Adajio®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AДАЖИО® (ADAGIO)

Composition:

Active substance: olanzapine;

1 tablet contains 5 mg or 10 mg of olanzapine;

Excipients: lactose monohydrate; hydroxypropylcellulose; crospovidone; microcrystalline cellulose; magnesium stearate;

Film coating: hypromellose, Opadry White 13B28444 (hypromellose, titanium dioxide (E 171), polyethylene glycol, polysorbate 80), carnauba wax, beeswax (60:40).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex film-coated tablets.

Pharmacotherapeutic group. Antipsychotics. ATC code N05A H03.

Pharmacological Properties.

Pharmacodynamics.

Olanzapine is an antipsychotic and antimanic agent with mood-stabilizing effects, demonstrating a broad pharmacological profile across several receptor systems. In preclinical studies, olanzapine showed affinity for various receptors (Ki; < 100 nM), including serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; muscarinic cholinergic receptors M1–M5; α1-adrenergic; and histamine H1 receptors. Animal behavioral studies revealed 5HT, dopaminergic, and cholinergic antagonism, consistent with olanzapine's receptor binding profile. Olanzapine demonstrated in vitro greater affinity for serotonin 5HT2 receptors than for dopamine D2 receptors, and greater 5HT2 activity than D2 in vivo. Electrophysiological studies showed that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, while exerting minimal effects on striatal (A9) pathways associated with motor function. Olanzapine inhibits conditioned avoidance response, indicating antipsychotic activity at doses lower than those causing catalepsy, a sign of motor side effects. In contrast to some other antipsychotic agents, olanzapine enhances responses to stimuli in anxiolytic testing.

After a single 10 mg oral dose of olanzapine, positron emission tomography (PET) studies in healthy volunteers showed that olanzapine had a higher level of binding to 5HT2A receptors than to dopamine D2 receptors. Furthermore, analysis of images obtained by single-photon emission computed tomography (SPECT) in patients with schizophrenia revealed that patients responsive to olanzapine had lower striatal D2 receptor occupancy compared to patients responsive to other antipsychotics and risperidone, and comparable to that observed in clozapine-responsive patients.

Clinical efficacy.

In two out of two placebo-controlled and two out of three comparator-controlled trials involving over 2900 patients with schizophrenia and positive and negative symptoms, olanzapine demonstrated statistically significant clinical improvement.

In international double-blind comparative trials involving 1484 patients with schizophrenia, schizoaffective disorder, and related disorders with depressive symptoms (16.6 points on the Montgomery–Åsberg Depression Rating Scale), a prospective secondary analysis from baseline to endpoint demonstrated statistically significant improvement (p = 0.001) with olanzapine treatment (–6.0) compared to haloperidol (–3.1).

In patients with manic or mixed episodes of bipolar disorder, olanzapine demonstrated high efficacy in reducing manic symptoms over 3 weeks compared to placebo and divalproex. Olanzapine's efficacy was comparable to haloperidol in terms of the proportion of patients achieving symptomatic remission from mania and depression at 6 and 12 weeks of treatment. In a study combining lithium or valproate therapy for 2 weeks with the addition of olanzapine 10 mg, significant reduction in manic symptoms was observed compared to monotherapy with lithium or valproate after 6 weeks.

In a 12-month relapse prevention study of manic episodes in patients who achieved remission with olanzapine and were then randomized to continue olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo at the primary endpoint for bipolar disorder relapse. Olanzapine also showed statistically significant advantages over placebo in preventing both manic and depressive relapses.

In a subsequent 12-month study preventing relapse of manic episodes in patients who achieved remission with combination therapy of olanzapine and lithium and were then randomized to olanzapine or lithium monotherapy, olanzapine was statistically non-inferior to lithium at the primary endpoint for bipolar disorder relapse (olanzapine 30%, lithium 38.3%; p = 0.055).

In an 18-month study, manic or mixed episodes were stabilized with olanzapine, followed by maintenance therapy with lithium or valproate as mood stabilizers. No statistically significant advantage was demonstrated over monotherapy with lithium or valproate in delaying relapse of bipolar disorders as defined by syndromal (diagnostic) criteria.

Children.

