Instruction for use: Zalasta Q-tab

Dosage form: tablets

Active substance: Olanzapine*

ATX

N05AH03 Olanzapine

Pharmacological group:

Neuroleptics

The nosological classification (ICD-10)

F20 Schizophrenia: Schizophrenic conditions; Exacerbation of schizophrenia; Schizophrenia; Chronic schizophrenia; Dementia praecox; Bleuler's disease; Psychotic discordant; Dementia early; The febrile form of schizophrenia; Chronic schizophrenic disorder; Psychosis of the schizophrenic type; Acute form of schizophrenia; Acute schizophrenic disorder; Cerebral Organic Insufficiency in Schizophrenia; Acute attack of schizophrenia; Schizophrenic psychosis; Acute schizophrenia; Sluggish schizophrenia; Sluggish schizophrenia with apathoabulic disorders; Acute stage of schizophrenia with excitation

F30 Manic episode: Manic-depressive disorder; Manic agitation; Manic state; Manic conditions; A manic condition; Manic syndrome; Acute manic syndrome

F31 Bipolar affective disorder: Mood disorders bipolar; Affective bipolar psychosis; Manic-melancholic psychosis; Intermittent psychosis; Circular psychosis; Cyclophrenia; Bipolar disorders; Bipolar psychosis; Affective insanity; Manic-depressive syndrome; Psycho Manic-Depressive; Depressive episode of bipolar disorder

F31.1 Bipolar affective disorder, current episode of mania without psychotic symptoms: Mania in bipolar disorders

F31.2 Bipolar affective disorder, current episode of mania with psychotic symptoms: Manic episode of bipolar disorder; Mania in bipolar disorders

F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenodepressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome with psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous Depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F33 Recurrent depressive disorder: Major depressive disorder; Secondary depression; Double depression; Depressive pseudodement; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive syndrome; Depressed masks; Depression; Depression is smiling; Involutional depression; Involutional depression; Masked Depression; Melancholic Attack; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Exogenous Depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

Composition

Tablets, dispersible in the oral cavity 1 tab.

active substance:

olanzapine 5/10 mg

auxiliary substances: mannitol; ICC; crospovidone; hypromellose low-substituted LH-21; aspartame; calcium silicate; magnesium stearate

Description of dosage form

Round, slightly biconcave tablets of yellow color. Insignificant individual inclusions and marbling are allowed.

Pharmachologic effect

Pharmacological action - antipsychotic, neuroleptic.

Pharmacodynamics

Olanzapine is an antipsychotic, antimanic and mood-stabilizing agent with a broad pharmacological profile due to its effect on several receptor systems.

In pre-clinical studies, affinity was established for various receptors (Ki <100 nmol / L): 5-HT2A / 2C-, 5-HT3-, 5-HT6-serotonin, D1-, D2-, D3-, D4-, D5-dopamine , m1-5-muscarinic cholinergic receptors, α1-adreno-and H1-histamine receptors. In animal studies evaluating the effect of olanzapine on behavior, the latter exhibited antagonism with respect to serotonin, dopamine and m-cholinergic receptors, consistent with the receptor binding profile.

Under in vitro and in vivo conditions, olanzapine has a more pronounced affinity and activity towards 5-HT2-serotonin than to D2-dopamine receptors. According to electrophysiological studies, olanzapine selectively decreases the activity of mesolimbic (A10) dopaminergic neurons and at the same time has an insignificant effect on the striatal neural pathways (A9) involved in the regulation of motor (motor) functions. Olanzapine reduces the conditioned reflex avoidance (in the test for antipsychotic activity) at doses lower than those that cause catalepsy (an effect indicative of motor (motor) undesirable reactions).

The use of olanzapine for 3 weeks in patients with a manic or mixed episode in bipolar disorder was more effective in reducing the manifestation of manic manifestations compared to placebo and the sodium valproate and valproic acid 1: 1 ratio. Olanzapine also showed efficacy comparable to haloperidol in terms of the proportion of patients who achieved symptomatic remission with respect to mania and depression at the 6th and 12th weeks of use. The use of olanzapine at a dose of 10 mg as part of combination therapy in combination with lithium or valproic acid for at least 2 weeks resulted in a greater decrease in the manifestation of mania than monotherapy with lithium or valproic acid after 6 weeks of application of the latter.

In a 12-month clinical trial of relapse prevention in patients with a manic episode who achieved remission with olanzapine and subsequently randomized to olanzapine or placebo, a statistically significant superiority of olanzapine over placebo in achieving a primary endpoint, a recurrence of bipolar disorder, was shown. It has also been shown that olanzapine is superior to placebo in the prevention of recurrence of both manic and depressive episodes.

In another 12-month clinical study of relapse prevention in patients with a manic episode who achieved remission with olanzapine in combination with lithium and subsequently randomized to olanzapine or lithium monotherapy, olanzapine was statistically not inferior in effectiveness to lithium with respect to the achievement of the primary endpoint, recurrence of bipolar disorder (olanzapine group - 30%, lithium drug group - 38.23%, p = 0.055).

