Clozapine

Package leaflet (information for patients)

Tradename
Clozapine

Dosage form
Tablets 100 mg.

Description
Round, flat, beveled to the edge white tablets with an imprint in the form of the brand name "V" on one side.

Structure
Active ingredient: Clozapine 100 mg.
Excipients: microcrystalline cellulose 102, calcium stearate, aerosil ® 200 (hydrophilic pyrogenic silicon dioxide).

Pharmacotherapeutic group
Antipsychotic drugs.

Pharmacological properties
An atypical antipsychotic, has a pronounced antipsychotic and sedative effect.
Pharmacodynamics
Clozapine is a derivative of tricyclic dibenzodiazepine, an antipsychotic drug that differs from standard antipsychotics both in its pharmacological properties and clinical action. In pharmacological experiments, clozapine does not induce catalepsy, does not inhibit apomorphine or amphetamine- induced stereotyped behavior. Clozapine slightly blocks dopamine D1-, D2-, D3- and D5-receptors and more D4 -receptors, in addition to strong anti-alpha-adrenergic, anticholinergic, antihistamine actions and suppression of the central nervous system activation reaction. In addition, the drug has been shown to have antiserotonergic properties. Clozapine has a rapid and pronounced sedative effect and has a strong antipsychotic effect, particularly in patients who are resistant to treatment with other drugs. There have been no studies of the acute effect of short-term treatment of suicidal behavior in patients with other mental disorders, therefore the use of Clozapine for these indications is not recommended. Clozapine should not be used in depressed patients with psychotic symptoms.
Clozapine practically does not cause serious extrapyramidal reactions such as acute dystonia. Parkinson -like side effects and akathisia are rare. Unlike the "classic" antipsychotics, clozapine does not increase or slightly increases prolactin levels, which avoids side effects such as gynecomastia, amenorrhea, galactorrhea and impotence.
Pharmacokinetics
Absorption
The absorption of clozapine after oral administration is 90-95%. Neither the speed nor the degree of absorption depends on the intake of food. Clozapine undergoes mild metabolism on its first pass ; absolute bioavailability is 50-60%. In a stationary state, against the background of a double dose of the drug, Cmax in the blood is reached on average after 2.1 hours (from 0.4 hours to 4.2 hours).
It was found that during the stationary period, with an increase in the dose of the drug from 37.5 mg to 75 mg and 150 mg (2 times a day), there is a linear dose-dependent increase in AUC and maximum and minimum levels in blood plasma.
Distribution / metabolism
The volume of distribution is 1.6 l / kg body weight. Plasma protein binding of clozapine is about 95%. Clozapine is almost completely biotransformed before elimination. Only one of its main metabolites, desmethyl clozapine, has pharmacological activity. Its action is similar to that of clozapine, but it is much weaker and shorter.
Withdrawal
Clozapine excretion is biphasic with an average elimination half-life of 12 hours (6–26 hours). After single doses of 75 mg, the average T½ was 7.9 hours. This value increased to 14.2 hours upon reaching a steady state as a result of the use of daily doses of 75 mg for at least 7 days. Only a small amount of unchanged drug was detected in urine and feces. About 50% of the dose taken is excreted in the form of metabolites in the urine and 30% in the feces.
Pharmacokinetics in special patient groups
Although pharmacokinetic studies have not been conducted, data on biotransformation and elimination of clozapine indicate the need for special care when treating patients with liver, biliary tract or kidney disease. Clozapine is contraindicated in severe cases of these diseases due to the risk of cumulation.

Indications for use
Treatment-resistant schizophrenia
Clozapine should only be administered to those patients with schizophrenia who are resistant to therapy or tolerant to standard antipsychotics with the following definitions. The criterion of "resistance to standard antipsychotics" is applied when previous treatment with standard antipsychotics at the appropriate dosage and for a sufficient period of time has not led to adequate clinical improvement. "Intolerance to standard antipsychotics" is used when severe uncontrollable neurological side effects (extrapyramidal symptoms or tardive dyskinesia) occur and make effective antipsychotic therapy with standard antipsychotics impossible.

