blood. AT experimental studies have shown that the drug does not cause catalepsy and does not suppress stereotyped behavior caused by the introduction of apomorphine or amphetamine.

    Clozapine weakly blocks D1-3- and D5-dophamine receptors and potent- D4dopamine receptors. In addition, it has a pronounced α-adreno, m-cholino, H1- histamine-blocking action, and also suppresses the activation reaction on the electroencephalogram (EEG). It is also shown that clozapine is able to block 5-HT-serotonin receptors. Clinically clozapine has a rapid and noticeable sedative effect, as well as an antipsychotic effect in patients with schizophrenia, resistant to other antipsychotic drugs. Clozapine has been shown to be effective against productive and negative symptoms in both short-term and long-term use. In patients with schizophrenia resistant to treatment with other drugs, clinically significant improvement was observed in approximately 30% of patients after 6 weeks of treatment with clozapine. When observed for 12 months, improvement was observed in 39-44% of patients.

    In addition, there was a positive dynamics of some cognitive impairments. In epidemiological studies it was also shown that in patients with schizophrenia and schizoaffective psychosis who received clozapine treatment,there is an almost 7-fold decrease in the frequency of suicidal attempts and a 4-6-fold decrease in mortality from suicide, compared to patients who have not received treatment.

    A distinctive quality of clozapine is that it practically does not cause significant extrapyramidal reactions, such as acute dystonia and tardive dyskinesia. Side effects in the form of parkinsonism and akathisia are rare. Unlike other neuroleptics, clozapine does not increase or very slightly increases the concentration of prolactin, which avoids such side effects as gynecomastia, amenorrhea, galactorrhea and impotence.

    Potentially serious unwanted reactions of clozapine therapy are granulocytopenia and agranulocytosis, the incidence of which is 3% and 0.7%, respectively.

    Pharmacokinetics:

    Suction. After oral administration clozapine absorbed by 90-95%. Food intake does not affect the rate and extent of absorption. Due to the moderate metabolism at the "first passage" through the liver, the absolute bioavailability of clozapine is 50-60%. At an equilibrium state against the background of taking the drug 2 times a day, the maximum concentration in the blood is reached, on average, after 2.1 hours (from 0.4 to 4.2 hours).

    Distribution. The volume of distribution is 1.6 l / kg.The binding of clozapine to plasma proteins is about 95%.

    Metabolism. Clozapine is almost completely metabolized. Of the main metabolites, only one activity - the desmethyl derivative - has activity. Its pharmacological action is similar to the action of clozapine, but it is much less pronounced and less prolonged. Unchanged clozapine is found in urine and feces only in trace amounts. About 50% of the accepted dose of clozapine is excreted in the form of metabolites with urine and 30% with feces.

    Excretion. The elimination of clozapine is biphasic, the half-life of the final phase averages 7.9 hours. This value increases to 14.2 hours when the equilibrium state is reached as a result of taking the drug at a dose of 75 mg per day for at least 7 days. It was noted that during the equilibrium period with an increase in the daily dose of the drug from 37.5 mg to 75 mg and 150 mg (prescribed in 2 doses), a linear dose-dependent increase in the area under the concentration-time curve (AUC), as well as an increase in the maximum and minimum plasma concentrations.

    Indications:Schizophrenia, resistant to therapy. TOlozapine is indicated for the treatment of patients with schizophrenia, resistant to therapy, i. which have no effect from the use of "typical" neuroleptics or who are noted for their intolerance.
    Lack of effect is defined as the lack of satisfactory clinical improvement despite treatment with at least two available antipsychotics given in adequate doses for the required period of time.

    Intolerance is defined as the inability to achieve sufficient clinical improvement with "typical" antipsychotics because of severe and unrecoverable adverse neurological reactions (extrapyramidal side effects or tardive dyskinesia).

