Zalasta Ku-tab, 10mg, 28pcs

Composition

for 1 tablet dispersed in the oral cavity,5 mg/7.5 mg / 10 mg/15 mg/20 mg

Active ingredient: olanzapine 5.00 mg/7.50 mg/10.00 mg/15.00 mg/20.00 mg

Auxiliary substances: mannitol, microcrystalline cellulose, crospovidone, hypromellose low-substituted LH-21, aspartame, calcium silicate, magnesium stearate

Pharmacological action

antipsychotic agent (neuroleptic)

Clinical Pharmacology

Pharmacodynamics

Olanzapine is an antipsychotic (neuroleptic) with a broad pharmacological spectrum of effects on a number of receptor systems. In preclinical studies, the affinity of olanzapine for_{serotonin 5 HT2A/2C},5 HT3_, 5_HT6; dopamine_D1, _D2, D3, D4, D5; muscarinic M_1-5; adrenergic_α1 and histamine_H1 receptors was established. In animal experiments, the presence of antagonism of olanzapine with respect to 5 HT, dopamine and cholinergic receptors was revealed. In vitro and in vivo, olanzapine 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 minor effect on striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned defense reflex (a test that characterizes antipsychotic activity) at doses lower than those that cause catalepsy (a disorder that reflects an adverse effect on motor function). Unlike other antipsychotics, olanzapine enhances the anti-anxiety effect when performing an “anxiolytic” test. Olanzapine provides statistically significant reduction of both productive (delusions, hallucinations, etc. ) and negative disorders.

Pharmacokinetics

Olanzapine tablets dispersed in the oral cavity are bioequivalent to olanzapine tablets and have a similar rate and degree of absorption. Olanzapine tablets dispersed in the oral cavity can be used instead of olanzapine tablets.

Suction

After oral use, olanzapine is well absorbed, and its maximum concentration (cmax) in plasma is reached in 5-8 hours. The absorption of olanzapine does not depend on food intake.

Distribution

At a plasma concentration of 7 to 1000 ng/ml, about 93% of olanzapine binds to plasma proteins. Olanzapine binds mainly to albumin and_a1-acid glycoprotein.

Metabolism

Olanzapine is metabolized in the liver by conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the blood-brain barrier. Cytochrome P 450 isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in animal studies had significantly less pronounced pharmacological activity in vivothan olanzapine. The main pharmacological activity of the drug is due to the initial substance-olanzapine.

Deduction

After oral use, the mean half-life (T_1/2) of olanzapine in healthy volunteers varied according to age and gender.

In healthy elderly volunteers (65 years and older), the average T_1/2 was delayed (51.8 hours), and clearance was reduced (17.5 l/h) compared to similar indicators in younger subjects (33.8 hours and 18.2 l/h, respectively).

In women compared to men, the mean T_1/2 was delayed (36.7 h compared to 32.3 h), and the plasma clearance of olanzapine was reduced (18.9 l/h compared to 27.3 l/h).

Patients with impaired renal function

In patients with impaired renal function (creatinine clearance < 10 ml / min) compared with healthy volunteers, there were no significant differences in mean T_1/2 (37.7 h compared to 32.4 h) and clearance (21.2 l/h compared to 25.0 l/h). About 57% of radioisotope-labeled olanzapine was excreted by the kidneys, mainly as metabolites.

Patients with impaired liver function

A small study of the effect of disturbances of liver function while taking olanzapine orally (by 2.5-7.5 mg dose) in 6 patients with clinically significant cirrhosis of the class A (n=5) and class B (n=1) according to the classification of child-Pugh showed a minor effect on the pharmacokinetics in patients with light and moderate hepatic impairment showed a slight increase in systemic clearance and shortening T_1/2 compared to patients without liver dysfunction (n=3). Among those with cirrhosis of the liver, there were more smokers (4/6; 67%) than among those without liver dysfunction (0/3; 0%).

Smoking patients

In smoking patients with mild hepatic impairment, the mean T_1/2 was shorter (39.3 h) and clearance was higher (18.0 l/h) compared to the same values in non-smoking healthy volunteers (48.8 h and 14.1 l/h, respectively).

In non-smoking patients (male and female), the average T_1/2 of olanzapine was longer than that in smoking patients (38.6 hours and 30.4 hours), and the clearance was lower (18.6 l / h and 27.7 l/h).

