Azaleptol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZALEPTOL (AZALEPTOL)

Composition:

Active substance: clozapine;

1 tablet contains 25 mg or 100 mg of clozapine;

Excipients: lactose monohydrate, magnesium stearate, potato starch, corn starch, povidone 25.

Pharmaceutical form. Tablets.

Main physicochemical properties:

25 mg tablets – single-layer, round-shaped tablets with flat upper and lower surfaces and bevelled edges, light yellow or light yellow with a greenish tint. Marbling may be present on the surface of the tablets. Under magnification, the cross-section reveals a relatively homogeneous structure;

100 mg tablets – single-layer, round-shaped tablets with flat upper and lower surfaces and bevelled edges, with a score line, light yellow or light yellow with a greenish tint. Marbling may be present on the surface of the tablets. Under magnification, the cross-section reveals a relatively homogeneous structure.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05AH02.

Pharmacological properties.

Pharmacodynamics.

Azaleptol is an atypical antipsychotic agent differing from classical antipsychotics.

Pharmacological experiments have demonstrated that clozapine does not induce catalepsy and does not suppress stereotypic behaviour induced by administration of apomorphine or amphetamine. The drug exerts only weak blocking activity at dopamine D1-, D2-, D3-, and D5-receptors, but shows high affinity for D4-receptors. It also exhibits anti-alpha-adrenergic, anticholinergic, antihistaminic effects, and suppresses activation response. Furthermore, it possesses antiserotonergic properties. Clinically, Azaleptol produces a rapid and pronounced sedative effect and exerts strong antipsychotic activity, particularly in patients with schizophrenia resistant to treatment with other medicinal products. In such cases, Azaleptol is effective against both positive and negative symptoms of schizophrenia. Clinically significant improvement was observed within the first 6 weeks of treatment in approximately one-third of patients, and with continued therapy up to 12 months, improvement occurred in approximately 60% of patients.

Additionally, improvement in certain aspects of cognitive dysfunction has been noted. Compared to standard neuroleptics, the use of clozapine has been associated with a significantly reduced risk of suicidal behaviour in patients with schizophrenia or schizoaffective disorders. Severe extrapyramidal reactions such as acute dystonia, parkinsonism-like side effects, and akathisia occur rarely. Unlike standard neuroleptics, Azaleptol does not increase or increases only minimally serum prolactin levels, thereby avoiding adverse effects such as gynecomastia, amenorrhea, galactorrhea, and impotence.

Pharmacokinetics.

Absorption

Following oral administration, Azaleptol is absorbed by 90–95%. Neither the rate nor the extent of absorption is affected by food intake. During first-pass metabolism, Azaleptol undergoes moderate metabolism; its bioavailability is 50–60%.

Distribution

At steady state with twice-daily dosing, peak plasma concentrations are reached on average within 2.1 hours (range: 0.4–4.2 hours). The volume of distribution is 1.6 L/kg. Plasma protein binding of clozapine is approximately 95%.

Biological transformation/metabolism

Clozapine is almost completely metabolized prior to elimination. Only one of its major metabolites, desmethylclozapine, exhibits pharmacological activity. Its effects resemble those of clozapine but are considerably weaker and shorter in duration.

Elimination

Elimination of clozapine is biphasic, with a mean elimination half-life of 12 hours (range: 6–26 hours). After single 75 mg doses, the mean elimination half-life was 7.9 hours. This value increased to 14.2 hours at steady state achieved after administration of 75 mg daily doses for at least 7 days. Only a small amount of unchanged drug is excreted in urine and feces. Approximately 50% of the administered dose is excreted as metabolites in urine and 30% in feces.

Linearity/non-linearity

A linear, dose-dependent increase in the area under the plasma concentration-time curve (AUC), as well as in maximum and minimum plasma concentrations, has been observed at steady state when the dose was increased from 37.5 mg to 75 mg and 150 mg twice daily.

Pharmacokinetics in specific patient populations

Although there are no specific pharmacokinetic and biotransformation studies, the drug should be used with particular caution in patients with hepatic impairment, biliary tract disorders, or renal disease. The use of the drug is contraindicated in severe cases of these conditions.

Clinical characteristics.

Indications.

Refractory schizophrenia

Azaleptol should be prescribed only to patients with schizophrenia who are resistant to therapy or intolerant of standard neuroleptics, as defined below.

Resistance to standard neuroleptics – a condition in which previous treatment with standard neuroleptics at appropriate doses and for a sufficient duration has failed to produce adequate clinical improvement.

Intolerance to standard neuroleptics – a condition in which severe, uncontrolled neurological adverse effects (extrapyramidal symptoms or tardive dyskinesia) occur, making effective neuroleptic therapy with standard agents impossible.

Risk of recurrent suicidal behaviour

Azaleptol is indicated for the long-term reduction of the risk of recurrence of suicidal behaviour in patients with schizophrenia or schizoaffective disorder who are judged to be at risk based on their medical history and current clinical presentation.

Psychotic disorders during Parkinson's disease therapy

Azaleptol is indicated for the treatment of psychotic disorders occurring during Parkinson's disease when standard therapy has proven ineffective.

Ineffectiveness of standard therapy is defined as lack of control over psychotic symptoms and/or emergence of functionally unacceptable worsening of motor symptoms after implementing the following measures:

• Discontinuation of anticholinergic agents, including tricyclic antidepressants;
• Attempt to reduce the dose of dopaminergic antiparkinsonian agents.

Contraindications.