Method of administration and dosage
When assessing the frequency of occurrence of various adverse reactions, the following gradations were used: very often - ≥ 1/10, often - ≥ 1/100 to <1/10, sometimes - ≥ 1/1000 to <1/100, rarely - ≥ 1/10000 to <1/1000, very rarely - <1/10000.
From the circulatory and lymphatic systems: often - leukopenia, neutropenia, eosinophilia, leukocytosis; infrequently - agranulocytosis ; rarely, lymphopenia ; very rarely - thrombocytopenia, thrombocytosis, anemia. Granulocytopenia and / or agranulocytosis are possible complications of clozapine therapy. Although agranulocytosis usually resolves after discontinuation of treatment, it can lead to sepsis and be fatal. Most cases of agranulocytosis (about 70%) develop during the first 18 weeks of therapy. To prevent the development of life-threatening agranulocytosis, you must quickly stop taking the drug. Therefore, you should regularly monitor the number of leukocytes in the blood. Leukocytosis and / or eosinophilia of unknown etiology may develop, especially during the first few weeks of therapy.
Metabolic disorders: often / very often - an increase in body weight (4–31%), which can be significant; rarely - impaired glucose tolerance, diabetes mellitus even in patients without hyperglycemia or a history of diabetes mellitus; very rarely - severe hyperglycemia, which very rarely leads to ketoacidosis or hyperosmolar coma, even in patients without a history of hyperglycemia or diabetes mellitus; hypercholesterolemia, hypertriglyceridemia.
Mental disorders: often - speech disorders; infrequently - stuttering; rarely - anxiety, agitation; very rarely - obsessive- compulsive disorder.
From the nervous system: very often - drowsiness and sedation (39–46%), dizziness (19–27%); often - blurred vision, headache, tremor, muscle stiffness, akathisia, extrapyramidal symptoms, epileptic seizures, convulsions, myoclonic twitching; rarely - confusion, delirium. Clozapine can cause changes in electroencephalography (EEG) readings, including spike and wave complexes. The drug lowers the seizure threshold in a dose-dependent manner and can cause myoclonic seizures or generalized seizures. These symptoms are more likely to develop with a rapid dose increase and in patients with a history of epilepsy. In such cases, it is necessary to reduce the dose and, if necessary, prescribe anticonvulsant therapy. Carbamazepine should be avoided due to its potential to inhibit bone marrow function. When prescribing other anticonvulsants, pharmacokinetic interactions should be considered. Fatal seizures have been reported. Extrapyramidal symptoms are milder and less frequent than those developing with standard antipsychotics. Acute dystonia has not been confirmed as an undesirable effect of clozapine therapy.
Tardive dyskinesia has been reported very rarely in patients treated with clozapine in conjunction with other antipsychotics, hence a causal relationship cannot be established. When taking clozapine, the severity of symptoms of tardive dyskinesia, which developed while taking other antipsychotics, decreased. There have been rare reports of neuroleptic malignant syndrome in patients receiving clozapine monotherapy or together with lithium preparations or with other centrally acting drugs. In such cases, the drug should be discontinued immediately and intensive therapy initiated. The main symptoms of neuroleptic malignant syndrome are rigidity, hyperthermia, changes in consciousness and autonomic lability.
From the side of the heart: very often - tachycardia (25%, especially in the first few weeks of treatment); very rarely - cardiac arrest. Changes in ECG indicators (ST segment depression, T-wave smoothing and inversion, conduction disturbances) may often develop. There have been isolated reports of arrhythmias, pericarditis (with or without pericardial effusion), cardiomyopathy and myocarditis (with or without eosinophilia), some of which have been fatal. Clinical symptoms may mimic those of myocardial infarction or influenza. Consideration should be given to the diagnosis of myocarditis in patients using clozapine who develop resting tachycardia, accompanied by arrhythmia, dyspnea, or symptoms of heart failure, and if this diagnosis is confirmed, treatment should be withdrawn. There have been very few reports of cardiomyopathy. When diagnosing cardiomyopathy, the drug should be canceled. In very rare cases, the phenomena of ventricular tachycardia and prolongation of the QT interval have been reported, which may be associated with ventricular tachycardia of the "pirouette" type, although a convincing causal relationship with the use of clozapine has not been identified.
From the vascular system: often - arterial hypertension, orthostatic hypotension, syncope; rarely - thromboembolism, including deaths and cases that occur in combination with necrosis of organs (for example, intestines); vascular collapse as a result of severe hypotension, especially in connection with a sudden increase in dose, with the potentially serious consequence of cardiac or respiratory arrest. The frequency and severity of hypotension depend on the rate and amount of the increased dose.
On the part of the respiratory system: rarely - aspiration of food (entering the respiratory tract); very rarely - depression / respiratory arrest. There have been reports of pneumonia that developed over the course of drug use (link not clear).
On the part of the digestive system: very often - constipation (14–25%), hypersalivation (31–48%); often - nausea, vomiting, dry mouth; rarely, dysphagia; very rarely - an increase in the salivary gland, intestinal obstruction, paralytic intestinal obstruction, fecal retention.
From the liver, biliary tract and pancreas: often - increased liver enzymes; rarely - hepatitis, jaundice, acute pancreatitis; very rarely - fulminant liver necrosis. If the patient develops jaundice, the drug should be discontinued immediately.
On the part of the skin and subcutaneous tissue: very rarely - skin reactions.
From the kidneys and urinary tract: often - urinary incontinence, urinary retention; very rarely - interstitial nephritis, renal dysfunction, renal failure.
Reproductive system disorders: very rarely - priapism, impotence, changes in ejaculation, dysmenorrhea.
Violations of the organ of vision: often - blurred vision.
Other disorders: often - fatigue, fever, benign hyperthermia, dysregulation of sweating and body temperature.
Laboratory indicators: rarely - an increase in the level of CPK; very rarely - hyponatremia.
Deaths during treatment
It is known that sudden death of unknown etiology can occur in patients with mental illness using standard antipsychotics, but it can also occur in patients who are not receiving treatment. Similar episodes have been reported with clozapine, even in younger patients. Perhaps the reason lies in the undesirable effects of clozapine on the cardiovascular system (ECG changes, arrhythmia, cardiomyopathy, myocarditis).
List of adverse reactions from spontaneous postmarking messages (frequency not known):
From the immune system: Quincke's edema, leukocytoclastic vasculitis.
From the nervous system: cholinergic syndrome, EEG changes, Pisa syndrome.
From the side of the cardiovascular system: myocardial infarction (with a possible fatal outcome), angina pectoris.
From the respiratory system: bronchospasm, nasal congestion.
From the digestive system: diarrhea, abdominal discomfort, heartburn, dyspepsia, colitis.
From the liver, biliary tract and pancreas: hepatic steatosis, liver necrosis, hepatotoxicity, liver fibrosis, liver cirrhosis, liver dysfunction with the development of liver failure, leading to the need for liver transplantation or death.
On the part of the skin and subcutaneous tissue: pigmentation disorders.
From the muscular system: muscle weakness, muscle spasms, muscle pain.
From the kidneys and urinary tract: renal failure, nocturnal enuresis.
On the part of the reproductive system: retrograde ejaculation.
Other: pseudo- pheochromocytoma (serious paroxysmal hypertension), systemic lupus erythematosus.

