Azapin tablets 100 mg blister No. 50

Instructions Azapin tablets 100 mg blister No. 50

Composition

active ingredient: clozapine;

1 tablet contains clozapine 25 mg or 100 mg;

Excipients: lactose monohydrate; corn starch; povidone; colloidal anhydrous silica; talc; magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: round tablets with a flat surface with beveled edges and a score, pale yellow color.

Pharmacotherapeutic group

Antipsychotic drugs. ATX code N05A H02.

Pharmacological properties

Pharmacodynamics.

Azapine is an antipsychotic that is different from classic antipsychotic medications.

Clozapine does not induce catalepsy or suppress stereotypic behavior induced by apomorphine or amphetamine. The drug has only a weak blocking effect on dopamine D1-, D2-, D3- and D5-receptors, but is highly effective at D4-receptors, and also has anti-alpha-adrenergic, anticholinergic, antihistamine effects and inhibits the activation response. It also exhibits antiserotonergic properties. Clinically, Azapine exhibits a rapid and pronounced sedative effect and has a strong antipsychotic effect, particularly in patients with schizophrenia resistant to treatment with other drugs. In such cases, Azapine is effective against both the productive and negative symptoms of schizophrenia. Severe extrapyramidal reactions, such as acute dystonia, parkinsonian side effects and akathisia, occur rarely. Unlike standard neuroleptics, Azapin does not increase or hardly increases prolactin levels, which makes it possible to avoid such undesirable effects as gynecomastia, amenorrhea, galactorrhea, and impotence.

Pharmacokinetics.

Absorption. Absorption of Azapine after oral administration is 90-95%. Neither the rate nor the extent of absorption is dependent on food intake. Azapine undergoes moderate first-pass metabolism; absolute bioavailability is 50-60%.

Distribution: In steady-state conditions, peak blood levels are reached on average after 2.1 hours (range 0.4 to 4.2 hours) following a double dose. The volume of distribution is 1.6 L/kg. Clozapine is approximately 95% bound to plasma proteins.

Biotransformation/metabolism. Clozapine is almost completely biotransformed before excretion. Only one of its main metabolites, desmethyl-clozapine, has pharmacological activity. Its action resembles that of clozapine, but is much weaker and of shorter duration.

Elimination: Clozapine is eliminated in a biphasic manner with a mean elimination half-life of 12 hours (6–26 hours). After single doses of 75 mg, the mean elimination half-life is 7.9 hours. This increases to 14.2 hours when steady state is reached with daily doses of 75 mg for at least 7 days. Only minor amounts of unchanged drug are found in the urine and feces. Approximately 50% of the administered dose is excreted as metabolites in the urine and 30% in the feces.

Linearity/non-linearity. It has been noted that during the steady-state period, when the dose of the drug is increased from 37.5 mg to 75 mg and 150 mg 2 times a day, there is a linear dose-dependent increase in the area under the plasma concentration/time curve (AUC), as well as an increase in maximum and minimum plasma concentrations.

Pharmacokinetics of certain patient groups

The drug should be used with extreme caution in patients with impaired liver function, biliary tract and kidney diseases. In severe cases, the use of the drug is contraindicated.

Indication

Treatment-resistant schizophrenia

Azapine should only be prescribed to patients with schizophrenia who are treatment-resistant or tolerant to standard neuroleptics according to the definitions below.

Resistance to standard neuroleptics is a condition where previous treatment with standard neuroleptics at an appropriate dosage and for a sufficient period of time has not resulted in adequate clinical improvement.

Intolerance to standard neuroleptics is a condition in which severe unmanageable undesirable effects of a neurological nature occur (extrapyramidal symptoms or tardive dyskinesia) that make effective neuroleptic therapy with standard neuroleptics impossible.

Risk of recurrence of suicide attempts

Azapine is indicated for the long-term reduction of the risk of relapse of suicidal behavior in patients with schizophrenia or schizoaffective disorder who are assessed for such risk based on their medical history and current clinical presentation.

Psychotic disorders during Parkinson's disease therapy

Azapine is indicated for the treatment of psychotic disorders that develop in the course of Parkinson's disease, if standard therapy has been ineffective.

