Atypical neuroleptic. Synonyms for clozapine: azaleptin, leponex, alemoxan, clazaril, iprox. In our country it is sold in two forms: azaleptin and leponex.
Clozapine
- one of the most powerful antipsychotics available today. It is included in the list of potent psychotropic drugs and therefore its circulation is especially controlled by the state (illegal trafficking may result in criminal liability).
In hospitals it is subject to special control and recording. It is prescribed to patients on special forms of strict accounting on numbered prescriptions of a special form: 148-1/u-88. Of all the antipsychotics, only two drugs have such enhanced control over their distribution and use: clozapine and levomepromazine (tisercin).
It was synthesized back in the 60s of the 20th century, the first experience of its use was in 1971, but it became widely used only in 1990. He is considered the founder of the second generation of antipsychotic drugs - atypical antipsychotics.
Unlike first-generation drugs, clozapine is able to influence negative symptoms (apathy, passivity, decreased emotions, withdrawal) and is noticeably less likely to cause extrapyramidal disorders.
Later, new antipsychotic drugs appeared and continue to appear, some of them are falling out of use, but clozapine is still widely used throughout the world as one of the most powerful antipsychotic drugs.
The mechanism of action is complex: it blocks dopamine (especially D-4) receptors in the brain. In addition, it has a similar effect on acetylcholine, adrenaline, histamine, GABA and serotonin receptors. Due to this, a strong sedative effect is achieved, excitement, impulsivity, and fear are relieved, and productive symptoms of psychosis (delusions, hallucinations) are reduced.
One of the intermediate products of clozapine metabolism is benzodiazepine, the active ingredient of many tranquilizers, which determines the anti-anxiety and hypnotic effects. In some cases, an antidepressant effect may also be observed.
Pharmacological properties of the drug Clozapine
Tricyclic dibenzodiazepine derivative. Neuroleptic, has antipsychotic and sedative effects. Blocks dopamine receptors in the central nervous system, has peripheral and central anticholinergic, as well as adrenolytic, antihistamine and antiserotonin effects. A distinctive feature of clozapine is that it practically does not cause significant extrapyramidal disorders and does not have a pronounced inhibitory effect. Treatment with clozapine does not cause an increase in prolactin levels in the blood and, therefore, does not lead to the development of gynecomastia, amenorrhea, galactorrhea and impotence.
Withdrawal syndrome
The drug has the property of being addictive. For this reason, in patients it is withdrawn slowly, gradually reducing the dose over several weeks. If a drug addict cannot take another dose for a certain reason, this leads to a strong withdrawal syndrome. It is accompanied by the following symptoms:
- irritability and aggression
- hypermobility
- tremors and convulsions
- hallucinations (most often visual, but can also be auditory)
- delirium and clouding of consciousness
Use of the drug Clozapine
Adults are usually prescribed on the 1st day at a dose of 25–50 mg. If well tolerated, the dose is slowly increased over 1–2 weeks by 25–50 to 300 mg/day (individual fluctuations in the daily dose from 200 to 450 mg are possible). Frequency of administration - several times a day; Moreover, a larger dose of the drug can be prescribed before bedtime. The maximum recommended dose is 600 mg/day, but some patients may require a dose of up to 900 mg/day; This dose can be achieved only with a very gradual (no more than 100 mg in one stage) increase. After achieving the maximum therapeutic effect, it is recommended to transfer the patient to maintenance treatment with clozapine at lower doses. The maintenance dose should be selected individually, with a gradual (in several stages) reduction of the initial dose. The maintenance daily dose averages 150–300 mg, although for some patients it may be lower. At a dose not exceeding 200 mg/day, clozapine can be taken once in the evening. In case of planned discontinuation of treatment, a gradual dose reduction over 1–2 weeks is recommended. If prompt withdrawal is necessary, the patient's mental status must be monitored. When resuming interrupted treatment, recommendations for an initial gradual dose increase should be followed. In patients with a history of seizures, as well as in persons with cardiovascular diseases and kidney and/or liver diseases, the initial dose of the drug should be low, and the dose should be increased very slowly.
Clozapine (Azaleptin, Leponex. Clozasten, Azaleprol)
Indications
Acute and chronic forms of schizophrenia, manic states, manic-depressive psychosis, psychomotor agitation in psychopathy, emotional and behavioral disorders (including in children), sleep disorders.
