Leponex

Leponex is an antipsychotic that differs significantly from standard neuroleptics and is used in the treatment of schizophrenia that is resistant to therapy with the above medications.

The tests performed on the drug did not reveal its ability to provoke catalepsy, nor to suppress stereotypical behavior, which is observed in the case of its use in treatment with amphetamine or apomorphine.

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Indications Leponexa

It is used in cases of schizophrenia, in situations where the use of conventional neuroleptics does not bring results or the patient has a strong sensitivity to these drugs.

The lack of effect from the use of a conventional neuroleptic is diagnosed if the patient does not experience positive dynamics when administering the drug in accordance with the selected dosage regimen and using 2+ medications from the above category.

Hypersensitivity relative to standard neuroleptics is determined in the absence of any positive dynamics, as well as the appearance of intense side effects of neurological etiology.

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Release form

The release of the medical product is realized in tablets, 10 pieces inside cellular packages. In a box of 5, 10 or 12 or 25 packages.

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Pharmacodynamics

The drug slightly slows down the activity of dopamine D1, D2, as well as D3 and D5 endings, but at the same time it very intensively blocks the action of dopamine D4 endings. The drug has powerful antihistamine, α-adrenolytic, and cholinolytic properties, and demonstrates antiserotonergic activity.

During clinical tests, the drug's ability to produce a pronounced and rapid sedative effect was determined, as well as a strong antipsychotic effect, observed in individuals with schizophrenia and resistance to treatment with other neuroleptics.

The effect of the drug is observed and relatively productive manifestations of schizophrenia, cognitive disorders and signs of loss. A direct connection between the positive dynamics and the duration of Leponex use has been found. When this drug is introduced, the number of suicide attempts decreases sevenfold compared to people who use standard neuroleptics.

An extremely low incidence of side effects (extrapyramidal disorders, Parkinsonian-like symptoms and akathisia) is observed, along with a weak effect on prolactin levels (this minimizes the likelihood of developing amenorrhea, impotence, gynecomastia or galactorrhea) compared to the administration of conventional neuroleptics.

However, the use of Leponex can provoke intense granulocytopenia or agranulocytosis, developing, respectively, in 3% and 0.7% of all cases. Given the severity of these diseases, the medication can only be prescribed if resistance or hypersensitivity to conventional neuroleptics is diagnosed.

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Pharmacokinetics

Leponex has an intensive absorption - 90-95% when taken orally, without regard to food intake.

Clozapine, which is the active component of the drug, is almost completely metabolized after the first intrahepatic passage. Of the formed metabolic components, only one has a medicinal effect (desmethyl derivative). It acts similarly to clozapine, but the intensity and duration of its activity are much lower.

The bioavailability of the drug is 50-60%. To obtain intraplasmic Cmax values, it takes in the range of 0.4-4.2 hours (average value is 2.1 hours).

Vd values are 1.6 l/kg. Intraplasmic synthesis with protein is 95%.

Elimination processes are realized in 2 stages. The half-life term of the terminal stage varies in the range of 6-26 hours with an average value equal to 12 hours. After a single administration of a dose of 75 mg, the average value of the half-life term of the terminal stage is 7.9 hours and increases to 14.2 hours with 7-day use of 75 mg per day. The AUC level depends on the portion sizes of the drug.

Excretion is realized mainly in the form of metabolic elements through renal and intestinal secretion (respectively, by 50% and 30%). Only traces of the active element are found in feces with urine.

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Dosing and administration

The medication can only be used with a doctor's prescription.

Because the drug can cause agranulocytosis, the doctor prescribes it to people with schizophrenia under the following conditions:

• people who do not respond well to conventional neuroleptics or who have hypersensitivity to such drugs;
• persons who have previously undergone testing of white blood cell values and the results are within normal limits (white blood cell count and white blood cell count);
• people who have no problems with regular monitoring of the number of neutrophils with leukocytes in the blood (once a week during the first 4 months of the course, and then once a month, and another 1 month after stopping the use of Leponex).

A medical professional must be very careful when prescribing a drug, first studying the patient's medical history and blood test data, and also finding out what drugs the patient uses systematically.

