Clozapine

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Clozapine: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Clozapinum

ATX code: N05AH02

Active ingredient: clozapine (clozapine)

Manufacturer: Federal State Unitary Enterprise "Moscow Endocrine Plant" (Russia); Borisov Plant of Medical Products (Republic of Belarus); Balkan Pharmaceuticals (Moldova)

Description and photo update: 2019-20-08

Clozapine is an antipsychotic drug with a sedative effect.

Release form and composition

Dosage form Clozapine - tablets: round, flat-cylindrical, beveled, yellow; risk, intended for dividing tablets into two equal parts, for a dosage of 100 mg (for a dosage of 25 mg - the risk is not available for all manufacturers) (10 pcs. in aluminum / polyvinyl chloride blister packs; in a cardboard box, 5 packs).

Composition of 1 tablet:

active substance: clozapine - 25 or 100 mg;
auxiliary components: povidone, potato starch, colloidal silicon dioxide, calcium stearate, lactose monohydrate.

Pharmacological properties

Pharmacodynamics

Clozapine is an atypical neuroleptic with sedative and antipsychotic effects. At the same time, it does not provoke pronounced extrapyramidal reactions and practically does not affect the level of prolactin in the blood. Experimental studies have confirmed that clozapine is not the cause of the development of catalepsy and does not contribute to the suppression of stereotyped behavior caused by the administration of amphetamine or apomorphine.

Clozapine is a weak blocker of dopamine D ₁ -, D ₂ -, D ₃ - and D ₅ -receptors, while exerting a pronounced blocking effect on D ₄ -receptors. Also, the substance demonstrates pronounced α-adrenergic blocking, antihistamine and anticholinergic effects, and inhibits the activation reaction on the electroencephalogram. Additionally, the drug exhibits antiserotonergic properties.

Application in clinical practice proves that clozapine has a rapid and pronounced sedative effect, and also has an antipsychotic effect, especially in patients with schizophrenia resistant to therapy with other antipsychotics.

Clozapine effectively eliminates the productive and negative symptoms of schizophrenia in both short and long term therapy. In addition, there was a positive trend in certain cognitive impairments.

Observation of 980 patients over 2 years showed that in patients undergoing clozapine treatment, the risk of suicidal behavior (taking into account the number of both suicide attempts and hospitalizations aimed at preventing suicide) was 24% lower than in those taking olanzapine. A feature of clozapine is that it practically does not lead to the appearance of pronounced extrapyramidal reactions, for example, tardive dyskinesia or acute dystonia. Side effects such as akathisia and parkinsonism are rare. Unlike other antipsychotics, the use of clozapine does not cause an increase or leads to a very slight increase in the content of prolactin, which prevents such adverse reactions as impotence, gynecomastia, galactorrhea and amenorrhea.

Potentially threatening side effects of clozapine treatment include agranulocytosis and granulocytopenia, with rates of 0.7% and 3%, respectively.

Pharmacokinetics

After oral administration, clozapine is approximately 90–95% absorbed. Food intake does not change the degree and rate of absorption. Since during the first passage through the liver, the substance is moderately involved in metabolic processes, its absolute bioavailability is 50-60%.

When clozapine is taken 2 times a day, its maximum equilibrium concentration in the blood is recorded on average after 2.1 hours (range is 0.4–4.2 hours), and the volume of distribution is 1.6 l / kg. The plasma protein binding of clozapine is approximately 95%.

Clozapine is metabolized almost 100% with the participation of CYP3A4 and CYP1A2 isoenzymes, and to some extent with the participation of CYP2D6 and CYP2C19 isoenzymes. Among the main metabolites, only one demonstrates pharmacological activity - desmethylclozapine, with a pharmacological effect similar to clozapine, but being shorter and much weaker.

Clozapine is excreted in a two-phase manner. In the final phase, the half-life is on average 12 hours (the range of variation is 6-26 hours). After a single dose of the drug at a dose of 75 mg, the average half-life in the final phase is 7.9 hours. This value increases to 14.2 hours after reaching an equilibrium state, as a result of taking the drug in a daily dose of 75 mg for at least 7 days. Clozapine in unchanged form is determined in feces and urine only in trace concentrations. Approximately 50% of the dose taken is excreted through the kidneys and 30% through the intestines in the form of metabolites.