Contraindications
History of granulocytopenia or agranulocytosis (except for the development of granulocytopenia or agranulocytosis due to previously used chemotherapy), suppression of bone marrow hematopoiesis, myasthenia gravis, comatose states, toxic psychosis (including alcoholic), pregnancy, lactation, children under 5 years of age, increased sensitivity to clozapine.
Dosage
Installed individually. For oral administration, a single dose is 50-200 mg, daily - 200-400 mg. Treatment is usually started with a dose of 25-50 mg, then gradually increased by 25-50 mg per day to 200-300 mg/day over 7-14 days. The daily dose can be used once before bedtime or 2-3 times a day after meals. If treatment is discontinued, the dose should be gradually reduced over 1-2 weeks. After achieving a therapeutic effect, they switch to a maintenance course.
If necessary, clozapine can be administered intramuscularly.
The maximum dose when taken orally is 600 mg/day.
In mild forms of the disease, for maintenance therapy, as well as in patients with liver and/or renal failure, chronic heart failure, cerebrovascular disorders, it is prescribed in lower daily doses (25-200 mg).
Side effects
From the central nervous system: drowsiness, headache, rarely - agitation, akathisia, confusion, extrapyramidal disorders (akinesia, hypokinesia, muscle rigidity, tremor), insomnia, restless sleep, depression, NMS, epileptic seizures, tardive dyskinesia, increased temperature of central origin .
From the cardiovascular system: tachycardia, arterial hypotension, orthostatic hypotension, accompanied by dizziness; rarely - flattening of the T wave on the ECG, arterial hypertension.
From the digestive system: hypersalivation, nausea, vomiting, dry mouth, heartburn.
Metabolism: weight gain, increased sweating.
From the hematopoietic system: rarely - eosinophilia, granulocytopenia up to agranulocytosis, leukopenia, thrombocytopenia.
Effects due to anticholinergic activity: dry mouth, accommodation disturbances, constipation, urination problems.
Other: myasthenia gravis, decreased potency, impaired accommodation.
Drug interactions
When used simultaneously with drugs that have a depressant effect on the central nervous system (including benzodiazepine derivatives), ethanol-containing drugs, ethanol, the severity and frequency of manifestations of the inhibitory effect on the central nervous system and increased depression of the respiratory center increase.
When used simultaneously with drugs that cause arterial hypotension, additive hypotensive effects are possible.
When used simultaneously with drugs that cause myelosuppression, the inhibitory effect on bone marrow hematopoiesis may be enhanced; with anticholinergic drugs - the anticholinergic effect may be enhanced.
When used simultaneously with digoxin or with drugs characterized by high protein binding (including heparin, warfarin, phenytoin), their concentrations in the blood plasma may increase, and clozapine may also be displaced by these drugs from the sites of its protein binding.
When used simultaneously with valproic acid, a change in the concentration of clozapine in the blood plasma is possible, while clinical manifestations of the interaction were practically absent.
When used simultaneously with carbamazepine, the concentration of clozapine in the blood plasma decreases. Cases of severe pancytopenia and neuroleptic malignant syndrome have been described.
When used simultaneously with caffeine, the concentration of clozapine in the blood plasma increases and the incidence of side effects may increase.
When used simultaneously with lithium carbonate, myoclonus, convulsions, neuroleptic malignant syndrome, delirium, and psychosis are possible.
When used simultaneously with risperidone, an increase in the concentration of clozapine in the blood plasma is possible, apparently due to a competitive effect on the CYP2D6 isoenzyme, which leads to inhibition of the metabolism of clozapine. When quickly replacing clozapine with risperidone, dystonia may develop.
Rifampicin may increase the rate of metabolism of clozapine by inducing the isoenzymes CYP1A2 and CYP3A.
When used simultaneously with phenytoin, a decrease in the concentration of clozapine in the blood plasma is possible; with fluoxetine, paroxetine, sertraline, fluvoxamine, it is possible to increase the concentration of clozapine in the blood plasma, which in some patients is accompanied by toxicity. This effect is especially pronounced when clozapine is used concomitantly with fluvoxamine.
When used simultaneously with ciprofloxacin, it is possible to increase the concentration of clozapine in the blood plasma.
special instructions
Use with caution in severe diseases of the cardiovascular system, severe renal and/or liver failure, angle-closure glaucoma, prostatic hyperplasia, intestinal atony, epilepsy, intercurrent diseases with febrile syndrome.
