Zalasta^® (Tablets) Instructions for Use

ATC Code

N05AH03 (Olanzapine)

Active Substance

Olanzapine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

Olanzapine is an antipsychotic agent (neuroleptic). It has affinity for serotonin 5-HT_2A/C, 5-HT₃, 5-HT₆ receptors; dopamine D₁, D₂, D₃, D₄, D₅ receptors; M_1-5 cholinergic receptors; α₁-adrenergic receptors and histamine H₁ receptors. It exhibits antagonism towards serotonin 5-HT, dopamine, and cholinergic receptors.

In vitro and in vivo, it has a more pronounced affinity and activity for serotonin 5-HT₂ receptors compared to dopamine D₂ receptors. According to electrophysiological studies, Olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons and, at the same time, has a slight effect on striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned avoidance response (a test characterizing antipsychotic activity) at lower doses than those required to achieve catalepsy (a disorder reflecting an adverse effect on motor function). Unlike other neuroleptics, Olanzapine enhances the anti-anxiety effect in the anxiolytic test.

When using olanzapine, both positive (including delusions, hallucinations) and negative disorders are reduced.

Pharmacokinetics

After oral administration, Olanzapine is well absorbed from the gastrointestinal tract, with C_max in plasma reached within 5-8 hours. Olanzapine plasma concentrations show a linear dependence on the dose (in the range from 1 to 20 mg). Food intake does not affect the absorption of olanzapine.

At plasma concentrations from 7 to 1000 ng/ml, protein binding is about 93%.

Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the blood-brain barrier. CYP1A2 and CYP2D6 isoenzymes are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Experimental studies in animals have shown that these metabolites have significantly less pronounced pharmacological activity in vivo than Olanzapine. The main pharmacological activity is due to unchanged olanzapine.

The activity of the CYP2D6 isoenzyme does not affect the metabolism rate of olanzapine.

In healthy volunteers after oral administration, the T_1/2 of olanzapine is 33 hours (21-54 hours), and the average plasma clearance is 26 L/h (12-47 L/h).

Approximately 57% of radioisotope-labeled olanzapine is excreted in the urine, mainly as metabolites.

The pharmacokinetic parameters of olanzapine vary depending on gender, age, and smoking status:

However, the degree of change in T_1/2 and plasma clearance under the influence of each of these factors is significantly less than the degree of individual variation of these parameters.

No significant differences were found between the mean values of T_1/2 and plasma clearance of olanzapine in patients with severe renal impairment compared to individuals with normal renal function.

In smoking patients with mild hepatic impairment, the plasma clearance of olanzapine is lower than in non-smokers without such impairment.

Indications

Treatment of exacerbations, maintenance and long-term relapse prevention therapy of schizophrenia and other psychotic disorders with pronounced positive (including delusions, hallucinations, automatism) and/or negative (including emotional flattening, reduced social activity, poverty of speech) symptoms, as well as associated affective disorders.

Treatment of acute manic or mixed episodes in bipolar affective disorder with/without psychotic manifestations and with/without rapid cycling.

ICD codes

Dosage Regimen

Tablets

The initial dose is 10-15 mg/day. The daily dose should be selected individually depending on the clinical condition of the patient. Therapeutic doses are 5-20 mg/day. Increasing the dose beyond the standard dose, which is (depending on the indication) 10-15 mg/day, is recommended only after appropriate clinical examination of the patient. The dose should be increased gradually, at intervals of at least 24 hours.

For elderly patients, as well as for patients with severe renal impairment or moderate hepatic impairment, the initial dose is 5 mg/day.

A reduction of the initial dose is recommended for patients with a combination of factors (female, elderly, non-smoking) in which a slowdown in olanzapine metabolism is possible.

Adverse Reactions

From the nervous system gait disturbance (in patients with Alzheimer’s type dementia), drowsiness, akathisia, dizziness; rarely – seizures, neuroleptic malignant syndrome (NMS).

From metabolism weight gain, peripheral edema.