Plasma clearance of olanzapine was lower in elderly patients compared to young patients, in women compared to men, and in non-smokers compared to smokers. However, the degree of influence of age, gender, or smoking on plasma clearance of olanzapine and T_1/2 of olanzapine is small compared to the overall variability between patients.

In a study involving individuals of European, Japanese, and Chinese descent, no differences in the pharmacokinetics of olanzapine related to race were found.

Indications

Adults

·  Olanzapine is indicated for the treatment of schizophrenia.

·  Olanzapine is effective in maintenance and long-term therapy in patients with schizophrenia who have experienced an initial treatment effect.

·  Olanzapine is indicated for the treatment of moderate to severe manic episodes.

·  Olanzapine is indicated for preventing relapses in patients with bipolar disorder, in whom it has been shown to be effective in treating a manic episode.

Use during pregnancy and lactation

Pregnancy

No studies have been conducted on the use of olanzapine in pregnant women. Patients should be advised that if pregnancy occurs or is planned during olanzapine treatment, they should inform their healthcare provider. Due to insufficient experience with olanzapine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the patient significantly exceeds the potential risk to the fetus.

Newborns whose mothers took antipsychotics (including olanzapine) in the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal disorders and withdrawal symptoms, varying in severity and duration. Cases of agitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome, and sucking disorders have been reported. In this regard, newborns whose mothers took olanzapine should be monitored.

Breast-feeding period

The study found that olanzapine is excreted in breast milk. The average dose received by the child (mg / kg) when the equilibrium concentration in the mother was reached was 1.8% of the maternal dose of olanzapine (mg/kg). Breast-feeding during olanzapine therapy is not recommended.

Fertility

The effect on fertility is unknown.

Contraindications

* Hypersensitivity to any of the components of the drug.

* Patients at risk of developing angle-closure glaucoma.

* Children under 18 years of age.

* Patients with phenylketonuria.

Interaction

Potential interactions affecting olanzapine

Since olanzapine is metabolized with the participation of the CYP1A2 isoenzyme, olanzapine metabolism can be altered by inhibitors or inducers of cytochrome P450 isoenzymes that exhibit specific activity against the CYP1A2 isoenzyme.

Induction of the CYP1A2 isoenzyme

Olanzapine metabolism can be induced by smoking or the use of carbamazepine, which can lead to a decrease in the concentration of olanzapine. There was only a small or moderate increase in olanzapine clearance. Clinical manifestations are likely to be limited, but clinical monitoring is recommended, and if necessary, an increase in the dose of olanzapine.

Inhibition of the CYP1A2 isoenzyme

Fluvoxamine, a specific inhibitor of the CYP1A2 isoenzyme, significantly suppresses olanzapine metabolism. C_maxolanzapine after fluvoxamine use increased on average by 54% in non-smoking female patients and by 77% in smoking male patients, and the AUC (area under the concentration-time curve) of olanzapine increased on average by 52% and 108%, respectively. A lower initial dose of olanzapine should be considered in patients receiving fluvoxamine or other CYP1A2 inhibitors, such as ciprofloxacin. At the beginning of the use of drugs related to inhibitors of the CYP1A2 isoenzyme, while taking olanzapine, the possibility of reducing the dose of the latter should be considered.

Reduced bioavailability

Activated charcoal reduces the bioavailability of olanzapine after oral use by 50-60% and should be used at least 2 hours before or after olanzapine use.

Fluoxetine (an inhibitor of the CYP2D6 isoenzyme), single doses of antacids (aluminum -, magnesium-containing) and cimetidine do not significantly affect the pharmacokinetics of olanzapine.

The ability of olanzapine to influence the pharmacokinetics of other drugs

Olanzapine may inhibit the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit major CYP450 isoenzymes in vitro (e. g.,1A2,2D6,2C9,2C19,3A4). According to the results of in vivo studies, the following drugs are not expected to interact significantly with olanzapine: tricyclic antidepressants (mainly metabolized with the participation of the CYP2D6 isoenzyme), warfarin (CYP2C19), theophylline (CYP1A2) and diazepam (CYP3A4 and CYP2C19).

Olanzapine did not interact with lithium and biperiden.

Monitoring of the valproate concentration in blood plasma did not reveal the need to adjust the dose of valproate after starting its use with olanzapine.

General activity of the central nervous system (CNS)

Caution should be exercised when using olanzapine in patients who consume alcohol or receive medications that cause CNS depression.

Concomitant use of olanzapine with Antiparkinsonian medications in patients with Parkinson’s disease and dementia is not recommended.