The patient must be informed of the need to regularly visit the doctor for consultations and follow all his recommendations. It is imperative to inform the doctor of any changes in well-being, especially if symptoms of infection or flu-like manifestations (sore throat, hyperthermia, etc.) appear, because they can be harbingers of neutropenia.

The dosage regimen is selected individually, starting with the introduction of low doses of the drug (12.5 mg once a day), and then determining the minimum effective dosage.

When systematically taking drugs that lead to clinically significant interactions with clozapine (SSRIs or benzodiazepines, etc.), it is necessary to select a regimen that takes these data into account, and, if necessary, to change the recommended dose accordingly.

Medication dosage regimens.

Initial portions.

On the 1st day, 12.5 mg is administered 1-2 times a day; on the 2nd day, 25-50 mg, 1-2 times a day. Later, if no negative symptoms are observed, the daily dosage is gradually increased by 25-50 mg, so that after 2-3 weeks of the course, a dose equal to 0.3 g is obtained.

If the doctor decides that a subsequent increase in the dose is required, it is necessary to do this less intensively - by 0.05-0.1 g, 2 times a week (but 1 time per 7 days is recommended).

Medicinal dosing.

The required antipsychotic effect is observed in most people with schizophrenia with the introduction of 0.3-0.45 g per day (the portion is divided into several uses (unevenness of parts is possible), the largest amount of the drug is prescribed in the evening). Taking into account the personal characteristics of the patient, as well as the course of the disease, the minimum effective portion can fluctuate in the range of 0.2-0.6 g per day.

The intensity and effectiveness of the developing medicinal influence is personally assessed by the attending physician.

Maximum portion sizes.

Personal response to ongoing treatment may require subsequent increases in the daily dosage (above 0.6 g), but it cannot be more than 0.9 g.

It is necessary to take into account that the intensity of negative symptoms is directly proportional to the increase in the dosage of the drug. It is necessary to very carefully monitor the patient's condition immediately after exceeding the daily dose of 0.45 g, which can increase the severity of negative symptoms (convulsions, etc.).

Maintenance portions.

After reaching the maximum medicinal activity, a transition to maintenance doses is often made. The dosage should also be reduced gradually. The maintenance course should last at least 6 months. After establishing such a dose, which is less than 0.2 g per day, Leponex can be taken 1 time, in the evenings.

Discontinuation of medication.

When the doctor plans to stop taking the drug, it is necessary to gradually reduce the portions to the minimum (over 7-14 days, to reduce the likelihood of withdrawal symptoms).

If there is a need to urgently discontinue the drug (if leukopenia is detected), it is necessary to strengthen medical supervision of the patient, because there is a possibility of exacerbation of psychotic symptoms and the development of withdrawal symptoms (with nausea, loose stools, vomiting and severe headaches) due to the cessation of the anticholinergic effect of the drug.

Administration of medication after an interval.

If the medication was missed for more than 2 days, it is resumed with a dose of 12.5 mg, 1-2 times a day. On the 2nd day, if there is no hypersensitivity, the dosage can be increased more intensively (until a therapeutic dose is obtained) than during initial therapy.

If during the first treatment cycle the patient experiences severe respiratory and cardiac dysfunction, when the drug is used again, the dosage is increased even more slowly and with extreme caution.

Dosage regimen of the drug in cases when switching to it from neuroleptics.

It is allowed to start using Leponex after at least 7 days have passed since stopping taking neuroleptics. If there is a need for urgent administration of the medication, at least 24 hours must have passed since the last use of the neuroleptic. Dosages are selected according to the schemes described above.

It is prohibited to combine the drug with other neuroleptics.

Use in the elderly.

For this group of patients, the initial daily dose should be a maximum of 12.5 mg, taken once a day. Later, the dosage is increased very slowly to the therapeutic level - a maximum of 25 mg per day.

It should also be taken into account that the medicinal effect and safety of Leponex in the treatment of schizophrenia in the elderly have not been sufficiently studied.

During testing, an increased severity of negative symptoms was found compared to younger patients (tachycardia, orthostatic collapse, etc.). In addition, in older people, an increased frequency of development of anticholinergic signs of drugs (constipation, urinary incontinence, etc.) is possible.

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Use Leponexa during pregnancy

During preclinical tests, no pathological effects of the drug on the fetus were noted, as well as reproductive disorders in women. However, given the small number of studies related to the safety of the drug in pregnant women, it is allowed to prescribe it during the specified period only with strict indications and a medical assessment of possible consequences.

