Zalasta, tablets 10 mg 28 pcs

Schizophrenia, Manic Depressive Psychosis, Anxiety

Adults

– Olanzapine is indicated for treatment of schizophrenia.

-Olanzapine is effective in maintenance and long-term therapy in patients with schizophrenia who have seen initial treatment effects.

– Olanzapine is indicated for treatment of a moderate to severe manic episode.

– Olanzapine is indicated for relapse prevention in patients with bipolar disorder in whom it has shown efficacy in treating a manic episode.

Active ingredient

Composition

for 1 tablet 2.5 mg/5 mg/7.5 mg/10 mg/15 mg/20 mg:

Active substance:

Olanzapine 2.50 mg/5.00 mg/7.50 mg/10.00 mg/15.00 mg/20.00 mg

Associates: cellactose1 [alpha-lactose monohydrate, cellulose], pregelatinized starch, corn starch, colloidal silicon dioxide, magnesium stearate

Cellactose1 is a spray-dried compound consisting of alpha-lactose monohydrate and cellulose powder, dry matter.

How to take, the dosage

Adults

Hizophrenia:the recommended starting dose of olanzapine is 10 mg once daily.

Manic episode:The initial dose is 15 mg once daily in monotherapy or 10 mg daily in combined therapy (with lithium or valproate).

Prevent relapse of bipolar disorder:The recommended starting dose of olanzapine is 10 mg once daily. Patients who have received olanzapine for treatment of a manic episode should continue therapy at the same dose to prevent relapse. If a new manic, mixed or depressive episode develops, therapy with olanzapine should be continued (with dose adjustment if necessary), with additional therapy for treatment of mood disorder symptoms according to clinical indications.

When treating schizophrenia, manic episode, and preventing bipolar disorder relapses, the daily dose may be adjusted from 5 mg to 20 mg per day. Initial dose increases should be made only after a proper clinical evaluation. Dose increases should be made at intervals of at least 24 hours. Olanzapine may be administered regardless of food intake because food intake has no effect on absorption of the drug.

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

Special patient groups

Elderly patients

The minimum starting dose (5 mg daily) is not usually indicated, but its use should be considered in patients ³ 65 years old if the clinical condition of the individual patient requires it.

Patients with renal and/or hepatic impairment

Patients with renal and/or hepatic failure should begin treatment with the minimum dose (5 mg daily). In moderate hepatic insufficiency (cirrhosis, class A or B according to Child-Pugh classification) the initial dose should be 5 mg, if necessary the dose should be increased with caution.

Smoking

The initial dose and dose range generally need not be changed depending on whether or not the patient smokes. Metabolism of olanzapine may be accelerated by smoking. Clinical monitoring is recommended; if necessary, the dose of olanzapine may be increased.

In the presence of more than one of the factors that may lead to delayed metabolism (female patients, elderly, nonsmokers), reduction of the initial dose may be recommended. Increasing the dose in such patients, if indicated, should be done conservatively.

Interaction

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

Potential interactions affecting olanzapine pharmacokinetics

Since olanzapine is metabolized by CYP1A2 isoenzyme, the substances that can selectively induce or inhibit this isoenzyme can change olanzapine pharmacokinetics.

Induction of CYP1A2 isoenzyme

smoking and carbamazepine can induce olanzapine metabolism, which may result in lower serum concentration of the latter. Mild to moderate increases in olanzapine clearance have been observed. Clinical results are limited; clinical monitoring is recommended, with dose escalation if necessary (see section “Dosage and administration”).

Inhibiting the CYP1A2 isoenzyme

Fluvoxamine, a specific CYP1A2 isoenzyme inhibitor, was shown to significantly inhibit olanzapine metabolism. The mean increase in plasma Cmax of olanzapine after fluvoxamine administration is 54% in non-smoking women and 77% in smoking men. The mean increases in the area under the concentration-time curve (AUC) were 52% and 108%, respectively. Patients using fluvoxamine or other CYP1A2 isoenzyme inhibitors, such as ciprofloxacin, should be prescribed a lower dose of olanzapine. Patients receiving therapy with a CYP1A2 isoenzyme inhibitor should consider reducing the dose of olanzapine.

