Potentially serious side effects of the drug Clozapine is granulocytopenia and agranulocytosis, the incidence of which is 3% and 0.7%, respectively. Agranulocytosis can pose a threat to life.
After the determination of the number of leukocytes and the absolute number of neutrophils became widespread, the incidence of agranulocytosis and the death rate among patients who had agranulocytosis decreased significantly. For this reason, the precautions listed below are mandatory.
A drug Clozapine should be used only in patients with schizophrenia or in patients with psychosis associated with Parkinson's disease who show no response or insufficient response to treatment with other antipsychotics or who, against the background of other antipsychotic drugs there are severe extrapyramidal side effects (in particular, late dyskinesias).
A drug Clozapine It can also be used in patients with schizophrenia or schizoaffective disorder who, according to their history and current clinical picture, have a long-term risk of recurrence of suicidal behavior.
In patients of all these categories, the drug Clozapine apply under the following conditions:
- Before the start of treatment should be normal as the number of white blood cells (≥ 3.5 × 109/ l [3500 / mm3]), and the number of other uniform elements of blood;
- patients should regularly monitor the number of leukocytes and, if possible, the absolute number of neutrophils (ASC) on the background of treatment (weekly for the first 18 weeks and then at least once a month) and within 1 month after the final discontinuation of the drug Clozapine.
Patients who in the past had a history of hematologic abnormalities, use the drug Clozapine it is contraindicated.
Doctors who use the drug must fully comply with the safety requirements.
During each consultation, the patient receiving the drug Clozapine, it is necessary to remind that if any signs of an infectious disease appear, he should immediately contact the attending physician. Special attention is required for complaints of influenza-like symptoms or other signs of infectious diseases (in particular, fever or sore throat), which may indicate neutropenia. In such cases, a general blood test should be performed immediately.
Special Precautions
Hematologic indices
Because the drug Clozapine may cause agranulocytosis, the following precautions should be observed.
Simultaneously with the drug Clozapine Do not use drugs that can significantly inhibit blood. Also, simultaneous use of the drug should be avoided Clozapine with depot forms of antipsychotics, since such drugs can depress hemopoiesis, and in an emergency situation (for example, with granulocytopenia), rapid removal of such medicinal forms from the body is impossible.
In patients with primary bone marrow diseases in the history of the drug Clozapine It should be used only if the expected benefit exceeds the possible risk. Such patients should be carefully examined by a hematologist before starting treatment.
Before using the drug Clozapine, in patients with a low number of leukocytes due to benign ethnic neutropenia, the hematologist should agree.
Monitoring the number of leukocytes and ACN
10 days before the start of treatment with the drug Clozapine it is necessary to determine the number of leukocytes and other blood elements to make sure that the preparation will be received only by patients with normal parameters (the number of white blood cells ≥ 3,5x109/ l [3500 / mm3]) and АЧН ≥ 2,0x109/ l [2000 / mm3]). During the first 18 weeks of treatment, the number of leukocytes and ACN should be determined every week, and during further treatment - at least 1 time per month; monitor these parameters should be and within one month after the termination of the drug Clozapine. During each consultation, the patient receiving the drug Clozapine, it must be recalled that at the first sign of fever, sore throat, other flu-like symptoms and, in particular, other symptoms of an infectious disease that may indicate neutropenia, he should immediately consult a doctor.In such cases, you should immediately determine the leukocyte formula.
Interruption of therapy due to non-hematological causes
Those patients who have drug therapy Clozapine, which lasted more than 18 weeks, was interrupted for more than 3 days (but less than 4 weeks), weekly monitoring of the number of leukocytes in the blood for an additional 6 weeks is shown. If no abnormalities are detected, you can go to control blood counts at intervals of 4 weeks (but at least). If the drug therapy Clozapine was interrupted for 4 weeks or more; in the next 18 weeks of treatment, blood counts should be monitored weekly.
Low number of leukocytes and ACN
If in the first 18 weeks of treatment with the drug Clozapine the number of leukocytes decreases to 3.0-3.5910 / l (3000-3500 / mm)3) and / or AFN decreases to 1.5- 2,0x109/ l (1500-2000 / mm)3), a general blood test should be performed at least 2 times a week. The same requirement also applies if, after 18 weeks of treatment, the number of leukocytes decreases to 2.5-3.0 x 109/ l (2500-3000 / mm3) and / or ASC decreases to 1.0-1,5x109/ l (1000-1500 / mm)3).