Experience in adolescents (aged 13 to 17 years) is limited. Data are available from studies on the short-term treatment of schizophrenia (6 weeks) and mania associated with bipolar disorders (3 weeks) involving fewer than 200 adolescents. The initial dose of olanzapine was 2.5 mg, titrated up to 20 mg/day. During olanzapine treatment, adolescents showed significantly greater weight gain compared to adults. Adolescents also exhibited increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin compared to adults. Data on maintenance of therapeutic effect and long-term use are limited.

Pharmacokinetics.

Absorption.

The drug is well absorbed after oral administration; peak plasma concentrations (Cmax) are reached within 5–8 hours. Food intake does not affect olanzapine absorption. Absolute bioavailability after oral administration compared to intravenous administration has not been established.

Distribution.

Plasma protein binding of olanzapine is approximately 93% over a concentration range of 7 ng/mL to 1000 ng/mL. Olanzapine binds primarily to albumin and α1-acid glycoprotein.

Biotransformation.

Olanzapine is metabolized in the liver via conjugation and oxidation. The primary circulating metabolite is 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochrome P450 enzymes CYP1A2 and CYP2D6 mediate the formation of N-desmethyl and 2-hydroxymethyl metabolites, which showed significantly lower pharmacological activity in vivo than olanzapine in animal studies. The primary pharmacological activity is attributed to the parent olanzapine compound.

Elimination.

After oral administration, the mean elimination half-life of olanzapine in volunteers varied depending on age and gender.

In healthy elderly volunteers (aged 65 years and older), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and plasma clearance lower (17.5 vs. 18.2 L/h) compared to younger volunteers. Pharmacokinetic variations observed in elderly volunteers remained within the range seen in younger volunteers. In 44 patients with schizophrenia aged >65 years receiving doses of 5–20 mg/day, no distinct adverse event profile was observed.

In women compared to men, the mean elimination half-life was longer (36.7 vs. 32.3 hours), and plasma clearance was lower (18.9 vs. 27.3 L/h). However, the safety profile of olanzapine (5–20 mg) was comparable between women (N = 467) and men (N = 869).

Patients with renal impairment.

In patients with renal impairment (creatinine clearance < 10 mL/min) compared to healthy volunteers, there was no significant difference in mean elimination half-life (37.7 vs. 32.4 hours) or plasma clearance (21.2 vs. 25.0 L/h). Studies showed that approximately 57% of radiolabeled olanzapine was excreted in urine, primarily as metabolites.

Patients with hepatic impairment.

A small study of the effect of impaired liver function in 6 patients with clinically significant cirrhosis (Child–Pugh class A (n = 5) and B (n = 1)) showed minimal impact on the pharmacokinetics of orally administered olanzapine (doses 2.5–7.5 mg). Patients with mild to moderate liver dysfunction showed slightly increased systemic clearance and shorter half-life compared to patients without liver dysfunction (n = 3). The cirrhosis group included more smokers (4/6; 67%) than the non-liver-impaired group (0/3; 0%).

Smoking patients.

In non-smokers compared to smokers (men and women), the mean elimination half-life was longer (38.6 vs. 30.4 hours), and plasma clearance was lower (18.6 vs. 27.7 L/h).

Plasma clearance of olanzapine is lower in elderly patients compared to younger ones, in women compared to men, and in non-smokers compared to smokers. Nevertheless, factors such as age, gender, and smoking have minimal influence on olanzapine plasma clearance and elimination half-life compared to inter-individual variability.

No differences in olanzapine pharmacokinetics were observed in clinical studies involving European, Japanese, and Chinese patients.

Children.

Olanzapine pharmacokinetics in adolescents and adults are similar. In clinical trials, the mean exposure to olanzapine was approximately 27% higher in adolescents. Demographic differences between adolescents and adults include lower average body weight and fewer smokers among adolescent patients. These factors likely contribute to the higher mean exposure to olanzapine observed in adolescents.

Clinical Characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical response during long-term therapy in patients who have shown a response to initial treatment.

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

Olanzapine is indicated for the prevention of recurrent episodes in patients with bipolar disorder who have responded to olanzapine treatment for mania.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Known risk of angle-closure glaucoma.

Interaction with other medicinal products and other forms of interaction.

