Adajio®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ADAGIO® (ADAGIO)

Composition:

Active substance: olanzapine;

1 tablet contains 2.5 mg of olanzapine;

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

Film coating: hypromellose, Opadry Yellow 03B220084 (hypromellose, titanium dioxide (E 171), talc, macrogol, iron oxide yellow (E 172)), carnauba wax, beeswax (60:40).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex tablets, film-coated, light yellow to yellow in colour.

Pharmacotherapeutic group. Antipsychotics. ATC code N05A H03.

Pharmacological Properties.

Pharmacodynamics.

Olanzapine is an antipsychotic and antimanic medicinal agent with mood-stabilizing properties, 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. In vitro, olanzapine demonstrated greater affinity for serotonin 5HT2 receptors than for dopamine D2 receptors, and greater in vivo activity at 5HT2 versus D2 receptors. Electrophysiological studies showed that olanzapine selectively reduces 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. Unlike some other antipsychotic agents, olanzapine enhances responses to stimuli during anxiolytic testing.

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

Clinical Efficacy. In two out of two placebo-controlled and two out of three comparator-controlled trials involving over 2900 patients with schizophrenia exhibiting 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 of varying severity associated with depressive symptoms (16.6 points on the Montgomery–Åsberg Depression Rating Scale), a prospective secondary analysis from baseline to endpoint showed statistically significant mood 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 with olanzapine (10 mg) for 2 weeks, significant reduction in manic symptoms was observed compared to monotherapy with lithium or valproate alone 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 showed statistically significant superiority over placebo in the primary endpoint assessing bipolar disorder relapse. Olanzapine also demonstrated statistically significant advantages over placebo in preventing both manic and depressive relapses.

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

In an 18-month study evaluating combination therapy for manic or mixed episodes, patients' conditions were stabilized with olanzapine, and then lithium or valproate was used as a mood stabilizer. No statistically significant advantage was demonstrated over monotherapy with lithium or valproate in delaying bipolar disorder relapses as defined by syndromal (diagnostic) criteria.

Children. Experience with use in adolescents (aged 13 to 17 years) is limited. Data are available from studies on short-term treatment efficacy for 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; plasma Cmax is 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. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to 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 compound olanzapine.

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

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 was reduced (17.5 vs. 18.2 L/h) compared to younger volunteers. However, pharmacokinetic variations observed in elderly volunteers remained within the range seen in younger volunteers. In 44 schizophrenia patients over 65 years of age 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 reduced (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 on the impact of impaired liver function, involving 6 patients with clinically significant cirrhosis (Child–Pugh class A (n = 5) and B (n = 1)), showed minimal effect 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 impairment (n = 3). The cirrhotic group included more smokers (4/6; 67%) than the non-impaired group (0/3; 0%).

Smoking Patients. In non-smokers compared to smokers (both men and women), the mean elimination half-life was longer (38.6 vs. 30.4 hours), and plasma clearance was reduced (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, sex, and smoking have only a modest 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. The pharmacokinetics of olanzapine 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 achieved clinical response during long-term therapy in patients who have responded 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 interactions 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 concomitant 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; however, clinical monitoring is recommended and dose adjustment of olanzapine may be necessary.

CYP1A2 inhibitors. Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces olanzapine metabolism. This results in a mean increase in Cmax of 54% in non-smoking women and 77% in smoking men after fluvoxamine administration. The mean increase in AUC of olanzapine is 52% and 108%, respectively. For patients receiving fluvoxamine or any other CYP1A2 inhibitors (e.g., 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.

Reduced bioavailability. Activated charcoal reduced the oral bioavailability of olanzapine by 50–60%; it should be administered at least 2 hours before or 2 hours after olanzapine intake.

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

Potential effect of olanzapine on 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, no significant interactions are 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 was observed when olanzapine was co-administered with lithium or biperiden.

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 medications that may cause central nervous system depression.