With a significant decrease in the number of leukocytes relative to the initial value, it is necessary to repeatedly determine the number of leukocytes and leukocyte formula.
A "significant" decrease is defined as a one-time decrease in the number of leukocytes by 3.0 × 109/ l (3000 / mm)3) or more, or as a total reduction of 3.0 × 109/ l (3000 / mm)3) or more for a 3-week period.
A drug Clozapine should be immediately canceled, if in the first 18 weeks of treatment the number of leukocytes decreases to <3.0х109/ l (3000 / mm)3) or ANCH decreases to <1.5 109/ l (1500 / mm3), or if in the period after 18 weeks of treatment the number of leukocytes decreases to <2.5 109/ l (2500 / mm)3) or ANCH decreases to < l , 0x109/ l (1000 / mm)3).
Subsequently, the number of leukocytes and the number of other blood elements should be determined daily, and patients should be closely monitored for the development of influenza-like symptoms or other symptoms, indicating an infectious disease. After drug withdrawal Clozapine monitor blood levels should be until they return to normal.
If, despite the cancellation of the drug Clozapine, the number of white blood cells decreased less 2,0x109/ l (2000 / mm)3) and / or ACHN decreased below 1.0х109/ l (1000 / mm)3), treatment of this condition should be conducted under the guidance of an experienced hematologist.
If possible, the patient should be referred to a specialized hematology unit, where it is possible to place it in a separate box and use GM-CSF (granulocyte-macrophagal colony-stimulating factor) or G-CSF (granulocyte colony-stimulating factor). The colony-stimulating factor is recommended to be canceled after the ASC is again increased to a level above 1.0x109/ l (1000 / mm)3).
In case of development of an infectious disease, antibiotic therapy should be started immediately due to the possibility of septic shock development.
Patients to whom the drug Clozapine was abolished because of the low number of leukocytes (see above), repeated use of the drug is not recommended Clozapine. To confirm the values of hematological parameters, the blood test is recommended to be carried out for two days in a row, however, the drug Clozapine should be canceled after receiving the results of the first analysis.
In the case of eosinophilia, discontinue the drug Clozapine It is recommended if the number of eosinophils exceeds 3,0x109/ l (3000 / mm)3), and the treatment can be resumed only after the reduction of the number of eosinophils to a level below 1.0x109/ l (1000 / mm)3).
In the case of thrombocytopenia, the drug Clozapine it is recommended to cancel if the platelet count has decreased to < 50x109/ l (50,000 / mm3).
Other Precautions
Cardiotoxicity
In patients with heart disease, the drug should be used at a low initial dose (on the first day - 12.5 mg at a time). The dose should be increased slowly and gradually. For the accuracy of dosing, use clozapine 25 mg tablets with a different manufacturer's risk. Patients with severe cardiovascular disease have a contraindicated drug. Patients with heart disease, history, or who have cardiac abnormalities in a physical examination should be referred to a specialist for further examination, which should include an ECG. In such patients, the drug Clozapine It should be used only if the expected benefit exceeds the possible risk. The attending physician should consider conducting an ECG before starting treatment.
Against the background of the drug Clozapine Orthostatic hypotension may occur with or without fainting. In rare cases (approximately in one patient out of 3000), collapse can be severe and accompanied by a cessation of blood circulation and / or breathing with possible fatal outcome. The likelihood of such phenomena increases at the stage of initial dose selection (especially in case of rapid dose increase); very rarely they occurred even after the first use of the drug.Such complications, apparently, occur more frequently when the drug is used simultaneously with benzodiazepines or other psychotropic drugs. In this regard, at the beginning of treatment with the drug Clozapine it is necessary to provide thorough medical supervision of the patient.
In the first two months of treatment, in rare cases, tachycardia of rest may occur, accompanied by arrhythmia, shortness of breath or symptoms of heart failure; In very rare cases, these phenomena can occur at later stages of treatment. If such symptoms occur (especially during the dose selection period), it should be done as early as possible diagnostic measures in order to exclude myocarditis. Symptoms of myocarditis caused by clozapine may also resemble the symptoms of myocardial infarction or influenza. There were also cases of myocardial infarction with a fatal outcome. However, due to the severe heart disease that was present in patients even before the start of treatment, it was difficult to assess the causal relationship with clozapine.