QTc Interval

Caution should be exercised when olanzapine is co-administered with medications that may prolong the QTc interval.

How to take, course of use and dosage

Olanzapine tablets, dispersed in the oral cavity, quickly dissolve under the influence of saliva and are easily swallowed.

It is difficult to remove the tablet from the mouth undissolved. Take a tablet from the blister should be dry hands. Due to its fragility, the tablet should be taken immediately after removal from the blister. In addition, just before taking the tablet, you can dissolve it in a glass of water.

Remove the tablet as follows:

1. Bend the blister along the fault line.

2. Open the blister by gently pulling on the edge of the foil.

3. Carefully remove the tablet.

4. Then the tablet should be immediately placed on the tongue.

Olanzapine can be taken regardless of the time of food intake, since food does not affect the absorption of olanzapine.

Olanzapine tablets dispersed in the oral cavity are bioequivalent to olanzapine tablets and have a similar rate and degree of absorption. Olanzapine tablets dispersed in the oral cavity are used in the same amount and with the same frequency as olanzapine tablets. Olanzapine tablets dispersed in the oral cavity can be used instead of olanzapine tablets.

Adult

Schizophrenia: The recommended starting dose of olanzapine is 10 mg once a day.

Manic episode: The initial dose is 15 mg once a day for monotherapy or 10 mg per day for combination therapy (with lithium or valproate).

Prevention of recurrent bipolar disorder: The recommended starting dose of olanzapine is 10 mg once a day. Patients who have received olanzapine for the treatment of a manic episode should continue therapy at the same dose to prevent relapse. If a new manic, mixed, or depressive episode develops, olanzapine therapy should be continued (with dose adjustments if necessary) with additional therapy to treat the symptoms of a mood disorder as clinically indicated.

In the treatment of schizophrenia, manic episode and prevention of relapse of bipolar disorder, the daily dose can be adjusted in the range from 5 mg to 20 mg per day. An increase in the initial dose should be made only after a proper clinical examination. Dose increases should be made at intervals of at least 24 hours. Olanzapine can be prescribed regardless of the time of food intake, since food intake does not affect the absorption of the drug.

When stopping treatment with olanzapine, the dose of the drug should be reduced gradually.

Special patient groups

Elderly patients

The minimum starting dose (5 mg per day) is usually not prescribed, but its use should be considered in patients over 65 years of age, if the clinical condition of the particular patient requires it.

Patients with renal and / or hepatic insufficiency

Patients with renal and / or hepatic insufficiency should start treatment with a minimum dose (5 mg per day). In patients with moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the initial dose should be 5 mg, and the dose should be increased with caution if necessary.

Smoking

The initial dose and dose range generally need not be changed depending on whether the patient smokes or not. Olanzapine metabolism can be accelerated by smoking. It is recommended to conduct clinical monitoring, if necessary, the dose of olanzapine can be increased.

In the presence of more than one of the factors that can lead to a slowdown in metabolism (female patients, the elderly, non-smokers) a reduction in the initial dose may be recommended. Increasing the dose in such patients, if indicated, should be carried out conservatively.

Overdose

Symptoms: very common (≥ 10%) symptoms of olanzapine overdose were tachycardia, psychomotor agitation/aggressiveness, dysarthria, various extrapyramidal disorders and consciousness disorders of varying severity (from sedation to coma).

Other clinically significant effects of olanzapine overdose included delirium, seizures, neuroleptic malignant syndrome (NMS), respiratory depression, aspiration, increased and decreased blood pressure, and cardiac arrhythmias ( The minimum dose for an acute overdose with a fatal outcome was 450 mg, the maximum dose for an overdose with a favorable outcome (survival) was 2 g of olanzapine.

Treatment: There is no specific antidote for olanzapine. It is not recommended to provoke vomiting. Standard procedures for overdose (gastric lavage, taking activated charcoal) are shown. Co-use of activated charcoal and olanzapine showed a reduction in oral bioavailability of olanzapine by up to 50-60%.

Symptomatic treatment and monitoring of vital organ functions should be provided, depending on the clinical picture, including treatment of arterial hypotension and vascular collapse, and maintenance of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetics that are beta-adrenergic agonists, as stimulation of these receptors may worsen hypotension. It is necessary to monitor cardiovascular parameters to detect possible arrhythmias. Careful monitoring of the patient’s condition is necessary until complete recovery.

Description

Round slightly biconvex tablets of yellow color. The presence of minor individual inclusions and marbling is allowed.

Special instructions

Contraindicated in persons under 18 years of age.