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

QTc interval. Olanzapine should be used with caution when co-administered 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. Careful monitoring of patients is required throughout 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 such 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 death was twice as high in patients receiving olanzapine compared to placebo (3.5% vs. 1.5%, respectively). Increased mortality was not associated with 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 and dehydration, presence of pulmonary disease (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 events (stroke, transient ischaemic attacks), including fatal cases, 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 medications is not recommended in patients with Parkinson's disease and dementia. In clinical trials, worsening of Parkinsonian symptoms and hallucinations occurred very commonly, more frequently than with placebo; for psychotic symptoms, olanzapine therapy was not more effective than placebo. From the beginning of these trials, patients were required to remain on the lowest effective dose of anti-Parkinson medications (dopamine agonists), and the same anti-Parkinson medications 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. Rare cases of NMS associated with olanzapine use have been reported. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic 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 onset of NMS or the presence of hyperthermia without full NMS manifestations requires immediate discontinuation of all antipsychotic agents, including olanzapine.

Hyperglycaemia and diabetes mellitus. Rare cases of hyperglycaemia and/or onset or worsening of pre-existing diabetes mellitus, associated with ketoacidosis or diabetic coma, as well as fatal outcomes, have been reported. Weight gain, which may be a risk factor, has sometimes been reported previously.

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

Anticholinergic activity. Although olanzapine has demonstrated anticholinergic activity in vitro, clinical trial experience has shown a low frequency of anticholinergic effects. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, the drug should be used cautiously in 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, particularly at the beginning of treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, symptoms of hepatic dysfunction, conditions associated with hepatic insufficiency, and 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 count and/or neutrophils for any reason, in patients receiving drugs that may cause neutropenia, in patients with a history of drug-induced bone marrow suppression/toxicity, in patients with bone marrow suppression due to concomitant diseases, radiation, or chemotherapy, in patients with hypereosinophilia or myeloproliferative disorders. Neutropenia has been frequently reported with concomitant use of olanzapine and valproate.

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

QT interval. In clinical trials involving patients receiving olanzapine, clinically significant prolongation of the QTc interval (corrected QT using Fridericia’s formula [QTcF] ≥500 ms at any time after baseline in patients with baseline QTcF <500 ms) was infrequent (0.1–1%), but no significant difference in cardiac-related events compared to placebo was observed. However, as with other antipsychotics, olanzapine should be used cautiously with drugs that prolong the QTc interval, particularly in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalaemia, or hypomagnesaemia.

Thromboembolism. Venous thromboembolism has been infrequently reported (≥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 a predisposition to thromboembolism, all possible risk factors, such as immobilization, should be considered and appropriate preventive measures taken.

General central nervous system (CNS) effects. Due to the primary CNS effects of olanzapine, caution should be exercised when administering it in combination 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 with caution in patients with a history of seizures or in the presence of factors that lower the seizure threshold. Seizures have been infrequently reported during olanzapine treatment. In most of these cases, patients had a history of seizures or were at increased risk of developing them.

Tardive dyskinesia. In clinical trials lasting 1 year or less, olanzapine treatment was associated with a statistically significant reduction in the incidence of treatment-emergent dyskinesia. Because the risk of developing tardive dyskinesia increases 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 infrequently reported 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.

Dopaminergic antagonism. Olanzapine exhibits in vitro dopamine receptor antagonism and theoretically may counteract the effects of levodopa and dopamine agonists, as do other antipsychotics.

Glucose. In clinical trials (up to 52 weeks), olanzapine caused greater changes in glucose levels compared to placebo. The difference in changes between olanzapine and placebo was greater in patients with a history of glucose dysregulation (including patients with diabetes or hyperglycaemia). In these patients, significant increases in HbA1c were observed compared to the placebo group.

The percentage of patients whose glucose levels changed from normal or borderline to high continuously increased.

In analyses of patients who completed 9–12 months of olanzapine therapy, elevated blood glucose levels decreased after 6 months.

Lipid level changes. Adverse changes in lipid levels may occur in patients treated with olanzapine. Lipid levels should be appropriately managed in patients with dyslipidaemia and in patients with risk factors for lipid metabolism disorders. Patients receiving antipsychotic treatment, including olanzapine, should have regular monitoring of blood lipid levels, for example: at the start of treatment, after 12 weeks, and every 5 years thereafter.

In clinical trials lasting more than 12 weeks, patients receiving olanzapine showed increases in total cholesterol, low-density lipoprotein (LDL), and triglycerides compared to the placebo group.