• Hypersensitivity to clozapine or to any other component of the medicinal product;
• Inability to perform regular blood monitoring in the patient;
• History of toxic or idiopathic granulocytopenia/agranulocytosis (except for granulocytopenia or agranulocytosis induced by prior chemotherapy);
• History of clozapine-induced agranulocytosis;
• Bone marrow dysfunction;
• Uncontrolled epilepsy;
• Alcohol- or other toxic psychoses, drug intoxications, comatose states;
• Vascular collapse and/or CNS depression of any etiology;
• Severe renal or cardiac disorders (e.g., myocarditis);
• Acute liver disease associated with nausea, loss of appetite, or jaundice; progressive liver disease, hepatic failure;
• Paralytic ileus;
• Concomitant use with medicinal products known to induce agranulocytosis; depot neuroleptics should also not be used concomitantly.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Azaleptol should not be used concomitantly with medicinal products that have a significant myelosuppressive effect on bone marrow function. Concomitant use with long-acting depot neuroleptics (which have myelosuppressive potential) is not recommended, as these agents cannot be rapidly eliminated from the body when necessary, for example in the case of neutropenia.

Azaleptol may potentiate the CNS effects of alcohol and monoamine oxidase inhibitors (MAOIs), as well as the CNS depressant effects of opioids, antihistamines, and benzodiazepines. Fatal cases have been reported following the use of clozapine in combination with these substances (including methadone). Particular caution is required when Azaleptol is prescribed in combination with benzodiazepines or other psychotropic agents, as this increases the risk of vascular collapse, which may occasionally be severe and lead to cardiac or respiratory arrest. It is unknown whether cardiac or respiratory collapse can be prevented by dose adjustment.

Concomitant use of lithium or other CNS-acting medicinal products increases the risk of neuroleptic malignant syndrome.

Due to the possibility of additive effects, concomitant use of medicinal products with anticholinergic, antihypertensive, or respiratory depressant effects should be undertaken with particular caution.

Due to its anti-alpha-adrenergic properties, Azaleptol may reduce the pressor effect of noradrenaline or other agents with predominantly alpha-adrenergic activity and may reverse the pressor effect of adrenaline.

The medicinal product may lower the seizure threshold, necessitating adjustment of antiepileptic drug dosages. Rare reports of severe epileptic seizures, including first-time seizure episodes and isolated cases of delirium, have been reported following concomitant use of Azaleptol and valproic acid. These effects may be due to pharmacodynamic interaction, the mechanism of which is not currently established.

The medicinal product may increase plasma concentrations of substances that are highly protein-bound (e.g., warfarin and digoxin) due to displacement from plasma protein complexes. Dosage adjustment of such protein-bound substances may be required.

Concomitant use with medicinal products that prolong the QTc interval or cause electrolyte imbalances is recommended with caution.

Pharmacokinetic interactions

Clozapine is a substrate for multiple CYP450 isoenzymes, particularly 3A4, 1A2, and 2D6. This minimizes the risk of metabolic interactions due to effects on a single isoenzyme. Nevertheless, careful monitoring of plasma clozapine levels is required in patients receiving concomitant medicinal products with affinity for one or more of these enzymes.

Concomitant use of substances affecting these isoenzymes may lead to increased or decreased plasma levels of clozapine and/or the co-administered substance.

Theoretically, clozapine may increase plasma levels of tricyclic antidepressants, phenothiazines, and class 1c antiarrhythmics, which are known to interact with cytochrome P450 2D6. Dose reduction of these agents may be necessary. However, no reports of clinically significant interactions are currently available.

Combination of Azaleptol with substances affecting CYP450 isoenzyme activity may result in decreased or increased plasma clozapine levels:

Inhibitors

• Concomitant use of enzyme inhibitors such as cimetidine (inhibitor of CYP1A2, 3A4, and 2D6) or erythromycin (inhibitor of CYP3A4), clarithromycin, azithromycin, fluvoxamine (1A2), perazine (1A2), ciprofloxacin (1A2), or oral contraceptives (1A2, 3A4, 2C19) with high doses of Azaleptol has been associated with increased plasma clozapine levels and increased frequency of adverse effects.
• Reports have been received of increased plasma clozapine levels in patients taking the medicinal product in combination with fluvoxamine (inhibitor of CYP3A4 and CYP1A2; up to 10-fold increase) or with other selective serotonin reuptake inhibitors (SSRIs), such as paroxetine (inhibitor of CYP1A2, 2D6), sertraline (inhibitor of CYP2C8/9, 2D6), fluoxetine (inhibitor of CYP2D6, up to 2-fold increase), or citalopram (possibly a weak inhibitor of CYP1A2, with possibly the lowest clinical interaction potential among SSRIs). However, reports of clinically significant interactions following concomitant use of citalopram and clozapine have been received. Increased clozapine concentrations have also been observed in patients taking this medicinal product in combination with venlafaxine.
• Azole antifungals and protease inhibitors are potent inhibitors/inducers of CYP3A4. Clinically significant interactions with clozapine may also be expected with these agents. However, no reports of such interactions have been received to date.

Substrates

• Caffeine (substrate of CYP1A2) may increase plasma clozapine levels. Plasma clozapine levels decrease by approximately 50% after five days without caffeine intake. This should be taken into account when the number of daily cups of coffee or tea changes. Significant increases in clozapine and N-desmethylclozapine levels have been observed after concomitant administration of 2x250 mg ciprofloxacin. Interactions with norfloxacin and enoxacin have also been reported.