There is evidence that in the equilibrium state, with an increase in the daily dose of clozapine from 37.5 mg to 75 mg and 150 mg (it is divided into 2 doses), there is a linear dose-dependent increase in AUC (area under the concentration-time curve), as well as increasing the minimum and maximum concentration in blood plasma.

Indications for use

According to the instructions, Clozapine is recommended for use in schizophrenia resistant to therapy, only in patients resistant or tolerant to standard antipsychotics that meet the following definitions:

resistance to standard antipsychotics: previous treatment with standard antipsychotics in an appropriate dose for a long period of time did not lead to an adequate clinical improvement;
intolerance to standard antipsychotics: during therapy, severe uncontrollable neurological side reactions occur (for example, extrapyramidal symptoms, tardive dyskinesia), which make it impossible for effective antipsychotic treatment using standard antipsychotics.

Clozapine is indicated to reduce the risk of recurrence of suicidal behavior in patients with schizophrenia or schizoaffective psychosis who have a chronic risk of recurrent suicidal behavior based on history and current clinical observations. Where suicidal behavior implies the patient's actions, with a high degree of probability, leading to his death.

For the correction of psychotic disorders in patients with idiopathic Parkinson's syndrome (Parkinson's disease), Clozapine is prescribed in case of ineffectiveness of standard therapy. What is defined as inadequate control of psychotic symptoms and / or deterioration of motor function, acceptable in terms of functional status, after the following measures have been taken:

withdrawal of anticholinergic drugs, including tricyclic antidepressants;
attempts to reduce the dose of an antiparkinsonian drug with a dopaminergic effect.

Contraindications

Absolute:

the inability to regularly monitor the patient's blood counts;
history of granulocytopenia / agranulocytosis (with the exception of the development of these diseases due to previous chemotherapy);
disruption of the bone marrow;
uncontrolled epilepsy;
psychoses of various etiologies (alcoholic, toxic), drug intoxication, coma;
oppression of the central nervous system (central nervous system) and vascular collapse of any etiology;
severe renal dysfunction;
liver disease in the acute phase, accompanied by loss of appetite, nausea, jaundice; liver failure, progressive liver disease;
severe dysfunction of the heart, myocarditis;
ileus (paralytic intestinal obstruction);
simultaneous administration with drugs that can cause agranulocytosis, and depot neuroleptics;
rare hereditary diseases: galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption;
period of breastfeeding;
children and adolescents up to 18 years old;
increased individual sensitivity to clozapine and / or ancillary components of the drug.

Relative contraindications, Clozapine is used with caution, after consulting a doctor and only for his purpose:

high risk of developing disorders of cerebral circulation (including in elderly patients with dementia);
agranulocytosis (clozapine can cause a critical decrease in the concentration of granulocytes). In the presence of a history of primary bone marrow disease, clozapine may be used, provided that the expected benefit from therapy significantly outweighs the risk of adverse effects. Before taking Clozapine, it is required to undergo an in-depth examination by a hematologist and obtain his consent, especially in patients with a low white blood cell count due to benign ethnic neutropenia;
anticholinergic activity: clozapine is an m-anticholinergic antagonist that causes corresponding side reactions from organs and systems, therefore, careful monitoring is required in patients with angle-closure glaucoma and prostatic hyperplasia. The anticholinergic efficacy of clozapine can also interfere with intestinal motility (from constipation to intestinal obstruction / coprolite blockage / paralytic intestinal obstruction), in rare cases, death is possible.

Instructions for the use of Clozapine: method and dosage

Clozapine tablets are taken orally.

The dose is selected individually and should be the minimum effective. It is allowed to divide the total daily dose into several doses in unequal parts, the largest of which is taken before bedtime.