Side effects
Undesirable effects distributed by system organ classes and frequency: very common (1/10); often (1/100, <1/10); infrequently (1/1000, <1/100); rarely (1/10 000, <1/1000); very rare (<1/10 000). Metabolic and eating disorders: often - anorexia. Disturbances from the gastrointestinal tract: very often - pain in the abdomen, nausea; often - vomiting, diarrhea, constipation, dyspepsia, increased appetite; infrequently - gastric ulcer (Most patients had a history of stomach ulcers or were receiving nonsteroidal anti-inflammatory drugs therapy). Mental disorders: very often - depression, insomnia. Nervous system disorders: very often - headache, dizziness; often - anxiety, confusion, carpal tunnel syndrome, paresthesia, hypesthesia, asthenia; infrequently - neuropathy. Heart disorders: often - heart failure; infrequently - myocardial infarction. Violations of the skin and subcutaneous tissues: very often - increased sweating; often - alopecia, rash, pruritus, dermatitis. Musculoskeletal and bone disorders: very often - joint and musculoskeletal pain (including arthralgia, pain in the extremities, back pain, arthritis, myalgia); often - fracture, osteoporosis. Violations of the organ of vision: often - visual impairment. Vascular disorders: very often - increased blood pressure, "hot flashes". Disorders from the liver and biliary tract: very often - an increase in the activity of hepatic enzymes, an increase in the concentration of bilirubin in the blood, an increase in the activity of alkaline phosphatase in the blood. Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, cough, bronchitis, sinusitis, pharyngitis, rhinitis, chest pain, upper respiratory tract infections. Kidney and urinary tract disorders: often - urinary tract infections. Disorders of the blood and lymphatic system: often - lymphedema. General disorders and disorders at the injection site: very often - pain, increased fatigue; often - peripheral edema, flu-like syndrome, fever, general weakness, infections. Approximately 20% of patients (especially those with initial lymphopenia) experienced a periodic decrease in the number of lymphocytes. However, the average number of lymphocytes in these patients did not change significantly over time, and no concomitant increase in the incidence of viral infections was observed. Post-marketing research. Immune system disorders: infrequently - hypersensitivity reactions. Liver and biliary tract disorders: rarely - hepatitis, cholestatic hepatitis. Skin and subcutaneous tissue disorders: often - urticaria; rarely - acute generalized exanthematous pustulosis.