Inducers

• Medicinal products that induce P450 CYP3A4 (e.g., carbamazepine and rifampicin) may reduce plasma clozapine levels. Discontinuation of concomitant carbamazepine use has led to increased plasma clozapine levels.
• It has been established that concomitant use of phenytoin leads to decreased plasma clozapine levels, resulting in reduced efficacy of a previously effective dose of Azaleptol.
• Tobacco smoking induces CYP1A2. Therefore, abrupt cessation of smoking in heavy smokers may lead to increased plasma clozapine levels and increased frequency of adverse effects.
• Omeprazole is an inducer of CYP1A2 and CYP3A4, and also an inhibitor of CYP2C19. Isolated reports of interactions with proton pump inhibitors (increased clozapine concentrations after omeprazole or pantoprazole administration, or combination of lansoprazole and paroxetine) have been received.

Special precautions for use.

Potentially serious adverse effects of treatment with Azaleptol include granulocytopenia and agranulocytosis, observed with frequencies of 3% and 0.7%, respectively. Agranulocytosis may be life-threatening.

The incidence of agranulocytosis and the associated mortality rate in patients who develop agranulocytosis have significantly decreased since the implementation of monitoring of white blood cell count and absolute neutrophil count (ANC). Therefore, the precautionary measures outlined below are mandatory.

Thus, Azaleptol may be used only in patients with schizophrenia or psychotic disorders associated with Parkinson's disease who have demonstrated no response or inadequate response to other neuroleptics, or who develop severe extrapyramidal side effects (including tardive dyskinesia) during treatment with other neuroleptics.

Azaleptol may also be used in patients with schizophrenia and schizoaffective disorder who, based on their medical history or current clinical picture, are at long-term risk of recurrent suicidal behavior.

Due to the risks associated with the use of Azaleptol, its prescription is permitted only if:

• patients have a baseline normal white blood cell count (total white blood cells ≥ 3500/mm³ [3.5 × 10⁹/L]) and normal differential white blood count, and
• weekly monitoring of total white blood cell count and, if possible, absolute neutrophil count (ANC) can be performed during the first 18 weeks of treatment, and at least every 4 weeks thereafter. Monitoring must continue throughout the entire treatment period and for 4 weeks after complete discontinuation of Azaleptol.

Patients with a history of drug-induced blood dyscrasia must not be prescribed Azaleptol (see "Contraindications").

Physicians prescribing this medication must strictly adhere to safety recommendations.

During each consultation, patients receiving Azaleptol should be reminded to contact their physician immediately if they develop any signs of infection. Particular attention should be paid to complaints suggestive of influenza-like illness, such as fever or sore throat, as well as other signs of infection that may indicate neutropenia. Patients and their caregivers should be informed that if any of these symptoms occur, immediate blood testing with complete blood count must be performed.

Monitoring of white blood cell count and absolute neutrophil count

White blood cell count and differential count should be determined within 10 days prior to initiating Azaleptol therapy to ensure that only patients with normal white blood cell counts (≥ 3.5 × 10⁹/L [3500/mm³]) and absolute neutrophil counts (≥ 2.0 × 10⁹/L [2000/mm³]) receive the medication. White blood cell count and, if possible, ANC should be monitored weekly during the first 18 weeks of treatment, and thereafter at least once monthly throughout the treatment period. Monitoring must continue throughout treatment and for four weeks after complete discontinuation of Azaleptol. At each visit, patients should be reminded to seek immediate medical attention if they develop early signs of infection, fever, sore throat, or other influenza-like symptoms. In such cases, a complete blood count with differential must be performed immediately.

Interruption of therapy for non-hematological reasons

For patients whose Azaleptol therapy, lasting more than 18 weeks, has been interrupted for more than 3 days but less than 4 weeks, weekly monitoring of white blood cell count is recommended for an additional 6 weeks. Provided no abnormalities are detected, subsequent monitoring may be conducted no more frequently than once every 4 weeks. If therapy with Azaleptol has been discontinued for 4 weeks or longer, weekly monitoring is required during the first 18 weeks of re-initiation, and the dose must be re-titrated.

Decreased white blood cell count and absolute neutrophil count

If during the first 18 weeks of Azaleptol treatment the white blood cell count decreases to 3.5 × 10⁹/L (3500/mm³) to 3.0 × 10⁹/L (3000/mm³), or the absolute neutrophil count decreases to 2.0 × 10⁹/L (2000/mm³) to 1.5 × 10⁹/L (1500/mm³), hematological parameters should be assessed at least twice weekly. The same monitoring frequency applies if, after 18 weeks of therapy, the white blood cell count decreases to 3.0 × 10⁹/L (3000/mm³) to 2.5 × 10⁹/L (2500/mm³), or the absolute neutrophil count decreases to 1.5 × 10⁹/L (1500/mm³) to 1.0 × 10⁹/L (1000/mm³).

Additionally, if a significant decrease in white blood cell count compared to baseline is observed, repeat testing of white blood cell count and differential is required. "Significant decrease" is defined as a single drop in white blood cell count to 3.0 × 10⁹/L (3000/mm³) or lower, or a sustained decrease to 3.0 × 10⁹/L (3000/mm³) or lower over three consecutive weeks.

Immediate discontinuation of Azaleptol is mandatory if the white blood cell count falls below 3000/mm³ (3.0 × 10⁹/L) or the ANC is less than 1500/mm³ (1.5 × 10⁹/L) after 18 weeks of treatment. Thereafter, white blood cell count and differential should be monitored daily, and patients must be closely observed for influenza-like symptoms or other signs of infection. Hematological monitoring should continue after discontinuation of Azaleptol until parameters return to normal.

If, after discontinuation of Azaleptol, further decline in white blood cell count occurs to levels below 2000/mm³ (2.0 × 10⁹/L) or absolute neutrophil count below 1000/mm³ (1.0 × 10⁹/L), treatment must be managed under the supervision of an experienced hematologist.