Treatment-resistant schizophrenia

initial dose: on the 1st day - 1 or 2 doses of ½ tablet 25 mg (12.5 mg); 2nd day - 1 or 2 doses of 1 tablet of 25 mg. With good tolerance, the dose can be gradually increased by 25–50 mg / day over 2–3 weeks until a daily dose of 300 mg is reached. Then, if necessary, the daily dose can be increased by 50-100 mg at intervals of 3-4 for (2 times a week), but preferably 1 time per week;
therapeutic dose: for most patients, the onset of antipsychotic efficacy occurs when taking daily doses in the range of 300-450 mg, divided into 2-4 doses. In some cases, lower daily doses may be adequate, while other patients may require more than 600 mg / day;
maximum dose: when higher doses are required to achieve the full therapeutic effect, the maximum allowable daily dose is 900 mg, and the maximum increase in 1 time is no more than 100 mg. Taking the drug in a daily dose above 450 mg increases the number of undesirable reactions (including paroxysms);
maintenance dose: after reaching the maximum therapeutic effect, many patients should switch to taking Clozapine in a maintenance dose, for which a gradual decrease is recommended. The duration of the course of maintenance therapy is at least six months. When the daily dose is ≤ 200 mg, a single evening dose of the drug is advisable;
cancellation of treatment: in case of planned discontinuation of the drug, it is recommended to reduce the dose gradually, over 1–2 weeks. If it is necessary to abruptly discontinue therapy, careful monitoring of the patient's condition is required due to the possibility of exacerbation of psychotic symptoms or associated with cholinergic rebound effect, such as headache, hyperhidrosis, nausea / vomiting and diarrhea;
resumption of treatment: when more than 2 days have passed since the last pill intake, therapy is resumed according to the "initial dose" item scheme. With good tolerance, increasing the dose until a therapeutic effect is achieved can be faster than with the initial treatment. But, if in the initial period the patient experienced a cessation of breathing or cardiac activity, after which the dose was successfully brought to the therapeutic one, with its repeated increase, one should be extremely careful;
switching from other antipsychotics to clozapine: as a rule, clozapine is not prescribed in combination with other antipsychotics. When it is necessary to start clozapine treatment in a patient already taking oral antipsychotics, if possible, stop taking them first, gradually reducing the dose over 1 week. The use of Clozapine can be started no earlier than 1 day after the complete cessation of taking other neuroleptic drugs.

Schizophrenia and schizoaffective psychosis

To reduce the risk of repeated suicidal behavior in patients with schizophrenia and schizoaffective psychosis, it is recommended to adhere to the route of administration and dosage given for patients with treatment-resistant schizophrenia. The duration of the course of therapy is at least 2 years. After that, you need to re-assess the risk of suicidal behavior, based on the results of which the need to continue treatment is determined.

Psychosis in Parkinson's disease

With the ineffectiveness of standard therapy for the relief of psychosis in patients with idiopathic Parkinson's syndrome (Parkinson's disease), Clozapine is used:

initial dose: from the 1st day - for 1 dose ½ tablet 25 mg (12.5 mg), in the evening; increase the dose to the maximum daily dose - 50 mg by 12.5 mg 1 time in 3-4 days. Before using the drug in a dose of 50 mg, at least 2 weeks should pass from the start of treatment. It is preferable to take the entire daily dose at one time, in the evening;
therapeutic dose: the average effective dose for most patients is 25–37.5 mg (1–1½ tablets of 25 mg) per day. If taking Clozapine at a daily dose of 50 mg for at least 1 week does not have a satisfactory therapeutic effect, it is allowed to increase the dose with caution further, but not more than 12.5 mg per week;
maximum dose: in exceptional cases, it is allowed to exceed the daily dose of 50 mg, but not higher than up to 100 mg. Increasing the dose must be slowed down or interrupted with the development of pronounced sedation, orthostatic hypotension or confusion. During the first weeks of therapy, it is necessary to monitor blood pressure indicators;
maintenance dose: if an increase in the dose of antiparkinsonian drugs is shown on the basis of an assessment of motor status, it is possible no earlier than 2 weeks after the complete relief of psychotic symptoms. When psychotic symptoms reappear with increasing doses, clozapine can be increased by 12.5 mg per week to a maximum daily dose of 100 mg;
Cancellation of treatment: at the end of the course, the daily dose is recommended to be gradually reduced by ½ tablet 25 mg (12.5 mg) once a week, and preferably once every 2 weeks. Treatment must be stopped immediately if neutropenia or agranulocytosis develops. In this case, the patient requires careful psychiatric observation, since symptoms can quickly recur.

For dosing accuracy, it is recommended to use Clozapine from the manufacturer, which has a separation risk on the 25 mg tablets.

Side effects

The most serious adverse effects of clozapine are convulsions, agranulocytosis, cardiovascular complications, and fever. The most common are dizziness, drowsiness / sedation, tachycardia, increased salivation, and constipation.