    Reducing the risk of repeated occurrence of suicidal behavior in patients with schizophrenia or schizoaffective psychosis. Clozapine is shown to reduce the risk of recurrence of suicidal behavior in patients with schizophrenia or schizoaffective psychosis who, according to anamnesis and clinical status, have a chronic risk of recurrence of suicidal behavior.

    Under suicidal behavior means the actions of the patient, as a result of which the risk of his death is high.

    Correction of psychotic disorders the patients with Parkinson's disease. Clozapine is indicated for the treatment of psychotic disorders arising from Parkinson's disease in cases of ineffectiveness of standard treatment.

    Ineffectiveness of standard treatmentI am defined as insufficient control of psychotic symptoms and / or deterioration of motor functions, unacceptable in terms of functional status, after the following measures are taken:

    - abolition of anticholinergic drugs, including tricyclic antidepressants;

    - attempts to reduce the dose of an antiparkinsonian drug that has a dopaminergic effect.

    Contraindications:

    - Hypersensitivity to clozapine or any other components of the drug;

    - the inability to regularly conduct a general blood test (with the definition of the leukocyte formula);

    - toxic or idiosyncratic granulocytopenia / agranulocytosis in the anamnesis (except for the development of granulocytopenia / agranulocytosis due to previously used chemotherapy);

    - impaired bone marrow function;

    - epilepsy, resistant to ongoing therapy;

    - alcoholic or other toxic psychosis, drug intoxication, coma;

    - Vascular collapse and / or CNS depression of any etiology;

    - severe kidney or heart disease (eg, myocarditis);

    - active liver disease, accompanied by nausea, anorexia, or jaundice;

    - progressive liver disease, liver failure;

    - paralytic intestinal obstruction;

    - children's age till 18 years;

    - lactose intolerance, lactase deficiency or glucose-galactase malabsorption.

    Carefully:

    The drug should be used with caution in patients with a high risk of developing cerebrovascular disorders, as well as elderly patients with dementia.

    Due to clozapine may cause agranulocytosis, a prerequisite is the observance of the following precautions.

    Simultaneously with clozapine should not be used drugs, strongly depressing the bone marrow. In addition, simultaneous use of long-acting antipsychotics (depot form) should be avoided,which have a potential mielosupressivnym action and can not be quickly removed from the body if necessary (for example, the occurrence of granulocytopenia).

    Patients with a history of primary bone marrow disease, clozapine can be prescribed only in the event that the expected effect of therapy exceeds the risk of developing unwanted reactions. Such patients before the start of treatment with clozapine should be carefully examined by a hematologist. Particular attention should be paid to patients who have a low number of white blood cells due to benign ethnic neutropenia. Treatment with clozapine in such cases can be initiated after obtaining the consent of the hematologist.

    Clozapine has m-cholinoblocking activity, which can cause side effects from various organs and body systems. Patients with prostatic hyperplasia or angle-closure glaucoma are closely monitored.

    Perhaps, because of their m-cholinoblocking properties clozapine can cause disturbances of intestinal peristalsis, the degree of which varies from constipation to obstruction by coprolites and paralytic intestinal obstruction; rare cases of death are described.

    Pregnancy and lactation:

    In studies of reproductive performance, no signs of impaired fertility or a negative effect of clozapine on the fetus were detected in animals. However, the safety of clozapine in pregnant women has not been studied, so the drug should be given to pregnant women only if the expected benefit to the mother significantly exceeds the possible risk to the fetus.

    Studies conducted in animals suggest that clozapine is excreted in breast milk; therefore, women taking clozapine, should stop breastfeeding.

    Dosing and Administration:

    Inside.

    Doses of the drug must be selected individually. Each patient should be given the minimum effective dose.

    Patients receiving drugs interacting with clozapine (such as benzodiazepines or selective serotonin reuptake inhibitors) need adequate dose adjustment.