Hospitalization in a specialized hematology unit should be considered, if possible; protective isolation and administration of GM-CSF (granulocyte-macrophage colony-stimulating factor) or G-CSF (granulocyte colony-stimulating factor) may be indicated. Colony-stimulating factor therapy should be discontinued once neutrophil count increases above 1.0 × 10⁹/L (1000/mm³).

In case of infection, immediate initiation of antibacterial therapy is required due to the risk of septic shock.

Patients in whom Azaleptol was discontinued due to decreased white blood cell count or ANC (see above) must not be re-prescribed this medication. It is recommended to confirm complete blood count results by repeating the test on two consecutive days. However, Azaleptol should be discontinued immediately upon receipt of the first abnormal blood test result.

Prescriptions for Azaleptol issued by physicians should be marked as “CBC” (complete blood count).

Azaleptol must be discontinued if eosinophil count exceeds 3.0 × 10⁹/L (3000/mm³; see "Adverse reactions"); therapy may be resumed only after eosinophil count decreases below 1.0 × 10⁹/L (1000/mm³).

In the case of thrombocytopenia (see "Adverse reactions"), Azaleptol should be discontinued if platelet count falls below 50 × 10⁹/L (50,000/mm³).

Cardiotoxicity

Initial dose for patients with cardiovascular disease should be low (12.5 mg once daily on the first day). Dose escalation should be slow and gradual (see "Dosage and administration"). The medication is contraindicated in patients with severe cardiovascular disease (see "Contraindications"). Patients with a history of heart disease or those with cardiovascular abnormalities detected during physical examination should be referred to a specialist for further evaluation, including ECG (see "Contraindications"). Such patients may receive Azaleptol only if the expected benefit clearly outweighs the risks. The physician should consider the need for pre-treatment ECG.

Orthostatic hypotension, with or without syncope, may develop during treatment with Azaleptol. In rare cases (approximately 1 in 3000 patients), collapse may be severe and may be associated with cardiac arrest and/or respiratory arrest, potentially resulting in death. These reactions are most likely to occur when Azaleptol is used concomitantly with benzodiazepines or other psychotropic agents, or during the initial dose titration phase due to rapid dose escalation; very rarely, such reactions have been observed even after the first dose. Therefore, careful medical supervision is required at the beginning of Azaleptol therapy. Blood pressure monitoring in supine and standing positions should be performed during the first weeks of treatment in patients with Parkinson's disease.

Tachycardia at rest, associated with arrhythmia, dyspnea, or symptoms of heart failure, may rarely occur within the first two months of treatment and very rarely thereafter (see "Adverse reactions"). If these symptoms occur, particularly during dose escalation, prompt diagnostic evaluation should be performed to rule out myocarditis. Other possible symptoms, in addition to those listed above, include symptoms of myocardial infarction or influenza-like illness. In some cases, myocardial infarction has been fatal.

However, pre-existing severe heart disease in a patient may significantly complicate the assessment of causality.

If myocarditis or cardiomyopathy is suspected, Azaleptol must be discontinued immediately, and the patient should seek immediate consultation with a cardiologist.

Similar signs and symptoms may also develop at later stages of therapy and may be associated with cardiomyopathy. In such cases, further investigations are indicated. If cardiomyopathy is confirmed, Azaleptol must be discontinued. Patients who have experienced clozapine-induced myocarditis or cardiomyopathy should not resume treatment with this medication.

In some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion, eosinophilia has also been reported; however, it is unknown whether eosinophilia is a reliable predictor of carditis development.

Mitral valve insufficiency may develop in patients diagnosed with cardiomyopathy during clozapine therapy. Available data describe cases of mitral valve insufficiency in patients with cardiomyopathy receiving clozapine. In these cases, mild to moderate regurgitation has been observed on two-dimensional echocardiography.

QT interval prolongation

As with other antipsychotic agents, caution is advised when prescribing Azaleptol to patients with known cardiovascular disease or a family history of QT interval prolongation.

As with other antipsychotics, caution is recommended when prescribing clozapine concomitantly with medications known to prolong the QTc interval.

Cerebrovascular adverse events

An approximately threefold increased risk of cerebrovascular adverse events has been observed with the use of some atypical antipsychotics in patients with dementia. The mechanism of these events is unknown. An increased risk cannot be excluded with the use of other antipsychotics or in other patient populations. Azaleptol should be used with caution in patients with risk factors for stroke.

Epilepsy

Azaleptol may lower the seizure threshold. Patients with a history of epilepsy require careful monitoring during Azaleptol therapy due to reports of seizures associated with the medication (see "Interaction with other medicinal products and other forms of interaction"). In such cases, dose reduction should be considered, and, if necessary, antiepileptic therapy should be initiated.

For patients with a history of seizures, treatment should be initiated with a single 12.5 mg dose on the first day, and dose escalation should be slow and gradual (see "Dosage and administration").

Elevated body temperature

During treatment with Azaleptol, transient elevation of body temperature above 38°C may occur, with peak incidence during the first three weeks of treatment. This temperature elevation is mostly benign. In some cases, it may be associated with increased or decreased white blood cell count. Patients with elevated body temperature should be carefully evaluated to exclude infection or development of agranulocytosis. High fever may be a sign of neuroleptic malignant syndrome (NMS). If NMS is diagnosed, Azaleptol must be discontinued immediately and appropriate therapeutic measures initiated.

Azaleptol may cause sedation and weight gain, increasing the risk of thromboembolism; therefore, such patients should avoid reduced physical activity.

Anticholinergic effects

Azaleptol has anticholinergic properties, which may cause systemic adverse effects. Careful monitoring is required in patients with benign prostatic hyperplasia or closed-angle glaucoma. Due to its anticholinergic properties, Azaleptol may cause gastrointestinal motility disturbances of varying severity: from constipation to fecal impaction, intestinal obstruction, paralytic ileus, intestinal ischemia, necrotizing colitis, or bowel necrosis. Rarely, these cases may be fatal (see "Adverse reactions").

