Zalasta Ku-tab, 5 mg 28 pcs

Schizophrenia, Anxiety, Manic Depressive Psychosis

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

per 1 oral dispersible tablet, 5 mg/7.5 mg/10 mg/15 mg/20 mg

per 1 oral dispersible tablet: justify;”> Active substance: olanzapine 5.00 mg/7.50 mg/10.00 mg/15.00 mg/20.00 mg

Supplements:mannitol, microcrystalline cellulose, crosspovidone, hypromellose low substituted LH-21, aspartame, calcium silicate, magnesium stearate

How to take, the dosage

Olanzapine tablets dispersed in the mouth dissolve quickly by saliva and are easily swallowed.

Taking the tablet out of the mouth undissolved is difficult. Take the tablet from the blister should be taken with dry hands. Because of its fragility the tablet must be taken immediately after taking it out of the blister. In addition, just before taking the tablet, you can dissolve it in a glass of water.

Extract the tablet as follows:

1. Bend the blister along the break line.

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

3. gently remove the tablet.

4. The tablet should then be immediately placed on the tongue.

Olanzapine can be taken regardless of meal times because food does not affect absorption of olanzapine.

Oral dispersible olanzapine tablets are bioequivalent to olanzapine tablets and have a similar rate and degree of absorption. Oral dispersible olanzapine tablets are used in the same quantity and frequency as olanzapine tablets. Oral dispersible olanzapine tablets may be used instead of olanzapine tablets.

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 the treatment of mood disorder symptoms as clinically indicated.

When treating schizophrenia, manic episode, and preventing relapse of bipolar disorder, 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 the time of food intake because food intake has no effect on absorption of the drug.

The drug dose should be reduced gradually when olanzapine treatment is stopped.

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 slower metabolism (female patients, elderly, nonsmokers), a reduction in the initial dose may be recommended. Increasing the dose in such patients, if indicated, should be done conservatively.

Interaction

Potential interactions affecting olanzapine

Since olanzapine is metabolized with the participation of CYP1A2 isoenzyme, metabolism of olanzapine may be changed under the influence of inhibitors or inducers of cytochrome Р450 system isoenzymes, specifically active against CYP1A2 isoenzyme.

Induction of CYP1A2 isoenzyme

Olanzapine metabolism may be induced by smoking or carbamazepine use, which may lead to decreased olanzapine concentrations. Only mild to moderate increases in olanzapine clearance have been noted. Clinical manifestations are likely to be limited, but clinical monitoring is recommended, and if necessary, increasing the olanzapine dose.

Inhibiting the CYP1A2 isoenzyme

Fluvoxamine, a specific CYP1A2 isoenzyme inhibitor, significantly inhibits olanzapine metabolism. The Cmax of olanzapine after fluvoxamine administration averaged a 54% increase in non-smoking female patients and a 77% increase in smoking male patients, and the AUC (area under the concentration-time curve) of olanzapine averaged a 52% and 108% increase, respectively. Consideration should be given to prescribing a lower starting dose of olanzapine in patients using fluvoxamine or other CYP1A2 isoenzyme inhibitors such as ciprofloxacin. At the beginning of the use of CYP1A2 isoenzyme inhibitor drugs against the background of olanzapine use, the possibility of reducing the dose of the latter should be considered.

Decreased bioavailability

Activated carbon reduces olanzapine bioavailability after oral administration by 50-60% and should be used at least 2 hours before or after olanzapine administration.

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 suppress the effects of direct and indirect dopamine agonists.

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

Olanzapine had no interaction with lithium and biperiden.

Monitoring plasma valproate concentrations showed no need for valproate dose adjustment after starting it with olanzapine.

General activity of the central nervous system (CNS)

Caution should be used when using olanzapine in patients using alcohol or receiving medications that cause CNS depression.

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

Interval QTc

Caution should be used when olanzapine is used concurrently with medications that can prolong the QTc interval.

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.

Clinical improvement with antipsychotic treatment may occur over several days to several weeks. Close monitoring of patients during this period is required.

Psychosis with a background of dementia and/or conduct disorder

Olanzapine is not indicated for treatment of psychosis against dementia and/or behavior disorders due to increased mortality and risk of cerebrovascular events in these patients. In placebo-controlled trials (lasting 6 to 12 weeks) in elderly patients (mean age 78 years) with psychosis for dementia and/or behavioral disorders, there was a twofold increase in deaths in the olanzapine group compared to the placebo group (3.5% and 1.5%, respectively). The higher mortality rate was not related to the dose of olanzapine (mean dose of 4.4 mg) or to the duration of treatment. Risk factors that may influence the predisposition of this group of patients to higher mortality with olanzapine treatment include age > 65 years, dysphagia, sedation, malnutrition and dehydration, presence of pulmonary pathology (e.g., pneumonia with or without aspiration) or concomitant use with benzodiazepines. However, mortality rates were higher in patients treated with olanzapine compared with patients treated with placebo, regardless of these risk factors.