Significant increases in lipid levels (total cholesterol, LDL, triglycerides) were more frequently observed in patients without a history of lipid metabolism disorders.

No statistically confirmed differences were observed in high-density lipoprotein (HDL) increases between patients receiving olanzapine and those receiving placebo.

The quantitative proportion of patients whose total cholesterol, LDL, or triglyceride levels changed from normal or borderline to high, or whose HDL levels changed from normal or borderline to low, was greater in long-term trials (≥48 weeks) compared to short-term trials. In patients completing 12 months of therapy, total cholesterol levels did not increase after 4–6 months.

Suicidality. Suicidal tendencies are inherent in patients with schizophrenia and bipolar I disorder, thus patients at high risk of suicide receiving olanzapine therapy require careful monitoring. To reduce the possibility of overdose, olanzapine should be prescribed in small quantities sufficient to ensure proper therapeutic effect.

Body weight. The potential consequences of weight gain should be considered before initiating olanzapine therapy. Patients receiving olanzapine should regularly monitor their body weight.

Olanzapine monotherapy in adults. In 13 placebo-controlled clinical trials, patients receiving olanzapine therapy showed an average weight gain of 2.6 kg compared to an average weight loss of 0.3 kg in the placebo group with a median treatment duration of 6 weeks; 22.2% of patients receiving olanzapine showed weight gain of at least 7% of baseline weight compared to 3% in the placebo group with a median treatment duration of 8 weeks; 4.2% of patients showed weight gain of at least 15% of baseline weight compared to 0.3% in the placebo group with a median treatment duration of 12 weeks. Clinically significant weight gain was observed across all BMI categories. Treatment discontinuation due to weight gain occurred in 0.2% of patients receiving olanzapine compared to 0% in the placebo group.

In long-term clinical trials (≥48 weeks), the mean weight gain in patients was 5.6 kg (median duration 573 days; N = 2021). The proportion of patients with weight gain of at least 7%, 15%, or 25% of initial weight during long-term olanzapine use was 64%, 32%, and 12%, respectively. Treatment discontinuation due to weight gain occurred in 0.4% of patients receiving olanzapine for at least 48 weeks.

Dysphagia. Esophageal motility disorders and respiratory distress have been associated with antipsychotic use. Aspiration pneumonia was a common cause of morbidity and mortality in patients with Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.

Body temperature regulation. Impaired ability of the body to reduce its temperature has been observed with antipsychotics. This should be considered when prescribing olanzapine to patients who may experience elevated body temperature, for example due to strenuous exercise, exposure to extreme temperatures, concomitant use of anticholinergic agents, or dehydration.

Use in patients with concomitant diseases. Clinical experience with olanzapine in patients with certain diseases is limited. Olanzapine enhances in vitro affinity for muscarinic receptors. In premarketing clinical trials, olanzapine use was associated with constipation, dry mouth, tachycardia, and other adverse effects possibly related to cholinergic antagonism. Such adverse reactions rarely led to discontinuation of olanzapine therapy, but olanzapine should be used cautiously in patients with clinically significant prostatic hypertrophy, narrow-angle glaucoma, history of paralytic ileus, or related conditions due to cholinergic antagonism that may worsen in the presence of olanzapine. In 5 placebo-controlled trials of olanzapine in elderly patients with dementia-related psychosis (n = 1184), treatment-emergent adverse reactions occurring at a frequency of at least 2% and significantly more frequently than in the placebo group included: falls, somnolence, peripheral oedema, gait disturbance, urinary incontinence, lethargy, weight gain, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of treatment discontinuation due to adverse events was higher in the olanzapine group compared to placebo (13% vs. 7%). Elderly patients with dementia-related psychosis receiving olanzapine have a higher mortality rate compared to the placebo group. Olanzapine is not indicated for the treatment of elderly patients with dementia-related psychosis. Olanzapine has not been used in a sufficient number of patients with recent myocardial infarction or unstable cardiac disease. Patients with these diagnoses were excluded from premarketing clinical trials. Olanzapine should be used cautiously in patients with cardiac disease due to the risk of orthostatic hypotension.

Laboratory tests. Fasting glucose and lipid profile should be monitored at the start of treatment and periodically during treatment.