In an 18-month clinical trial of combination therapy with olanzapine in combination with a normotimic drug (lithium or valproic acid) in patients with a manic or mixed episode, no statistically significant superiority of long-term combination therapy over lithium or valproic acid monotherapy with respect to the onset of recurrent bipolar disorder, determined in accordance with diagnostic (syndromic) criteria.

Use in children

The experience with olanzapine in adolescents (aged 13-17) is limited to studies of its short-term efficacy in schizophrenia (for 6 weeks) and mania associated with type 1 bipolar disorder (within 3 weeks), in less than 200 adolescents . Olanzapine was used in a flexible dosing regimen (from 2.5 to 20 mg / day). On the background of olanzapine therapy, adolescents had a more pronounced increase in body weight compared to adults. Changes in serum concentrations of total XC, Xc-LDL, triglycerides and prolactin (see "Specific guidance" and "Side effects") in adolescents were more pronounced than in adults. There is no information on the stability of the effect of olanzapine, only limited information on long-term safety (see "Special instructions" and "Side effects"). Information on long-term safety is limited mainly to open, uncontrolled research.

Pharmacokinetics

The preparation Zalasta® Q-tab®, tablets dispersible in the oral cavity, bioequivalent to olanzapine tablets and have a similar speed and degree of absorption. Zalasta® Q-tab® preparation, tablets dispersible in the oral cavity, are used in the same amount and at the same frequency as the Zalast® preparation, tablets. Tablets dispersible in the oral cavity may be used in place of olanzapine in a tablet dosage form.

Suction. After ingestion, olanzapine is well absorbed, its Cmax in plasma is reached after 5-8 hours. Food intake does not affect absorption. Absolute bioavailability when taken orally compared with IV in the introduction was not determined.

Distribution. The association of olanzapine with plasma proteins is 93% (in the concentration range 7-1000 ng / ml). Olanzapine predominantly binds to albumin and to the α1-acid glycoprotein.

Metabolism. Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which does not penetrate the GEB. Isozymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl- and 2-hydroxymethylmetabolites; in animal studies, both metabolites showed significantly less pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to the initial compound - olanzapine.

Excretion. After oral administration, the average terminal T1 / 2 of olanzapine in healthy volunteers depends on age and sex.

Pharmacokinetics in selected patient groups

Elderly age. In healthy elderly volunteers (65 years and older), compared with those of younger age, the mean T1 / 2 (51.8 vs. 33.8 hours) increased and the clearance decreased (17.5 vs 18.2 l / h). The pharmacokinetic variability in elderly volunteers corresponded to a range of younger individuals. In 44 patients with schizophrenia older than 65 years, the use of olanzapine in doses of 5-20 mg / day did not lead to differences in the profile of adverse events.

Floor. The average T1 / 2 in women compared with men is slightly increased (36.7 vs. 32.3 hours), and the clearance is lower (18.9 vs 27.3 l / h). However, the safety profile of olanzapine (in doses of 5-20 mg / day) in female patients (n = 467) is comparable to that of male patients (n = 869).

Renal failure. In patients with renal insufficiency (Cl creatinine <10 ml / min) compared with healthy volunteers, significant differences in mean T1 / 2 (37.7 vs. 32.4 h) or clearance (21.2 vs. 25.0 l / h) was not noted. A study of the material balance showed that approximately 57% of radiolabeled olanzapine is found in urine, mainly in the form of metabolites.

Smoking. Smokers with mild hepatic insufficiency (Class A Child-Pugh classification) increased mean T1 / 2 (39.3 h) and decreased clearance (18 l / h) similar to non-smoking healthy individuals (48.8 h and 14.1 l / h, respectively).

In non-smoking patients, compared with smokers (men and women), the mean T1 / 2 increased (38.6 vs. 30.4 hours), and the clearance decreased (18.6 vs 27.7 liters / hour). The plasma clearance of olanzapine is lower in elderly people compared to younger men, compared to women and non-smokers compared to smokers. However, the dependence of clearance and T1 / 2 olanzapine on age, sex and smoking in comparison with the general interindividual variability is small.

Race affiliation. In a study involving individuals of European, Japanese and Chinese origin, no differences in the pharmacokinetics of olanzapine have been established.

Children. (adolescents 13-17 years of age). The pharmacokinetics in adolescents and in adult patients are similar. According to clinical studies, the average exposure of olanzapine in adolescents is approximately 27% higher than in adults. Demographic differences between adults and adolescents include lower average body weight and lower prevalence of smoking among adolescents. These factors probably lead to an increased average exposure, noted in adolescents.