Failure of standard therapy is defined as lack of control of psychotic symptoms and/or the appearance of a functionally unacceptable increase in motor symptoms after the following measures have been taken:

withdrawal of anticholinergic drugs, including tricyclic antidepressants;

Contraindication

Hypersensitivity to clozapine or to any other component of the drug;

inability to regularly monitor the patient's blood parameters;

history of toxic or idiosyncratic granulocytopenia/agranulocytosis (except for the development of granulocytopenia or agranulocytosis due to previous chemotherapy);

history of agranulocytosis induced by Azapine;

bone marrow dysfunction;

uncontrolled epilepsy;

alcoholic or other toxic psychoses, drug intoxications, comatose states;

vascular collapse and/or central nervous system (CNS) depression of any etiology;

severe kidney or heart disorders (e.g., myocarditis);

acute liver disease accompanied by nausea, loss of appetite or jaundice; progressive liver disease, liver failure;

paralytic intestinal obstruction;

Azapine should not be administered concomitantly with drugs known to cause agranulocytosis; depot neuroleptics should also not be administered concomitantly.

Interaction with other medicinal products and other types of interactions

Concomitant use contraindicated

Azapin should not be used concomitantly with drugs that have a significant suppressive effect on bone marrow function. Azapin should not be used concomitantly with long-acting depot neuroleptics (which have myelosuppressive potential), since these substances cannot be rapidly eliminated from the body in case of need, for example, in case of neutropenia.

Due to the possible potentiation of the sedative effect, alcohol should not be consumed simultaneously with the use of the drug Azapin.

Precautions including dose adjustment

Azapine may potentiate the CNS depressant effects of narcotics, antihistamines, and benzodiazepines. Special caution is required when Azapine is administered in combination with benzodiazepines or other psychotropic drugs, as the risk of vascular collapse, which may rarely be severe and result in cardiac or respiratory arrest, is increased in such cases. It is unclear whether cardiac or respiratory collapse can be prevented by dose adjustment.

Due to the possibility of additive effects, special caution should be exercised when administering concomitant medications that have anticholinergic, antihypertensive, or respiratory depressant effects.

Due to its anti-alpha-adrenergic properties, Azapine can weaken the pressor effect of noradrenaline or other drugs with a predominant alpha-adrenergic effect and eliminate the pressor effect of adrenaline.

Concomitant use of substances known to inhibit the activity of some cytochrome P450 enzymes may result in increased clozapine levels and the dose of clozapine may need to be reduced to prevent adverse effects. This is most important with CYP 1A2 inhibitors such as caffeine (see below) and selective serotonin reuptake inhibitors such as fluvoxamine. Several other serotonin reuptake inhibitors such as fluoxetine, paroxetine and to a lesser extent sertraline are CYP 2D6 inhibitors and, as a result, major pharmacokinetic interactions with clozapine are unlikely. In addition, pharmacokinetic interactions with CYP 3A4 inhibitors such as azole antifungals, cimetidine, erythromycin and protease inhibitors are unlikely, although some have been reported. Since plasma concentrations of clozapine increase with caffeine and decrease by almost 50% after 5 days without caffeine, changes in daily coffee consumption may require changes in clozapine dosage. Abrupt cessation of smoking may increase plasma concentrations of clozapine, leading to increased adverse effects.

There have been reports of interactions between citalopram and clozapine, which may increase the risk of adverse events associated with clozapine. The nature of this interaction has not been fully elucidated.

Concomitant use of substances known to induce cytochrome P450 enzyme activity may reduce clozapine plasma levels, leading to reduced efficacy. Substances known to induce cytochrome P450 enzyme activity and reported to interact with clozapine include, for example, carbamazepine (should not be co-administered with clozapine due to its myelosuppressive potential), phenytoin and rifampicin. Known inducers of CYP1A2, such as omeprazole, may lead to reduced clozapine levels. The potential for reduced efficacy of clozapine when used in combination with these substances should be considered.

Other

Concomitant use with lithium drugs or other substances that affect CNS activity may increase the risk of developing neuroleptic malignant syndrome (NMS).

