Instruction for use: Zyprexa Zydis

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

F22.0 Delusional Disorder: Delirium; Acute paranoid state; Othello Syndrome; Paranoid-hallucinatory state; Paranoid state; Paranoid delirium; paranoid psychosis; Paranoid delirium; Attack of delirium; The attack of polymorphic delirium; Psychotic disorder with a predominance of hallucinatory-paranoid symptoms and disorders of thinking; Anxious-delirious component; Anxiety and Paranoid Syndrome

F23 Acute and transient psychotic disorders: Psychogenic psychosis; Psychosis acute; Short-term psychotic disorder

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

F31.3 Bipolar affective disorder, current episode of mild or moderate depression

F31.6 Bipolar affective disorder, current episode of mixed character

F31.7 Bipolar affective disorder, current remission

R44.3 Hallucinations, unspecified: Hallucinatory conditions; Hallucinations; Acute hallucinatory state; Chronic hallucinatory conditions

Composition and release form

Tablets are dispersible 1 tab.

olanzapine 5 mg; 10 mg; 15 mg; 20 mg

auxiliary substances: gelatin, mannitol, aspartame, sodium methylparahydroxybenzoate, sodium propyl parahydroxybenzoate

in blisters for 7 pcs .; in the box 4 blisters.

Description of dosage form

Tablets are dispersible - yellow, round.

Characteristic

Antipsychotic drug (neuroleptic) with a wide pharmacological spectrum of influence on a number of receptor systems.

Pharmachologic effect

The pharmacological action is neuroleptic.

Pharmacodynamics

In preclinical studies, the affinity of olanzapine for serotonin 5-HT2A / 2C, 5-HT3, 5-HT6 was established; dopamine D1, D2, D3, D4, D5; muscarinic M1-5; α1-adrenoreceptors and histamine H1-receptors. In experimental animal studies, the presence of olanzapine antagonism against serotonin 5-HT, dopamine and cholinergic receptors has been identified. In in vitro and in vivo conditions, 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 an insignificant effect on striatal (A9) neural pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test characterizing antipsychotic activity) at doses lower than the doses causing catalepsy (a disorder reflecting a side effect on the motor function). Olanzapine increases the anti-anxiety effect during the anxiolytic test.

Olanzapine provides statistically significant reduction in both productive (including delirium, hallucinations) and negative disorders.

Pharmacokinetics

Dispersible olanzapine tablets and olanzapine coated tablets are bioequivalent and have a similar rate and degree of absorption. Dispersible olanzapine tablets are used in the same amount and at the same frequency as the coated tablets of olanzapine. Dispersible olanzapine tablets can be used instead of coated tablets of olanzapine.

Suction. After ingestion olanzapine is well absorbed from the digestive tract. Cmax in plasma is achieved after 5-8 hours. Absorption of olanzapine is not dependent on food intake. In studies with different doses ranging from 1 to 20 mg, it is shown that olanzapine concentrations in the plasma vary linearly and in proportion to the dose.

Distribution. At a plasma concentration of 7 to 1000 ng / ml, binding to plasma proteins is about 93%. Olanzapine is mainly associated with albumin and acid α1-glycoprotein.

Metabolism. Olanzapine is metabolized in the liver as a result of conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the BBB. Isozymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl- and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in experimental animal studies have significantly less pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to unchanged substance - olanzapine, which has the ability to penetrate the BBB.

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

Excretion. In healthy volunteers after oral administration, the mean T1 / 2 is 33 hours (21-54 hours for 5-95%), and the average clearance of olanzapine in plasma is 26 l / h (12-47 l / h for 5-95%). About 57% of radiolabelled olanzapine is excreted in urine and 30% with feces, mainly in the form of inactive metabolites.

Pharmacokinetics in special clinical cases

The variability of pharmacokinetic parameters of olanzapine depending on smoking, sex and age is presented in the table.