    Schizophrenia, resistant to therapy

    The initial stage of treatment: on the first day, appoint 12.5 mg (1/2 tablets of 25 mg) 1 or 2 times a day; the second day - 1 or 2 tablets of the drug for 25 mg.In the future, under the condition of good tolerance, the dose of the drug can be slowly increased by 25-50 mg so that within 2-3 weeks to reach a daily dose of 300 mg. Then, if necessary, the daily dose can be increased further, by 50-100 mg every 3-4 days or, better, 7 days.

    Therapeutic range of doses. In most patients, the antipsychotic effect of the drug can be expected with a daily dose of 300-450 mg (in several steps). In some patients, smaller doses may be effective, others may require doses up to 600 mg per day. The daily dose can be divided into individual methods unevenly, assigning it most before bedtime.

    The maximum dose. To achieve the full therapeutic effect, some patients are required to prescribe higher doses of the drug. In this case, it is advisable to gradually increase the dose (each time not more than 100 mg) to reach 900 mg per day. It should be taken into account the possibility of more frequent development of side effects (in particular, the appearance of seizures) with the intake of more than 450 mg of the drug per day.

    Maintenance dose. After reaching the maximum therapeutic effect in many patients, it is possible to switch to receiving lower maintenance doses.Reduce the dose should be slow and cautious. Supportive treatment should last at least 6 months. If the daily dose of the drug does not exceed 200 mg, you can switch to a single evening drug intake.

    Termination of therapy. In the event of a planned discontinuation of clozapine treatment, a dose reduction is recommended, gradually, within 1-2 weeks. If necessary, a sudden withdrawal of the drug (e.g., in the case of leukopenia) should establish careful monitoring of patients in connection with the possible exacerbation of psychotic symptoms and the syndrome "cancel", which manifests itself as profuse sweating, headache, nausea, vomiting and diarrhea, and associated cessation of the m-cholinoblocking action of clozapine.

    Resumption of treatment. If after more than 2 days, the treatment should be resumed starting with a dose of 12.5 mg (1/2 tablets of 25 mg), applied 1-2 times during the first day. If this dose of the drug is tolerated well, then in the future, increasing the dose to achieve a therapeutic effect can be carried out more quickly than is recommended for initial treatment.However, if a patient in the initial treatment period was observed respiratory arrest or cardiac activity, but then the dose of the drug was able to successfully bring to therapy, increasing the dose on repeated administration of the drug should be performed with extreme caution.

    Transition from previous treatment with neuroleptics to clozapine therapy. Use clozapine in combination with other antipsychotics is not recommended. In the event that treatment with the drug must begin in a patient already taking an antipsychotic inside, reducing the dose or canceling the previous drug should be gradual. Based on the clinical data, the attending physician should determine whether to stop taking another neuroleptic before starting clozapine therapy.

    Reducing the risk of repeated suicidal behavior in schizophrenia and schizoaffective psychosis

    In the treatment of patients with schizophrenia and schizoaffective psychosis having recurrence risk of suicidal behavior, should follow the same recommendations for the application and dosage regimen, which are given for schizophrenic patients resistant to therapy.

    To reduce the risk of suicidal behavior, it is recommended that clozapine, at least for 2 years. After a two-year course of treatment, it is recommended to reassess the risk of suicidal behavior in the patient. Further, the need for continuation of clozapine therapy is determined on the basis of regular careful assessment of the risk of repeated occurrence of suicidal behavior.

    Psychosis in Parkinson's disease (in cases of ineffectiveness of standard therapy)

    The initial dose of clozapine should not exceed 12.5 mg per day (1/2 tablets of 25 mg), it should be taken in the evening. Then the dose should be increased by 12.5 mg, not more than twice a week, to a maximum of 50 mg. A dose of 50 mg can be prescribed no earlier than the end of the second week after the start of treatment. The entire daily dose is preferably taken in 1 evening.

    The average effective dose is 25-37.5 mg per day on average. In the event that treatment for at least one week at a daily dose of 50 mg does not provide a satisfactory therapeutic effect, a further cautious increase in the daily dose of not more than 12.5 mg per week is possible.

    The dose of 50 mg per day can be exceeded in exceptional cases. Do not exceed the dose of 100 mg per day.