Particular attention is required for patients with a history of colorectal disease or abdominal surgery, or those receiving concomitant medications that may cause constipation (especially agents with anticholinergic properties, such as various neuroleptics, antidepressants, antiparkinsonian agents, and opioids), as their condition may worsen. Prompt recognition and treatment of constipation is extremely important. Prophylactic laxative therapy should be considered when prescribing Azaleptol to patients with a history of constipation or intestinal obstruction.

Particular caution is required when prescribing Azaleptol concomitantly with other benzodiazepines (or other centrally acting agents; see "Interaction with other medicinal products and other forms of interaction").

Metabolic disturbances

Atypical antipsychotics, including Azaleptol, are associated with metabolic disturbances that may increase the risk of cardiovascular/cerebrovascular events. These may include hyperglycemia, dyslipidemia, and weight gain.

Hyperglycemia

Cases of diabetes mellitus and severe hyperglycemia, sometimes leading to ketoacidosis or hyperosmolar coma, have been reported, even in patients without prior history of hyperglycemia or diabetes. A causal relationship with Azaleptol has not been established, although in most patients glucose levels returned to normal after discontinuation of Azaleptol. In some cases, re-administration of the drug was associated with recurrence of hyperglycemia. The effect of Azaleptol on glucose metabolism in patients with pre-existing diabetes has not been studied. Patients diagnosed with diabetes who are treated with atypical antipsychotics should have their glucose levels closely monitored. Patients with risk factors for diabetes (such as obesity, family history) initiating antipsychotic therapy should undergo fasting blood glucose testing at the start of treatment and periodically during treatment. Patients receiving Azaleptol who develop hyperglycemia with symptoms such as polydipsia, polyuria, polyphagia, or weakness may have impaired glucose tolerance. Patients with symptoms of hyperglycemia should undergo fasting blood glucose testing. In some cases, glucose levels normalize after discontinuation of atypical antipsychotics; in others, hyperglycemia requires ongoing treatment even after stopping antipsychotics.

For patients with marked hyperglycemia associated with treatment, discontinuation of Azaleptol should be considered.

Dyslipidemia

Adverse events related to weight changes have been observed in patients receiving atypical antipsychotics, including Azaleptol. Clinical monitoring, including lipid assessment, is recommended at the start of treatment and periodically during treatment.

Weight gain

Weight gain may occur with Azaleptol. Clinical monitoring of body weight is recommended.

Special patient populations

Patients with stable liver disease may receive Azaleptol but require regular monitoring of liver function tests during therapy. In patients who develop symptoms suggestive of possible liver function impairment—such as nausea, vomiting, and/or anorexia—liver function tests should be performed. If test results show clinically significant elevations or if symptoms of jaundice develop, treatment with Azaleptol should be discontinued. Therapy may be resumed only when liver function test results return to normal. In such cases, liver function should be closely monitored after re-initiation of Azaleptol.

Renal disorders

The initial dose for patients with mild to moderate renal impairment should be low (12.5 mg once daily on the first day of treatment) (see "Dosage and administration").

Use in patients aged 60 years and older

Initiation of treatment in elderly patients is recommended at the lowest dose (see "Dosage and administration").

Treatment with Azaleptol may be associated with orthostatic hypotension; cases of tachycardia, which may be persistent, have also been reported. Elderly patients, especially those with compromised cardiovascular function, may be more susceptible to these effects.

Elderly patients may also be more susceptible to anticholinergic effects of Azaleptol, such as urinary retention and constipation.

Patients aged 60 years and older with dementia

Data from two large observational studies indicate that elderly patients with dementia treated with antipsychotic medications have a slightly increased risk of mortality compared to those not receiving treatment. Risk factors reported in the literature include cardiac arrhythmia and pulmonary disease (e.g., pneumonia, with or without aspiration). Available data are insufficient to precisely quantify the magnitude of risk; the cause of the increased risk remains unknown.

An increased risk of mortality has been observed in elderly patients (≥60 years) with dementia-related psychotic/behavioral disorders treated with atypical antipsychotics compared to those receiving placebo. Analysis of 17 placebo-controlled studies showed a 1.6- to 1.7-fold higher mortality risk in this patient population compared to placebo. Risk factors for increased mortality with antipsychotic use include sedation, cardiovascular disease (e.g., arrhythmia, sudden cardiac death), or pulmonary disease (e.g., pneumonia with or without aspiration).

Azaleptol is not approved for the treatment of behavioral disorders associated with dementia in patients aged 60 years and older.

Rebound/withdrawal symptoms

If abrupt discontinuation of the medication is necessary (e.g., due to development of leukopenia), patients should be closely monitored for recurrence of psychotic symptoms and symptoms related to re-emergence of cholinergic activity, such as profuse sweating, headache, nausea, vomiting, and diarrhea.

Azaleptol contains lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding.

Pregnancy

Toxic effects have been observed in animal studies. Clinical data on use in pregnant women are lacking. Controlled studies in humans have not been conducted; therefore, the safety of the medication in pregnant women has not been established.

Azaleptol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women of reproductive potential

Normalization of menstrual function may occur when switching from another neuroleptic to Azaleptol. Therefore, women of reproductive age should use appropriate contraceptive methods.

Non-teratogenic effects

Neonatal exposure to antipsychotic medications (including Azaleptol) during the third trimester of pregnancy may result in adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms. Cases of agitation, unusual increase or decrease in muscle tone, tremor, somnolence, respiratory disturbances, or feeding difficulties have been reported. These complications may vary in severity; in some cases, symptoms resolve spontaneously, while in others, neonates require intensive care and prolonged hospitalization.