Contraindication
- hypersensitivity to clozapine or to any other component of the drug;
- the inability to regularly monitor the patient's blood counts;
- a history of granulocytopenia or agranulocytosis (with the exception of the development of granulocytopenia or agranulocytosis due to previous chemotherapy);
- dysfunction of the bone marrow;
- epilepsy uncontrollable;
- alcoholic or other toxic psychoses, drug intoxication, coma;
- vascular collapse and / or depression of the central nervous system (CNS) of any etiology;
- severe kidney or heart disorders, myocarditis;
- Acute liver disease accompanied by nausea, loss of appetite, or jaundice; progressive liver disease, liver failure;
- paralytic ileus;
- clozapine should not be administered concurrently with drugs that are known to cause agranulocytosis ; you should also not use simultaneously deoneuroleptics.

Overdose
Severe overdose (by accident or with the intent of committing suicide) poses a serious danger to the patient!
In the case of an acute, intentional or accidental overdose of the drug, the result of which became known, the mortality rate is about 12%. Most of the deaths were due to heart failure or aspiration pneumonia and occurred after taking the drug in doses exceeding 2000 mg. There have been reports of patients who have recovered from an overdose caused by a dose higher than 10,000 mg. However, in several adult patients, mainly in those who had not previously used clozapine, taking the drug at a dose of only 400 mg led to the development of comatose conditions that were life threatening, and in one case - to death. In young children, administration of 50-200 mg led to marked sedation or coma, but without death.
Signs and symptoms: drowsiness, lethargy, coma, areflexia; confusion, hallucinations, agitation, delirium; extrapyramidal symptoms, increased reflexes, convulsions, increased salivation, dilated pupil, blurred vision; fluctuations in body temperature (possibly a significant decrease in body temperature); arterial hypotension, collapse, tachycardia, arrhythmia (especially AV blockade and extrasystole), impaired cardiac conduction; aspiration pneumonia, shortness of breath, depression or respiratory failure.
Treatment
The specific antidote is unknown. Such non-specific measures are shown:
- immediate and repeated gastric lavage followed by the introduction of activated charcoal within 6 hours after administration of the drug. Peritoneal dialysis and hemodialysis are unlikely to be effective;
- cardiorespiratory intensive therapy (ECG, continuous monitoring);
- constant monitoring of electrolytes and acid-base balance;
- peritoneal dialysis or hemodialysis in case of oliguria or anuria (although this will not significantly accelerate the rate of excretion due to the high binding of the drug to proteins).
Some symptoms that may respond to medication include:
- anticholinergic effects: parasympathomimetic substances - physostigmine (penetrates the BBB), pyridostigmine or neostigmine ;
- arrhythmia: potassium, sodium bicarbonate or digitalis preparations, depending on the symptomatology; quinidine and procainamide are contraindicated;
- hypotension: infusion of albumin or plasma substitutes. Dopamine and angiotensin are the most effective stimulants of blood circulation. Epinephrine and other β-sympathomimetics are contraindicated (may increase vasodilation);
- convulsions: diazepam or phenytoin slowly intravenously. Long-acting barbiturates are contraindicated.
Due to the possibility of delayed reactions, the patient should be observed for at least 5 days.