When suspected of myocarditis or cardiomyopathy, the drug Clozapine should be immediately canceled, and the patient should be sent to the cardiologist without delay.
Similar signs and symptoms may occur at later stages of treatment, and in very rare cases may be associated with cardiomyopathy. In such cases, further examination is shown. When confirming the diagnosis of cardiomyopathy, the drug Clozapine should be canceled.
In patients who have had myocarditis or cardiomyopathy caused by clozapine, repeated use is not recommended.
In some cases, eosinophilia was noted simultaneously with myocarditis (approximately 14% of cases) and pericarditis / pericardial effusion; however, whether eosinophilia is a reliable predictor of carditis, is unknown. It is possible to develop mitral valve insufficiency in patients diagnosed with cardiomyopathy on the background of drug treatment. There have been reports of cases of mitral valve insufficiency in patients with cardiomyopathy associated with clozapine therapy. In these cases, with two-dimensional echocardiography, moderate or moderate regurgitation is noted.
Patients with Parkinson's disease in the first weeks of treatment should monitor blood pressure in the standing and lying position.
Interval lengthening QT
Like other antipsychotics, clozapine it is recommended to be used with caution in patients who have CCC or interval disease QT in a family history. Like others antipsychotic drugs, clozapine it is recommended to be used with caution at the same time as medications that can lengthen the interval QTc.
Cerebrovascular events
Against the background of the use of some atypical antipsychotics in patients with dementia, the risk of unwanted cerebrovascular events increased approximately 3-fold. The reason why the risk of such phenomena increases, is not established. The increased risk of such events can not be ruled out for other antipsychotics or for other categories of patients. In this regard, the drug Clozapine should be used with caution in patients who have risk factors for stroke.
Epilepsy
A drug Clozapine can reduce the convulsive threshold. Since the use of the drug Clozapine epileptic seizures were noted, the frequency and severity of which depended on the doses of the drug, the patients with epilepsy in the history during the treatment with the drug Clozapine should be closely monitored.In such cases, you should reduce the dose of the drug and, if necessary, start anticonvulsant therapy.
In patients with convulsive attacks in the anamnesis, the dose of the drug on the first day should be 12.5 mg once a day; Further increase in the dose should be done slowly and gradually. For the accuracy of dosing, use clozapine 25 mg tablets with a different manufacturer's risk.
Fever
Against the background of taking the drug Clozapine body temperature in patients may temporarily increase to 38 ° C or higher (with the greatest probability in the first 3 weeks of treatment). As a rule, such a fever is benign. In some cases, it may be accompanied by an increase or decrease in the number of leukocytes.
Patients with fever should be carefully screened to exclude an infectious disease or agranulocytosis. In the case of high fever, the possibility of NSA should be taken into account. If the NSA is diagnosed, the drug should be immediately discontinued Clozapine and begin the necessary therapeutic activities.
A drug Clozapine can have a sedative effect and cause an increase in body weight,thereby increasing the risk of thromboembolism; for this reason, immobilization should be avoided.
Anticholinergic effects
A drug Clozapine has anticholinergic activity, which can cause side effects from various organs and body systems, so patients with prostate enlargement and angle-closure glaucoma clozapine should be used under close supervision. Perhaps because of its anticholinergic action clozapine can cause disturbances of intestinal peristalsis, the degree of expression of which varies from constipation to stool, intestinal obstruction and intestinal paresis. In rare cases, such events led to a lethal outcome.
With extreme caution, the drug should be used in patients with colon disease or surgery on the lower abdominal organs in history, which simultaneously produce drugs that can cause constipation (especially drugs with anticholinergic activity, for example, various antipsychotics, antidepressants and antiparkinsonic drugs ), since the latter can aggravate the situation.Constipation is extremely important to recognize and actively treat.
Particular caution is required when considering the use of the drug Clozapine simultaneously with benzodiazepines (or with other drugs of central action).