Reduced bioavailability

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

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

The ability of olanzapine to affect the pharmacokinetics of other drugs

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

Olanzapine does not inhibit major isoenzymes of the cytochrome P450 system under in vitro conditions (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). in vivo studies confirm the absence of inhibition of the metabolism of the following drugs: tricyclic antidepressants (metabolized mainly with the participation of CYP2D6 isoenzyme), warfarin (CYP2C19), theophylline (CYP1A2) and diazepam (CYP3A4 and CYP2C19).

Olanzapine does not interact with lithium and biperidene.

Valproic acid plasma concentration readings indicated that the simultaneous use of olanzapine did not require valproic acid dose adjustment.

General activity of the central nervous system (CNS)

Caution should be used in patients consuming alcohol or taking CNS depressant medications.

Simultaneous use of olanzapine with antiparkinsonian drugs in patients with Parkinson’s disease and dementia is not recommended (see “Special Precautions”).

Interval QTc

Caution should be used when olanzapine is used concurrently with medications that prolong QTc interval (see “Special Considerations”).

Special Instructions

It is contraindicated in persons under 18 years of age.

Elderly patients

The minimum starting dose (5 mg daily) is not usually indicated, but its use should be considered in patients ³ 65 years old if the clinical condition of the individual patient requires it.

Patients with renal and/or hepatic impairment

Patients with renal and/or hepatic failure should start treatment with the minimum dose (5 mg daily). In moderate hepatic insufficiency (cirrhosis, class A or B according to Child-Pugh classification) the initial dose should be 5 mg, if necessary the dose should be increased with caution.

The improvement in the clinical condition of the patient with antipsychotic therapy can take several days to several weeks, this period requires careful patient monitoring.

Suicide risk

Patients with schizophrenia and bipolar disorder type 1 have a tendency to commit suicide, in connection with this during pharmacotherapy requires close monitoring of patients at high risk of suicide. In order to reduce the risk of overdose, the minimal amount of the drug should be prescribed 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 risk of cerebrovascular complications. In placebo-controlled trials (lasting 6-12 weeks) in elderly patients (mean age 78 years) with psychosis and/or behavioral disorders due to dementia, there was a two-fold increased mortality rate in patients receiving olanzapine compared to patients in the placebo group (3.5% vs. 1.5%, respectively). The increased incidence of death was independent of the dose of olanzapine (mean daily dose of 4.4 mg) and the duration of treatment. Risk factors that may predispose to increased mortality in this patient population are age over 65 years, dysphagia, sedation, malnutrition and dehydration, lung disease (e.g., pneumonia with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in patients who received olanzapine compared with those who received placebo, regardless of these risk factors.

The results of the same clinical trials reported cerebrovascular adverse events (CVA) (e.g., stroke, transient ischemic attack), including fatal outcomes. There was a threefold increase in the incidence of CVIA in patients receiving olanzapine compared to patients receiving placebo (1.3% vs. 0.4%, respectively). All patients receiving olanzapine and placebo who had cerebrovascular events had risk factors. Risk factors for CVNI associated with olanzapine treatment were age over 75 years and vascular/mixed dementia. Olanzapine has not been shown to be effective in these studies.

Parkinson’s disease

The use of olanzapine to treat psychosis due to dopamine receptor agonists in Parkinson’s disease is not recommended. In clinical trials, worsening of the course of Parkinsonian symptoms and hallucinations were observed very frequently (and with higher frequency than in the placebo group) (see section “Side effects”), the effectiveness of olanzapine for relief of psychotic symptoms did not exceed placebo. Criteria for inclusion in these studies were: stable lowest effective dose of antiparkinsonian drugs (dopamine receptor agonist) and use of the same antiparkinsonian drugs and doses throughout the study. Use of olanzapine was started at 2.5 mg/day with dose increases at the investigator’s discretion to 15 mg/day.

Malignant neuroleptic syndrome (MNS)

MNS is a potentially fatal symptom complex caused by antipsychotic medications. Rare cases of MNS have also been reported with olanzapine. Clinical manifestations of MNS include hyperthermia, muscle rigidity, altered mental status and autonomic disturbances (unstable pulse or blood pressure, tachycardia, increased sweating and arrhythmias). Additional signs may include: increased serum CPK activity, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms of MNS or unexplained high fever without additional manifestations of MNS, all antipsychotic medications, including olanzapine, should be stopped.