Caution should be exercised in patients receiving concomitant treatment with other substances that are either inhibitors or inducers of cytochrome P450 enzymes. To date, no clinically significant interactions have been observed with tricyclic antidepressants, phenothiazines and type 1C antiarrhythmics, which are known to bind to cytochrome P450 2D6.

As with other antipsychotics, caution should be exercised when prescribing clozapine with drugs known to increase the QTc interval or to cause electrolyte imbalance.

A summary of the drug interactions considered most important for clozapine is provided in Table 1. This list is not exhaustive.

The most common drug interactions with clozapine

Table 1

Application features

The use of Azapin may cause the development of agranulocytosis. The incidence of agranulocytosis and the mortality rate in patients who develop agranulocytosis have decreased significantly since the introduction of monitoring of leukocyte counts and absolute neutrophil counts. Therefore, the following precautions are mandatory and should be carried out in accordance with official recommendations.

Due to the risks associated with the use of the drug Azapin, its prescription is possible if:

• patients have normal baseline white blood cell count (total white blood cell count ≥ 3500/mm3 (3.5x109/L) and absolute neutrophil count (ANC) ≥ 2000/mm3 (2.0x109/L))

and

• In patients, total white blood cell count and absolute neutrophil count (ANC) may be performed weekly for the first 18 weeks of treatment and at least every 4 weeks thereafter. Monitoring should continue throughout treatment and for 4 weeks after complete discontinuation of Azapine.

Before starting treatment with clozapine, the patient should have a blood test, a medical history, and a physical examination. Patients with a history of heart disease or findings suggestive of cardiovascular abnormalities during physical examination should be referred to a specialist for further investigation, which should include an ECG; the patient should only be treated if the expected benefits of treatment clearly outweigh the risks. The physician should consider the need for an ECG before starting treatment.

Physicians who prescribe this medicine must fully comply with the necessary safety precautions.

Before initiating treatment, physicians should be sure, to the best of their knowledge, that the patient has not previously experienced adverse haematological reactions to clozapine that would require discontinuation of the drug. A prescription for the drug should not be issued for a period longer than the interval between two blood tests.

At any time during treatment with Azapin, immediate discontinuation of the drug is mandatory if the leukocyte count is less than 3000/mm3 (3.0x109/l) or the ANC is less than 1500/mm3 (1.5x109/l). Patients who have had Azapin discontinued due to a decrease in leukocyte count or ANC should not be re-administered this drug.

During each consultation, the patient receiving Azapine should be reminded to contact the doctor immediately if the patient develops any infectious disease. Particular attention should be paid to complaints related to a flu-like condition, such as fever or sore throat, as well as other signs of infection that may indicate the development of neutropenia. Patients and their caregivers should be informed that if any of these symptoms occur, patients should immediately undergo a blood test with a cell count. Physicians who prescribe this medicine are advised to keep a record of all blood test results of the patient and take all necessary measures to prevent accidental re-prescription of the medicine to patients in the future.

Patients with a history of primary bone marrow disorders should be prescribed the drug only when the expected effect of treatment outweighs the risk. Such patients should be examined by a hematologist before starting treatment with Azapin.

Patients with low white blood cell counts due to benign ethnic neutropenia should be given special attention, and treatment with Azapin should only be initiated after obtaining the consent of a hematologist.

Monitoring of white blood cell count and absolute neutrophil count

A white blood cell count and differential should be performed 10 days before starting treatment with Azapin to ensure that only patients with normal white blood cell counts (≥ 3.5x109/L [3500/mm3] and absolute neutrophil counts (≥ 2.0x109/L [2000/mm3]) receive the drug. The white blood cell count and, if possible, the absolute neutrophil count should be monitored weekly for the first 18 weeks, then at least monthly throughout the treatment period. Monitoring should continue throughout the treatment period and for four weeks after complete discontinuation of Azapin or until hematological parameters have recovered. At each visit, the patient should be reminded to seek immediate medical attention at the first sign of infection, fever, sore throat, or other flu-like symptoms. In such cases, a white blood cell count should be performed immediately.