Studies on interaction with other medicinal products have been conducted only in adults.

Substances that may affect olanzapine.

Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

CYP1A2 inducers.

The metabolism of olanzapine may be induced by smoking and by the use of carbamazepine, which may lead to reduced olanzapine concentrations. Only mild or moderate increases in olanzapine clearance have been observed. The clinical consequences are likely limited, but clinical monitoring is recommended and dose adjustment of olanzapine may be necessary.

CYP1A2 inhibitors.

Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in an average increase in Cmax of 54% in non-smoking women and 77% in smoking men after fluvoxamine administration. The average increase in AUC of olanzapine is 52% and 108%, respectively. For patients receiving fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, a lower initial dose of olanzapine should be prescribed. Dose reduction of olanzapine should be considered if treatment with a CYP1A2 inhibitor is planned.

Reduction of bioavailability.

Activated charcoal reduces the oral bioavailability of olanzapine by 50–60%. It should be administered at least 2 hours before or 2 hours after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacids (aluminum, magnesium), or cimetidine do not significantly affect the pharmacokinetics of olanzapine.

Potential effect of olanzapine on the action of other medicinal products.

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

Olanzapine did not inhibit most CYP450 isoenzymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, significant interactions are not expected, as confirmed by in vivo studies, where no inhibition of olanzapine metabolism was observed when co-administered with the following active substances: tricyclic antidepressants (mainly metabolized by CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and 2C19).

No interaction between olanzapine and lithium or biperiden has been observed.

Therapeutic monitoring of plasma valproate levels did not reveal the need for dose adjustment of valproate when co-administered with olanzapine.

General central nervous system activity.

Caution should be exercised in patients consuming alcohol or receiving medicinal products that may cause central nervous system depression.

Concomitant use of olanzapine with antiparkinsonian agents in patients with Parkinson's disease and dementia is not recommended.

QTc interval.

Olanzapine should be administered with caution together with other medicinal products that may prolong the QTc interval.

Special precautions for use.

Improvement in the patient's clinical condition during antipsychotic treatment may take from several days to several weeks. Close monitoring of patients is required during this period.

Psychosis associated with dementia and/or behavioural disorders. Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioural disturbances and is not recommended for use in these patients due to increased mortality and risk of cerebrovascular events. In placebo-controlled clinical trials (6–12 weeks duration) involving elderly patients (mean age 78 years) with psychosis associated with dementia and/or behavioural disturbances, the incidence of mortality was twice as high in patients receiving olanzapine compared to placebo (3.5% vs. 1.5%, respectively). Increased mortality was not related to the dose of olanzapine (mean daily dose 4.4 mg) or duration of treatment. Risk factors for increased mortality include age ≥65 years, dysphagia, sedation, malnutrition, dehydration, presence of lung pathology (e.g., pneumonia with or without aspiration), and concomitant use of benzodiazepines. However, mortality was higher with olanzapine therapy than with placebo regardless of risk factors.

Cerebrovascular adverse reactions (including stroke and transient ischaemic attacks), some fatal, were observed in clinical trials. The incidence of cerebrovascular adverse events was three times higher in patients receiving olanzapine compared to placebo (1.3% vs. 0.4%, respectively). All patients who experienced cerebrovascular adverse events while receiving olanzapine or placebo had risk factors. Age ≥75 years and vascular/mixed-type dementia were identified as risk factors for cerebrovascular adverse events during olanzapine therapy. The efficacy of olanzapine was not established in these trials.

Parkinson’s disease. Olanzapine is not recommended for the treatment of psychosis associated with dopamine agonists. Concomitant use of olanzapine and anti-Parkinson drugs is not recommended in patients with Parkinson’s disease and dementia. In clinical trials, worsening of Parkinsonian symptoms and hallucinations occurred very frequently, more often than with placebo; olanzapine therapy was not more effective than placebo in treating psychotic symptoms. From the beginning of these trials, patients were required to remain on the lowest effective dose of anti-Parkinson drugs (dopamine agonists), and the same anti-Parkinson drugs and doses were maintained throughout the study. Olanzapine therapy was initiated at a dose of 2.5 mg/day, titrated up to a maximum of 15 mg/day.