    Increase in the dose should be limited or postponed in the case of development of orthostatic hypotension, expressed sedation or confusion. During the first weeks of treatment, blood pressure control is necessary.

    An increase in the dose of antiparkinsonian drugs (levodopa), if it is shown on the basis of the assessment of the motor status, is possible not earlier than 2 weeks after complete relief of psychotic symptoms; to improve the condition of motor functions, it is possible to increase the dose of levodopa by 17-68% of the initial dose.

    If this increase causes the recurrence of psychotic symptoms, the dose of clozapine can be increased by 12.5 mg per week to a maximum dose of 100 mg per day taken in 1-2 doses (see above).

    At the conclusion of therapy it is recommended to gradually reduce the daily dose by 12.5 mg not more often than once a week (preferably in 2 weeks).

    Treatment should be immediately discontinued if neutropenia or agranulocytosis develops. In this situation, a thorough psychiatric observation is necessary, since the symptoms can quickly recur.

    Use clozapine It follows only if before the start of treatment the number of leukocytes ≥3500 / mm3, the absolute number of neutrophils ≥2000 / mm3 and the indicators are within the normal range, and if there is an opportunity to regularly determine the number of leukocytes and the absolute number of neutrophils: weekly for the first 18 weeks, then at least once every 4 weeks throughout the course of treatment and 4 weeks after the end of treatment.

    In the case of eosinophilia, clozapine It is recommended if the number of eosinophils exceeds 3000 / mm3, and resumption of treatment is possible only after a decrease in the number of eosinophils less than 1000 / mm3.

    In case of thrombocytopenia, it is recommended to cancel clozapine, if the number of platelets decreases less than 50,000 / mm3.

    Regular control of the number of leukocytes and the absolute number of neutrophils. 10 days before the start of clozapine treatment, it is necessary to determine the number of leukocytes and the leukocyte formula to make sure that only patients with normal parameters (the number of white blood cells ≥3500 / mm3 and the absolute number of neutrophils ≥2000 / mm3). After starting clozapine therapy, the number of white blood cells and the absolute number of neutrophils should be monitored weekly for 18 weeks,in the subsequent - at least once every four weeks during the entire period of taking the drug, and 4 weeks after the complete withdrawal of clozapine.

    During each visit, the treating physician should remind the patient of the need for immediate treatment in the event of any infection, fever, sore throat, or other flu-like symptoms. In case of any symptoms of infection, the leukocyte blood formula should be determined immediately. Reducing the number of leukocytes and / or the absolute number of neutrophils. In the event that in the first 18 weeks of treatment with clozapine, the number of leukocytes decreases to 3500-3000 / mm3 and / or the absolute number of neutrophils is reduced to 2000-1500 / mm3, these indicators should be monitored at least 2 times a week. After 18 weeks of clozapine therapy, hematological control with a frequency of at least 2 times a week is necessary in the event that the number of white blood cells decreases to 3000-2500 / mm3 and / or the absolute number of neutrophils - up to 1500-1000 / mm3.

    In addition, if during the period of clozapine therapy there is a significant decrease in the number of leukocytes in comparison with the initial one, a repeated determination of the number of leukocytes and the leukocyte formula should be carried out.Decrease in the number of leukocytes is considered essential at its single reduction to 3000 / mm3 and below or in the case of a total reduction of 3000 / mm3 or more for 3 weeks.

    The drug should be immediately withdrawn if, during the first 18 weeks of clozapine therapy, the number of leukocytes decreased to <3000 / mm3 or the absolute number of neutrophils decreased to <1500 / mm3, and if in the period after 18 weeks of clozapine therapy the number of leukocytes decreased to <2500 / mm3 or the absolute number of neutrophils decreased to <1000 / mm3. In these cases, the number of white blood cells and the leukocyte count must be determined daily, and the patients carefully monitored for flu-like symptoms or other signs of infection. After discontinuation of the drug, hematological control is carried out until the hematologic parameters are fully normalized.