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in the same clinical trials. In placebo-controlled trials, the incidence of cerebrovascular adverse events was three times higher in patients in the olanzapine group compared to the placebo group (1.3% versus 0.4%, respectively). All patients with cerebrovascular disorders receiving olanzapine and placebo had prior risk factors for cerebrovascular adverse events. Age > 75 years and dementia of vascular or mixed type were defined as risk factors for cerebrovascular adverse events with olanzapine treatment. The efficacy of olanzapine has not been established in these studies.

Parkinson’s disease

The use of olanzapine in treating psychosis induced by dopamine receptor agonists in Parkinson’s disease is not recommended.

In clinical trials, worsening of Parkinson’s disease symptoms and hallucinations were reported very frequently and with higher frequency than in the placebo group, and efficacy in treating psychotic symptoms with olanzapine did not exceed placebo. In these clinical trials, patients were initially required to achieve stabilization on the lowest effective dose of Parkinson’s disease drugs (dopamine agonists) and to continue them at the same dose for the duration of the study. The starting dose of olanzapine was 2.5 mg per day and could be increased to a maximum of 15 mg per day at the discretion of the investigator.

Malignant neuroleptic syndrome (MNS)

Malignant neuroleptic syndrome is a potentially life threatening condition that occurs against the background of neuroleptic use. Rare cases of MNS have also been reported with olanzapine. Clinical manifestations of MNS include hyperpyrexia, muscle rigidity, altered mental status and autonomic disturbances (irregular pulse or blood pressure, tachycardia, diaphoresis and heart rhythm disturbances). Additional signs may include increased CPK activity, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of MNS or significant unexplained increase in body temperature without other symptoms of MNS require withdrawal of all neuroleptics, including olanzapine.

Hyperglycemia and diabetes

Infrequent cases of hyperglycemia and/or development or decompensation of diabetes, in some cases accompanied by ketoacidosis and diabetic coma, including fatal. In some cases there was an increase in body weight, which may have been a predisposing factor. Close clinical monitoring of patients with diabetes mellitus and patients with risk factors for diabetes mellitus is recommended according to the following guidelines: measurement of baseline blood glucose concentration, 12 weeks after initiation of olanzapine and annually thereafter. In patients taking antipsychotic drugs, including olanzapine, check for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, weakness). Patients with diabetes mellitus or risk factors for diabetes mellitus need regular monitoring of blood glucose concentration. It is necessary to carry out regular control of body weight: before treatment start, 4, 8 and 12 weeks after olanzapine start and then every 3 months.

Changes in lipid profile

In placebo-controlled studies, unwanted changes in lipid spectrum were observed in patients receiving olanzapine. Changes in lipid profile should be corrected according to clinical necessity, especially in patients with dyslipidemia and in patients with risk factors for lipid metabolism disorders. In patients taking antipsychotics, including olanzapine, the lipid profile should be checked regularly as recommended: before treatment, 12 weeks after the start of olanzapine, and every 5 years thereafter.

Anticholinergic activity

Although olanzapine exhibited anticholinergic activity in invitro studies, the use of olanzapine in clinical trials revealed a low incidence of related complications. However, since clinical experience with olanzapine in patients with comorbidities is limited, caution should be exercised when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic ileus and similar conditions.

Liver function disorders

Transient asymptomatic increases in “liver” aminotransferases (ACT and ALT) have been reported frequently, particularly in the early stages of therapy. Special caution is required in ACT and/or AJIT increase in serum activity in patients with symptoms of liver dysfunction, with earlier diagnosed conditions, connected with restriction of liver functional reserve or in patients treated with potentially hepatotoxic medicines. If hepatitis (including hepatocellular, cholestatic or mixed) is diagnosed, olanzapine should be discontinued.

Neutropenia

Caution should be used with olanzapine in patients with low blood leukocyte and/or neutrophil counts; in patients receiving drugs that may cause neutropenia; in patients with a history of drug-induced suppression of bone marrow function; in patients with suppressed bone marrow function due to a concurrent disease, radiation or chemotherapy; and in patients with eosinophilia or myeloproliferative diseases. Cases of neutropenia have often been reported with concomitant use of olanzapine and valproate.