Neuroleptics, including Azaleptol, should not be used during pregnancy except when absolutely necessary. If discontinuation of Azaleptol is required during pregnancy, the medication should not be abruptly withdrawn.

Ability to affect reaction speed when driving or operating machinery.

Azaleptol affects the patient's reaction speed and ability to drive or operate machinery.

Azaleptol has a sedative effect and may lower the seizure threshold. Therefore, patients should refrain from activities such as driving vehicles or operating machinery, especially during the first weeks of treatment.

Dosage and Administration

Dosage must be individually adjusted. The lowest effective dose should be used for each patient.

Treatment with Azaleptol should only be initiated when the patient’s total white blood cell count is ≥ 3500/mm³ (3.5 x 10⁹/L) and absolute neutrophil count (ANC) is ≥ 2000/mm³ (2.0 x 10⁹/L), with values within the standardized normal reference range.

Dose adjustment is recommended for patients concurrently receiving medicinal products that interact pharmacodynamically or pharmacokinetically with Azaleptol, such as benzodiazepines or selective serotonin reuptake inhibitors.

The following dosage recommendations are advised.

Treatment-Resistant Schizophrenia

Initial Dose

On Day 1, administer 12.5 mg (half of a 25 mg tablet) once or twice daily, and 1 or 2 tablets of 25 mg on Day 2. If well tolerated, the dose may be gradually increased by 25–50 mg/day to reach a dose of 300 mg/day within 2–3 weeks. Thereafter, if necessary, the daily dose may be increased by 50–100 mg at intervals of twice weekly, or preferably once weekly.

Therapeutic Range

In most patients, antipsychotic effect is expected at a dose of 300–450 mg/day, divided into multiple doses. Some patients may respond adequately to lower daily doses, while others may require up to 600 mg/day.

The total daily dose may be divided into unequal doses, with the largest dose administered at bedtime.

Maximum Dose

Some patients may require higher doses to achieve full therapeutic effect; in such cases, dose escalation should be gradual (i.e., dose increments should not exceed 100 mg) up to a maximum of 900 mg/day. Increased incidence of adverse reactions (particularly seizures) may occur at doses exceeding 450 mg/day.

Maintenance Dose

After achieving maximum therapeutic effect, many patients can be effectively maintained on lower doses. Gradual dose reduction is recommended. Treatment should continue for at least 6 months. If the daily dose does not exceed 200 mg, once-daily evening administration may be appropriate.

Discontinuation of Therapy

When planned discontinuation of Azaleptol is required, gradual dose reduction over 1–2 weeks is recommended. In cases of abrupt discontinuation (e.g., due to leukopenia), close monitoring of the patient is essential due to the risk of psychotic symptom exacerbation or cholinergic rebound symptoms (e.g., excessive sweating, headache, nausea, vomiting, and diarrhea).

Reinitiation of Therapy

If more than 48 hours have passed since the last dose of Azaleptol, the drug should be reintroduced gradually to achieve the therapeutic dose, to minimize the risk of sedation, seizures, orthostatic hypotension, and convulsions. Slow dose titration is crucial, as rapid escalation may lead to overdose.

Treatment should be restarted at a dose of 12.5 mg (half of a 25 mg tablet), administered once or twice on the first day. If this dose is well tolerated, dose escalation to achieve therapeutic effect may proceed more rapidly than during initial treatment. However, if the patient previously experienced respiratory or cardiac arrest during initial treatment, even after successful dose escalation to a therapeutic level, re-escalation should be performed with extreme caution.

Switching from Previous Antipsychotic Therapy to Azaleptol

Generally, Azaleptol should not be administered in combination with other antipsychotics. If initiation of Azaleptol is necessary in a patient already receiving oral antipsychotics, it is recommended, if possible, to first discontinue the other antipsychotic with gradual dose reduction over one week. Azaleptol treatment may be initiated as described above, no sooner than 24 hours after complete discontinuation of the previous antipsychotic.

Risk of Suicide Attempt Recurrence

Dosage and administration recommendations are the same as for treatment-resistant schizophrenia.

Psychotic Disorders in Parkinson’s Disease

The initial dose should not exceed 12.5 mg/day (half of a 25 mg tablet), administered as a single evening dose. Subsequent dose increases should be in increments of 12.5 mg, with a maximum increase of twice weekly, up to 50 mg, to be reached by the end of the second week. The total daily dose should generally be administered as a single evening dose.

The average effective dose typically ranges from 25 mg to 37.5 mg/day. If treatment with 50 mg/day for at least one week does not provide an adequate therapeutic response, the dose may be cautiously increased by 12.5 mg/week.

Doses exceeding 50 mg/day should only be used in exceptional circumstances, and the maximum dose must never exceed 100 mg/day.

Dose escalation should be limited or discontinued if orthostatic hypotension, excessive sedation, or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.

When complete remission of psychotic symptoms has persisted for at least 2 weeks, the antipsychotic dose may be increased if justified by motor status. If this leads to a relapse of psychotic symptoms, the Azaleptol dose may be increased in increments of 12.5 mg/week up to the maximum dose of 100 mg/day, administered as a single dose or in two divided doses.

Discontinuation of Therapy

Gradual dose reduction by 12.5 mg over at least 1 week (preferably 2 weeks) is recommended. Treatment must be immediately discontinued in case of neutropenia or agranulocytosis. Close psychiatric monitoring is required in such cases, as symptoms may rapidly reappear.