According to clinical studies, the proportion of patients who discontinued clozapine therapy due to adverse reactions associated with clozapine was 7.1-15.6%. The most common of these were drowsiness, dizziness, leukopenia, psychotic disorders.

Undesirable side effects of clozapine registered from systems and organs during clinical trials:

blood and lymphatic system: often - leukopenia (drop in the number of leukocytes), eosinophilia, neutropenia, leukocytosis; infrequently - agranulocytosis; rarely, lymphopenia, anemia; extremely rare - thrombocytosis, thrombocytopenia;
metabolism and nutrition: often (4–31%) - weight gain; rarely - impaired glucose tolerance, worsening / development of diabetes mellitus; extremely rarely - ketoacidosis, hyperosmolar coma, hypercholesterolemia, severe hyperglycemia, hypertriglyceridemia;
psyche: often - dysarthria; infrequently - stuttering (dysfemia); rarely - anxiety, agitation;
nervous system: very often - drowsiness, sedation (39–46%), dizziness (19–27%); often - seizures, convulsions (including fatal), myoclonic seizures, headache, akathisia, extrapyramidal symptoms, tremor, muscle stiffness; infrequently - ZNS (neuroleptic malignant syndrome); rarely - delirium, confusion; extremely rare - obsessive-compulsive disorder, tardive dyskinesia;
organ of vision: often - blurred vision;
heart: very often, especially in the first weeks of therapy, tachycardia (25%); often - ECG changes (electrocardiogram); rarely - arrhythmia, circulatory collapse, pericarditis, myocarditis; extremely rarely - cardiomyopathy, up to cardiac arrest;
vascular system: often - orthostatic hypotension, fainting, arterial hypertension; rarely - thromboembolism, including deaths and a combination of thromboembolism with necrosis of organs (intestines), shock due to severe arterial hypotension (especially against the background of an aggressive increase in the dose of the drug), with potentially serious consequences such as circulatory / respiratory arrest;
respiratory system, chest and mediastinal organs: rarely - food aspiration, infection of the lower respiratory tract, pneumonia (in some cases, even death); extremely rarely - depression / respiratory arrest;
Gastrointestinal tract (gastrointestinal tract): very often - constipation (14-25%), hypersalivation (31-48%); often - nausea / vomiting, dry mouth; rarely, dysphagia; extremely rarely - intestinal obstruction, paralytic intestinal obstruction, blockage by coprolites, growth of the parotid salivary gland;
hepatobiliary system: often - increased activity of liver enzymes; rarely - hepatitis, pancreatitis, cholestatic jaundice; extremely rare - fulminant hepatic necrosis;
skin and subcutaneous tissue: extremely rare - skin reactions;
kidneys and urinary tract: often - urinary retention / incontinence; extremely rare - interstitial nephritis;
genitals and mammary gland: extremely rare - priapism;
general disorders: often - violation of sweating / thermoregulation, benign hyperthermia, fatigue; very rarely - sudden death (no reasons identified);
laboratory and instrumental studies: rarely - increased activity of CPK (creatine phosphokinase); extremely rare - hyponatremia.

Undesirable side effects of clozapine, recorded from systems and organs in the course of spontaneous reports and publications, from a population of uncertain size with an unknown frequency:

infections and invasions: sepsis;
immune system: leukocytoclastic vasculitis, angioedema;
endocrine system: pseudopheochromocytoma;
nervous system: changes in the electroencephalogram (EEG), cholinergic syndrome, leaning tower of Pisa syndrome, characterized by a lateral tilt of the trunk and head, sometimes with some rotation, with posterior deviation of the trunk;
heart: palpitations, chest pain, angina pectoris, atrial fibrillation, mitral valve insufficiency in clozapine-associated cardiomyopathy, myocardial infarction with a possible fatal outcome;
vascular system: arterial hypotension;
respiratory system, chest and mediastinal organs: nasal congestion, bronchospasm;
Gastrointestinal tract: heartburn, abdominal discomfort, diarrhea, dyspepsia, colitis;
hepatobiliary system: hepatotoxicity, steatosis / necrosis / fibrosis / cirrhosis of the liver, hepatic, cholestatic, mixed liver damage (including life-threatening conditions), liver failure requiring a liver transplant, or leading to death;
skin and subcutaneous tissue: pigmentation disorders;
musculoskeletal and connective tissue: muscle weakness, muscle spasms / pain, systemic lupus erythematosus;
kidneys and urinary tract: bedwetting, renal failure;
genitals and mammary gland: retrograde ejaculation.