Cessation of therapy

In rare cases (≥0.01% and < 0.1%) the following acute symptoms have been reported when olanzapine was stopped abruptly: increased sweating, insomnia, tremor, anxiety, nausea or vomiting.

Interval QT

In clinical trials, clinically significant QTc interval prolongation (Friederick formula QT correction [QTcF] > 500 ms at any time after treatment initiation at baseline QTcF < 500 ms) occurred infrequently (0.1%-1%) in patients treated with olanzapine, with no significant difference in associated cardiac complications compared with placebo. However, caution should be exercised when prescribing olanzapine together with drugs that prolong the QTc interval, especially in elderly patients with congenital long QT interval syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia and hypomagnesemia.

Thromboembolism

An infrequent (³ 0.1% and < 1%) case of a temporal association between the development of venous thromboembolism and olanzapine therapy was reported. A causal relationship between olanzapine administration and venous thromboembolism has not been established. However, considering that patients with schizophrenia often have acquired risk factors for thromboembolism, all possible risk factors for this complication should be identified, including immobilization of patients, and necessary preventive measures should be taken.

General activity with respect to the CNS

Given olanzapine’s primary CNS activity, care should be taken when olanzapine is used in combination with other central acting medications and alcohol. Because olanzapine may exhibit antagonism to dopamine receptors under in vitro conditions, it may be an antagonist to 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. Cases of seizures have been infrequent in patients taking olanzapine, and in most of these cases, a history of seizures or risk factors for seizures have been reported.

Late dyskinesia

In comparative studies lasting up to one year, olanzapine treatment was significantly less likely to develop dyskinesia requiring medication correction. However, an increased risk of tardive dyskinesia with prolonged therapy with neuroleptics should be considered. If signs of tardive dyskinesia develop, dose reduction or withdrawal of olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after drug withdrawal.

Postural hypotension

Postural hypotension was not frequently observed in clinical trials of olanzapine in elderly patients. It is recommended that blood pressure be measured periodically in patients over 65 years of age.

Sudden cardiovascular death

A sudden death was reported from postmarketing observations of olanzapine. In a retrospective observational study, the risk of suspected sudden cardiovascular death in patients receiving olanzapine was approximately double that of patients not taking neuroleptics. In this study, the risk with olanzapine was comparable to the risk with atypical neuroleptics 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® Cu-tab® contains aspartame, which serves as a source of phenylalanine. The drug may not be safe for people with phenylketonuria.

There have been no studies of the effect of the drug on the ability to drive and operate vehicles. Patients taking olanzapine should exercise caution when driving vehicles and operating machinery, as olanzapine may cause drowsiness and dizziness.

Synopsis

Circular slightly biconvex tablets of yellow color. Slight individual specks and marbling are allowed.

Contraindications

– Hypersensitivity to any component of the drug.

– Patients at risk for closed angle glaucoma.

– Children under age 18.

– Patients with phenylketonuria.

Overdose

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

Other clinically significant effects of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome (MNS), respiratory depression, aspiration, high and low blood pressure, cardiac 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 procedures for overdose are indicated (gastric lavage, activated charcoal administration). Concomitant use of activated carbon and olanzapine showed a decrease in bioavailability of olanzapine when taken orally to 50-60%.

Symptomatic treatment and control of vital organ function, depending on clinical presentation, including management of arterial hypotension and vascular collapse and maintenance of respiratory function should be provided. Epinephrine, dopamine, and other sympathomimetics that are beta-adrenoreceptor agonists should not be used because stimulation of these receptors may exacerbate arterial hypotension. Cardiovascular parameters should be monitored to detect possible arrhythmias. Close monitoring of the patient’s condition is necessary until the patient is fully recovered.

Pregnancy use

Pregnancy

No studies of olanzapine use in pregnant women have been conducted. Patients should be warned that if they become pregnant or plan to become pregnant during treatment with olanzapine, they should inform their treating physician. Because of insufficient experience with the use of olanzapine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the patient significantly exceeds the potential risk to the fetus.

In infants whose mothers have taken neuroleptics (including olanzapine) in the third trimester of pregnancy, there is a risk of adverse reactions, including extrapyramidal disorders and withdrawal symptoms of varying severity and duration. Cases of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, and impaired sucking have been reported. Therefore, newborns whose mothers have taken olanzapine should be monitored.

Breastfeeding period

The study found that olanzapine was excreted with breast milk. The average dose received by the infant (mg/kg) when reaching equilibrium concentration in the mother was 1.8% of the mother’s olanzapine dose (mg/kg). Breastfeeding is not recommended during therapy with olanzapine.

Fertility

The effect on fertility is unknown.

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