Hyperglycemia and diabetes

Infrequently, hyperglycemia and/or development or decompensation of diabetes mellitus, sometimes accompanied by ketoacidosis or diabetic coma, including several fatal cases have been reported (see section “Adverse effects”). In some cases, a previous increase in body weight has been reported, which may be a predisposing factor. Careful clinical monitoring is recommended in accordance with current guidelines for antipsychotic therapy, such as measuring baseline blood glucose concentrations, 12 weeks after initiation of olanzapine therapy and annually thereafter. Patients receiving any antipsychotic, including olanzapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus or risk factors for its development should have their blood glucose concentrations regularly monitored. Body weight should be checked regularly, e.g., before initiation, 4, 8, and 12 weeks after initiation of olanzapine and quarterly thereafter.

Lipid metabolism disorders

In placebo-controlled studies, adverse changes in lipid profile have been observed in patients receiving olanzapine (see “Adverse Effects”). Lipid metabolism disorders should be corrected especially in patients with dyslipidemia and patients with risk factors for lipid metabolism disorders. In patients receiving any antipsychotic agents, including olanzapine, the lipid profile should be monitored regularly according to current antipsychotic therapy guidelines (e.g., before starting treatment, 12 weeks after the start of therapy and every 5 years thereafter).

Anticholinergic activity

Although olanzapine exhibited anticholinergic activity in in vitro conditions, olanzapine therapy was rarely accompanied by anticholinergic side effects in clinical trials. However, clinical experience with olanzapine in patients with comorbidities is limited, so caution is advised when prescribing the drug to patients with prostatic hypertrophy, paralytic ileus and similar conditions.

Liver function disorders

Administration of olanzapine was often, especially in the early stages of therapy, accompanied by a transient, asymptomatic increase in plasma “hepatic” aminotransferase (ACT and ALT) activity. In patients with increased activity of ALT and (or) ACT in plasma, symptoms of liver failure, conditions, causing decrease of liver functional reserve, or in patients, using potentially hepatotoxic drugs, caution should be observed and follow-up monitoring should be conducted. In patients with hepatitis (including hepatic-cellular, cholestatic and mixed liver damage) treatment with olanzapine should be cancelled.

Neutropenia

Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts regardless of the cause, a history of drug-induced bone marrow suppression/toxicity, bone marrow suppression due to concomitant disease, radiation or chemotherapy, and in patients with hypereosinophilic states or myeloproliferative disease. Neutropenia has often been reported with concomitant use of olanzapine and valproic acid (see section “Side effects”).

Cessation of therapy

When olanzapine was abruptly withdrawn, increased sweating, insomnia, tremor, anxiety, nausea and vomiting were rarely (≥0.01% and < 0.1%) registered.

Interval QT

In clinical trials, clinically significant QT interval prolongation (Friederichi-corrected QT interval [QTcF] ≥500 ms at baseline, equal to QTcF < 500 ms) was observed infrequently (0.1-1%) in patients receiving olanzapine with no significant difference from placebo in the incidence of cardiac adverse events. However, like other antipsychotics, caution should be exercised when prescribing olanzapine concomitantly with drugs that may prolong the QTc interval, especially in elderly patients, patients with congenital prolongation of the QT interval, chronic heart failure, myocardial hypertrophy, hypokalemia or hypomagnesemia.

Thromboembolism

The development of venous thromboembolism (VTE) has been reported infrequently (≥0.1% and < 1%) on olanzapine therapy. A causal relationship between olanzapine use and VTE has not been established. However, considering that patients with schizophrenia often have acquired risk factors for venous thromboembolism, all possible risk factors for VTE (e.g., immobilization of patients) should be identified and necessary preventive measures taken.

General activity of the central nervous system (CNS)

With the primary effect of olanzapine on the CNS, care should be taken when olanzapine is used concurrently with other central acting medications and ethanol. Because olanzapine is antagonistic to dopamine receptors under in vitro conditions, it may block the effects of direct and indirect dopamine receptor agonists.

Cramp

Olanzapine should be used with caution in patients with a history of seizures or those exposed to factors that reduce seizure threshold. Seizures have been infrequently reported during treatment with olanzapine. In most cases, a history of seizures or risk factors for seizures was reported.