Indications of Zalast Q-tab

Olanzapine is indicated in adults for the treatment of the following diseases and conditions:

schizophrenia;

maintenance of clinical improvement within the framework of long-term therapy of patients with schizophrenia responding to initial treatment;

a manic episode of moderate to severe severity;

patients with bipolar disorder (prevention of recurrence), in whom olanzapine was effective in treating a manic episode (see Pharmacodynamics);

therapeutically-resistant depression in adult patients (major depressive episodes with a history of ineffective use of two antidepressants, dose and duration of treatment appropriate for this episode) in combination with fluoxetine (not shown in monotherapy);

a depressive episode in the structure of bipolar disorder - in combination with fluoxetine (not shown in monotherapy).

Contraindications

hypersensitivity to any of the components of the drug;

the risk of developing an angle-closure glaucoma;

phenylketonuria;

children's age till 18 years.

Application in pregnancy and lactation

Adequate and strictly controlled studies in pregnant women were not conducted. Patients should be warned about the need to notify the attending physician about the onset of pregnancy or the desire to become pregnant during treatment with olanzapine. However, due to limited experience with human use, olanzapine should be used during pregnancy if the potential benefit to the mother exceeds the potential risk to the fetus.

Newborns whose mothers took olanzapine during the third trimester of pregnancy are at risk of developing unwanted reactions, including extrapyramidal symptoms and / or withdrawal symptoms, which may vary in severity and duration after delivery. There was reported agitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome and eating disorders. In this regard, newborns should be closely monitored.

In a study in lactating healthy women, it was found that olanzapine penetrates into breast milk. The average dose received by the child (mg / kg) in the equilibrium state was 1.8% of the mother's olanzapine dose (mg / kg). Patients who are taking olanzapine are advised not to breast-feed.

Fertility. There is no information on the effect on fertility.

Side effects

Security Profile Summary

Adults. The most frequent (noted in ≥1% of patients) adverse reactions due to the use of olanzapine in clinical studies were drowsiness, weight gain, eosinophilia, increased prolactin concentration, Xc, glucose and triglycerides in blood plasma (see "Special instructions"), glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see "Special instructions"), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic hepatic activity (see "Special instructions"), skin rashes, asthenia, fatigue, fever, arthralgia, increased activity of AP in the blood plasma, increased activity of GGT in the blood plasma, hyperuricemia, increased activity of CK in the blood plasma and edema.

The undesirable reactions and laboratory data noted in clinical studies and spontaneous reports are listed below. In each category, unwanted reactions are in order of decreasing severity. The following classification is used: very often (≥1 / 10); often (≥1 / 100 to <1/10); infrequently (≥1 / 1000 to <1/100); rarely (≥1 / 10000 to <1/1000); very rarely (<1/10000); unknown (can not be determined based on available data).

On the part of the blood and lymphatic system: often - eosinophilia, leukopenia10, neutropenia10; rarely - thrombocytopenia11.

From the immune system: infrequently - hypersensitivity11.

From the side of metabolism and nutrition: very often - weight gain1; often - an increase in serum concentration of Xc2.3, an increase in glucose concentration4, an increase in serum triglyceride concentration of 2.5, glucosuria, an increase in appetite; infrequently, the development or aggravation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, including several lethal cases11 (see "Special instructions"); rarely - hypothermia12.

From the nervous system: very often - drowsiness; often - dizziness, akathisia6, parkinsonism6, dyskinesia6; infrequently - convulsions in patients with seizures in the history or in the presence of risk factors for seizures11, dystonia (including oculogyric crisis) 11, tardive dyskinesia11, amnesia9, dysarthria; rarely - malignant neuroleptic syndrome (CNS) (see "Special instructions") 12, withdrawal symptoms 7, 12.

From the heart: infrequent bradycardia, prolongation of the QTc interval (see "Special instructions"); rarely - ventricular tachycardia / ventricular fibrillation, sudden death (see "Special instructions") 11.

From the side of the vessels: very often - orthostatic hypotension10; infrequently - thromboembolism (including pulmonary embolism and deep vein thrombosis) (see "Special instructions").

From the respiratory system, chest and mediastinum: infrequently - epistaxis9.

On the part of the digestive system: often - light, transient anticholinergic effects, including constipation and dryness of the oral mucosa; infrequently - bloating; rarely - pancreatitis.

On the part of the liver and bile ducts: often - a transient asymptomatic increase in serum activity of hepatic aminotransferases (ALT, AST), especially in the early treatment period (see "Special instructions"); rarely - hepatitis (including hepatic-cell, cholestatic and mixed liver damage) 11.

From the skin and subcutaneous tissues: often - skin rash; infrequently - photosensitivity reaction; alopecia; unknown - drug-induced skin reaction accompanied by eosinophilia and systemic manifestations (DRESS-syndrome).

From the musculoskeletal system and connective tissue: often - arthralgia9; rarely rhabdomyolysis.

From the side of the kidneys and urinary tract: infrequently - incontinence, urinary retention, delay in urination 11.

Pregnancy, postpartum and perinatal conditions: unknown - withdrawal syndrome in newborns (see "Application in pregnancy and lactation").

From the genitals and the breast: often - erectile dysfunction, decreased libido in men and women; infrequently - amenorrhea, breast augmentation, galactorrhea in women, gynecomastia / breast augmentation in men; rarely - priapism.