Elderly patients

The minimum starting dose (5 mg per day) is usually not prescribed, but its use should be considered in patients over 65 years of age, if the clinical condition of the particular patient requires it.

Patients with renal and / or hepatic insufficiency

Patients with renal and / or hepatic insufficiency should start treatment with a minimum dose (5 mg per day). In patients with moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the initial dose should be 5 mg, and the dose should be increased with caution if necessary.

Clinical improvement in antipsychotic treatment may occur within a few days to several weeks. Careful monitoring of patients during this period is required.

Psychosis with dementia and / or behavioral disorders

Olanzapine is not indicated for the treatment of psychosis with dementia and / or behavioral disorders due to the increased mortality rate and risk of developing cerebral circulatory disorders in these patients. In placebo-controlled trials (6-12 weeks), elderly patients (mean age 78 years) with dementia-related psychosis and/or behavioral disorders experienced a twofold increase in deaths in the olanzapine group compared to the placebo group (3.5% and 1.5%, respectively). The higher mortality rate is not associated with the olanzapine dose (average dose 4.4 mg) or with the duration of treatment.Risk factors that may affect the predisposition of this group of patients to higher mortality with olanzapine treatment include age > 65 years, dysphagia, sedation, malnutrition and dehydration, the presence of lung pathology (for example, pneumonia with or without aspiration) or combined use with benzodiazepines. However, the death rate was higher in patients treated with olanzapine compared to patients treated with placebo, regardless of these risk factors.

In the same clinical trials, cerebrovascular adverse events (for example, stroke, transient ischemic attack), including cases with a fatal outcome, were noted. In placebo-controlled studies, there was a three-fold higher incidence of cerebrovascular adverse events in patients in the olanzapine group compared to the placebo group (1.3% vs. 0.4%, respectively). All patients with cerebrovascular disorders treated with olanzapine and placebo had prior risk factors for developing cerebrovascular adverse events. Age > 75 years and vascular or mixed dementia were identified as risk factors for developing cerebrovascular adverse events during olanzapine treatment. In these studies, the effectiveness of olanzapine has not been established.

Parkinson’s disease

Olanzapine is not recommended for the treatment of psychoses induced by dopamine receptor agonists in Parkinson’s disease.

In clinical trials, Parkinson’s disease symptoms and hallucinations were very frequent and more frequent than in the placebo group, and the effectiveness in treating psychotic symptoms with olanzapine did not exceed placebo. In these clinical trials, patients initially had to achieve stabilization on the minimum effective dose of Parkinson’s disease medications (dopamine agonists) and continue taking them at the same dose throughout the study. The initial dose of olanzapine was 2.5 mg per day and could be increased to a maximum of 15 mg per day by the decision of the researcher.

Neuroleptic malignant syndrome (NMS)

Neuroleptic malignant syndrome is a potentially life-threatening condition that occurs with the use of neuroleptics. Rare cases of NMS have also been reported with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic disorders (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include increased CPK activity, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of NMS or a significant unexplained increase in body temperature without other symptoms of NMS require discontinuation of all neuroleptics, including olanzapine.

Hyperglycemia and diabetes mellitus

Infrequently, there were cases of hyperglycemia and / or development or decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis and diabetic coma, including with a fatal outcome. In some cases, there was an increase in body weight, which could serve as a predisposing factor. Careful clinical monitoring of patients with diabetes mellitus and patients with risk factors for diabetes mellitus is recommended in accordance with the following guidelines: measurement of the initial blood glucose concentration,12 weeks after the start of olanzapine use, and thereafter annually. Patients taking antipsychotic medications, including olanzapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, weakness). Patients with diabetes mellitus or risk factors for diabetes mellitus need regular monitoring of blood glucose concentrations. Regular weight monitoring should be performed: before starting treatment,4,8, and 12 weeks after starting olanzapine, and every 3 months thereafter.

Changing the lipid profile

In placebo-controlled studies, patients treated with olanzapine experienced undesirable changes in the lipid spectrum. Changes in the lipid profile should be adjusted according to clinical necessity, especially in patients with dyslipidemia and in patients with risk factors for developing lipid metabolism disorders. Patients taking antipsychotic medications, including olanzapine, should have their lipid profile checked regularly as recommended: before starting treatment,12 weeks after starting olanzapine, and every 5 years thereafter.