Precautions
Potential severe side effects of clozapine therapy are granulocytopenia and agranulocytosis, with an established incidence of 3% and 0.7%, respectively. Agranulocytosis can be life threatening. The incidence and mortality rate in patients who develop agranulocytosis have significantly decreased since the introduction of monitoring of leukocyte count and absolute neutrophil count. Therefore, precautions are imperative. Because of these risks, the use of clozapine is limited only to patients with schizophrenia or psychotic disorders developing with Parkinson's disease, who have shown a lack of response or with an inadequate response to other antipsychotics, or who develop severe extrapyramidal side effects (in particular tardive dyskinesia) when taking others antipsychotics. Clozapine can be used in patients with schizophrenia or schizoaffective disorders who, based on their medical history or current clinical presentation, are at long-term risk of recurrent suicidal behavior. The use of clozapine in all these groups of patients is carried out under the following conditions: before starting therapy with the drug, the leukocyte count (≥3.5 × 109 / L [3500 / mm3]) and the leukocyte formula should be normal, patients should be monitored for the number of leukocytes and, if possibly the absolute number of neutrophils at regular intervals during the treatment period (weekly in the first 18 weeks, then once a month) and within 1 month after complete withdrawal of clozapine. In no case should clozapine be prescribed to patients with a history of blood pathological changes induced by medication.
Physicians prescribing this drug must fully comply with all necessary safety measures. During each consultation, the patient using clozapine should be reminded to see a doctor immediately if any infection occurs. Particular attention should be paid to flu-like symptoms or other symptoms, such as fever or sore throat, that indicate possible infection. In such cases, a general clinical blood test should be performed immediately.
Special precautions
Hematology
Given the risk of agranulocytosis, the following precautions must be observed. Along with clozapine, drugs that have a pronounced inhibitory effect on bone marrow function are not used. In addition, the simultaneous use of the drug with depot neuroleptics, which, due to their potential myelosuppressive action, are slowly excreted from the body in emergency situations, for example, with granulocytopenia, should be avoided. For patients with a history of primary bone marrow disorders, clozapine should be prescribed only when the expected effect of therapy outweighs the risks. Such patients should be examined by a hematologist before starting treatment. Patients with low leukocyte counts due to benign ethnic neutropenia should seek the consent of a hematologist before prescribing clozapine.
Monitoring leukocyte count and absolute neutrophil count
10 days before starting clozapine treatment, the white blood cell count should be determined to ensure that only patients with normal white blood cell counts (> 3.5 × 109 / L [3500 / mm3] and absolute neutrophil counts (> 2.0 × 109 / L [2000 / mm3]) The number of leukocytes and, if possible, the absolute number of neutrophils should be monitored weekly during the first 18 weeks, then at least once a month during the entire treatment and during 1 month after complete cessation of clozapine 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 which case the leukocyte count should be determined immediately.
Interruption of the course of therapy due to reasons not related to hematological parameters
For those patients whose clozapine therapy lasted more than 18 weeks was interrupted for more than 3 days but less than 4 weeks, weekly monitoring of the white blood cell count for an additional 6 weeks is indicated. Provided that there are no deviations of the indicators from the norm, further monitoring can be carried out no more often than once every 4 weeks. If clozapine therapy has been interrupted for 4 weeks or more, weekly monitoring is required for the next 18 weeks of treatment.
Decreased leukocyte count and absolute neutrophil count
If, in the first 18 weeks of clozapine treatment, the leukocyte count decreases to 3.5 × 109 / L (3500 / mm3) - 3.0 × 109 / L (3000 / mm3) and / or the absolute number of neutrophils decreases to 2.0 × 109 / l (2000 / mm3) - 1.5 × 109 / l (1500 / mm3), analyzes of hematological parameters must be carried out at least 2 times a week. The same scheme is applied if, after 18 weeks of therapy, the leukocyte count decreases to 3.0 × 109 / L (3000 / mm3) - 2.5 × 109 / L (2500 / mm3) and / or the absolute number of neutrophils to 1.5 × 109 / l (1500 / mm3) - 1.0 × 109 / l (1000 / mm3).
In addition, if there is a significant decrease in the number of leukocytes compared to the initial level, it is necessary to re-determine the number of leukocytes and leukocyte formula. “Significant decrease” is defined as a one-time decrease in white blood cell count to 3.0 x 109 / L (3000 / mm3) or more, or a total decrease to 3.0 x 109 / L (3000 / mm3) or more over 3 weeks.
Immediate withdrawal of clozapine therapy
If during the first 18 weeks of therapy, the leukocyte count is <3.0 × 109 / L (3000 / mm3) and / or the absolute neutrophil count is <1.5 × 109 / L (1500 / mm3), or if after the first 18 weeks of therapy, the number leukocytes <2.5 × 109 / L (2500 / mm3) or absolute neutrophil count <1.0 × 109 / L (1000 / mm3), clozapine is immediately canceled. Counting the number of leukocytes and leukocyte counts should be performed daily, a patient downward-and benevolent observe concerning occurrence had flu-like symptoms or other symptoms suggestive of infection. After discontinuation of the drug, hematological control should be continued until the values return to the initial level. If, after discontinuation of clozapine, there is a decrease in the number of leukocytes <2.0 × 109 / L (2000 / mm3) or the absolute number of neutrophils <1.0 × 109 / L (1000 / mm3), the treatment of this condition should be carried out under the guidance of an experienced hematologist.
If possible, the patient should be placed in a specialized hematology box, protective isolation and administration of granulocyte- macrophage colony-stimulating factor or granulocyte colony-stimulating factor may be indicated. It is recommended to discontinue therapy with a colony-stimulating factor after an increase in the number of neutrophils to a level exceeding 1.0 × 109 / L (1000 / mm3). Because of the risk of septic shock, antibiotic therapy should be started immediately if an infection develops. Patients who have been discontinued clozapine due to white blood cell deficiency (see above) should not be given clozapine again. It is recommended to count the amount for 2 consecutive days to confirm the blood test results. However, the drug should be discontinued after the first blood test is obtained. Prescriptions for clozapine must be labeled as “complete blood count” as directed by your doctor. The use of the drug should be discontinued if the number of eosinophils exceeds 3.0 × 109 / l (3000 / mm3); treatment should be resumed only after a decrease in the number of eosinophils <1.0 × 109 / l (1000 / mm3). If thrombocytopenia develops, clozapine should be discontinued if the platelet count falls <50 × 109 / L (50,000 / mm3).
Other precautions
Cardiotoxicity