Use in Elderly Patients

Initiation of treatment with a particularly low dose is recommended (12.5 mg as a single dose on Day 1), with subsequent dose increases not exceeding 25 mg/day.

Use in Patients with Cardiovascular Disorders

Initiation of treatment with a low dose is recommended (12.5 mg once daily on Day 1), followed by slow and small dose increments.

Use in Patients with Renal Impairment

For patients with mild to moderate renal impairment, the initial dose should be 12.5 mg once daily on Day 1, followed by slow and cautious dose escalation.

Use in Patients with Hepatic Impairment

Azaleptol should be used with caution in patients with hepatic impairment, and liver function parameters should be monitored regularly.

Children

The safety and efficacy of Azaleptol in children have not been established; therefore, the drug should not be used in pediatric patients.

Overdose

Severe overdose, whether accidental or intentional, poses a serious risk to the patient.

Mortality in acute intentional or accidental overdose of Azaleptol is approximately 12%. Most fatalities have been due to cardiac failure or aspiration pneumonia and occurred after ingestion of doses exceeding 2000 mg. There have been reports of patients recovering after ingesting more than 10,000 mg. However, in several adult patients, particularly those previously unexposed to Azaleptol, ingestion of only 400 mg has led to life-threatening coma, and in one case, death. In young children, ingestion of 50–200 mg has resulted in marked sedation or coma, but without fatal outcome.

Symptoms

Somnolence, lethargy, coma, areflexia, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, seizures; increased salivation, mydriasis, temperature fluctuations; arterial hypotension, collapse, tachycardia, arrhythmia; aspiration pneumonia, dyspnea, respiratory depression or suppression, respiratory failure.

Treatment

No specific antidote is known. The following nonspecific measures are indicated: immediate and repeated gastric lavage and/or administration of activated charcoal within six hours of drug intake. Peritoneal dialysis and hemodialysis are unlikely to be effective; cardiopulmonary intensive care (ECG, continuous patient monitoring); continuous monitoring of electrolytes and acid-base balance. Peritoneal dialysis or hemodialysis may be considered in cases of oliguria or anuria (although this does not significantly accelerate elimination due to the drug’s high protein binding).

For anticholinergic effects, parasympathomimetic agents such as physostigmine (which crosses the blood-brain barrier), pyridostigmine, or neostigmine may be used.

For arrhythmia, potassium preparations, potassium bicarbonate, or digitalis should be administered depending on symptoms; quinidine and procainamide are contraindicated.

For arterial hypotension, infusion of albumin or plasma substitutes is recommended. Dopamine or angiotensin are the most effective vasopressors. Epinephrine and other beta-sympathomimetics are contraindicated (risk of increased vasodilation).

In case of seizures, intravenous diazepam or slow intravenous phenytoin should be administered. Long-acting barbiturates are contraindicated.

Due to the risk of delayed reactions, the patient should be observed for at least 5 days.

Adverse Reactions

The adverse event profile of clozapine is mostly predictable based on its pharmacological properties. An important exception is its potential to cause agranulocytosis. Due to this risk, the use of clozapine is restricted to the treatment of treatment-resistant schizophrenia and psychosis associated with Parkinson's disease when standard therapy has proven ineffective. Although blood monitoring is an essential part of patient surveillance during clozapine therapy, physicians must also be aware of other rare but serious adverse reactions that can only be diagnosed at early stages through careful clinical observation and patient questioning, in order to prevent morbidity and mortality.

Blood and lymphatic system disorders

Common: decreased total white blood cell count, neutropenia, leukopenia, eosinophilia.

Uncommon: agranulocytosis.

Rare: lymphopenia.

Very rare: thrombocytopenia, thrombocytosis, anemia.

Granulocytopenia and/or agranulocytosis are possible complications of Azaleptol therapy. Although agranulocytosis is usually reversible upon discontinuation of treatment, it may lead to sepsis and can be fatal. Most cases of agranulocytosis (approximately 70%) occur within the first 18 weeks of therapy. To prevent life-threatening agranulocytosis, Azaleptol must be discontinued promptly. Regular monitoring of white blood cell counts is therefore required.

Leukocytosis and/or eosinophilia of unknown etiology may occur, particularly during the first few weeks of treatment.

Metabolic and nutritional disorders

Common – very common: weight gain (4 – 31%), which can be substantial.

Rare: impaired glucose tolerance, diabetes mellitus, even in patients with no prior history of hyperglycemia or diabetes.

Very rare: severe hyperglycemia, ketoacidosis, hyperosmolar coma, even in patients with no prior history of hyperglycemia or diabetes; hypercholesterolemia, hypertriglyceridemia.

Psychiatric disorders

Common: dysarthria.

Uncommon: dysphemia.

Rare: anxiety, agitation.

Very rare: obsessive-compulsive disorders.

Nervous system disorders

Very common: somnolence and sedative effect (39 – 46%), dizziness (19 – 27%).

Common: headache, tremor, muscle rigidity, akathisia, extrapyramidal symptoms, epileptic seizures, convulsions, myoclonic jerks.

Rare: confusion, delirium.

Azaleptol may cause changes in EEG parameters, including spike-and-wave complexes. The drug lowers the seizure threshold in a dose-dependent manner and may provoke myoclonic seizures or generalized seizures. These symptoms are more likely to occur with rapid dose escalation and in patients with a prior history of epilepsy. In such cases, dose reduction is necessary and anticonvulsant therapy should be initiated if needed. Carbamazepine should be avoided due to its potential to suppress bone marrow function. Cases of fatal convulsions have been reported. When prescribing other anticonvulsants, possible pharmacokinetic interactions should be considered. Extrapyramidal symptoms are milder and occur less frequently compared to conventional antipsychotics. Acute dystonia has not been confirmed as an adverse effect of Azaleptol therapy.