During the treatment period, systematic monitoring of peripheral blood patterns is necessary.
When using clozapine, alcohol consumption should be avoided.
The safety and effectiveness of clozapine in children and adolescents under 16 years of age has not been established.
Impact on the ability to drive vehicles and operate machinery
Patients taking clozapine should refrain from potentially hazardous activities that require concentration and increased psychomotor speed.
Pregnancy and lactation
Clozapine is contraindicated during pregnancy and lactation (breastfeeding).
Use in childhood
Contraindicated in children under 5 years of age. The safety and effectiveness of clozapine in children and adolescents under 16 years of age has not been established.
For impaired renal function
Use with caution in severe renal failure. In patients with renal failure, the drug is prescribed at a lower daily dose (25-200 mg).
For liver dysfunction
Use with caution in severe liver failure. In patients with liver failure, the drug is prescribed at a lower daily dose (25-200 mg).
Side effects of the drug Clozapine
The risk of occurrence and/or intensification of side effects increases when clozapine is prescribed in a daily dose exceeding 450 mg. Hematological: granulocytopenia, agranulocytosis (usually develops during the first 18 weeks of treatment); the development of eosinophilia and/or leukocytosis of unknown etiology is possible (especially during the first weeks of treatment). From the side of the central nervous system: most often - drowsiness, increased fatigue; Possible dizziness, headache, relatively rarely - extrapyramidal symptoms, usually of mild severity. There are reports of the development of rigidity, tremor, akathisia, as well as very rare reports of the development of neuroleptic malignant syndrome. From the autonomic nervous system: a feeling of dry mouth, disturbances of accommodation, sweating and thermoregulation, hyperthermia, excessive salivation. From the cardiovascular system: possible tachycardia, orthostatic hypotension, less often - fainting (especially in the first weeks of treatment), relatively rarely - hypertension (arterial hypertension). In rare cases, collapse has been reported, accompanied by depression or respiratory arrest. There are isolated reports of changes in the ECG, the development of arrhythmia, and myocarditis. From the digestive tract and liver: nausea, vomiting, constipation are possible. An increase in the activity of liver enzymes has been reported, and in rare cases, the development of cholestasis. From the urinary system: there are reports of cases of urinary incontinence and urinary retention. Other: weight gain; There are isolated reports of the development of skin reactions. Cases of sudden death have been described, occurring with equal frequency both among people with mental disorders receiving antipsychotic drugs and among patients who do not receive these drugs.
PsyAndNeuro.ru
The most commonly reported toxic side effect of clozapine is agranulocytosis. Cardiovascular side effects, although rare, include life-threatening myocarditis and dilated cardiomyopathy. There are currently no published guidelines for monitoring patients for these conditions.
Recent trial results of various new antipsychotic drugs have "proven to be inconclusive" in providing clinicians with alternative pharmacological treatment options for treatment-resistant schizophrenia.
The incidence of clozapine-associated myocarditis is currently “poorly defined” and is estimated at 0.2–3%. A review of the literature found that >80% of myocarditis cases occurred within the first 4 weeks of clozapine treatment. Clozapine-induced cardiomyopathy is less common, <1/1000 patients. This condition also has a delayed onset; Symptoms usually appear between 3 weeks and 4 years after starting the drug, with an average of 14.4 months.
The significant underlying risk of cardiovascular disease present in patients with mental disorders can be considered a major risk factor. According to the meta-analysis, 10% of patients had ≥1 concomitant cardiovascular disease.
Because sinus tachycardia is a common effect of clozapine use, it is not considered in itself to be evidence of clozapine-induced cardiotoxicity. However, the development of new sinus tachycardia should prompt the patient to be evaluated.
Currently, there are no clear diagnostic criteria for clozapine-induced cardiotoxicity.
Myocarditis
1) ECG is a routine method, but does not provide reliable data. Sinus tachycardia may occur.
2) Biomarkers. It is advisable to study troponin levels. With myocarditis, there is a sharp increase in its level. Nonspecific, is a marker of myocardial damage of any origin.
3) Additional biomarkers. CRP is a marker of inflammation.
4) Visualization. EchoCG – regional or global left ventricular or biventricular dysfunction with normal myocardial thickness. MRI - in addition to contractile dysfunction, reflects the presence of edema and scar changes.
5) Biopsy. "Gold standard", but rarely used.
Myocardiopathy
1) ECG is a routine method.