    If, after the withdrawal of clozapine, there is a further decrease in the number of white blood cells below 2000 / mm3 and / or the absolute number of neutrophils below 1000 / mm3, treatment of this condition should be conducted under the guidance of an experienced hematologist. If possible, the patient should be transferred to a specialized hematology unit,where he can be placed in a separate box and he may be prescribed granulocyte-macrophagal or granulocyte colony-stimulating factor.

    It is recommended to stop colony-stimulating therapy after increasing the number of neutrophils to a value exceeding 1000 / mm3.

    Patients who clozapine was canceled due to leukopenia and / or neutropenia, it can not be re-administered.

    To confirm the hematological parameters it is recommended that a second blood test be performed the next day, however clozapine should be canceled after receiving the results of the first analysis.

    Table 1. Control of blood values ​​during the first 18 weeks of treatment with clozapine

    Number of blood cells

    Necessary actions

    Number of white blood cells / mm3 (m)

    Absolute number of neutrophils mm3

    (m)

    ≥3500 (≥3,5x109)

    ≥2000 (≥2x109)

    Continuation of clozapine treatment

    3000-3500 (3-3.5x 109)

    15 00-2000 (1.5-2x109)

    Continuation of clozapine treatment. Control of the blood test 2 times a week until the indicators stabilize or the number of neutrophils and other leukocytes increases.

    <3000 (<3x109)

    <1500 (<1.5x109)

    Immediate cessation of clozapine treatment. Control of blood tests every day until the indicators are normalized. Control of infectious complications. The use of clozapine does not resume.

    Table 2.Monitoring blood levels after the first 18 weeks of treatment with clozapine

    Number of blood cells

    Necessary actions

    Number of white blood cells / mm3 (m)

    Absolute number of neutrophils mm3 (m)

    ≥3000 (≥3х109)

    ≥1500 (≥1.5x109)

    Continuation of clozapine treatment

    2500-3000 (2.5-3 x 109)

    1000-1500 (1-1.5x109)

    Continuation of clozapine treatment. Control of the blood test 2 times a week until the indicators stabilize or the number of neutrophils and other leukocytes increases.

    <2500 (<2.5 x 109)

    <1000 (<1x109)

    Immediate cessation of clozapine treatment. Control of blood tests every day until the indicators are normalized. Control of infectious complications. Reception of clozapine does not renew

    Interruption of therapy due to non-hematological causes

    Patients with clozapine therapy lasting more than 18 weeks were interrupted for more than 3 days (but less than 4 weeks), weekly monitoring of the number of leukocytes and neutrophils in the blood was shown for an additional 6 weeks. If no hematologic changes are noted, further monitoring of hematologic indices can be carried out at least once every 4 weeks. If clozapine therapy was interrupted for 4 weeks or more, weekly hematological control is required in the next 18 weeks of treatment.

    Use in patients aged 65 years and older

    It is recommended to start treatment with very small doses (12.5 mg once a day on the first day) and then increase the dose by no more than 25 mg per day.

    The experience of using clozapine in patients aged 65 years and older does not make it possible to conclude that there are age differences in response to treatment with clozapine.

    Use in patients with a history of seizures, cardiovascular disease or kidney disease

    In patients with a history of seizures, with cardiovascular disease or kidney disease, the dose given on the first day should be 12.5 mg once a day; further increase in the dose should be done slowly and gradually (severe cardiovascular diseases and kidney diseases are contraindications to the appointment of clozapine).

    Side effects:

    The undesirable effects of clozapine are largely predictable on the basis of its pharmacological properties, with the exception of agranulocytosis.

    The frequency of undesired reactions is estimated as follows: "very often" (> 1/10), "often" (> 1/100, <1/10), "infrequently" (> 1/1000, <1/100), " rarely "(> 1/10 000, <1/1000)," very rarely "(<1/10 000), including individual messages.