However, the degree of changes in T1 / 2 and clearance due to each of the factors listed in the table is significantly inferior to the degree of difference between these indicators among individuals.

There were no significant differences between the mean T1 / 2 values and the plasma clearance of olanzapine in persons with severe renal dysfunction, compared to those with normal renal function.

In smokers with minor violations of liver function, the clearance of olanzapine is lower than that of non-smokers without impaired liver function.

In a study involving persons of European, Japanese and Chinese origin, no differences in the pharmacokinetics of olanzapine associated with race were established.

Indication for the Zyprexa Zydis

treatment of exacerbations of schizophrenia;

supportive and long-term anti-relapse therapy for patients with schizophrenia and other psychotic disorders with marked productive (including delirium, hallucinations, automatisms) and / or negative symptoms (emotional flatness, decreased social activity, impoverishment of speech), symptomatology, as well as concomitant affective disorders);

treatment of acute manic or mixed episodes in bipolar affective disorder with / without psychotic manifestations and with / without rapid phase change (in the form of monotherapy or in combination with lithium or valproate);

prevention of recurrence in patients with bipolar disorder, in whom olanzapine was effective in treating the manic phase;

treatment of depressive conditions associated with bipolar disorder (in combination with fluoxetine).

Contraindications

Hypersensitivity to the components of the drug.

Application in pregnancy and lactation

There is a lack of clinical experience with olanzapine during pregnancy, so the prescription is only possible in cases where the expected benefit of therapy for the mother significantly exceeds the potential risk to the fetus.

Patients should be warned that in the event of the onset or planning of pregnancy during treatment with olanzapine, they need to inform their physician.

The study found that olanzapine is excreted in breast milk. The average dose (mg / kg) the child received when reaching the CSS in the mother was 1.8% of the maternal dose (mg / kg). If it is necessary to use the drug during lactation, it is recommended to stop breastfeeding.

Application for violations of the kidney kidney function. For patients with moderate hepatic insufficiency and severe severe renal failure, it is recommended that the initial dose of olanzapine be reduced to 5 mg / day.

Side effects

Very often (≥10%) - drowsiness, weight gain; 34% increased plasma prolactin concentration, which was weakly expressed and transient (the mean value of maximal concentrations of prolactin did not reach the upper limit of the norm (VGN) and statistically significantly differed from placebo). Clinical manifestations of hyperprolactinaemia associated with taking olanzapine (ie, gynecomastia, galactorrhea, and breast enlargement) have been rare. In most patients normalization of prolactin levels was observed without the abolition of olanzapine.

Often (≥1%, but <10%) - dizziness, asthenia, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dry mouth and constipation. In clinical studies (n = 107), in 1.9% of cases, triglyceride levels were observed in 2 times and more than those of VGN (there were no more than 3-fold excess of IGN).

Rarely: transient, asymptomatic increase in hepatic transaminases (AST and ALT) in blood serum.

In a few cases: an increase in plasma glucose levels up to ≥200 mg / dl (suspected diabetes mellitus), as well as ≥160 mg / dl but up to <200 mg / dL (suspected hyperglycemia) in patients with baseline glucose ≤140 mg / dl.

In some cases: asymptomatic eosinophilia.

Undesirable effects in special groups of patients

In patients with psychosis associated with dementia, very often (≥10%) there was a violation of gait and fall.

In elderly patients with psychosis associated with dementia, often (≥1%, but <10%) - incontinence and pneumonia.

In patients with psychosis induced by the drug (dopamine agonist) in Parkinson's disease, an increase in symptoms of parkinsonism, hallucinations, was noted very often (≥10%) and with a higher frequency than in the placebo group.

In patients with bipolar mania receiving olanzapine in combination with lithium or valproate, very often (≥10%) there was an increase in body weight, dry mouth, increased appetite, tremor; often (≥1%, but <10%) is a speech disorder.

The following are the main side effects and their frequency recorded during clinical trials and / or post-marketing period.