Very rare cases of tardive dyskinesia have been reported in patients receiving Azaleptol, either alone or in combination with other antipsychotics. However, symptoms of pre-existing tardive dyskinesia caused by other antipsychotics may improve during Azaleptol treatment.

Uncommon reports of neuroleptic malignant syndrome have occurred in patients receiving monotherapy with Azaleptol or in combination with lithium or other centrally acting agents. In such cases, the drug should be discontinued immediately and intensive treatment initiated. The main symptoms of neuroleptic malignant syndrome include muscle rigidity, hyperthermia, mental status changes, and autonomic instability.

Eye disorders

Common: blurred vision.

Cardiac disorders

Very common: tachycardia (especially during the first weeks of Azaleptol therapy; 25%).

Very rare: cardiac arrest.

ECG changes (ST segment depression, flattening and inversion of T-waves, conduction disturbances) may commonly occur. Isolated reports of arrhythmia, pericarditis (with or without pericardial effusion), cardiomyopathy, and myocarditis (with or without eosinophilia) have been reported; some of these cases were fatal. Clinical symptoms may resemble those of myocardial infarction or influenza. Therefore, myocarditis should be considered in patients taking Azaleptol who develop resting tachycardia accompanied by arrhythmia, dyspnea, or signs of heart failure; if the diagnosis is confirmed, treatment with the drug should be discontinued.

Very rare cases of cardiomyopathy have been reported. If cardiomyopathy is diagnosed, Azaleptol must be discontinued.

Vascular disorders

Common: arterial hypertension, orthostatic hypotension, syncope.

Rare: thromboembolism, including fatal cases and cases associated with organ necrosis (e.g., intestinal); circulatory collapse due to severe arterial hypotension, particularly related to rapid dose escalation, with potentially severe consequences such as cardiac or respiratory arrest.

The frequency and severity of hypotension depend on the rate and magnitude of dose increase.

Respiratory, thoracic and mediastinal disorders

Rare: food aspiration (into airways) during swallowing (due to dysphagia).

Very rare: respiratory depression or arrest. Cases of pneumonia and lower respiratory tract infections, some with fatal outcomes, have been reported during Azaleptol therapy.

Gastrointestinal disorders

Very common: constipation (14 – 25%), hypersalivation (31 – 48%).

Common: nausea, vomiting, anorexia, dry mouth, abdominal distension, abdominal pain.

Rare: dysphagia.

Very rare: salivary gland enlargement, intestinal obstruction, paralytic ileus, fecal impaction, intestinal ischemia, necrotizing colitis, intestinal necrosis, up to fatal outcomes.

Hepatobiliary, biliary tract and pancreatic disorders

Common: elevated liver enzymes.

Rare: hepatitis, cholestatic jaundice, pancreatitis.

Very rare: fulminant hepatic necrosis.

If jaundice develops, the drug should be discontinued.

Skin and subcutaneous tissue disorders

Very rare: skin reactions.

Renal and urinary disorders

Common: urinary incontinence, urinary retention.

Very rare: interstitial nephritis, impaired renal function, renal failure.

Reproductive system disorders

Very rare: priapism, impotence, ejaculation disorders, dysmenorrhea.

General disorders

Common: fatigue, increased body temperature, disturbances in thermoregulation and sweating.

Laboratory findings

Rare: elevated creatine phosphokinase levels.

Very rare: hyponatremia.

Very rare cases of ventricular tachycardia, cardiac arrest, and QT interval prolongation, possibly associated with torsades de pointes-type ventricular tachycardia, have been reported; however, a definitive causal relationship with the use of this medicinal product cannot be established in these cases.

Fatal cases during treatment

It is known that sudden death of undetermined etiology may occur in patients with psychiatric disorders treated with conventional antipsychotics, but it may also occur in untreated patients.

Such cases of sudden death have also occurred in patients receiving Azaleptol, including younger patients. The cause may be related to adverse effects of the drug on the cardiovascular system (ECG changes, arrhythmias, cardiomyopathy, myocarditis).

List of adverse effects based on spontaneous post-marketing reports (frequency unknown)

Infections and parasitic diseases

Sepsis.

Immune system disorders

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); Quincke's edema, leukocytoclastic vasculitis.

Endocrine system disorders

Pseudo-pheochromocytoma.

Metabolism and nutrition disorders

Obesity.

Nervous system disorders

Cholinergic syndrome; EEG changes, pleurothotonus (Pisa syndrome).

Cardiac disorders

Myocardial infarction, potentially fatal; angina pectoris, palpitations, atrial fibrillation, mitral valve insufficiency associated with clozapine-induced cardiomyopathy.

Respiratory, thoracic and mediastinal disorders

Bronchospasm, nasal congestion.

Gastrointestinal disorders

Diarrhea; abdominal discomfort/heartburn/dyspepsia, colitis.

Hepatobiliary, biliary tract and pancreatic disorders

Hepatic steatosis; hepatic necrosis; hepatotoxicity; hepatic fibrosis; liver cirrhosis; liver function disorders associated with life-threatening outcomes such as liver failure, need for liver transplantation, and even death.

Skin and subcutaneous tissue disorders

Pigmentation disorders.

Musculoskeletal and connective tissue disorders

Muscle weakness, muscle spasms, myalgia, systemic lupus erythematosus.

Renal and urinary disorders

Nocturnal enuresis; renal failure.

Reproductive system and breast disorders

Retrograde ejaculation.

Shelf life. 3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister; 5 blisters in a cardboard box.

50 tablets in a container; 1 container in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

JSC "Technologia".

Manufacturer's location and address of business site.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.