    Disorders from the blood and lymphatic system: often - leukopenia, neutropenia, eosinophilia, leukocytosis; infrequently - agranulocytosis; rarely anemia; very rarely - thrombocytopenia, thrombocytosis.

    Disorders from the metabolism and nutrition: often - weight gain; rarely - impaired glucose tolerance, the development of diabetes mellitus, exacerbation of the concomitant diabetes, it is very rare - ketoacidosis, hyperosmolar coma, severe hyperglycemia, hypercholesterolemia, hypertriglyceridemia.

    Disorders from the psyche: often - dysarthria; infrequently, dyspharmia; rarely - anxiety, agitation.

    Disturbances from the nervous system: very often - drowsiness / sedation, dizziness; often - "blurred" vision, headache, tremor, muscle rigidity, akathisia, extrapyramidal symptoms, convulsions / myoclonic seizures; rarely confusion, delirium; very rarely - tardive dyskinesia, obsessive-compulsive disorder.

    Heart Disease: very often - tachycardia; often - ECG changes; rarely - arrhythmias, myocarditis, pericarditis; very rarely - cardiomyopathy.

    Vascular disorders: often - increased blood pressure, orthostatic hypotension, fainting; rarely - collapse, thromboembolism.

    Disturbances from the respiratory system, chest and mediastinal organs: rarely - aspiration of food, pneumonia and lower respiratory tract infection (in some cases, with a fatal outcome); very rarely - respiratory depression / respiratory arrest.

    Disorders from the gastrointestinal tract: very often - constipation, hypersalivation; often - nausea, vomiting, dry mouth; rarely - dysphagia; very rarely - an increase in parotid salivary gland, intestinal obstruction (including paralytic), blockage by coprolites.

    Disturbances from the liver and bile ducts: often - increased activity of "liver" enzymes; rarely - hepatitis, cholestatic jaundice, pancreatitis; very rarely - fulminant liver necrosis.

    Disturbances from the skin and subcutaneous tissues: very rarely - skin reactions.

    Disorders from the kidneys and urinary tract: often - urinary incontinence, urinary retention, very rarely - interstitial nephritis.

    Violations of the genitals and breast: very rarely - priapism.

    General disorders and disorders at the site of administration: often - a feeling of fatigue, benign hyperthermia, sweating / thermoregulation disorders, infrequently - malignant neuroleptic syndrome, very rarely - sudden death (causes unknown).

    Laboratory and instrumental data: rarely - increased activity of creatine phosphokinase.

    Very rarely, when taking clozapine, there was a development of ventricular tachycardia, cardiac arrest and lengthening of the interval QT, which can be manifested by the appearance torsade des pointes (polymorphic ventricular tachycardia), but the cause-and-effect relationship of these phenomena with taking the drug is not established.

    In the treatment of clozapine patients older than 65 years possibly the development of orthostatic hypotension. In addition, there have been reports of rare cases of tachycardia, which can persist for a long time. Patients of this age group, especially those with impaired cardiovascular function, may be more sensitive to these effects. Elderly patients may be particularly sensitive to the m-cholinoblocking effects of clozapine, resulting in such manifestations as urinary retention and constipation.

    Overdose:

    Symptoms: deafness, drowsiness, co-morbidity, respiratory depression, coma, delirious disorders, development of large epileptic seizures, anxiety, agitation, lability of body temperature, tachycardia, lowering of arterial pressure, cardiac arrhythmias, collapse, atony of intestines.

    Treatment: gastric lavage with the appointment of sorbents, maintenance of respiratory function and cardiovascular system, control of electrolyte balance and acid-base state; symptomatic treatment. For 4 days after the disappearance of the symptoms of poisoning, the patient is monitored because of possible late complications. Peritoneal dialysis or hemodialysis are ineffective.

    Interaction:

    Simultaneously with clozapine, drugs that significantly inhibit bone marrow function can not be used.

    Clozapine can enhance the central effect of alcohol, monoamine oxidase (MAO) inhibitors and CNS depressant drugs (such as general anesthetics, H blockers1-gistaminovyh receptors and benzodiazepines).