Neuroleptic malignant syndrome (NMS). NMS is a potentially fatal syndrome associated with antipsychotic drugs. Cases of NMS associated with olanzapine use have been reported rarely. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered consciousness, and signs of cardiovascular instability (irregular pulse or blood pressure changes, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. The clinical presentation of NMS or hyperthermia without full NMS symptoms requires immediate discontinuation of all antipsychotic agents, including olanzapine.

Hyperglycaemia and diabetes mellitus. Hyperglycaemia and/or development or worsening of pre-existing diabetes mellitus, sometimes associated with ketoacidosis or diabetic coma, have been reported rarely, including fatal cases. Weight gain, which may be a risk factor, has sometimes been reported prior to onset.

Appropriate clinical monitoring is recommended for patients with diabetes and those with risk factors for developing diabetes, including measurement of blood glucose levels at baseline, at 12 weeks, and annually thereafter. Patients receiving antipsychotic agents, including olanzapine, should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness). Blood glucose levels should be regularly monitored in patients with diabetes and those at risk for developing diabetes. Body weight should be monitored regularly, e.g., at baseline, at 4 weeks, 8 weeks, 12 weeks, and quarterly thereafter.

Anticholinergic activity. While olanzapine has demonstrated anticholinergic activity in vitro, clinical trial experience has shown a low incidence of anticholinergic effects. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, caution should be exercised when prescribing olanzapine to patients with benign prostatic hyperplasia, paralytic ileus, or conditions related to these disorders.

Hepatic function. Transient, asymptomatic elevations in liver aminotransferases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), have been frequently observed with olanzapine use, particularly at the beginning of treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, symptoms of hepatic dysfunction, or conditions associated with hepatic insufficiency, as well as in patients receiving potentially hepatotoxic drugs. Olanzapine treatment should be discontinued in cases of diagnosed hepatitis (including hepatocellular, cholestatic, or mixed liver injury).

Neutropenia. Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts from any cause, patients receiving drugs that may cause neutropenia, patients with a history of drug-induced bone marrow suppression/toxicity, patients with bone marrow suppression due to concomitant diseases, radiation, or chemotherapy, and patients with hypereosinophilia or myeloproliferative disorders. Neutropenia has been frequently reported with concomitant use of olanzapine and valproate.

Discontinuation of therapy. Acute symptoms, including excessive sweating, insomnia, tremor, agitation, nausea, or vomiting, have been reported rarely (≥0.01% and <0.1%) following abrupt discontinuation of therapy.

QT interval. In studies involving patients receiving olanzapine, clinically significant QTc prolongation (QTc corrected by Fridericia [QTcF] ≥500 ms at any time after baseline in patients with baseline QTcF <500 ms) was reported infrequently (0.1–1%), but no significant difference in cardiac-related reactions was observed compared to placebo. However, as with other antipsychotics, caution should be exercised when prescribing olanzapine with drugs that prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalaemia, or hypomagnesaemia.

Thromboembolism. Venous thromboembolism has been reported infrequently (≥0.1% – <1%) during olanzapine treatment. A causal relationship between olanzapine treatment and venous thromboembolism has not been established. However, considering that patients with schizophrenia often have an increased predisposition to thromboembolism, all possible risk factors, such as patient immobilization, should be taken into account, and appropriate preventive measures should be implemented.

General central nervous system (CNS) effects. Due to the primary CNS effects of olanzapine, caution should be exercised when co-administering with other centrally acting drugs and alcohol. Olanzapine exhibits in vitro antagonism at dopamine receptors and may counteract the effects of direct and indirect dopamine agonists.

Seizures. Olanzapine should be used cautiously in patients with a history of seizures or in the presence of factors that lower the seizure threshold. Seizures have been reported infrequently during olanzapine treatment. In most of these cases, patients had a history of seizures or an increased risk of seizure occurrence.

Tardive dyskinesia. In clinical trials of up to one year duration, olanzapine was associated with a statistically significant reduction in the incidence of treatment-induced dyskinesia. However, due to the increasing risk of tardive dyskinesia with long-term use of antipsychotics, appropriate dose reduction or discontinuation of the drug should be considered if symptoms of tardive dyskinesia appear. These symptoms may worsen over time or even emerge after discontinuation of treatment.

