Clozapine (Azaleptin, Leponex. Clozasten, Azaleprol)

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.

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.

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

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.

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.

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.

Clozapine

In 1959, the first drug of a new generation of psychotropic drugs was synthesized - clozapine (closarin, leponex, azaleptin), which subsequently opened the way for the synthesis of atypical antipsychotics.

Clozapine appeared on the pharmaceutical market in 1968. In 1975, eight patients in Finland died due to infectious complications resulting from clozapine-induced agranulocytosis. At the end of the 70s, this medication was banned for use in most countries of the world due to the risk of severe side effects when taking it. However, in 1988, D. Kein et al. again suggested the high effectiveness of clozapine in the treatment of schizophrenia. After receiving positive results from a multicenter study of clozapine in the United States in 1990, it returned to the pharmaceutical market.

Chemical group: dibenzodiazepine.

Release form: 12.5, 25 and 100 mg

Pharmacokinetics: half-life from 5 to 15 hours, peak concentration 1-4 hours after administration, stabilization of concentration 3-4 days of therapy, bioavailability - 60%.

Dosing rules: Clozapine therapy is usually started with a daily dose of 12.5 or 25 mg and then gradually over 10 days the dose of the drug is increased by an average of 25 mg per day, monitoring the safety of its use. After reaching a dose of 100 mg, you should stop increasing the dose for several days, waiting for the effect. The average dose of the drug corresponds to 300-600 mg, the maximum - 900 mg. When prescribing clozapine to children, the initial dose of the drug is 12.5 mg per day, increasing the dose in the future by no more than 3-6 mg per kg of weight. The dosage range for elderly patients is 10-100 mg per day.

Most pharmacological guidelines recommend monitoring clozapine plasma levels during treatment. A level of 400 ng/ml is considered preferable for therapy.

Indications: clozapine can be used to treat schizophrenia, especially for the treatment of its resistant variants, since in this case in 30-50% of cases it is possible to achieve a clear clinical improvement (Bochner F. et al, 2000; Bridler R., Umbricht D., 2003 ). Moreover, the clear positive effect of clozapine can continue even after a year of therapy with this drug.

Clozapine is almost seven times more effective than chlorpromazine (aminazine) in the treatment of resistant variants of schizophrenia. The new atypical antipsychotics that were subsequently synthesized were safer than clozapine, but, as a rule, they were inferior to it in the effectiveness of treating schizophrenia.

Indications for treatment of schizophrenia with clozapine

• Resistant variants
• Persistent suicidal thoughts
• Frequent manifestations of aggression and dysphoria
• Comorbid substance dependence
• Severe manifestations of cognitive deficit
• Tardive dyskinesia

Clozapine has a certain thymoleptic effect and, as a result, is able to reduce the symptoms of depression comorbid with schizophrenia. It has been effective in preventing suicide in patients with schizophrenia, especially in patients who have expressed thoughts of suicide for a long time (Purucker M., et.al., 2007).

Constant irritability and manifestations of aggression, signs of tardive dyskinesia are also considered today as an indication for treatment with clozapine. When prescribed clozapine, patients are less likely to discontinue treatment than when taking traditional drugs.

The drug has proven effective in treating not only schizophrenia, but also schizoaffective disorders.

Most patients respond to clozapine therapy within the first month of taking it, but some patients respond to therapy even after 3-4 months of treatment. If clozapine therapy is ineffective within 4-6 months, a change in drug is necessary.

Mechanism of action: clozapine modulates the activity of a number of mediator systems, while significantly blocking D1 and relatively weakly D2, D3, D4 dopamine receptors (D1/ D4 > D2/ D3).

As noted above, clozapine is considered a fairly strong antagonist of dopamine D4 receptors and in this regard is superior to traditional antipsychotics.

The drug also blocks the depolarization of A10-dopamine neurons. This is consistent with data obtained by assessing clozapine-induced increases in c-fos protein expression (a novel marker of cellular activity) in the nucleus accumbens, ventral striatum, anterior cingulate and medial prefrontal cortex. Haloperidol, unlike clozapine, activates the expression of the c-fos protein in structures innervated by dopaminergic neurons belonging to the A9 group, located in the dorsal striatum.

It has an affinity for many receptors, including serotonin (blockade of 5HT2A, 5HT2C is more pronounced than 5HT3, 5HT6, 5HT7 receptors), histamine (H1), acetylcholine, alpha1 and alpha2 adrenergic receptors and cholinergic receptors (muscarinic M1 and nicotinic). When using clozapine, 80-90% of serotonin 5HT2A receptors are blocked by a dose of the drug that simultaneously blocks only 20% of dopamine D2 receptors.

In the experiment, clozapine does not cause catalepsy, does not block stereotypies provoked by apomorphine or amphetamine, and does not increase the level of prolactin in the blood serum.