Decreased white blood cell count and absolute neutrophil count

During treatment with Azapin, immediate discontinuation of treatment is mandatory if the leukocyte count is less than 3000/mm3 (3.0 x 109/l) or the ANC is less than 1500/mm3 (1.5 x 109/l).

Thereafter, the white blood cell count and differential should be monitored daily, and patients should be closely observed for the development of flu-like symptoms or other symptoms suggestive of infection. It is recommended to confirm haematological values by performing two blood tests on two consecutive days, but Azapin should be discontinued after the first blood test.

After discontinuation of the drug Azapin, hematological parameters should be analyzed until they are restored.

Table 2

If, after discontinuation of Azapin, a further decrease in the number of leukocytes to a level below 2000/mm3 (2.0 x 109/l) or an absolute neutrophil count below 1000/mm3 (1.0 x 109/l) is observed, treatment should be carried out under the guidance of an experienced hematologist.

Interruption of therapy for reasons related to hematological parameters

Patients in whom Azapine has been discontinued due to a decrease in white blood cell count or AKI (see above) should not be re-administered.

Physicians prescribing Azapin are advised to keep records of all patient blood test results and take all necessary measures to prevent accidental re-prescription of the drug to such patients in the future.

Interruption of therapy for reasons unrelated to hematological parameters

For those patients in whom Azapine therapy, which lasted more than 18 weeks, was interrupted for more than 3 days, but less than 4 weeks, weekly monitoring of the leukocyte count is indicated for an additional 6 weeks. Provided that there are no deviations from the norm, further monitoring can be carried out no more often than once every 4 weeks. If Azapine therapy was interrupted for 4 weeks or more, weekly monitoring is necessary for the next 18 weeks of treatment, and the dose of the drug should be re-titrated.

Other precautions

Azapine contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In the event of eosinophilia, it is recommended to discontinue the use of Azapin if the eosinophil count rises above 3000/mm3 (3.0 x 109/l); treatment can only be restarted after the eosinophil count has decreased to below 1000/mm3 (1.0 x 109/l).

In case of thrombocytopenia, it is recommended to discontinue the use of Azapin if the platelet count is below 50,000/mm3 (50 x 109/l).

Cardiovascular disorders

The use of Azapine is known to be associated with an increased risk of myocarditis, especially during the first two months of treatment, but not limited to this period. Myocarditis has sometimes been fatal. Pericarditis/pericardial effusion and cardiomyopathy have also been reported in association with the use of Azapine; these reports also include cases with fatal outcomes. The development of myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmia, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnea) or symptoms that mimic myocardial infarction. Other symptoms that may occur in addition to the above symptoms include flu-like symptoms. If the development of myocarditis or cardiomyopathy is suspected, treatment with Azapin should be discontinued immediately and the patient should be immediately referred to a cardiologist.

There is a risk of mitral valve insufficiency when Azapine is used in patients with cardiomyopathy. Mitral valve insufficiency has been reported in cases of cardiomyopathy associated with clozapine treatment. Mitral valve insufficiency (detected by two-dimensional echocardiography (2D-Echo)) cases reported with clozapine were mild to moderate in severity.

Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-treated with Azapine.

Myocardial infarction

Myocardial infarction, which may be fatal, has been reported. Assessment of the cause in most cases was complicated by pre-existing severe heart disease.

QT prolongation

As with other antipsychotic drugs, caution is recommended when using the drug in patients with known cardiovascular disease or a family history of QT prolongation.

As with other antipsychotic drugs, caution is advised when prescribing clozapine with drugs known to increase the QTc interval.

Cerebrovascular adverse events

An increased risk of cerebrovascular adverse events has been observed with the use of some antipsychotics. The mechanism of these events is unknown. Azapine should be used with caution in patients with risk factors for stroke.

Metabolic disorders

Atypical antipsychotics, including Azapine, are associated with metabolic abnormalities that may increase the risk of cardiovascular/cerebrovascular events. These events may include hyperglycemia, dyslipidemia, and weight gain.