Orthostatic hypotension. Cases of orthostatic hypotension have been reported infrequently in elderly patients during clinical trials. Periodic blood pressure monitoring is recommended for patients aged 65 years and older.

Sudden cardiac death. Cases of sudden cardiac arrest have been reported in post-marketing surveillance of olanzapine. According to a retrospective observational cohort study, the risk of sudden cardiac arrest in patients receiving olanzapine was approximately twice that in patients not taking antipsychotics. In this study, the risk associated with olanzapine use was comparable to that of other atypical antipsychotics included in the pooled analysis.

Lipid level changes. Unfavourable changes in lipid levels may occur in patients treated with olanzapine. Lipid level changes should be appropriately managed in patients with dyslipidaemia and in those with risk factors for lipid metabolism disorders. Lipid levels in blood should be monitored regularly in patients receiving antipsychotic agents, including olanzapine, e.g., at baseline, at 12 weeks, and every 5 years thereafter.

The medicinal product contains lactose. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies of olanzapine use in pregnant women. Patients should inform their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Since clinical experience with olanzapine in pregnancy is limited, olanzapine should be used during pregnancy only if the potential benefits justify the potential risk to the foetus.

Newborns whose mothers have taken antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, the symptoms of which may vary in severity and duration after birth. Reported symptoms include agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns should be carefully monitored.

Breastfeeding

Olanzapine has been detected in breast milk in a study of healthy breastfeeding women. The average infant exposure (mg/kg) at steady state was approximately 1.8% of the maternal dose (mg/kg).

Patients should be advised not to breastfeed while taking olanzapine.

Fertility

The effect on fertility is unknown.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of olanzapine on reaction speed while driving or operating machinery have not been conducted. Since olanzapine may cause somnolence and dizziness, patients should be warned of the potential danger associated with operating machinery, including motor vehicles.

Dosage and Administration

Adults.

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

Manic episodes. The initial dose is 15 mg as a single daily dose when used as monotherapy, or 10 mg daily when used in combination therapy.

Prevention of relapse in bipolar disorder. The recommended initial dose is 10 mg daily. For patients already receiving olanzapine for treatment of manic episodes, continuation of therapy at the same dose is recommended for relapse prevention. If new manic, mixed, or depressive episodes occur, olanzapine treatment should be continued (with dose adjustment as needed) along with additional therapy to manage mood symptoms as clinically indicated.

During treatment of schizophrenia, manic episodes, and prevention of relapse in bipolar disorder, the daily dose may be adjusted according to the patient's clinical condition within the range of 5–20 mg/day. Dose increases above the recommended initial dose should only be considered after appropriate re-evaluation and generally should not occur at intervals less than 24 hours.

Olanzapine may be administered regardless of food intake, as food does not affect drug absorption. When discontinuing olanzapine, a gradual dose reduction is recommended.

Elderly patients. In patients aged 65 years and older, a lower initial dose (5 mg/day) should be considered if clinically appropriate factors are present.

Renal and/or hepatic impairment. A lower initial dose (5 mg) is recommended for these patients. In patients with moderate hepatic impairment (Child-Pugh class A or B cirrhosis), the initial dose should be 5 mg. Dose increases should be made cautiously.

Smokers. Dose adjustment based on smoking status is not required.

Smoking may increase olanzapine metabolism. Clinical monitoring is recommended, and dose increase of olanzapine should be considered if necessary. A lower initial dose may be considered in patients with a combination of factors (female gender, advanced age, non-smoking status) that may reduce olanzapine metabolism. Dose increases in such patients, if indicated, should be performed gradually and cautiously.

Children.

Olanzapine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy. In short-term studies in adolescents, greater increases in body weight and changes in lipid levels and prolactin were observed compared to adult patients.

Overdose.

Symptoms. Very common symptoms of overdose (frequency > 10%) include tachycardia, agitation/aggression, dysarthria, various extrapyramidal symptoms, and decreased level of consciousness ranging from sedation to coma.