General disorders and disorders at the injection site: often - asthenia, fatigue, edema, fever10.

Laboratory and instrumental data: very often - an increase in the concentration of prolactin in the blood plasma8; often - an increase in serum activity of APF10, an increase in serum activity of KFK11, an increase in serum GGT10 activity, hyperuricemia10; infrequently, an increase in the serum concentration of total bilirubin.

Long-term therapy (at least 48 weeks)

The proportion of patients who had undesirable clinically significant changes in body weight, glucose concentration, total XPS / LDL / HDL, or triglycerides increased over time. In adults who underwent a 9-12-month course of therapy, the rate of increase in mean glucose concentration in the blood decreased after 6 months.

Additional information about special patient groups

In clinical studies in elderly patients with dementia, olanzapine therapy compared with placebo resulted in an increased incidence of lethal outcomes and cerebrovascular unwanted reactions (see also "Specific guidance"). Very frequent undesirable reactions caused by the use of olanzapine in this group of patients were gait and fall disturbances. Often observed pneumonia, fever, lethargy, erythema, visual hallucinations and urinary incontinence.

In clinical studies in patients with drug (dopamine receptor agonists) psychosis due to Parkinson's disease, very often (more often than with placebo), the deterioration of parkinsonian symptoms and hallucinations was reported.

In one clinical study in patients with bipolar mania, combination therapy with valproic acid and olanzapine in 4.1% of cases led to neutropenia. A possible cause of neutropenia is a high plasma concentration of valproic acid. The use of olanzapine with lithium or valproic acid led to an increase in the frequency of development (≥10%) of tremor, dryness of the oral mucosa, increased appetite and weight gain. In addition, the disorder of speech was often reported. With combined therapy with olanzapine and lithium or a combination of sodium valproate and valproate in a ratio of 1: 1, an increase in body weight of ≥7% of the baseline body weight was observed in 17.4% of patients in a short course of treatment (up to 6 weeks). Long-term therapy with olanzapine (up to 12 months) in order to prevent relapse in patients with bipolar disorder led to an increase of ≥7% of the baseline in 39.9% of patients.

Children. Olanzapine is not indicated for the treatment of children and adolescents under the age of 18 years.

Despite the fact that clinical studies aimed at comparing adolescents with adult patients were not performed, the data obtained in studies in adolescents were compared with the results of studies in adult patients.

The following undesirable reactions noted in adolescents (aged 13-17 years), with a greater frequency compared with adult patients or unwanted reactions, revealed only in adolescents in the context of short-term clinical trials, are summarized below. Clinically significant weight gain (≥7%) is likely to occur more often in adolescents than in adult patients (with comparable exposures). The amount of weight gain and the proportion of adolescents with a clinically significant increase in body weight is higher with long-term therapy (at least 24 weeks) than with short-term therapy.

In each category, unwanted reactions are in order of decreasing severity. The following classification is used: very often (≥1 / 10); often (≥1 / 100 to <1/10).

From the side of metabolism and nutrition: very often - an increase in body weight, 13 an increase in serum triglyceride concentration, 14 an increase in appetite; often - an increase in serum concentration Xc15.

From the side of the nervous system: very often sedation (including hypersomnia, lethargy, drowsiness).

From the gastrointestinal tract: often - dryness of the oral mucosa.

From the liver and bile ducts: very often - increased serum activity of hepatic aminotransferases (ALT, AST, see "Special instructions").

Laboratory and instrumental data: very often a decrease in the serum concentration of total bilirubin, an increase in serum GGT activity, an increase in the plasma concentration of prolactin16.

1 Clinically significant weight gain was observed in all patient groups (regardless of baseline BMI). After a short course of therapy (median duration of 47 days), an increase in body weight ≥7% of the baseline was observed very often (22.2%), ≥15% frequently (4.2%) and ≥25% infrequently (0.8%) . In patients receiving long-term treatment (at least 48 weeks), an increase of ≥7, ≥15 and ≥25% was very frequent (64.4, 31.7 and 12.3%, respectively).

2 The average increase in serum lipid concentration of fasting lipids (total cholesterol, LDL, triglycerides) was more pronounced in patients without initial signs of lipid metabolism.

3 An increase in serum concentration of total XC from normal fasting values (<5.17 mmol / l) to elevated (≥6.2 mmol / l) was often observed. The change in the concentration of total fasting XC from the borderline indices (≥5.17 - <6.2 mmol / l) to elevated (≥6.2 mmol / l) was very frequent.

4 Fasting glucose was often increased from normal values (<5.56 mmol / l) to elevated (≥7 mmol / l). The change in fasting glucose from the borderline (≥ 5.56 - <7 mmol / l) to elevated (≥7 mmol / l) was very frequent.

5 An increase in serum fasting triglyceride concentrations from normal values (<1.69 mmol / l) to elevated (≥2.26 mmol / l) was often observed. The change in serum fasting triglyceride concentration from borderline indices (≥1.69 - <2.26 mmol / l) to elevated (≥2.26 mmol / l) was very frequent.

