Leponex^® (Tablets, Solution) Instructions for Use

ATC Code

N05AH02 (Clozapine)

Active Substance

Clozapine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Antipsychotic agent (neuroleptic), a dibenzodiazepine derivative. It has a pronounced antipsychotic and sedative effect. It practically does not cause extrapyramidal disorders; in this regard, Clozapine is classified as a so-called “atypical” neuroleptic.

The antipsychotic effect is due to the blockade of dopamine D₂ receptors in the mesolimbic and mesocortical structures of the brain.

The sedative effect is due to the blockade of α-adrenergic receptors of the brainstem reticular formation; the antiemetic effect is due to the blockade of dopamine D₂ receptors of the trigger zone of the vomiting center; the hypothermic effect is due to the blockade of dopamine receptors in the hypothalamus. It has peripheral and central anticholinergic, α-adrenergic blocking action. It does not affect the concentration of prolactin in the blood.

The antipsychotic effect is close to that of aliphatic phenothiazines, but without a “submelancholic tinge” and unpleasant subjective sensations, does not have a cataleptogenic effect, and lowers the seizure threshold.

It does not affect higher intellectual functions.

The development of the therapeutic effect is characterized by stages: rapid onset of hypnotic and sedative action; relief of anxiety, psychomotor agitation and aggressiveness (after 3-6 days); antipsychotic action (after 1-2 weeks); effect on symptoms of negativism (after 20-40 days).

Pharmacokinetics

When taken orally, it is absorbed from the gastrointestinal tract quickly and almost completely. C_max in plasma is reached on average within 2.5 hours. C_ss is reached after 8-10 days of administration. It undergoes intensive metabolism during the “first pass” through the liver with the formation of metabolites of low activity or inactive. It is metabolized with the participation of the CYP1A2 isoenzyme. Distribution is intensive and rapid, it penetrates the blood-brain barrier. Protein binding is 95%.

T_1/2 is characterized by variability and after a single dose of 75 mg is 8 hours (4-12 hours), after taking 100 mg twice a day – 12 hours (4-66 hours).

It is excreted by the kidneys – 50% and through the intestines – 30%.

Indications

Acute and chronic forms of schizophrenia, manic states, manic-depressive psychosis, psychomotor agitation in psychopathies, emotional and behavioral disorders (including in children), sleep disorders.

ICD codes

Dosage Regimen

Tablets, Solution

The dose is set individually. For oral administration, a single dose is 50-200 mg, a daily dose is 200-400 mg. Treatment usually starts 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 taken once before bedtime or 2-3 times a day after meals. When discontinuing treatment, the dose should be gradually reduced over 1-2 weeks. After achieving a therapeutic effect, switch to a maintenance course.

If necessary, Clozapine can be administered intramuscularly.

Maximum dose for oral administration is 600 mg/day.

For mild forms of the disease, for maintenance therapy, as well as in patients with hepatic and/or renal insufficiency, chronic heart failure, cerebrovascular disorders, it is prescribed in lower daily doses (25-200 mg).

Adverse Reactions

From the central nervous system drowsiness, headache, rarely – agitation, akathisia, confusion, extrapyramidal disorders (akinesia, hypokinesia, muscle rigidity, tremor), insomnia, restless sleep, depression, neuroleptic malignant syndrome, epileptic seizures, tardive dyskinesia, fever 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.

From 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, urinary disorders.

Other myasthenia, decreased potency, accommodation disturbance.

Contraindications

History of granulocytopenia or agranulocytosis (except for the development of granulocytopenia or agranulocytosis due to previously used chemotherapy), bone marrow depression, myasthenia gravis, comatose states, toxic psychosis (including alcoholic), pregnancy, lactation period, children under 5 years of age, hypersensitivity to clozapine.

Use in Pregnancy and Lactation

Clozapine is contraindicated during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in severe hepatic insufficiency. In patients with hepatic insufficiency, the drug is prescribed at a lower daily dose (25-200 mg).

Use in Renal Impairment

Use with caution in severe renal insufficiency. In patients with renal insufficiency, the drug is prescribed at a lower daily dose (25-200 mg).

Pediatric Use

Contraindicated in children under 5 years of age. The safety and efficacy of clozapine in children and adolescents under 16 years of age have not been established.

Special Precautions

Use with caution in severe cardiovascular diseases, severe renal and/or hepatic insufficiency, angle-closure glaucoma, with prostatic hyperplasia, intestinal atony, epilepsy, intercurrent diseases with febrile syndrome.

During treatment, systematic monitoring of the peripheral blood picture is necessary.

When using clozapine, alcohol consumption should be avoided.

The safety and efficacy of clozapine in children and adolescents under 16 years of age have not been established.

Effect on ability to drive vehicles and operate machinery

Patients taking Clozapine should refrain from potentially hazardous activities that require concentration and increased speed of psychomotor reactions.

Drug Interactions

With simultaneous use 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 depressant effect on the central nervous system increase, and the depression of the respiratory center increases.

With simultaneous use with agents that cause arterial hypotension, an additive hypotensive effect is possible.

With simultaneous use with agents that cause myelodepression, an increase in the inhibitory effect on bone marrow hematopoiesis is possible; with anticholinergic agents – an increase in anticholinergic action is possible.

With simultaneous use with digoxin or with drugs characterized by high protein binding (including heparin, warfarin, phenytoin), an increase in their plasma concentrations is possible, and displacement of clozapine by these agents from its protein binding sites is also possible.

With simultaneous use with valproic acid, a change in the plasma concentration of clozapine is possible, while clinical manifestations of the interaction were practically absent.

With simultaneous use with carbamazepine, the plasma concentration of clozapine decreases. Cases of severe pancytopenia and malignant neuroleptic syndrome have been described.

With simultaneous use with caffeine, the plasma concentration of clozapine increases and an increase in the frequency of side effects is possible.

With simultaneous use with lithium carbonate, myoclonus, convulsions, malignant neuroleptic syndrome, delirium, and psychoses are possible.

With simultaneous use with risperidone, an increase in the plasma concentration of clozapine is possible, apparently due to a competitive effect on the CYP2D6 isoenzyme, which leads to inhibition of clozapine metabolism. With rapid replacement of clozapine with risperidone, dystonia may develop.

Rifampicin may increase the rate of clozapine metabolism by inducing CYP1A2 and CYP3A isoenzymes.

With simultaneous use with phenytoin, a decrease in the plasma concentration of clozapine is possible; with fluoxetine, paroxetine, sertraline, fluvoxamine, an increase in the plasma concentration of clozapine is possible, which in some patients is accompanied by manifestations of toxicity. This effect is especially pronounced with the simultaneous use of clozapine with fluvoxamine.

With simultaneous use with ciprofloxacin, an increase in the plasma concentration of clozapine is possible.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.