In patients over 60 years of age, orthostatic hypotension may develop as a result of taking Clozapine. There is evidence of rare cases of long-term tachycardia. Elderly patients, especially those with impaired cardiovascular function, may be more sensitive to these effects. They also show greater sensitivity to the anticholinergic action of clozapine, which can lead to urinary retention and constipation.

The aggravation of these side effects or the appearance of any other negative actions are not indicated [in the instructions, it is required to inform the attending physician.

Overdose

At the moment, there have been reports of acute intentional or accidental overdose of clozapine, which ended in death in 12% of cases. In most of them, the patient's death was associated with aspiration pneumonia or heart failure, and they occurred after taking the drug in doses exceeding 2000 mg. It is known about cases of recovery of victims after taking clozapine in doses over 10,000 mg. However, in several adult patients (mostly who had not previously taken the drug), taking clozapine at a dose of 400 mg provoked coma, which posed a threat to life, and in one case, death.

Symptoms of clozapine overdose include shortness of breath, depression of the respiratory center or respiratory failure, aspiration pneumonia, seizures, lethargy, drowsiness, clouding of consciousness, revitalization of reflexes, coma, extrapyramidal symptoms, areflexia, delirium, agitation, hallucinations, arterial hypotension, tachycardia, tachycardia collapse, hypersalivation, fluctuations in body temperature, blurred vision, dilated pupils.

There is no specific antidote for clozapine. In the first 4 hours after taking the drug inside, it is recommended to wash the stomach and / or take activated charcoal. Symptomatic therapy is also prescribed, subject to constant monitoring of the functions of the cardiovascular system, control of acid-base balance and electrolyte concentration, and maintenance of respiratory function.

In the case of oligonuria or anuria, hemodialysis and peritoneal dialysis are used, however, when using them, a significant increase in excretion is unlikely due to the high ability of the substance to bind to blood plasma proteins.

To correct certain symptoms of an overdose, the following methods are allowed:

anticholinergic effects: administration of cholinesterase inhibitors, including neostigmine, pyridostigmine and physostigmine (crosses the blood-placental barrier);
seizures: intravenous diazepam or slow intravenous infusion of phenytoin; the appointment of long-acting barbiturates is not allowed; since in this case delayed reactions may develop, careful medical monitoring must be carried out for at least 5 days;
arterial hypotension: intravenous administration of a solution of albumin or other solutions that are substitutes for plasma, as well as the use of dopamine and angiotensin derivatives, which are considered the most effective stimulants of blood circulation; the appointment of epinephrine or other beta-adrenergic agonists that can lead to the development of additional vasodilation is contraindicated;
arrhythmia: prescribing digitalis drugs or sodium / potassium bicarbonate drugs, depending on the symptomatology; the use of procainamide and quinidine is not allowed.

special instructions

Potentially dangerous side effects of clozapine are granulocytopenia and agranulocytosis, with an incidence of 3% and 0.7%, respectively. Agranulocytosis can pose a real threat to the patient's life.

After the determination of the number of leukocytes and the absolute number of neutrophils became widespread, the incidence of agranulocytosis, as well as the mortality rate among patients with agranulocytosis, significantly decreased. In this connection, it is imperative to observe the precautions prescribed by the attending physician.

Clozapine is used exclusively in patients with schizophrenia or psychosis associated with Parkinson's disease who show no response or insufficient response to therapy with other antipsychotics, or who develop severe extrapyramidal side reactions (especially tardive dyskinesias) while using other antipsychotics.

You can also prescribe clozapine to patients with schizophrenia / schizoaffective disorder, for whom, based on the history and current clinical picture, there is a long-term risk of recurrence of suicidal behavior.

In patients of the above categories, Clozapine is used subject to the following requirements:

Before the start of therapy, the number of leukocytes and other blood cells should be within normal limits [for leukocytes, the indicator is at least 3.5 × 10 ⁹ / l (3500 / mm ³)];
Regular monitoring of the number of leukocytes and, if possible, the absolute number of neutrophils (ANC) is required during therapy (for the first 18 weeks - weekly, and then at least 1 time per month), after the final withdrawal of Clozapine - within 1 month.