Hyperglycemia

There have been reports of diabetes mellitus and severe hyperglycemia, sometimes leading to ketoacidosis or hyperosmolar coma, even in patients with no history of hyperglycemia or diabetes. A causal relationship to clozapine has not been established, although in most patients blood glucose levels returned to normal after discontinuation of Azapine. Occasionally, re-administration of the drug was accompanied by a recurrence of hyperglycemia. The effect of Azapine on glucose metabolism in patients with pre-existing diabetes mellitus has not been studied. In patients taking Azapine and developing hyperglycemia with symptoms such as polydipsia, polyuria, polyphagia or weakness, the possibility of impaired glucose tolerance should be considered. In patients with severe treatment-related hyperglycemia, discontinuation of Azapine should be considered. Patients with diabetes mellitus who are taking atypical antipsychotics should have their glucose levels monitored closely. Patients with risk factors for diabetes mellitus (such as obesity, family history) who are starting antipsychotic treatment should have fasting blood glucose testing at the start of treatment and periodically during treatment. Patients with symptoms of hyperglycemia should have fasting blood glucose testing.

Dyslipidemia

Lipid-related adverse events have been observed in patients treated with atypical antipsychotics, including Azapine. Clinical monitoring, including lipid evaluation, is recommended at the beginning of treatment and periodically during treatment.

Weight gain

Weight gain has been observed with the use of Azapin. Clinical monitoring of body weight is recommended.

Patients with existing stable liver disease may receive Azapin, but require regular monitoring of liver function tests during therapy. Patients who develop symptoms of possible liver dysfunction, such as nausea, vomiting and/or anorexia, should have liver function tests performed during treatment with Azapin. If the increase in values is clinically significant (more than 3 times the upper limit of normal (ULN)) or if symptoms of jaundice develop, Azapin treatment should be discontinued. Treatment should only be resumed when liver function tests return to normal. In such cases, liver function should be closely monitored after re-administration of Azapin.

Azapine exhibits anticholinergic activity, which may lead to the development of undesirable effects throughout the body. Careful monitoring is necessary in the presence of prostate enlargement and narrow-angle glaucoma. Presumably due to its anticholinergic properties, Azapine can cause intestinal motility disorders of varying severity: from constipation to intestinal obstruction, fecal impaction and paralytic ileus. Rarely, these cases can be fatal. Particular caution is required in patients with a history of colon disease or lower abdominal surgery who are receiving concomitant medications known to cause constipation (especially drugs with anticholinergic properties, such as some antipsychotics, antidepressants and antiparkinsonian drugs), as such drugs may worsen the situation. Identification and treatment of constipation is of utmost importance.

During therapy with Azapin, patients may experience a transient increase in body temperature above 38 °C with a peak incidence in the first 3 weeks of treatment. This increase in temperature is usually benign. Sometimes it may be associated with an increase or decrease in the number of leukocytes in the blood. Patients with an increased body temperature should be carefully examined to exclude the possibility of an underlying infection or the possibility of agranulocytosis. In patients with a high body temperature, the possibility of developing neuroleptic malignant syndrome (NMS) should be considered. If this diagnosis is confirmed, the use of the drug should be discontinued immediately and appropriate therapeutic measures should be taken.

Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus have been reported rarely during treatment with clozapine. The mechanism of this phenomenon is currently unknown. Cases of severe hyperglycemia, accompanied by ketoacidosis or hyperosmolar coma, have been reported very rarely in patients with no history of hyperglycemia; some of these cases were fatal. Discontinuation of clozapine has been shown to result mainly in a reversal of impaired glucose tolerance, and rechallenge has been shown to result in a recurrence of the disorder. Discontinuation of clozapine should be considered in patients in whom active medical treatment of hyperglycemia has failed.

Since the use of Azapine may be associated with the development of thromboembolism, immobilization of patients should be avoided. Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotic drugs often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Azapine and preventive measures should be taken.

Acute withdrawal reactions have been reported following abrupt discontinuation of clozapine, and gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g., due to leukopenia), the patient should be closely monitored for recurrence of psychotic symptoms and symptoms associated with resumption of cholinergic activity, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Use in patients over 60 years of age

It is recommended to start treatment in elderly patients with the lowest dose of the drug (12.5 mg once a day on the first day of treatment).