    Particular caution is recommended when the treatment with clozapine is started in patients,(or recently received) benzodiazepines or any other psychotropic drugs, as this increases the risk of collapse, which in rare cases can be severe and lead to cardiac arrest and / or respiratory depression.

    Because of the possibility of additive action, care should be taken when using drugs that have m-holin-blocking, hypotensive effects, as well as drugs that depress respiration. Simultaneous administration of lithium drugs or other drugs that affect the functions of the central nervous system may increase the risk of developing a malignant neuroleptic syndrome.

    Thanks to its αadrenoblocking effect, clozapine can alleviate the hypertensive effects of norepinephrine or other drugs with an advantageous α-adrenomimeticheskim action, and eliminate the vasoconstrictive effect of epinephrine. There are some reports of severe seizures, including patients without epilepsy, and cases of delirium, while using clozapine with valproic acid. These cases may be the result of pharmacodynamic interaction, the mechanism of which remains unclear.

    As well as other antipsychotics, clozapine should be used with caution in conjunction with other drugs that can lengthen the interval QT or cause electrolyte disturbances.

    In patients with Parkinson's disease receiving clozapine with the relief of psychotic symptoms, it is possible to increase the dose of levodopa by 17-68% from the initial for the purpose of improving the condition of motor functions (in 15 months improvement by 11-22% on the motor scale).

    Special instructions:

    Use clozapine It follows only if before the start of treatment the number of leukocytes ≥3500 / mm3, the absolute number of neutrophils ≥2000 / mm3, and the indices are within the normal range, and if there is an opportunity to regularly determine the number of leukocytes and the absolute number of neutrophils: weekly for the first 18 weeks, then at least once every 4 weeks throughout the course of treatment and 4 weeks after the end of treatment . In the case of eosinophilia, clozapine It is recommended if the number of eosinophils exceeds 3000 / mm3, and resumption of treatment is possible only after a decrease in the number of eosinophils less than 1000 / mm3.

    In case of thrombocytopenia, it is recommended to cancel clozapine, if the number of platelets decreases less than 50,000 / mm3.

    Against the background of clozapine, orthostatic hypotension may develop, accompanied or not accompanied by a syncope. In rare cases (approximately one in 3,000 patients receiving clozapine) may develop a severe collapse, which may be accompanied by cardiac arrest and / or breathing. The likelihood of such complications is higher during the initial selection of the dose of the drug, when it is increased too quickly. In very rare cases, these complications developed even after the first administration of the drug. In this regard, the beginning of treatment with clozapine requires careful medical supervision of patients.

    In rare cases, in the first month of therapy and very rarely later, tachycardia may occur at rest, accompanied by arrhythmias, shortness of breath or signs and symptoms of heart failure. When these signs and symptoms appear, especially during the dose selection period, an urgent examination is necessary to exclude the diagnosis of myocarditis. When confirming the diagnosis of myocarditis clozapine should be canceled. Further in the course of treatment, it is extremely rare to see similar signs and symptoms, possibly associated with cardiomyopathy.If the diagnosis of cardiomyopathy is confirmed in assessing the signs / symptoms that have been confirmed, treatment should be canceled, unless the expected benefit from the application obviously exceeds the risk to the patient.

    In patients with Parkinson's disease, control of blood pressure in the vertical and horizontal position during the first weeks of treatment is necessary.

    In patients with a history of seizures, with cardiovascular disease or kidney disease, the dose given on the first day should be 12.5 mg once a day; further increase in the dose should be done slowly and gradually (note: severe cardiovascular diseases and kidney diseases are contraindications to the appointment of clozapine).

    Patients with concomitant liver diseases of stable course may receive clozapine, but need a regular study of liver function indicators in the process of therapy. If clozapine develops symptoms during the treatment that may indicate liver dysfunction (such as nausea, vomiting, and / or anorexia), liver function tests should be performed immediately.In the case of a clinically significant increase in these indicators or the appearance of jaundice, treatment with clozapine should be discontinued. Resume treatment is possible only if the liver function is normalized. After the resumption of treatment, it is necessary to continue to monitor liver function indicators on a regular basis.