On the part of the body as a whole: ≥10% - weight gain1; ≥1%, but <10% is asthenia; ≥0,1%, but <1% - hypersensitivity to light2; <0.01% - allergic reaction3, 4; reaction to cancellation3, 5.

From the cardiovascular system: ≥0,1%, but <1% - bradycardia2; ≥1%, but <10% - orthostatic hypotension1; <0.01% - venous thromboembolism3.

From the digestive system: ≥1%, but <10% - constipation2; dry mouth2; increased appetite2; <0.01% - hepatitis; pancreatitis.

From the side of metabolism: <0.01% - diabetic coma3; diabetic ketoacidosis3, 4; hyperglycemia; hypertriglyceridemia; 3, 7; ≥1%, but <10% - peripheral edema1.

From the musculoskeletal system: <0.01% - rhabdomyolysis3.

From the side of the central nervous system: ≥1%, but <10% - akathisia2; dizziness; ≥0.01%, but <0.1% - convulsive seizures3; ≥10% - drowsiness.

Dermatological reactions: ≥0.01%, but <0.1% - rash3.

On the part of the reproductive system: <0.01% - priapism.

On the part of laboratory indicators: ≥1%, but <10% - increase in ALT1 and AST1 levels; isolated cases of elevated blood glucose levels from ≥160 mg / dl to <200 mg / dl (suspected hyperglycaemia) 1; single cases of elevated blood glucose levels up to ≥200 mg / dL (suspected diabetes mellitus) 1; single cases of increase in triglycerides level ≥2 times VGN1; ≥10% - an increase in the level of prolactin1.

On the part of the hematopoiesis system: in ≥1%, but <10% of cases - eosinophilia1; in ≥0.01%, but <0.1% of cases - leukopenia3; <0.01% - thrombocytopenia3.

1 score of indicators from the database of clinical trials

2 side effects recorded in the clinical trials database

3 side effects recorded spontaneously in post-marketing studies

4example: anaphylactic reaction, angioedema, itching or urticaria

5t.e. sweating, nausea, or vomiting

6 in the COSTART classification is referred to as diabetic acidosis

7c in the COSTART classification is referred to as hyperlipidemia.

Interaction

The metabolism of olanzapine can be altered by inhibitors or inducers of cytochrome P450 isoenzymes exhibiting specific activity against CYP1A2. The clearance of olanzapine increases in smoking patients and in patients taking carbamazepine (due to an increase in activity of CYP1A2). Known potential inhibitors of CYP1A2 can reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, therefore, when olanzapine is administered, the pharmacokinetics of drugs, mainly metabolized with the participation of CYP1A2 (such as theophylline), does not change.

In clinical studies, it has been shown that a single dose of olanzapine on the background of therapy with the following drugs was not accompanied by a suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (CYP2D6, CYP3A, CYP1A2), warfarin (CYP2C19), theophylline (CYP1A2) or diazepam (CYP3A4, CYP2C19). There were no signs of drug interaction when using olanzapine in combination with lithium or biperiden.

Against the background of a stable concentration of olanzapine, there was no change in the pharmacokinetics of ethanol. However, the administration of ethanol along with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, sedation.

Single doses of antacids containing aluminum or magnesium or cimetidine did not interfere with the bioavailability of olanzapine when ingested. Co-administration of activated carbon reduced the bioavailability of olanzapine when administered orally to 50-60%. Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in Cmax of olanzapine by an average of 16% and a decrease in the clearance of olanzapine by an average of 16%. The degree of influence of this factor is significantly inferior to the severity of individual differences in these indicators, so it is usually not recommended to change the dose of olanzapine when it is prescribed in combination with fluoxetine.

Fluvoxamine, an inhibitor of CYP1A2, reduces the clearance of olanzapine. The result is an average increase in Cmax of olanzapine with fluvoxamine administration of 54% in nonsmoking women and 77% in male smokers, an average increase in olanzapine AUC 52 and 108%, respectively. Small doses of olanzapine should be given to patients who are jointly receiving fluvoxamine.