Metabolic disorders
Against the background of the use of atypical antipsychotics, including the drug Clozapine, there were metabolic disorders that could increase the risk of complications from CVS and cerebral circulation disorders. Such metabolic disorders may include hyperglycemia, dyslipoproteinemia and weight gain. Although some metabolic disorders can occur against the background of the use of any atypical antipsychotics, each drug of this class has its own spectrum of side effects.
Hyperglycaemia
Cases of diabetes mellitus and severe hyperglycemia (sometimes leading to ketoacidosis or hyperosmolar coma) have been reported, which even arose when clozapine was used in patients without a history of hyperglycemia. The causal relationship between these phenomena and the use of clozapine has not been established,although after the withdrawal of the drug in most patients the concentration of glucose in the blood returned to normal. In a small number of cases, there was a positive association with the repeated use of the drug. The effect of clozapine on glucose metabolism in patients with pre-existing diabetes mellitus has not been studied. In patients with diabetes mellitus who start using atypical antipsychotics, serum glucose concentration should be regularly determined. In patients with risk factors for diabetes mellitus (in particular, with excessive body weight and diabetes in the family history), who start using atypical antipsychotics, the concentration of fasting blood glucose should be determined before treatment begins and periodically during treatment. If patients using the drug Clozapine, there is hyperglycemia with symptoms such as polydipsia, polyuria, polyphagia or weakness, should consider the development of a violation of glucose tolerance. Patients who, against the background of atypical antipsychotics cause symptoms of hyperglycemia, should determine the concentration of glucose on an empty stomach.In some cases, after the abolition of atypical antipsychotics, glucose concentration returned to normal; in other cases, hyperglycemia required further treatment, despite the withdrawal of drugs. In patients with severe hyperglycemia, developed against the background of the drug, should consider the question of drug cancellation Clozapine.
Dislipoproteinemia
Patients who use atypical antipsychotics, including clozapine, there were violations of lipid metabolism. The parameters of lipid metabolism in such patients are recommended to be controlled (at the beginning and regularly during treatment).
Weight gain
In patients taking atypical antipsychotics, including clozapine, there was an increase in body weight. Regular weight control should be monitored in these patients.
Special categories of patients
Dysfunction of the liver
The use of atypical antipsychotics, incl. preparation Clozapine in patients with liver disease is possible with regular monitoring of liver function. If during treatment with the drug Clozapine develop symptoms that may indicate a violation of liver function (such as nausea, vomiting, or loss of appetite), should immediately determine the liver function. In the case of a clinically significant increase in these indicators or the appearance of symptoms of jaundice, drug treatment Clozapine should be discontinued. Resume treatment is possible only if the liver function is normalized. In such cases, patients should be closely monitored.
Renal impairment
In patients with impaired renal function of mild and moderate severity the drug should be used in a low initial dose (on the first day - 12.5 mg at a time). For the accuracy of dosing, use clozapine 25 mg tablets with a different manufacturer's risk.
Patients aged> 60 years
In patients of this age group, treatment is recommended starting at a lower dose.
Against the background of the drug Clozapine Orthostatic hypotension may occur. There have also been rare cases of tachycardia, which may not disappear for a long time. This category of patients, in particular, patients with CCC function disorder, may be more likely to be affected by these effects than younger patients.In addition, some patients aged> 60 years may be particularly prone to the anticholinergic effects of the drug Clozapine (eg, urinary retention and constipation).
Psychosocial / behavioral disorders in patients aged > 60 years with dementia
Clozapine is not indicated for the treatment of psychosis / psychotic disorders in patients older than 60 with dementia, as the efficacy and safety of clozapine in patients in this category have not been proven.
Against the backdrop of the use of atypical antipsychotics in patients aged> 60 years with psychosis / or behavioral disorders, due to dementia, the risk of death increased. The analysis of the data showed that in patients of this category the risk of death against the background of the use of these agents was 1.6-1.7 times higher than against the background of the placebo application. Factors that increase the risk of death on the background of the use of antipsychotics include: sedation, SSS disease (eg, arrhythmia, sudden cardiac death) or lung disease (eg, pneumonia with or without aspiration).
Reflective symptoms / withdrawal symptoms
If necessary, a drastic withdrawal of the drug Clozapine (for example, for reasons leukopenia), the patient should be carefully examined for the return of psychotic symptoms and ricochet cholinergic symptoms, in particular increased sweating, headache, nausea, vomiting and diarrhea.