From the endocrine system increased prolactin levels (clinical manifestations of hyperprolactinemia were rare, in most cases normalization of prolactin levels occurred without discontinuing olanzapine); in isolated cases – hyperglycemia, diabetic coma, diabetic ketoacidosis.

From the cardiovascular system orthostatic hypotension; rarely – bradycardia.

From the digestive system constipation, dry mouth, increased appetite, increased ALT and AST activity; rarely – hepatitis.

Dermatological reactions rarely – photosensitivity, rash.

From the genitourinary system rarely – priapism.

From the hematopoietic system eosinophilia; rarely – leukopenia, thrombocytopenia.

Other asthenia.

Contraindications

Hypersensitivity to olanzapine.

Use in Pregnancy and Lactation

Adequate and strictly controlled clinical studies on the safety of olanzapine use during pregnancy have not been conducted. Use is possible only in cases where the expected benefit of therapy for the mother significantly outweighs the potential risk to the fetus.

Currently, there are no data on the excretion of olanzapine in breast milk. If use during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

In moderate hepatic impairment, the initial dose is 5 mg/day.

Use in Renal Impairment

In severe renal impairment, the initial dose is 5 mg/day.

Pediatric Use

The safety and efficacy of olanzapine in patients under 18 years of age have not been studied.

Geriatric Use

For elderly patients, the initial dose is 5 mg/day.

Special Precautions

Use with particular caution in cases of increased AST and ALT activity in patients with hepatic impairment, limited hepatic functional reserve, or in patients receiving treatment with potentially hepatotoxic drugs. If AST and/or ALT activity increases during treatment with olanzapine, careful monitoring of the patient is required, and, if necessary, dose reduction.

Use with caution in patients with a history of epileptic seizures or those exposed to factors that lower the seizure threshold.

Use with caution in patients with a reduced number of leukocytes and/or neutrophils due to various reasons; with a history of drug-induced depression/toxic impairment of bone marrow function; with bone marrow depression due to a concomitant disease, history of radiotherapy or chemotherapy; with hypereosinophilia or myeloproliferative disease. In clinical studies, the use of olanzapine in patients with a history of clozapine-dependent neutropenia or agranulocytosis was not accompanied by a relapse of these disorders.

Use with caution in patients with clinical manifestations of prostatic hyperplasia, paralytic ileus, narrow-angle glaucoma and similar conditions.

When treating with neuroleptics, including Olanzapine, the development of neuroleptic malignant syndrome (NMS) is possible. Clinical manifestations of NMS or a significant increase in body temperature without other symptoms of this syndrome require discontinuation of all neuroleptics, including Olanzapine.

With long-term neuroleptic therapy, there is a risk of developing tardive dyskinesia. If signs of tardive dyskinesia appear, a reduction in the dose or discontinuation of olanzapine is recommended. Symptoms of tardive dyskinesia may appear or worsen after discontinuation of therapy.

Given the nature of olanzapine’s effect on the central nervous system, it should be used with caution in combination with other centrally acting drugs and ethanol.

The safety and efficacy of olanzapine in patients under 18 years of age have not been studied.

Effect on ability to drive vehicles and operate machinery

During the treatment period, caution should be exercised when engaging in activities requiring concentration and high speed of psychomotor reactions.

Drug Interactions

With simultaneous use with drugs that have a depressant effect on the central nervous system, and with ethanol, the depressant effect on the central nervous system and the antihypertensive effect are enhanced.

The metabolism of olanzapine may be altered under the influence of inhibitors or inducers of the CYP1A2 isoenzyme. The plasma clearance of olanzapine is increased in smoking patients and in patients taking carbamazepine (due to increased CYP1A2 activity). Strong inhibitors of CYP1A2 may reduce the plasma clearance of olanzapine.

Simultaneous intake of activated charcoal reduces the bioavailability of olanzapine by 50-60%.

With simultaneous use with fluvoxamine, the concentration of olanzapine in the blood plasma increases.

Taking fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) causes an average increase in the C_max of olanzapine in plasma by 16% and an average decrease in the plasma clearance of olanzapine by 16%.

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.