Other clinically significant consequences of overdose include delirium, seizures, coma, malignant neuroleptic syndrome, respiratory depression, aspiration, arterial hypertension or hypotension, cardiac arrhythmia (in < 2% of overdose cases), and cardiopulmonary shock. Fatal outcomes have been reported following acute overdose of 450 mg; however, survival has been reported after acute ingestion of approximately 2 g of olanzapine orally.

Treatment. There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for overdose management should be implemented (including gastric lavage and administration of activated charcoal). Concomitant use of activated charcoal reduces the bioavailability of oral olanzapine by 50–60%.

Symptomatic treatment and monitoring of vital organ functions are recommended based on clinical manifestations, including management of hypotension, vascular collapse, and maintenance of respiratory function. Epinephrine, dopamine, or other beta-agonist sympathomimetic agents should not be used, as beta-stimulation may worsen hypotension.

Cardiovascular monitoring is required to detect possible arrhythmias. Close medical supervision and monitoring should continue until patient recovery.

Adverse reactions.

The most commonly observed adverse reactions associated with olanzapine use in clinical trials (reported in ≥1% of patients) were: somnolence, weight gain, eosinophilia, increased levels of prolactin, cholesterol, glucose, and triglycerides in blood, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of liver transaminases, rash, asthenia, fatigue, hyperthermia, arthralgia, increased levels of alkaline phosphatase, gamma-glutamyl transferase, uric acid, creatine phosphokinase, and edema.

Table 1 summarizes the main adverse reactions and their frequency observed during clinical trials and/or based on post-marketing experience. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Frequency is classified as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from available data).

Table 1.

1 Clinically significant weight gain was observed in all BMI (body mass index) categories of patients. With short-term treatment (mean duration 47 days), weight gain of ≥ 7 % was reported very commonly (22.2 % of cases), ≥ 15 % commonly (4.2 % of cases), and ≥ 25 % uncommonly (0.8 % of cases). In patients receiving long-term therapy (at least 48 weeks), weight gain of ≥ 7 %, ≥ 15 %, and ≥ 25 % was reported very commonly (64.4 %, 31.7 %, and 12.3 % of cases, respectively).

2 Mean increases in fasting lipid levels (total cholesterol, LDL-C, and triglycerides) were greater in patients who initially had no lipid dysregulation.

3 Observed in patients with normal baseline fasting levels (< 5.17 mmol/L) that increased to high levels (≥ 6.2 mmol/L). Marked increases in fasting total cholesterol from baseline levels (≥ 5.17 — < 6.2 mmol/L) to high levels (≥ 6.2 mmol/L) were reported very commonly.

4 Observed in patients with normal baseline fasting levels (< 5.56 mmol/L) that increased to high levels (≥ 7 mmol/L). Marked increases in fasting glucose from baseline levels (≥ 5.56 — < 7 mmol/L) to high levels (≥ 7 mmol/L) were reported very commonly.

5 Observed in patients with normal baseline fasting levels (< 1.69 mmol/L) that increased to high levels (≥ 2.26 mmol/L). Marked increases in fasting triglycerides from baseline levels (≥ 1.69 — < 2.26 mmol/L) to high levels (≥ 2.26 mmol/L) were reported very commonly.

6 During clinical trials, the incidence of parkinsonism and dystonia in patients treated with olanzapine was quantitatively higher compared to placebo, but not statistically significantly different. The incidence of parkinsonism, akathisia, and dystonia in patients treated with olanzapine was lower than with titrated doses of haloperidol. Due to lack of information on the history of acute or late extrapyramidal movement disorders, it cannot be established that olanzapine causes tardive dyskinesia and/or other late extrapyramidal syndromes less frequently.

7 Upon abrupt discontinuation of olanzapine therapy, acute symptoms have been reported, including excessive sweating, insomnia, tremor, anxiety, nausea, and vomiting.

8 During clinical trials (up to 12 weeks), plasma prolactin concentrations were found to exceed the upper limit of normal in 30 % of patients treated with olanzapine. In most patients, this increase was mild and remained within values less than twice the upper limit of normal.

9 Adverse reactions identified in clinical trials, based on the integrated olanzapine database.

10 Assessment of findings from clinical trials according to the integrated olanzapine database.

11 Frequency of adverse reactions reported in spontaneous post-marketing reports, determined based on the integrated olanzapine database.