Anticholinergic activity

Although olanzapine has shown anticholinergic activity in in vitro studies, the use of olanzapine in clinical trials has shown a low incidence of associated complications. However, since there is limited clinical experience with olanzapine in patients with concomitant diseases, caution should be exercised when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic intestinal obstruction, and similar conditions.

Often, especially in the early stages of therapy, there was a transient asymptomatic increase in the activity of “hepatic” aminotransferases (ACT and ALT). Special care should be taken when increasing the activity of ACT and / or AJIT in the blood serum in patients with symptoms of impaired liver function, with previously diagnosed conditions associated with limited liver function reserve, or in patients receiving treatment with potentially hepatotoxic drugs. When diagnosing hepatitis (including hepatocellular, cholestatic or mixed), the use of olanzapine should be discontinued.

Neutropenia

Olanzapine should be used with caution in patients with a low number of white blood cells and/or neutrophils in the blood; in patients receiving drugs that may cause neutropenia; in patients with a history of drug-induced bone marrow suppression; in patients with bone marrow suppression due to concomitant disease, radiation or chemotherapy; and in patients with eosinophilia or myeloproliferative diseases. Neutropenia has often been reported with the concomitant use of olanzapine and valproate.

Discontinuation of therapy

In rare cases (≥ 0.01% and

QT Interval

In clinical studies, clinically significant prolongation of the QTc interval (Friederik’s QTcF correction > 500 ms at any time after the start of treatment at baseline QTcF > However, caution should be exercised when prescribing olanzapine in combination with drugs that increase the QTc interval, especially in elderly patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia and hypomagnesemia.

Thromboembolism

Infrequently (3 0.1% and No causal relationship has been established between olanzapine and venous thromboembolism. However, given that patients with schizophrenia often have acquired risk factors for developing thromboembolism, it is necessary to identify all possible risk factors for this complication, including patient immobilization, and take the necessary preventive measures.

General activity in relation to the central nervous system

Due to the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other centrally acting drugs and alcohol. Since olanzapine can exhibit dopamine receptor antagonism in vitro, it can be an antagonist of the effects of direct and indirect dopamine receptor agonists.

Convulsions

Olanzapine should be used with caution in patients with a history of seizures or who are exposed to factors that reduce the threshold of seizure readiness. Seizures were uncommon in patients taking olanzapine, and most of these cases reported a history of seizures or risk factors for seizures.

Tardive dyskinesia

In comparative studies lasting up to one year, treatment with olanzapine was significantly less likely to be accompanied by the development of dyskinesia requiring drug correction. However, an increased risk of tardive dyskinesia should be considered with long-term antipsychotic therapy. If signs of tardive dyskinesia develop, it is recommended to reduce the dose or cancel olanzapine. Symptoms of tardive dyskinesia may increase or manifest after discontinuation of the drug.

Postural hypotension

Postural hypotension has been infrequently observed in olanzapine clinical trials in elderly patients. It is recommended to periodically measure blood pressure in patients over 65 years of age.

Sudden death from cardiovascular failure

According to the results of post-marketing observations of olanzapine, a case of sudden death was recorded.In a retrospective observational study, the risk of presumed sudden death from cardiovascular failure in patients treated with olanzapine was approximately twice as high as in patients who did not take antipsychotics. In this study, the risk associated with olanzapine was comparable to that associated with atypical antipsychotics included in the pooled analysis.

Olanzapine use in children

Olanzapine is not recommended for use in children and adolescents. Various adverse reactions, including weight gain, lipid metabolism disorders, and hyperprolactinemia, have been reported in adolescents aged 13-17 years.

Special information on excipients

Zalasta ® Cu-tab® contains aspartame, which is a source of phenylalanine. The drug may not be safe for people with phenylketonuria.

Studies of the effect of the drug on the ability to drive vehicles and mechanisms have not been conducted. Patients taking olanzapine should exercise caution when driving vehicles and mechanisms, as olanzapine can cause drowsiness and dizziness.

Form of production

Tablets dispersed in the oral cavity,5 mg,7.5 mg,10 mg,15 mg,20 mg.

7 tablets in a blister made of a combined OPA/Al / PVC material-aluminum foil.

Storage conditions

Storage conditions

At a temperature not exceeding 25 ° C, in the original packaging.

Keep out of reach of children.

Expiration date

Shelf

life is 5 years.

Do not use the drug after the expiration date.

Active ingredient

Olanzapine

Conditions of release from pharmacies

By prescription

Dosage form

tablets for resorption

Purpose

For adults as directed by your doctor

Indications

Schizophrenia, Manic-depressive psychosis