6 The incidence of parkinsonism and dystonia in patients taking olanzapine in clinical trials was quantitatively higher, but was not statistically significant from placebo. In patients taking olanzapine, parkinsonism, akathisia, dystonia were observed less often than in patients receiving the selected doses of haloperidol. Due to the lack of detailed information on the history of acute and late extrapyramidal motor disorders in patients, it can not at present be concluded that olanzapine is less likely to cause late dyskinesia and / or other late extrapyramidal syndromes.

7 With severe abolition of olanzapine, symptoms such as sweating, insomnia, tremors, anxiety, nausea and vomiting were observed.

8 In clinical studies of up to 12 weeks, the concentration of prolactin in the blood plasma exceeded HHG in approximately 30% of patients with normal baseline serum prolactin concentration. In most of these patients, the increase in serum prolactin concentration was mild and did not exceed more than 2 times the IGN.

9 An undesirable phenomenon identified in clinical studies in the integrated olanzapine database.

10 According to the values in clinical studies in the integrated olanzapine database.

11 An undesirable phenomenon detected during post-registration surveillance. The frequency was established using the olanzapine integrated database.

12 An undesirable phenomenon detected during post-registration surveillance. The frequency is set at the upper boundary of the 95% CI of the integrated olanzapine database.

13 After a short course of therapy (median duration of 22 days), an increase in body weight ≥ 7% of the initial value (kg) was very frequent (40.6%), ≥15% often (7.1%) and ≥25% infrequently (2 ,5%). At long-term treatment (at least 24 weeks), an increase of ≥7% was noted in 89.4% of cases, ≥15 - 55.3% and ≥25 - 29.1% of cases from the initial body weight.

14 An increase in serum fasting triglyceride concentrations from normal values (<1.016 mmol / l) to elevated (≥1.467 mmol / L) and a change in serum fasting triglyceride concentration from borderline values (≥1,016 - <1,467 mmol / l) to elevated (≥ 1.467 mmol / l) was very frequent.

15 An increase in serum concentration of total XC from normal fasting values (<4.39 mmol / l) to elevated (≥5.17 mmol / l) was often observed. The change in serum concentration of total fasting XC from the borderline values (≥4,39 - <5,17 mmol / l) to elevated (≥5,17 mmol / l) was very frequent.

16 Elevated plasma concentrations of prolactin were detected in 47.4% of adolescents.

Interaction

The study of drug interaction was conducted exclusively in adult patients.

Potential interactions affecting the pharmacokinetics of olanzapine

Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances capable of selectively inducing or inhibiting this isoenzyme may alter the pharmacokinetics of olanzapine.

Induction of the isoenzyme CYP1A2. Smoking and carbamazepine are able to induce olanzapine metabolism, which can lead to a decrease in serum concentration of olanzapine. There was an increase in the clearance of olanzapine from mild to moderate. Clinical results are limited, it is recommended to carry out clinical follow-up with an increase in dose as necessary (see "Method of administration and dose").

Inhibition of the isoenzyme CYP1A2. It was shown that fluvoxamine, a specific inhibitor of the isoenzyme CYP1A2, significantly inhibits the metabolism of olanzapine. The average increase in Cmax of olanzapine in blood plasma after application of fluvoxamine is 54% in nonsmoking women and 77% in male smokers. The average increase in AUC was 52% and 108%, respectively. Patients using fluvoxamine or other inhibitors of the CYP1A2 isoenzyme, such as ciprofloxacin, should be given a smaller dose of olanzapine. Patients receiving therapy with an inhibitor of the isoenzyme CYP1A2 should consider the possibility of reducing the dose of olanzapine.

Decreased bioavailability

Activated charcoal reduces bioavailability of olanzapine ingested by 50-60%, so it should be used 2 hours before or after taking olanzapine.

Fluoxetine (inhibitor of the isoenzyme CYP2D6), single doses of antacids (aluminum, magnesium-containing) and cimetidine have no significant effect on the pharmacokinetics of olanzapine.

The ability of olanzapine to influence the pharmacokinetics of other drugs

Olanzapine can block the effects of direct and indirect dopamine receptor agonists.

Olanzapine does not inhibit the main isoenzymes of the cytochrome P450 system in vitro (eg CYP1A2, 2D6, 2C9, 2C19, 3A4). The results in in vivo studies confirm the absence of inhibition of the metabolism of the following pharmaceutical substances: a tricyclic antidepressant (representing predominantly the CYP2D6 pathway), warfarin (CYP2C19), theophylline (CYP1A2), and diazepam (CYP3A4 and CYP2C19).

Olanzapine does not interact with lithium and biperiden.

Values of plasma concentrations of valproic acid have shown that the simultaneous use of olanzapine does not require a correction of the dose of valproic acid.

General activity of the central nervous system

Caution should be exercised in patients who consume alcohol or who take medications that depress the central nervous system.