2) Biomarkers. The level of brain natriuretic peptide (BNP, N-BNP) is examined. Its increase indicates overstretching of the heart muscle.
3) Visualization. EchoCG - expansion and thinning of the LV myocardium, systolic dysfunction.
Currently, the mainstay of therapy for clozapine-induced cardiotoxicity is consideration of clozapine discontinuation followed by evaluation by a cardiologist and specific treatment.
Current literature indicates that myocarditis resolves both symptomatically and biochemically upon discontinuation of clozapine. There is no evidence of cardiomyopathy, but in one case it was reported that the condition may be partially reversible after discontinuation of clozapine. In patients with underlying cardiac disease, a cardiologist can provide appropriate advice regarding the safety of initiating clozapine therapy.
Author of the translation: Cherapkin E. S.
Sources
Special instructions for the use of Clozapine
Given the high risk of developing agranulocytosis during treatment with clozapine, it should be prescribed only to those patients with schizophrenia who have no effect from treatment with classical antipsychotics or in case of their intolerance. A prerequisite is also that the patient initially has a normal quantitative and qualitative composition (leukocyte formula) of leukocytes in the blood. During treatment with clozapine, systematic monitoring of the number of leukocytes and leukocyte formula is necessary: weekly for the first 18 weeks and at least once a month thereafter throughout the course of treatment. Caution should be exercised when prescribing clozapine to patients with prostatic hypertrophy and angle-closure glaucoma; diseases of the liver, kidneys, heart. In these patients, systematic monitoring of the function of the liver, kidneys, and cardiovascular system is necessary. Due to the ability of clozapine to cause sedation and lower the seizure threshold, patients should avoid driving vehicles or operating potentially dangerous machinery, especially during the first weeks of treatment. The safety of clozapine during pregnancy has not been established. If clozapine is prescribed during breastfeeding, breastfeeding should be interrupted.
Reasons for using the drug in drug addicts
The pronounced sedative, inhibitory effect of Clozapine has long been known among drug addicts. The drug’s ability to enhance the effect of using other types of illegal drugs (depressants) is also used to obtain euphoria. This drug is used much more often than other antipsychotics for recreational purposes.
Clozapine's ability to make it easier to fall asleep is known among drug addicts. They often cannot rest fully at night, and widely use this antipsychotic to eliminate insomnia. In addition to the mixture, underground manufacturers of synthetic substances may use Azaleptin or another type of antipsychotic to potentiate the effect. They care little about the consumer's health; making a profit is much more important to them.
In terms of the degree of anticholinergic effect on the body, Clozapine is often compared with Tropicamide. The latter remedy comes in the form of drops and is considered by many as a cheap type of drug. Since 2013, Azaleptin has been included in the list of potent drugs in the Russian Federation. Its sale without a special prescription form is prohibited by law.
Drug interactions Clozapine
Clozapine can potentiate the central effects of ethanol, MAO inhibitors and CNS depressants (narcotic analgesics, antihistamines, benzodiazepine derivatives). With the simultaneous administration of clozapine and benzodiazepines, as well as in the case of recent treatment with benzodiazepines, the risk of developing hypotensive reactions, collapse, as well as respiratory depression and arrest is increased. Mutual enhancement of effects is possible with the simultaneous administration of clozapine and drugs that have anticholinergic, hypotensive properties, as well as drugs that depress respiration. With the simultaneous administration of clozapine and drugs that have a high degree of binding to plasma proteins (for example, warfarin), it is possible to increase the content of the free fraction of any of the active substances in the blood, which can lead to side effects.
Clozapine drug overdose, symptoms and treatment
Drowsiness, coma, areflexia, confusion, agitation, delirium, increased reflexes, convulsions, increased salivation, mydriasis, impaired visual acuity, changes in body temperature, tachycardia, arterial hypotension, collapse, arrhythmia, myocardial conduction disorders, respiratory depression. Treatment: gastric lavage; if necessary, prescribe activated carbon. Symptomatic treatment while monitoring the function of the cardiovascular and respiratory systems; control of water-electrolyte balance and COR. In case of arterial hypotension, the use of adrenaline and its derivatives should be avoided. Medical supervision is required for at least 4 days due to the possibility of late reactions. Peritoneal dialysis and hemodialysis are ineffective.
List of pharmacies where you can buy Clozapine:
- Moscow
- Saint Petersburg