Patients with a history of heart disease or abnormalities in the cardiovascular system identified during a medical examination should see a specialist for further examination, which should include an ECG. For such patients, clozapine should be used only if the expected benefit clearly outweighs the risks. The doctor should consider the need for an ECG prior to treatment. During clozapine therapy, orthostatic hypotension with or without loss of consciousness may develop. In rare cases (about 1 in 3000 patients), the collapse can be severe and may be accompanied by cardiac and / or respiratory arrest with possible death. Such reactions develop most often at the initial stage of increasing the dose of the drug due to the rapid increase in the dose. In very rare cases, they were even noted after the first dose of the drug. Such complications occur more often with the simultaneous use of benzodiazepines or other psychotropic drugs. Close medical supervision is necessary at the beginning of clozapine therapy. Blood pressure control in the standing and lying position should be carried out in the first weeks of treatment in patients with Parkinson's disease.
Tachycardia that occurs at rest and is accompanied by arrhythmia, shortness of breath, or symptoms of heart failure may occur in some cases, in the first 2 months of treatment, and very rarely later. If these symptoms occur, especially during the dose escalation period, diagnostics should be prescribed as soon as possible to rule out myocarditis. The symptoms of clozapine- associated myocarditis may also mimic those of myocardial infarction or flu.
There have been reports of cases of myocardial infarction, which can be fatal. Evaluation of the causes of occurrence in most cases was difficult with pre-existing severe heart disease.
If myocarditis or cardiomyopathy is suspected, clozapine should be discontinued immediately and the patient should immediately consult a cardiologist. These same signs and symptoms can also develop later in therapy and may be associated with cardiomyopathy. In such cases, further examinations are indicated. When the diagnosis of cardiomyopathy is confirmed, the drug should be discontinued. Patients with clozapine -induced myocarditis or cardiomyopathy should not be administered again clozapine. In some cases of myocarditis (about 14%) and pericarditis / pericardial effusion, eosinophilia has been reported simultaneously ; however, it is not known whether eosinophilia is a reliable predictor of carditis.
Prolongation of the QT interval
As with other antipsychotics, caution is advised when prescribing clozapine to patients with known cardiovascular disease or a family history of QT prolongation.
Cerebrovascular Adverse Events
In the group of people with dementia, there was an approximately 3-fold increase in the risk of cerebrovascular accident when taking some antipsychotic substances. The reason for this phenomenon has not been clarified. Clozapine should be used with caution in patients with risk factors for stroke.
Epilepsy
During clozapine therapy, it is necessary to closely monitor the condition of patients with epilepsy, since there have been reports of dose-dependent seizures. In such cases, the dose should be reduced and, if necessary, anticonvulsant therapy should be prescribed. In patients with a history of paroxysms or disorders of the cardiovascular system or kidneys (severe disorders of the liver, kidneys and cardiovascular system are contraindications), treatment should be started with a single dose of 12.5 mg on day 1, and increasing the dose should be done slowly and with small increments.
Liver dysfunction
Patients with preexisting stable liver disease can use clozapine, but liver function should be monitored regularly. During clozapine treatment, any patient with symptoms of possible liver disease (eg, nausea, vomiting, loss of appetite) should be immediately tested for liver function tests. In the case of a clinically significant increase in these indicators or the appearance of symptoms of jaundice, clozapine treatment should be discontinued. It can be restored only if the liver function indicators are normalized. In such cases, careful monitoring is necessary.
Metabolic disorders
Atypical antipsychotic drugs, including clozapine, are associated with metabolic disorders that can increase the risk of cardiovascular / cerebrovascular disorders. These phenomena can include hyperglycemia, dyslipidemia, and weight gain.
Cases of diabetes mellitus and severe hyperglycemia have also been reported, sometimes resulting in ketoacidosis or hyperosmolar coma, even in patients without a history of hyperglycemia or diabetes mellitus. A causal relationship with clozapine has not been established, although blood glucose levels returned to normal in most patients after drug withdrawal. In some cases, repeated administration of the drug was accompanied by a relapse of hyperglycemia. The effect of clozapine on glucose metabolism in patients with a history of diabetes mellitus has not been studied. In patients taking clozapine who develop hyperglycemia with symptoms such as polydipsia, polyuria, polyphagia, or weakness, impairment of glucose tolerance should be considered. In patients with severe hyperglycemia associated with treatment, discontinuation of the drug should be considered.
In patients receiving atypical antipsychotic drugs, including clozapine, clinical monitoring is recommended, including an assessment of blood lipids (baseline and periodically throughout treatment) and body weight control.
Other precautions
During clozapine therapy, patients may experience a transient increase in body temperature above 38 ° C, with a peak incidence in the first 3 weeks of treatment. This rise in body temperature is usually benign. Sometimes this can be due to an increase or decrease in the number of leukocytes in the blood. Patients with an elevated body temperature should be carefully examined to exclude the possibility of an infection underlying this phenomenon or the development of agranulocytosis. In patients with high body temperature, the possibility of neuroleptic malignant syndrome should be considered as a possible cause.
Clozapine can cause sedation and weight gain, thereby increasing the risk of thromboembolism, so immobilization of patients should be avoided.
Clozapine has inherent anticholinergic properties that can have unwanted effects on the entire body. Close monitoring is essential for enlarged prostate and angle-closure glaucoma. Probably, due to its anticholinergic properties, clozapine can lead to disturbances of intestinal motility of varying severity: from constipation to stool, intestinal obstruction and paralytic intestinal obstruction. Rarely, these cases can be fatal.
Patients with a history of colon disease or surgery in the lower abdomen who are receiving concomitant medications that are likely to cause constipation (especially medications with anticholinergic properties, such as various antipsychotics, antidepressants and antiparkinsonian medications) should be treated with extreme caution. such drugs can make the situation worse. It is extremely important to identify and treat constipation.
With extreme caution, clozapine should be administered concurrently with other benzodiazepines (or other centrally acting drugs). Orthostatic hypotension may occur in patients taking clozapine. Rarely have there been reports of tachycardia that may be persistent.
The drug contains lactose. In patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, the use of the drug is not recommended.