The simultaneous use of olanzapine with anti-Parkinsonian drugs in patients with Parkinson's disease and dementia is not recommended (see "Special instructions").

QTc Interval

Caution should be exercised while using olanzapine with medications that extend the QTc interval (see "Special instructions").

Dosing and Administration

Inside, keep in the mouth.

The preparation Zalasta® Q-tab®, tablets dispersible in the oral cavity, dissolves quickly in the oral cavity under the action of saliva, after which it is easily swallowed. Because the tablets are fragile, they should be taken immediately after removal from the blister. Alternatively, just before use, the tablet can be dissolved in a full glass of water.

Procedure for extracting the tablet from the package

1. Take the blister, bend along the fault line.

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

3. Remove the tablet.

4. Immediately put it on the tongue.

Zalasta® Q-tab® preparation, tablets dispersible in the oral cavity, bioequivalent to Zalast® preparation, tablets. Zalast® Q-tab®, tablets dispersible in the oral cavity, is used in the same amount and at the same frequency as the Zalast® preparation, tablets. Tablets dispersible in the oral cavity may be used in place of olanzapine in a tablet dosage form.

Olanzapine may be taken regardless of the time of ingestion, since eating does not affect the absorption of the drug. If you cancel olanzapine dose should be reduced gradually.

Adults

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

Manic or mixed episodes of bipolar affective disorder. The initial dose is 15 mg once a day with monotherapy or 10 mg / day as part of a combination therapy (see Pharmacodynamics).

Prevention of recurrence of bipolar disorder. The recommended initial dose of olanzapine is 10 mg once a day. Patients receiving olanzapine to treat a manic episode should continue therapy at the same dose to prevent relapse. If a new manic, mixed or depressive episode arises, olanzapine therapy should be continued (if necessary, correcting the dose), resorting to additional therapy to treat mood disorders in accordance with clinical need.

In the treatment of schizophrenia, a manic episode and the prevention of recurrence of bipolar disorder, it is then possible to select a dose individually (in the range of 5-20 mg once a day) depending on the clinical state of the patient. An increase in the dose above the recommended initial dose should be made only after evaluation of the clinical picture and at intervals of not less than 24 hours.

Therapeutically resistant depression. Olanzapine should be prescribed in combination with fluoxetine 1 time per day, in the evening, regardless of the time of ingestion. Typically, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, you can change the dose of both olanzapine and fluoxetine.

Antidepressant activity was confirmed with olanzapine in a dose of 6-12 mg and fluoxetine in a dose of 25-30 mg. When using the drug, it is necessary to regularly evaluate the need for continuing therapy.

Depressive episode in the structure of bipolar disorder. Olanzapine should be prescribed in combination with fluoxetine 1 time per day, in the evening, regardless of the time of ingestion. Typically, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, you can change the dose of both olanzapine and fluoxetine. Antidepressant activity was confirmed with olanzapine in a dose of 6-12 mg and fluoxetine in a dose of 25-30 mg. When using the drug, it is necessary to regularly evaluate the need for continuing therapy.

Special patient groups

Elderly age. A smaller initial dose (5 mg / day) is generally not shown, but it should be considered in patients 65 years of age or older if required by the clinical condition (see "Special instructions").

Renal and / or hepatic insufficiency. Such patients should consider the appointment of an initial dose of 5 mg. For hepatic insufficiency of the middle degree (cirrhosis, classes A or B according to the Child-Pugh classification), the initial dose should be 5 mg, which is increased with caution.

Smoking. In comparison with smokers, a change in the initial dose or range of doses for non-smokers is not required. It is recommended to conduct clinical monitoring, if necessary, consider the need to increase the dose (see "Interaction").

If there is more than one factor that can slow the metabolism (female, elderly, non-smokers), consider reducing the dose. If it is necessary to increase the dose, it should be performed with caution in such patients (see "Interaction" and "Pharmacokinetics").

Children. Olanzapine is not recommended for use in children and adolescents under the age of 18 due to limited safety and efficacy data. In short-term studies in adolescents, compared with adult patients, weight gain, lipid metabolism and serum prolactin concentrations were more pronounced (see "Special instructions", "Side effects", "Pharmacodynamics" and "Pharmacokinetics").

Overdose

Symptoms: very frequent (frequency ≥10%) symptoms with olanzapine overdose are tachycardia, agitation / aggressiveness, dysarthria, various extrapyramidal symptoms and a decrease in consciousness of varying severity (from sedation to coma).

Other clinically significant effects of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome (CNS), respiratory depression, aspiration, hypertension or hypotension, arrhythmias (<2% overdose), and cardiac arrest and respiratory arrest. The minimum dose for acute overdose with a lethal outcome was 450 mg, the maximum dose for an overdose with a favorable outcome (survival) is 2 g of olanzapine.

Treatment: there is no specific antidote for olanzapine. It is not recommended to provoke vomiting. Typical for overdose procedures, for example, gastric lavage, reception of activated charcoal are shown. The intake of activated charcoal with simultaneous ingestion of olanzapine showed a decrease in the bioavailability of olanzapine to 50-60%.