Clozapine is contraindicated for patients with a history of hematological disorders associated with the use of drugs.

Doctors administering drug therapy must fully comply with patient safety requirements.

At each consultation, the healthcare professional should remind the patient receiving Clozapine that the manifestation of any signs of infectious disease requires immediate attention to the attending physician. Particular attention should be paid to flu-like symptoms and other signs of infection (fever, sore throat), as this may indicate neutropenia. In such cases, an immediate general blood test is required.

Influence on the ability to drive vehicles and complex mechanisms

Since Clozapine is able to have a sedative effect, as well as reduce the threshold of convulsive readiness, one should refrain from driving vehicles and complex mechanisms during the period of therapy.

Application during pregnancy and lactation

There is no information on the use of Clozapine in pregnant women. For this category of patients, it should be prescribed only if the potential benefit of treatment to the mother outweighs the possible risks to the fetus.

Antipsychotics, including Clozapine, are allowed to be used during pregnancy only if absolutely necessary. If the drug is discontinued during pregnancy, this should be done gradually.

Newborns who have been exposed to antipsychotic drugs in the third trimester of pregnancy are at risk of postnatal withdrawal and / or extrapyramidal disorders. In some cases, these children had symptoms such as eating disorders, agitation, respiratory distress syndrome, drowsiness, muscle hypertension, tremor, hypotension. Symptoms ranged in severity from mild to severe, with the latter requiring intensive care and prolonged hospitalization.

Clozapine passes into breast milk and affects the newborn, therefore, when prescribing the drug during lactation, it is recommended to stop breastfeeding.

Some women of reproductive age may develop amenorrhea with certain antipsychotics. The transfer of such patients to clozapine therapy sometimes helps to normalize the menstrual cycle. In this regard, women are advised to use reliable methods of contraception during fertility.

Pediatric use

Due to the lack of reliable data on the efficacy and safety of using Clozapine in children and adolescents under 18 years of age, the drug is not used in pediatrics.

With impaired renal function

The appointment of Clozapine is contraindicated in severe kidney disease.

Patients with mild and moderate renal dysfunction are used at a low initial dose (on the first day, no more than 12.5 mg per day at a time). For higher dosing accuracy, it is recommended to use tablets at a dosage of 25 mg with a dividing line.

For violations of liver function

The appointment of Clozapine is contraindicated in liver diseases in the active phase, accompanied by nausea, anorexia, jaundice, as well as in progressive liver diseases and fulminant hepatic failure.

The use of atypical antipsychotic drugs, including clozapine, in patients with liver disease is allowed provided that its function is regularly monitored. If, during therapy, symptoms develop that indicate abnormal liver function, such as nausea, vomiting, loss of appetite, an analysis of liver function indicators is required immediately. With a clinically significant increase in these indicators or the appearance of symptoms of jaundice, clozapine is discontinued. It is permissible to resume therapy, provided that the functional parameters of the liver are normalized, under close medical supervision.

Use in the elderly

In elderly patients over 60 years of age, the drug should be used with caution, starting with the minimum dose.

Elderly patients with dementia treated with antipsychotic drugs have been found to have an increased risk of death compared with those who do not. Clozapine is not recommended for the treatment of dementia-related behavioral disorders in elderly patients over 60 years of age.

Drug interactions

Pharmacodynamic interaction:

drugs that significantly inhibit the function of the bone marrow, long-acting antipsychotics (in the form of a depot) with a potential myelosuppressive effect, which cannot be quickly removed from the body if necessary (for example, when neutropenia occurs): it is forbidden to use simultaneously with clozapine;
ethanol, monoamine oxidase inhibitors, drugs that depress the central nervous system (drugs for anesthesia, blockers of H2-histamine receptors, benzodiazepines): clozapine can enhance their central action, with the use of these combinations, there have been cases of death;
benzodiazepines, other psychotropic drugs: concomitantly with clozapine is used with extreme caution, since patients receiving (recently received) this combination increase the risk of collapse, in rare cases severe, leading to cardiac arrest (respiration); it is not known whether dose adjustment can prevent the development of such a stop;
lithium preparations, other agents affecting the function of the central nervous system: may increase the risk of developing NMS;
anticholinergic, antihypertensive, respiratory depressant drugs: can exhibit an additive effect with clozapine, the combination requires caution;
norepinephrine, other α-adrenergic agonists: due to the α-adrenergic blocking action, clozapine is able to weaken their hypertensive effect and paradoxically change the vasoconstrictor effect of epinephrine;
antiepileptic drugs: clozapine can lower the seizure threshold, which may require dose adjustment; with the simultaneous use of clozapine and valproic acid, severe convulsive seizures were observed, including in patients without epilepsy, and cases of delirium, possibly resulting from the pharmacodynamic interaction of substances, the mechanism of which has not yet been clarified;
drugs with a pronounced ability to bind to blood plasma proteins, for example, digoxin and warfarin: an increase in their plasma concentration is possible due to competitive interaction with clozapine at the level of blood plasma proteins; if necessary, their doses are adjusted;
drugs that cause prolongation of the QT interval or electrolyte disturbances: concomitantly with clozapine, as with other antipsychotics, should be used with caution.

Pharmacokinetic interaction:

isozymes of the cytochrome CYP450 group (1A2 and 3A4 and 2D6): clozapine is their substrate, which reduces the risk of metabolic interactions at the level of each individual isoenzyme; however, patients receiving treatment with several drugs with an affinity for one or more of these isoenzymes need to control the concentration of clozapine in blood plasma, since it is possible to increase or decrease the concentration of clozapine or drugs used concomitantly with it. Theoretically, clozapine can increase the plasma concentration of phenothiazine derivatives, tricyclic antidepressants, class 1C antiarrhythmic drugs that bind to the CYP2D6 isoenzyme, this may require a reduction in doses of these drugs.
inhibitors of isoenzymes of the cytochrome CYP450 system - cimetidine (CYP1A2, 2D6, 3A4); erythromycin (CYP3A4); clarithromycin, azithromycin, fluvoxamine (1A2); perazine (1A2); ciprofloxacin (1A2); hormonal contraceptives for oral administration (1A2, 3A4, 2C19), citalopram, fluoxetine, venlafaxine, etc.: use with clozapine in high doses causes an increase in the plasma concentration of the latter and the occurrence of undesirable reactions;
potent inhibitors / inducers of the CYP3A4 isoenzyme - azole antimycotic drugs, protease inhibitors: potentially capable of affecting the plasma concentration of clozapine, but so far no such interaction has been observed;
caffeine (a substrate of the isoenzyme CYP1A2): can increase the concentration of clozapine in the blood plasma, the concentration of which, after caffeine withdrawal, decreases by half in about 5 days; this is important to consider when changing your coffee or tea consumption regime.
ciprofloxacin (at a dose of 250 mg): increased the plasma concentration of clozapine and N-desmethylclozapine;
norfloxacin, enoxacin: there have been cases of interaction with clozapine;
inducers of the CYP3A4 isoenzyme of the cytochrome P450 system (carbamazepine, rifampicin): can reduce the plasma concentration of clozapine; the abolition of carbamazepine increased the level of clozapine;
phenytoin: reduces the concentration of clozapine in blood plasma, reducing the effect of the previously effective dose;
components of tobacco smoke (inducers of the CYP1A2 isoenzyme): with a sharp cessation of smoking, it is possible to increase the plasma concentration of clozapine in heavy smokers and, as a result, increase the severity of its side effects;
omeprazole (inducer of the isoenzyme CYP1A2 and CYP3A4, and an inhibitor of the isoenzyme CYP2C19), pantoprazole, a combination of lansoprazole and paroxetine: increase the level of clozapine in blood plasma.

Analogs

Clozapine analogs are: Amisulpride, Aripiprazole, Ziprasidone, Quetiapine, Sertindol, Risperidone, Olanzapine.

Terms and conditions of storage

Store in a cool, dry place, out of reach of children.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews of Clozapine

Mostly positive reviews about Clozapine are left by both doctors and patients who report a good therapeutic effect from its use and a small number of adverse reactions, in particular, extrapyramidal disorders. The most commonly described side effects when taking the drug are a sharp decrease in pressure, drowsiness, hypersalivation.

The price of Clozapine in pharmacies

The price of Clozapine is currently unknown because the drug is not available for sale.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!