12 Frequency of adverse reactions reported in spontaneous post-marketing reports, estimated using the upper limit of the 95 % confidence interval based on the integrated olanzapine database.

Effects with long-term use (at least 48 weeks). The percentage of patients experiencing adverse reactions such as clinically significant weight gain, changes in glucose, total cholesterol/LDL-C/HDL-C, or triglyceride levels continuously increased. In adult patients who completed a 9–12 month treatment course, the rate of increase in fasting blood glucose slowed approximately after 6 months of treatment.

Adverse reactions in specific populations. In clinical trials in elderly patients with dementia, olanzapine treatment was associated with increased mortality and cerebrovascular adverse reactions compared to the placebo group. Very common adverse effects associated with olanzapine use in this patient group were gait disturbance and falls. Pneumonia, increased body temperature, somnolence, erythema, visual hallucinations, and urinary incontinence were commonly observed.

In clinical trials among patients with medication-induced (dopamine agonist) psychosis associated with Parkinson’s disease, worsening of parkinsonian symptoms and hallucinations occurred very commonly and more frequently than in the placebo group.

In one clinical trial in patients with bipolar mania, neutropenia occurred in 4.1 % of patients receiving olanzapine in combination with valproate, possibly due to increased plasma valproate levels.

With olanzapine use in combination with lithium or valproate, tremor, dry mouth, weight gain, and increased appetite were observed (≥ 10 %). Speech disorder was also reported. During olanzapine therapy in combination with lithium or divalproex for a short-term treatment period (up to 6 weeks), weight gain of ≥ 7 % compared to baseline was observed in 17.4 % of patients. Long-term olanzapine therapy (up to 12 weeks) for relapse prevention in patients with bipolar disorders resulted in weight gain of ≥ 7 % compared to baseline in 39.9 % of patients.

Children.

Olanzapine is not indicated for the treatment of children and adolescents. Although clinical trials comparing olanzapine use in adolescents and adults have not been conducted, data obtained from adolescent trials were comparable to results from adult trials.

Below are adverse reactions occurring more frequently in adolescents (aged 13–17 years) than in adults, and adverse reactions identified only during short-term clinical trials in adolescents. Clinically significant weight gain (≥ 7 %) was observed more frequently in adolescents compared to adults. With long-term treatment (at least 24 weeks), clinically significant weight gain was higher than with short-term treatment.

Within each frequency group, adverse reactions are listed in decreasing order of severity. The frequency of the adverse reactions listed below is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders.

Very common: weight gain¹³, increased triglycerides¹⁴, increased appetite.

Common: increased cholesterol¹⁵.

Nervous system disorders.

Very common: sedation (including hypersomnia, lethargy, somnolence).

Gastrointestinal disorders.

Common: dry mouth.

Hepatobiliary disorders.

Very common: increased liver transaminases (ALT and AST).

Investigations.

Very common: decreased total bilirubin, increased gamma-glutamyl transferase, increased plasma prolactin levels¹⁶.

13 With short-term treatment (mean duration 22 days), weight gain of ≥ 7 % was observed very commonly (40.6 % of cases), ≥ 15 % commonly (7.1 % of cases), and ≥ 25 % (2.5 % of cases). During long-term treatment (at least 24 weeks), weight gain of ≥ 7 % was observed in 89.4 % of patients, ≥ 15 % in 55.3 %, and ≥ 25 % in 29.1 %.

14 Observed in patients with normal baseline fasting levels (< 1.016 mmol/L) that increased to high levels (≥ 1.467 mmol/L). Marked increases in fasting triglycerides from baseline levels (≥ 1.016 — < 1.467 mmol/L) to high levels (≥ 1.467 mmol/L) were reported very commonly.

15 Observed in patients with normal baseline fasting cholesterol levels (< 4.39 mmol/L) increasing to high levels (≥ 5.17 mmol/L). Marked increases in fasting total cholesterol from baseline levels (≥ 4.39 — < 5.17 mmol/L) to high levels (≥ 5.17 mmol/L) were reported very commonly.

16 Increased plasma prolactin levels were observed in 47.4 % of adolescents.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 2 years.

Do not use the medicine after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required.

Keep out of reach of children.

Packaging. 10 tablets in a blister. 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activities.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.