In addition, during preclinical tests, the ability of the drug to be excreted in breast milk was discovered, therefore, breastfeeding and taking the drug cannot be combined.

Contraindications

Main contraindications:

• severe intolerance to the components of the drug;
• established agranulocytosis or granulocytopenia of idiosyncratic or toxic origin (except for the indicated diseases that developed due to the use of chemotherapeutic agents);
• presence of bone marrow dysfunction;
• established epilepsy that cannot be treated;
• psychoses associated with the abuse of alcoholic beverages or other toxic substances, as well as comatose states and drug poisoning;
• vascular collapse or severe slowing of the central nervous system in various forms;
• the presence of severe nephro- or cardiological disorders (for example, myocarditis);
• diagnosed intensive hepatopathologies of various origins, during which loss of appetite, nausea and jaundice are observed.

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Side effects Leponexa

Side effects include:

• damage to the hematopoietic function: a significant increase in the likelihood of developing granulocytopenia or agranulocytosis. Most often, they appear (about 85% of cases) during the first 4 months of therapy. Due to agranulocytosis, sepsis with subsequent death may develop, therefore, before using the drug and during treatment, it is necessary to monitor the leukocyte count along with the leukocyte formula. If such a disease develops, the drug is immediately discontinued. Eosinophilia or leukocytosis may develop (most often observed in the first weeks of the course). Thrombocytopenia may occur;
• CNS disorders: severe drowsiness or fatigue, dizziness with a high sedative effect, headaches and changes in ECG readings. Myoclonic signs or generalized seizures may occur, the severity of which depends on the dose. The risk of these disorders increases significantly in the case of a sharp and rapid increase in the dose of the drug and in case of epilepsy in the patient. After the appearance of such symptoms, it is necessary to immediately reduce the dose of Leponex and prescribe (if necessary) anticonvulsants (except for carbamazepine, because it suppresses the bone marrow). Increased anxiety, delirium, disorders of consciousness, muscle weakness, nervous excitement, tremor, extrapyramidal disorders (they are expressed more weakly than in the case of conventional neuroleptics) and akathisia are also possible. In case of a combination of drugs with lithium agents, CNS occurs;
• problems associated with the autonomic nervous system: hyposecretion affecting the salivary glands, or hypersalivation, hyperhidrosis, visual disturbances and disorders associated with the thermoregulatory center;
• disorders of the cardiovascular system: intense orthostatic collapse or tachycardia, which may lead to loss of consciousness (noted in the first weeks of treatment), increased blood pressure, severe vascular collapse, changes in ECG data and thromboembolism. In addition, myocarditis, pericarditis or heart palpitations may develop, which may cause death. It is necessary to closely monitor the patient's condition and, if signs of myocarditis appear (with subsequent diagnosis of the disease), discontinue the medication;
• respiratory disorders: suppression of the respiratory center (may reach a complete stop of respiratory processes), which may be accompanied by vascular collapse. Aspiration of stomach contents may be observed (food inside the stomach or gastric juice penetrates into the respiratory ducts), an increased risk of which is noted in people with dysphagia or when taking large doses of drugs;
• lesions affecting the digestion and gastrointestinal tract: nausea, constipation, intestinal obstruction and vomiting. In addition, liver inflammation, temporary increase in the activity of intrahepatic enzymes, active phase of pancreatic inflammation, intrahepatic cholestasis (the drug should be discontinued) and hypertrophy affecting the parotid glands are noted;
• disorders associated with the urogenital system: urinary retention or involuntary development of this process, as well as priapism. An active phase of tubulointerstitial nephritis may be observed;
• Other symptoms include weight gain, epidermal rashes, benign hyperthermia (usually during the first weeks of treatment) and severe hyperglycemia leading to ketoacidosis.

The fact of unexplained deaths in psychiatric patients with intolerance to therapy, and also in connection with taking medication or other antipsychotics, has been diagnosed.

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Overdose

This medicine should be dosed with extreme caution, because in case of poisoning, death occurs in 12 cases out of 100. The consequences of intoxication are personal and do not depend on the portion size.