Symptomatic treatment is shown in accordance with the clinical condition and control of vital body functions, including correction of arterial hypotension, circulatory disorders and maintenance of respiratory function. Do not use epinephrine, dopamine and other adrenomimetics, which are β-adrenoreceptor agonists, since stimulation of these receptors can aggravate arterial hypotension. In order to identify possible arrhythmias, cardiovascular activity should be monitored. Careful medical supervision should be continued until the patient is fully recovered.

Special instructions

Improving the clinical state of the patient with antipsychotic therapy can take from several days to several weeks, this period requires careful monitoring of the patient.

Risk of suicide. Patients with schizophrenia and bipolar disorder of type 1 tend to commit suicide, and in connection with this, when pharmacotherapy is performed, careful monitoring of patients with a high risk of suicide is required. In order to reduce the risk of overdose, a minimum amount of the drug should be prescribed, sufficient to ensure the proper therapeutic effect.

Psychosis and (or) behavioral disorders due to dementia. Olanzapine is not recommended for use in patients with psychosis and / or behavioral disorders due to dementia, due to increased mortality and the risk of cerebrovascular complications. In placebo-controlled studies (6-12 weeks) in elderly patients (mean age 78 years) with psychosis and / or behavioral disorders due to dementia, there was a two-fold increase in the death rate in patients receiving olanzapine compared with patients from the placebo group (3.5 vs. 1.5%, respectively).

The increased frequency of deaths was independent of the dose of olanzapine (mean daily dose of 4.4 mg) and duration of treatment. Risk factors that may predispose to increased mortality among this patient population are age over 65 years, dysphagia, sedation, malnutrition and dehydration, lung diseases (eg pneumonia with or without aspiration) or simultaneous use of benzodiazepines.

However, the incidence of death in patients receiving olanzapine compared with those receiving placebo was higher regardless of these risk factors.

The results of the same clinical studies indicate cerebrovascular undesirable events (CVD) (for example, stroke, transient ischemic attack), including lethal outcomes.

There was a three-fold increase in the incidence of CVD in patients receiving olanzapine, compared with patients receiving placebo (1.3 vs. 0.4%, respectively). All patients who received olanzapine and placebo, who had cerebrovascular events, had risk factors. Risk factors for developing CVDs associated with olanzapine treatment are age over 75 years and vascular / mixed dementia. Olanzapine did not show efficacy in these studies.

Parkinson's disease. The use of olanzapine for the treatment of psychoses caused by the use of dopamine receptor agonists in Parkinson's disease is not recommended. In clinical studies, there was a marked deterioration in the course of parkinsonian symptoms and hallucinations (and with a higher frequency than in the placebo group) (see "Side effects"), the effectiveness of olanzapine for the relief of psychotic symptoms did not exceed placebo. The criteria for inclusion in these studies were the stable lowest effective dose of antiparkinsonian drugs (dopamine receptor agonist) and the use of the same antiparkinsonian drugs and doses throughout the study. The use of olanzapine was started from 2.5 mg / day with increasing dose at the investigator's discretion up to 15 mg / day.

ZNS. ZNS is a potentially lethal symptom complex due to antipsychotic drugs. Rare cases of ZNS have been recorded with olanzapine.

Clinical manifestations of CNS: hyperthermia, muscle rigidity, changes in mental status and vegetative disorders (unstable pulse or AD, tachycardia, increased sweating and arrhythmias).

Additional signs may include increased serum activity of CK, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms of the NSH or an unexplained high fever occurs without additional manifestations of the NSH, all antipsychotics, including olanzapine, should be discarded.

Hyperglycemia and diabetes mellitus. Infrequent reports of hyperglycemia and (or) development or decompensation of diabetes mellitus, sometimes accompanied by ketoacidosis or diabetic coma, including several lethal cases (see "Side effects") were rarely reported. In some cases, a previous increase in body weight was reported, which may serve as a predisposing factor. Clinical monitoring is recommended in accordance with the current guidelines for antipsychotic therapy, for example, measuring the baseline blood glucose concentration, 12 weeks after starting therapy with olanzapine and then annually. Patients receiving any antipsychotics, including olanzapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness), and patients with diabetes mellitus or risk factors for its development should be monitored regularly to reduce glycemic control. You should regularly check body weight, for example, before the beginning, 4, 8 and 12 weeks after the start of olanzapine and then quarterly.

Disorders of lipid metabolism. In placebo-controlled studies, patients who received olanzapine experienced undesirable changes in the lipid profile (see "Side effects"). It is necessary to correct lipid metabolism disorders especially in patients with dyslipidemia and patients with risk factors for lipid metabolism disorders. Patients receiving any antipsychotics, including olanzapine, should regularly monitor the lipid profile according to the current guidelines for antipsychotic therapy (for example, their baseline concentration after 12 weeks from the start of therapy and then every 5 years).