In vitro studies using human liver microsomes showed that olanzapine slightly suppresses the process of formation of valproate glucuronide (the main pathway of valproate metabolism). Valproate also slightly affects the metabolism of olanzapine in vitro. Therefore, clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

In vitro, olanzapine exhibits antagonism against dopamine and, like other antipsychotics (neuroleptics), can theoretically suppress the action of levodopa and dopamine agonists.

Absorption of olanzapine is not dependent on food intake.

According to in vitro studies using human liver microsomes, olanzapine also demonstrated an extremely low potential in suppressing the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.

Dosing and Administration

Inside, regardless of food intake. Because of the fragility, the tablet should be taken immediately after removal from the blister. Dispersible tablets of olanzapine dissolve rapidly in saliva and are easily swallowed. In addition, immediately before taking the pill can be dissolved in a glass of water or other liquid (orange juice, apple juice, milk or coffee).

The daily dose must be selected individually, depending on the clinical condition of the patient.

For the treatment of schizophrenia and similar psychotic disorders, the recommended initial dose of olanzapine is 10 mg 1 time / day. Therapeutic doses of olanzapine range from 5 to 20 mg / day. An increase in the dose of a more standard daily dose of 10 mg is recommended only after an appropriate clinical examination of the patient.

For the treatment of acute mania with bipolar disorder, the recommended initial dose of olanzapine is 15 mg 1 time / day - as monotherapy or 10 mg 1 time / day - in combination with lithium or valproate. The therapeutic doses of olanzapine range from 5 to 20 mg per day. An increase in the dose above the standard daily dose of 15 mg is recommended only after an appropriate clinical examination of the patient. Increase the dose should be gradual, with intervals of at least 24 hours.

Supportive therapy for bipolar disorder: patients taking olanzapine for the treatment of acute mania should continue supporting therapy at the same dose. In patients in a state of remission, the recommended initial dose of olanzapine is 10 mg 1 time / day. In the future, the daily dose should be selected individually depending on the clinical state of the patient, ranging from 5 to 20 mg / day.

Olanzapine in combination with fluoxetine should be prescribed 1 time / day, regardless of food intake. Typically, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, changes in the dosage of both olanzapine and fluoxetine are allowed.

For elderly patients or patients with other clinical risk factors, including severe renal failure or moderate-level liver failure, it is recommended that the initial dose of olanzapine be reduced to 5 mg / day.

For patients with a combination of factors in which there may be a slowdown in the metabolism of olanzapine (female, elderly, non-smokers), a reduction in the initial dose of olanzapine may also be recommended.

The data of olanzapine studies in therapy in children and adolescents under the age of 18 are limited.

Overdose

Symptoms: very often (≥10%) - tachycardia, agitation / aggressiveness, articulation disorder, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma). Other clinically significant symptoms are convulsions, malignant neuroleptic syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of overdoses), 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 1.5 g.

Treatment: shows the standard procedures for overdose (gastric lavage, the appointment of activated charcoal). There is no specific antidote for olanzapine. It is not recommended to induce vomiting. Co-administration of activated charcoal showed a decrease in bioavailability of olanzapine upon ingestion of up to 50-60%.

It is shown that symptomatic therapy is performed in accordance with the clinical condition and control of the functions of vital organs, including treatment of arterial hypotension, circulatory disorders and maintenance of respiratory function. Do not use epinephrine, dopamine and other sympathomimetics, which are β-adrenoreceptor agonists, because stimulation of these receptors can aggravate arterial hypotension.