When used once in a dose of over 2 g, Leponex often causes death as a result of developing an aspiration type of pneumonia or cardiac arrest. But there are also reports of recovery in people who used the drug in a dose of over 10 g.

In addition, there is information about the development of a life-threatening comatose state (sometimes with a fatal outcome) in people who took 0.4 g of the substance once (an increased risk of such an intense effect of the drug on the body is observed in adults who use it for the first time).

The introduction of 0.05-0.2 g of the drug in pediatrics leads to the development of a strong sedative effect with the development of coma (but death does not occur).

In case of overdose of the drug, the following symptoms are observed: lethargy, impaired consciousness, severe drowsiness, the appearance of visions, coma, loss of reflexes, increased emotional arousal and extrapyramidal disorders. In addition, delirium, tachycardia, hyperreflexia, mydriasis, visual diseases, hypersalivation, convulsions, collapse, heart rhythm disorders, temperature changes, a drop in blood pressure, breathing problems (up to its cessation) and aspiration pneumonia are observed.

If such symptoms develop, you should follow these instructions:

• if less than 6 hours have passed since the drug was taken, gastric lavage must be performed and the patient must be given adsorbents;
• Peritoneal or hemodialysis should not be performed, because there is no information regarding the effectiveness of such procedures in case of poisoning with Leponex;
• perform appropriate symptomatic procedures, while constantly monitoring the functioning of the respiratory system and cardiovascular system, as well as the acid-base balance values (in case of low blood pressure, the use of adrenaline is prohibited);
• monitor the patient's clinical condition for at least 5 days, because there is a possibility of delayed development of intoxication symptoms.

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Interactions with other drugs

Drug interactions.

Administration with drugs that cause severe bone marrow dysfunction may cause additive toxicity to bone marrow function, which is why these drugs should not be combined.

The drug enhances the therapeutic effect of MAOIs, benzodiazepines, ethyl alcohol with antihistamines, and systemic anesthetics.

Administration in combination with psychotropic substances (or the use of Leponex after the use of psychotropic substances) is prohibited or is performed with extreme caution, because such a combination may cause collapse with the likelihood of developing severe (or complete) suppression of cardiac and respiratory activity.

Administration together with antihypertensive and anticholinergic drugs, as well as agents that slow down the activity of the respiratory system, causes mutual potentiation of the therapeutic effect.

When combined with lithium substances and medications that affect the central nervous system, a potentiation of the risk of developing NMS is noted.

The drug weakens the hypotensive effect of α-adrenomimetics and norepinephrine.

Combination with adrenaline leads to blocking of the vasoconstrictor effect of this substance.

Use together with valproic acid can cause intense epileptic seizures (even in individuals without this diagnosis), and in addition, an acute mental disorder in which severe changes in consciousness and vision are observed (delirium).

Interaction according to pharmacokinetic characteristics.

Substances that induce or inhibit the action of hemoprotein P450 isoenzymes can lead to changes in the activity of drug metabolism processes.

Agents that induce the activity of hemoprotein P450 enzymes can reduce plasma levels of the drug.

Elements that inhibit the action of hemoprotein P450 enzymes lead to hyperconcentration of the drug in the blood.

In the event of a sharp decrease in nicotine levels in the patient's body (for example, due to sudden cessation of smoking), serum hyperconcentration of the drug develops, which leads to an increase in its negative impact on the body.

When used with erythromycin, cimetidine or fluvoxamine, changes in the metabolic processes of the drug are noted.

Use together with substances that inhibit protease activity, as well as with fungicidal agents, can increase plasma values of the drug, thereby increasing its toxicity.

Paroxetine, fluoxetine and caffeine with sertraline significantly increase blood levels of Leponex.

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Storage conditions

Leponex must be stored in a dry and dark place, at a temperature of no more than 30°C.

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Shelf life

Leponex is permitted to be used for a period of 3 years from the date of sale of the pharmaceutical product.

Application for children

Appropriate testing regarding medicinal effect and safety in pediatrics has not been performed.

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Analogues

Analogues of the drug are Adagio, Nantarid, Zolafren and Azaleptin with Olan, and in addition to this Azaleptol, Parnasan with Azapine, Clozapine and Seroquel with Hedonin. Also on the list are Zyprexa, Olanzapine, Quetiron with Egolanza and Ketilept with Skizoril.

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