Late dyskinesia

In comparative studies lasting one year or less, olanzapine treatment was statistically significantly less likely to develop iatrogenic dyskinesia. Nevertheless, the risk of tardive dyskinesia increases with prolonged therapy with olanzapine. Therefore, if signs or symptoms of tardive dyskinesia occur in a patient using olanzapine, a dose reduction or withdrawal of olanzapine should be considered. After discontinuation of therapy, these symptoms may temporarily worsen or even reappear.

Postural hypotension

In clinical trials of olanzapine, postural hypotension was not frequently reported in elderly patients. Similar to other antipsychotics, periodic blood pressure monitoring is recommended in patients over 65 years of age.

Sudden cardiovascular death

According to post-registration experience with olanzapine, cases of sudden death from cardiovascular failure were reported. In a retrospective observational cohort study, the risk of suspected sudden cardiovascular death in patients receiving olanzapine was approximately twice as high as in patients not receiving antipsychotics. The risk of olanzapine in the study was comparable to that of the atypical antipsychotics included in the pooled analysis.

Application of olanzapine in children

Olanzapine is not recommended in children and adolescents. Various adverse reactions, including weight gain, impaired lipid metabolism, and hyperprolactinemia, have been reported in studies in adolescents 13-17 years old.

Special information on excipients

The drug Zalasta® contains lactose, therefore it is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

The studies on the effect on the ability to drive vehicles and other mechanisms have not been conducted. Because olanzapine may cause drowsiness and dizziness, patients should be warned about the dangers of operating machinery, including vehicles.

Synopsis

Tablets 2.5 mg:

Round slightly biconvex tablets of light yellow color. Darker color flecks are possible.

Tablets 5 mg:

Round slightly biconvex tablets, light yellow, engraved 5. Darker color flecks are allowed.

Tablets 7.5 mg:

Circular slightly biconvex tablets of light yellow color engraved 7.5. Darker color flecks are allowed.

Tablets 10 mg:

Round slightly biconvex tablets of light yellow color engraved 10. Darker color flecks are allowed.

Tablets 15 mg:

Round slightly biconvex tablets of light yellow color engraved 15. Darker color flecks are allowed.

Tablets 20 mg:

Round slightly biconvex tablets of light yellow color engraved 20. Darker color flecks are allowed.

Contraindications

– Hypersensitivity to any component of the drug.

– Patients at risk for closed angle glaucoma.

– Children under age 18.

– Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Overdose

Symptoms: Very common symptoms (≥10%) in olanzapine overdose are tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and decreased consciousness of varying severity (from sedation to coma).

Other clinically significant effects of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome (MNS), respiratory depression, aspiration, arterial hypertension or hypotension, arrhythmias (< 2 % of overdoses), and cardiac and respiratory arrest. The minimum dose in acute fatal overdose was 450 mg, the maximum dose in favorable overdose (survival) was 2 g olanzapine.

Treatment:there is no specific antidote for olanzapine. Inducing vomiting is not recommended. Standard overdose procedures are indicated, e.g. gastric lavage, administration of activated charcoal. Administration of activated charcoal while taking olanzapine at the same time showed a decrease of olanzapine bioavailability up to 50-60%.

Symptomatic treatment according to the clinical condition and control of vital body functions, including correction of arterial hypotension, circulatory disorders and maintaining respiratory function is indicated. Epinephrine, dopamine and other adrenomimetics that are agonists of β-adrenoreceptors should not be used, since stimulation of these receptors may aggravate arterial hypotension. Cardiovascular monitoring should be performed to detect possible arrhythmias. Close medical monitoring should continue until the patient is fully recovered.

Pregnancy use

Pregnancy

Adequate and closely controlled studies in pregnant women have not been conducted. Patients should be cautioned to notify their physician if they become pregnant or plan 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 outweighs the possible risk to the fetus.

Newborns whose mothers took olanzapine during the third trimester of pregnancy are at risk for adverse reactions, including extrapyramidal disorders and/or “withdrawal” symptoms, which may vary in severity and duration after delivery. Agitation, hypertonicity, hypotonicity, tremor, somnolence, respiratory distress syndrome, and eating disorders have been reported. In this regard, newborns should be closely monitored.

Breastfeeding period

In studies in nursing healthy women, olanzapine was found to penetrate into breast milk. The average dose received by the infant (mg/kg) at equilibrium was 1.8% of the mother’s olanzapine dose (mg/kg). Patients are advised not to breastfeed when using olanzapine.

Fertility

No information about effects on fertility.

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