Special instructions

Malignant neuroleptic syndrome (ZNS) - a potentially fatal symptom complex - can develop in the treatment of any neuroleptic, including olanzapine. However, to date, there is no evidence to support a reliable association of olanzapine with the development of this condition. Clinical manifestations of CNS include a significant increase in body temperature, rigidity of the musculature, changes in mental status and autonomic disorders (unstable pulse or AD, tachycardia, cardiac arrhythmias, increased sweating). Additional signs may include increased levels of CK, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of malignant neuroleptic syndrome or a significant increase in body temperature without other symptoms of NSH require the removal of all antipsychotics, including olanzapine.

In comparative studies, treatment with olanzapine was significantly less often accompanied by the development of dyskinesia requiring medical correction than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia with prolonged therapy with neuroleptics should be considered. When developing signs of tardive dyskinesia, a dose adjustment of an antipsychotic is recommended. It should be borne in mind that when transferring to olanzapine, the symptoms of tardive dyskinesia may develop as a result of the simultaneous withdrawal of previous therapy.

In some cases, the use of olanzapine, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in the levels of hepatic transaminases (AST and ALT) in the blood serum. There were rare cases of hepatitis. Particular caution is needed when increasing levels of AST and / or ALT in the blood serum in patients with hepatic insufficiency, with limited functional reserve of the liver or in patients receiving potentially hepatotoxic drugs. In the case of increased levels of AST and / or ALT during treatment with olanzapine, careful monitoring of the patient and, if necessary, a reduction in dose are required.

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. As with some other antipsychotics, cases of hyperglycemia, diabetes mellitus, exacerbation of pre-existing diabetes, ketoacidosis and diabetic coma were very rare. There is no causal relationship between antipsychotic drugs and these conditions. A thorough clinical monitoring of patients with diabetes mellitus and patients with risk factors for developing diabetes is recommended.

Olanzapine should be used with caution in patients with epileptic seizures in the history or exposed to factors that reduce the threshold of convulsive readiness. In such patients, seizures were rare in the treatment with olanzapine.

Cerebrovascular unwanted reactions (for example, stroke, transient ischemic attack), including death, were noted in studies of olanzapine in elderly patients with psychosis associated with dementia. In placebo-controlled studies, a higher incidence of cerebrovascular adverse events was observed in patients in the olanzapine group than in the placebo group (1.3 vs. 0.4%, respectively).

All patients with cerebrovascular disorders had previous risk factors for developing cerebrovascular unwanted reactions (for example, the previously noted case of cerebrovascular unwanted reaction or transient ischemic attack, hypertension, smoking), as well as concomitant diseases and / or medications associated with cerebrovascular undesired reactions. Olanzapine is not indicated for the treatment of patients with psychosis associated with dementia.

As with the use of other neuroleptics, caution should be exercised when olanzapine is used in the following groups of patients:

- with a reduced number of leukocytes and / or neutrophils in the peripheral blood, due to various causes;

- with signs of oppression / toxic damage to bone marrow function under the influence of drugs in the anamnesis;

- with oppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in history;

- with hypereosinophilia or myeloproliferative disease.

In clinical studies, the use of olanzapine in patients with clozapine-dependent neutropenia or agranulocytosis in a history was not accompanied by relapses of these disorders.

In clinical trials, olanzapine therapy was rarely accompanied by anticholinergic side effects. However, the clinical experience with olanzapine in patients with concomitant diseases is limited, so caution should be exercised in prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic intestinal obstruction, occlusive glaucoma, and similar conditions.

Taking into account the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other central drugs, as well as alcohol.

Impact on the ability to drive vehicles and manage mechanisms

Patients taking olanzapine should exercise caution in managing mechanical means, including motor vehicles, since olanzapine may cause drowsiness.

Conditions of leave from pharmacies

On prescription.

Storage conditions of the drug Zyprexa Zydis

In dry, the dark place at a temperature of 15-30 ° C.

Keep out of the reach of children.

Shelf life of the drug Zyprexa Zydis

tablets dispersible 5 mg - 3 years.

tablets dispersible 10 mg - 3 years.

tablets dispersible 15 mg - 2 years.

tablets dispersible 20 mg - 2 years.

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