Interaction with other medicinal products
Pharmacodynamic interactions
Simultaneously with clozapine, drugs should not be used that have a significant inhibitory effect on bone marrow function. Clozapine should not be used simultaneously with long-acting deponeuroleptics (with myelosuppressive potential), since these substances, if necessary, cannot be quickly eliminated from the body, for example, in the case of neutropenia. Clozapine can increase the effect of alcohol and MAO inhibitors on the central nervous system, as well as the depressive effect of drugs, antihistamines and benzodiazepines on the central nervous system. There have been reports of deaths when using a combination of clozapine with similar substances (including methadone).
Particular care is required when clozapine is prescribed in combination with benzodiazepines or other psychotropic drugs, or is prescribed to patients who have received similar drugs several days before starting drug use, since in such cases the risk of vascular collapse increases, which in rare cases can be severe and lead to cardiac or respiratory arrest. It is unclear whether cardiac or respiratory collapse can be prevented by dose adjustment.
Concomitant use of lithium or other drugs that affect the central nervous system may increase the risk of developing neuroleptic malignant syndrome. Due to the possibility of additive effects, it is necessary to use with extreme caution simultaneously drugs that have anticholinergic, antihypertensive effects or the property of respiratory depression. Due to its anti-α-adrenergic properties, clozapine can reduce the pressor effect of norepinephrine or other drugs with a predominant α-adrenergic effect and eliminate the pressor effect of epinephrine. Clozapine can lower the seizure threshold, so a dose adjustment of the antiepileptic drug may be required. There have been isolated reports of severe epileptic seizures, including the occurrence of seizures in patients without epilepsy, and in some cases - on the development of delirium with the combined use of clozapine with valproic acid. It is possible that these effects develop due to pharmacodynamic interactions, the mechanism of which has not been determined. Clozapine can increase plasma concentrations of drugs with high binding to proteins (for example, warfarin and digoxin) due to their movement from blood plasma proteins. If necessary, the doses of substances that bind to proteins should be adjusted.
Clozapine should be used with caution in combination with drugs that can increase the QT interval or affect electrolyte balance.
Pharmacokinetic interactions
Clozapine is a substrate for many CYP 450 isoenzymes, in particular 3A4, 1A2 and 2D6. The risk of metabolic interactions caused by the action of a single isoform should be minimized. However, one should closely monitor the plasma levels of clozapine in patients receiving concomitant therapy with other agents that have an affinity for one or more of these enzymes. The simultaneous use of substances that affect these isoenzymes can lead to an increase or decrease in plasma levels of clozapine and / or drugs taken simultaneously.
In theory, clozapine may cause an increase in plasma levels of tricyclic antidepressants, phenothiazines, and class I C antiarrhythmics, which are characterized by binding to cytochrome P450 2D6. Therefore, it may be necessary to administer lower doses than usual. However, so far there have been no reports of clinically significant interactions.
The combination of clozapine with substances known to affect the activity of the isoenzymes of the CYP 450 family can lead to an increase or decrease in plasma levels of clozapine.
Inhibitors
The simultaneous use of enzyme inhibitors such as cimetidine (an inhibitor of CYP 1A2, 3A4 and 2D6) or erythromycin (an inhibitor of CYP 3A4), clarithromycin or azithromycin with high doses of clozapine, led to an increase in clozapine levels in blood plasma and the development of undesirable effects.
Increases in plasma clozapine levels have been reported in patients who received the drug concurrently with fluvoxamine (an inhibitor of CYP 3A4 and CYP 1A2; up to a 10-fold increase) or with other selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (a CYP 1A2 inhibitor, 2D6), sertraline (a CYP 2C8 / 9, 2D6 inhibitor), fluoxetine (a CYP 2D6 inhibitor; up to 2-fold), or citalopram (possibly a weak CYP 1A2 inhibitor with probably the lowest potential of all SSRIs for developing clinically significant interactions). However, there have been reports of clinically significant interactions after concomitant use of citalopram and clozapine. Elevated clozapine concentrations have also been observed in patients receiving the drug in combination with venlafaxine.
Azole antimycotics and protease inhibitors are potent inhibitors / inducers of CYP ZA4. Therefore, they can be expected to elicit clinically significant interactions with clozapine as well. However, there have been no reported interactions at this time.
Substrates
Caffeine (a CYP 1A2 substrate) can increase plasma levels of clozapine. After 5 days without caffeine, plasma clozapine levels drop by about 50%. Keep this in mind if the number of cups of coffee or tea you drink daily changes.
Significant increases in clozapine and N- desmethyl - clozapine levels were noted when concomitant treatment was given with 2–250 mg ciprofloxacin. The interactions of norfloxacin and enoxacin have been reported.
Inductors
Drugs that induce CYP ZA4 (eg, carbamazepine and rifampicin) can lower plasma levels of clozapine. Withdrawal of the concomitant use of carbamazepine led to an increase in plasma levels of clozapine. It has been found that the combined use of phenytoin reduces the plasma level of clozapine, which leads to a decrease in the effectiveness of the previously effective dose of clozapine. Smoking induces CYP 1A2. Therefore, sudden cessation of smoking in heavy smokers can lead to an increase in plasma levels of clozapine and, thus, an increase in the severity of unwanted effects. Omeprazole is an inducer of CYP 1A2 and CYP ZA4, as well as an inhibitor of CYP 2C19. There have been isolated reports of interactions with proton pump inhibitors (increased concentrations of clozapine when taken with omeprazole and pantoprazole or combinations of lansoprazole and paroxetine).