Anticholinergic activity. Despite the fact that olanzapine exhibited anticholinergic activity under in vitro conditions, olanzapine therapy was rarely accompanied by anticholinergic side effects during clinical trials. However, the clinical experience with olanzapine in patients with concomitant diseases is limited, so caution should be exercised when prescribing patients with prostatic hypertrophy, paralytic intestinal obstruction, and similar conditions.

Dysfunction of the liver. The use of olanzapine often, especially at early stages of therapy, was accompanied by a transient, asymptomatic increase in the activity of hepatic aminotransferases (ACT and ALT) in blood plasma. In patients with increased ALT activity and / or ACT in the blood plasma, symptoms of hepatic insufficiency, conditions that cause a decrease in the functional reserve of the liver, or use potentially hepatotoxic drugs, care should be taken and follow-up followed. In patients with hepatitis (including liver-cell, cholestatic and mixed liver damage), treatment with olanzapine should be discontinued.

Neutropenia. Olanzapine should be used with caution in patients with low white blood cell count and (or) neutrophils regardless of the cause, history of bone marrow suppression / toxicity, bone marrow depression due to concomitant disease, radiation or chemotherapy, as well as in patients with hypereosinophilic conditions or myeloproliferative disease. Neutropenia has often been reported with the simultaneous use of olanzapine and valproic acid (see "Side effects").

Termination of therapy. When olanzapine was abruptly abolished, excessive sweating, insomnia, tremor, anxiety, nausea, and vomiting were rare (≥0.01 and <0.1%).

QT interval. In clinical trials, a clinically significant prolongation of the QT interval (QT interval with a Frederick correction (QTcF) ≥500 ms with a baseline value of QTcF <500 ms) was infrequent (0.1-1%) in patients receiving olanzapine in the absence of significant differences with placebo on the incidence of adverse cardiac events. However, like other antipsychotics, caution should be exercised when prescribing olanzapine concomitantly with drugs that can prolong the QTc interval, especially in elderly patients, patients with congenital QT interval prolongation, CHF, myocardial hypertrophy, hypokalemia, or hypomagnesemia.

Thromboembolism. On the background of olanzapine therapy infrequently (≥0.1 and <1%), the development of VTE was reported. The causal relationship between the use of olanzapine and VTE is not established. However, given that patients with schizophrenia often have acquired risk factors for developing VTE, it is necessary to identify all possible risk factors for developing VTE (for example, patient immobilization), and to take the necessary preventive measures.

General activity of the central nervous system. Given the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine concomitantly with other central-action drugs and ethanol. Since olanzapine exhibits antagonism against dopamine receptors in vitro, it can block the effects of direct and indirect dopamine receptor agonists.

Convulsions. Olanzapine should be used with caution in patients with a history of seizures or exposed to factors that reduce the threshold of convulsive readiness. The treatment with olanzapine infrequently recorded seizures. In most cases, history of seizures or risk factors for seizures has been reported.

Late dyskinesia. In comparative studies lasting a year or less, olanzapine treatment was statistically significantly less associated with the development of iatrogenic dyskinesia. However, the risk of developing tardive dyskinesia increases with prolonged therapy with olanzapine. Therefore, if a patient who uses olanzapine has signs or symptoms of tardive dyskinesia, a dose reduction or olanzapine cancellation should be considered. After discontinuing therapy, these symptoms may temporarily worsen or even reappear.

Postural hypotension. In clinical trials of olanzapine, postural hypotension was rarely observed in elderly patients. Like other antipsychotics, patients over 65 years of age are advised to periodically monitor blood pressure.

Sudden cardiac death. According to the post-marketing experience of olanzapine, cases of sudden cardiac death were recorded. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients receiving olanzapine was approximately 2-fold higher than in patients who did not receive antipsychotics. The risk of olanzapine in the study was comparable to the risk of atypical antipsychotics included in the pooled analysis.

The use of olanzapine in children. Olanzapine is not recommended for use in children and adolescents. In studies in adolescents aged 13-17, various adverse reactions were noted, including weight gain, lipid metabolism and hyperprolactinemia (see "Side effects" and "Pharmacodynamics").

Phenylalanine. The drug Zalasta-Q-tab® contains aspartame, which serves as a source of phenylalanine. The drug may be unsafe for people suffering from phenylketonuria.

Influence on the ability to drive vehicles, mechanisms. Studies of the impact on the ability to drive vehicles and other mechanisms have not been carried out. Since olanzapine may cause drowsiness and dizziness, patients should be warned about the dangers of working with machinery, including vehicles.

Release form

Tablets dispersible in the oral cavity, 5 mg, 10 mg. By 7 tab. in a blister of the combined material OPA / Al / PVC-aluminum foil. At 4 bl. put in a pack of cardboard.

When packing the Russian company OOO Krka-Rus: 4 bl. put in a pack of cardboard.

Conditions of leave from pharmacies

On prescription.

Storage conditions of the drug Zalasta Q-tab

At a temperature of no higher than 25 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life of the drug Zalasta Q-tab

5 years.

Do not use after the expiry date printed on the package.