Side effects: Compared with traditional antipsychotics, clozapine extremely rarely causes early and late extrapyramidal disorders. The absence of symptoms of parkinsonism, akathisia, acute dystonic reactions, and tardive dyskinesia is explained by the low affinity of clozapine for D2 receptors (the blockade of dopamine receptors is more pronounced in the limbic system than in the striatal system). Moreover, the drug can even be used to treat tardive dyskinesia and severe akathisia.

Among the most dangerous side effects of the drug, neutropenia should be noted, which develops during the first 4-18 weeks of therapy (cases of agranulocytosis have been described a year after starting clozapine).

Side effects of clozapine

• Disturbance of the hematopoietic process (neutropenia, agranulocytosis)
• Neurological disorders (epileptiform seizures - 1-2%, myoclonic tics, atonic paroxysms)
• Drowsiness, especially in older patients
• Gastroenterological disorders (constipation, increased salivation, especially at night)
• Cardiovascular disorders (orthostatic hypotension at the initial stage and hypertension at the later stages of therapy, tachycardia, myocarditis, pulmonary embolism) Accommodation disturbance (cycloplegia)
• Metabolic disorders (impaired carbohydrate and fat metabolism, the latter due to antagonism to H1 and 5HT2C receptors)
• Nocturnal enuresis

During clozapine treatment, neutropenia occurs in 1-3% of patients, usually occurring within the first 18 weeks of therapy, and is more likely to occur in older patients and may develop slowly or occur suddenly.

With age, the risk of neutropenia when taking clozapine, according to some authors, decreases, annually decreasing by an average of 17% per decade; on the contrary, the risk of agranulocytosis increases. On average, the development of agranulocytosis is observed in 0.38-1% of patients, and it appears more likely in females than in males.

It is believed that agranulocytosis occurs due to the direct toxic effect of the drug on the hematopoietic (clozapine metabolite norclozapine has a toxic effect on bone marrow cells) and immune systems of the body. Due to the above, it is dangerous to prescribe drugs to patients with schizophrenia, like clozapine, that affect the process of hematopoiesis, for example, carbamazepine.

Prescribing clozapine is especially dangerous for those patients who had neutropenia before starting treatment.

It has been noted that among Africans and residents of the Afro-Caribbean region, the likelihood of developing neutropenia during treatment with clozapine is higher than among other people.

Risk factors for the development of agranulocytosis differ from risk factors for the development of neuropenia, and therefore it has been suggested that neutropenia does not always develop into agranulocytosis.

Agranulocytosis is more likely to be due to a predisposition to this condition and is more common in people of Asian origin receiving clozapine therapy.

During treatment with clozapine and for several weeks after its discontinuation, weekly monitoring of the number of leukocytes in the patient’s blood is mandatory. If leukocytes decrease below 3000 or by 50% of the initial level, immediate discontinuation of the drug is necessary.

If agranulocytosis occurs, the patient must be placed in an isolation room to eliminate the possible risk of infection. To enhance the regeneration of leukocytes, patients are prescribed filgastrim, a granulocyte colony-stimulating factor (Ann S., Coyle J., 2007).

When discontinuing the drug, symptoms of withdrawal syndrome may be observed for a short time: nausea, vomiting, diarrhea, increased salivation; in rare cases, psychosis may occur (cholinergic effect).

Seizures have been reported at doses of clozapine greater than 600 mg per day (carbamazepine should be avoided if seizures occur). The risk of seizures is relatively high, ranging from 3 to 10%, and especially increases with high dosages of the drug. In addition, the drug can cause myoclonic (myoclonic twitching usually precedes a full-blown seizure) and atonic paroxysms. To avoid the development of such complications, it is recommended to start therapy with small doses and then slowly increase the dose of the medication. Some guidelines also recommend clozapine therapy in combination with valproate.

Side effects of clozapine include excessive drowsiness. It is especially noticeable in older people, in the initial stages of therapy and in the process of increasing the dose of the drug. Somewhat less common are increased salivation, weight gain and constipation.

The drug negatively affects the cardiovascular system, promoting orthostatic hypotension (in the later period - hypertension) and tachycardia. A toxic effect of clozapine on the heart muscle has been noted. In the first weeks of treatment, myocarditis may occur.

The drug has a slight effect on the level of prolactin in the blood. Clozapine may disrupt glucose homeostasis through indirect insulin and growth hormone secretion, an effect associated with blockade of serotonin and histamine receptors (Melkersson U. et al., 1999). Disorders of fat and carbohydrate metabolism are currently associated with the effect of the drug on the receptors of the serotonergic system.

It is necessary to take into account the anticholinergic effect of clozapine; with its long-term use, cycloplegia, a disturbance of accommodation, may appear.

Currently, due to the large number of serious side effects, clozapine is rarely prescribed.

Interactions with medications: Co-administration of clozapine with other medications requires special attention (Table 29).

Table 29. Interaction effects of clozapine with other drugs

In the literature one can find recommendations about the benefits of the combined use of clozapine and lithium, since the latter increases the number of leukocytes, however, according to most researchers, the results of such studies are unrepresentative.

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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