Special instructions
Use with caution in severe diseases of the cardiovascular system, severe renal and / or hepatic failure, angle-closure glaucoma, with prostatic hyperplasia, intestinal atony, epilepsy, intercurrent diseases with febrile syndrome.
During the treatment period, systematic monitoring of the peripheral blood picture is necessary.
When using clozapine, alcohol should be avoided.
The safety and efficacy of clozapine in children and adolescents under the age of 16 has not been established.
Influence on the ability to drive vehicles and mechanisms
Patients taking clozapine should refrain from potentially hazardous activities associated with the need for concentration and increased speed of psychomotor reactions.

Pregnancy and elbowing
There is no clinical data available regarding the use of this drug in pregnant women.
Controlled studies involving humans have not been carried out, and therefore the safety of the drug during pregnancy has not been established. Newborns whose mothers took antipsychotics in the third trimester of pregnancy are at risk of extrapyramidal symptoms and / or drug withdrawal symptoms, which can vary in severity and length of life after delivery. Cases of agitation, increased or decreased muscle tone, tremors, drowsiness, respiratory depression, and eating disorders have been reported. Consequently, newborns should be carefully HA observance.
Thus, the drug should be prescribed to pregnant women only when the expected effect of treatment for the mother clearly outweighs the possible risk to the fetus.
In animal studies, clozapine has been identified in breast milk. Therefore, mothers taking clozapine should not breastfeed.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Vacation conditions
On prescription.

Packaging
Clozapine 100 mg Tablets. There are 25 tablets in a blister. 4 blisters are packed in a cardboard box together with an enclosed leaflet.