    During clozapine therapy, a transient increase in body temperature to 38 ° C or more is possible, the frequency of this phenomenon being highest in the first 3 weeks of treatment. This increase in temperature is usually benign in nature. Sometimes it can be accompanied by an increase or decrease in the number of leukocytes in the blood. Fevering patients should be carefully examined to avoid the presence of an infectious disease or the development of agranulocytosis. In the presence of high fever should be remembered about the possibility of developing a malignant neuroleptic syndrome.

    Patients without a history of carbohydrate metabolism disorders rarely had severe hyperglycemia during clozapine treatment, sometimes resulting in a ketoacidosis / hyperosmolar coma.Although the causal relationship with the administration of clozapine was not accurately established, most patients after stopping the drug treatment normalized the glucose concentration in the blood, and the resumption of therapy in some cases again led to hyperglycemia. The effect of clozapine on carbohydrate metabolism in diabetic patients has not been studied. There was reported a violation of glucose tolerance, hyperglycemia, ketoacidosis and hyperosmolar coma in patients who did not have a history of hyperglycemia. It should be remembered about the possibility of impaired glucose tolerance when appearing in patients taking clozapine such symptoms of hyperglycemia as polydipsia, polyuria, polyphagia or weakness. In patients with severe hyperglycemia, developed against the background of taking the drug, should consider the question of the abolition of clozapine.

    There is a risk of metabolic disorders, leading to a slight disruption in the regulation of glucose metabolism and, possibly, the development of manifestations of the pre-diabetic state or worsening of the course of concomitant diabetes mellitus.

    Because the clozapine can cause sedation and weight gain, which increases the risk of thromboembolism, immobilization of patients should be avoided.

    In a number of cases, patients with dementia who received atypical antipsychotics had an increased risk of developing cerebrovascular accidents (the pathogenesis of these disorders is not established). It is impossible to exclude the possibility of increasing the risk of developing cerebrovascular disorders in other categories of patients or when using "typical" antipsychotics.

    When appointing clozapine, as with the appointment of other neuroleptics, patients with cardiovascular disease or having a family history of the syndrome of an elongated interval QT, careful monitoring of this category of patients is recommended. It is also necessary to use caution clozapine together with other drugs capable of lengthening the interval QT.

    The efficacy and safety of clozapine in elderly patients with mental disorders in dementia have not been studied. In observational studies with the use of antipsychotics, there was an increase in the mortality of such patients. The risk factors for the development of lethal outcome (information from published sources) in this category of patients against the background of antipsychotic drugs maysedation, cardiovascular diseases (eg, arrhythmias), lung diseases (eg, pneumonia, including those caused by aspiration).

    In some patients, amenorrhea may develop on the background of treatment with neuroleptics other than clozapine. When transferring patients to clozapine treatment, a normal menstrual cycle can be restored. Therefore, women of childbearing age should adhere to adequate contraceptive measures.

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

    During the administration of the drug, patients are advised to refrain from driving and other mechanisms, as well as to be cautious when engaging in activities that require increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Tablets, 25 mg and 100 mg.

    Packaging:

    50 tablets each with a dosage of 25 mg in a polymer container; 1 container, together with the instruction for use, is placed in a pack of cardboard.

    For 10 tablets with a dosage of 100 mg in the blister; 5 blisters together with instructions for use are placed in a pack of cardboard.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001204
    Date of registration:14.11.2011
    Expiration Date:14.11.2016
    The owner of the registration certificate:LEKHIM, AO LEKHIM, AO Ukraine
    Manufacturer: & nbsp
    Representation: & nbspAlfa Grand TD, LLCAlfa Grand TD, LLCRussia
    Information update date: & nbsp04.02.2017
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