Hyperprolactinaemia. Like other agents with dopamine D2 receptor antagonist properties, olanzapine increases serum prolactin levels, and this elevation persists during long-term use. Hyperprolactinaemia may suppress hypothalamic GnRH, resulting in decreased pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by disrupting gonadal spermatogenesis in both men and women. Galactorrhoea, amenorrhoea, gynaecomastia, and impotence have been reported in patients receiving drugs that elevate prolactin levels. Long-term hyperprolactinaemia associated with hypogonadism may lead to decreased bone density in both men and women.

Additional investigations / laboratory data. Given that neutropenia associated with other psychotropic agents and leucopenia associated with olanzapine were observed in some animal studies (see below "Toxicological studies in animals"), haematological parameters were evaluated with particular attention in premarketing olanzapine trials. In the premarketing olanzapine database, there were no indications of a risk of clinically significant neutropenia associated with olanzapine treatment.

Post-marketing reports. Reports of adverse reactions after olanzapine marketing, including neutropenia, were temporally associated with its use but not necessarily causally related.

Toxicological studies in animals. In animal studies with olanzapine, the main haematological reactions were reversible peripheral cytopenia in individual dogs at a dose of 10 mg/kg (17 times the maximum recommended daily oral dose for humans on a mg/m² body surface area basis), dose-dependent decreases in lymphocyte and neutrophil counts in mice, and lymphopenia in rats. Reversible neutropenia and/or reversible haemolytic anaemia developed in several dogs receiving 10 mg/kg between months 1 and 10 of treatment. Dose-dependent decreases in lymphocyte and neutrophil counts were observed in mice receiving 10 mg/kg (equivalent to twice the maximum recommended daily oral dose for humans on a mg/m² body surface area basis) in 3-month studies. Non-specific lymphopenia, associated with reduced body weight gain, was observed in rats receiving 22.5 mg/kg (11 times the maximum recommended daily oral dose for humans on a mg/m² body surface area basis) for 3 months or 16 mg/kg (8 times the maximum recommended daily oral dose for humans on a mg/m² body surface area basis) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any of the species studied. Bone marrow cells were normocellular or hypercellular, indicating that the reduction in circulating blood cells was likely due to peripheral (non-bone marrow-related) factors.

The medicinal product contains lactose. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is required 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. Women receiving olanzapine should inform their physician if they become pregnant or intend to become pregnant. Since experience with olanzapine use during pregnancy is limited, olanzapine should be used during pregnancy only if the expected 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 developing adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, the symptoms of which may vary in intensity and duration after birth. Agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. 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 when 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 once daily 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 changes according to clinical indications.

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 status within the range of 5–20 mg/day. Dose increases above the recommended initial dose should only be made after appropriate clinical reassessment and should occur at intervals of no less than 24 hours.

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

Elderly patients. A lower initial dose (5 mg/day) should be considered in patients aged 65 years and older, based on appropriate clinical factors.

Renal and/or hepatic impairment. A lower initial dose (5 mg) is recommended for these patients. In cases of 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 enhance the metabolism of olanzapine. Clinical monitoring is recommended, and consideration should be given to increasing the olanzapine dose if necessary.

A lower initial dose may be considered for 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 made gradually and with caution.

Children. Olanzapine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy. In short-term studies, adolescents showed greater increases in body weight and greater changes in lipid levels and prolactin 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 documented 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 managing overdose should be implemented (including gastric lavage and administration of activated charcoal). Concomitant administration of activated charcoal reduced the bioavailability of oral olanzapine by 50–60%.

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

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

Adverse Reactions

During clinical studies, the most commonly observed adverse reactions (occurring in ≥ 1% of patients) associated with olanzapine use 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 studies 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 (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Table 1

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

2 Mean increase in fasting lipid levels (total cholesterol, LDL [low-density lipoproteins], and triglycerides) was more pronounced in patients who initially had no lipid dysregulation.

3 Observed in patients with normal baseline fasting levels (< 5.17 mmol/L), which increased to high levels (≥ 6.2 mmol/L). Rapid increase in fasting total cholesterol from baseline levels (≥ 5.17 to < 6.2 mmol/L) to high levels (≥ 6.2 mmol/L) was reported very commonly.

4 Observed in patients with normal baseline fasting levels (< 5.56 mmol/L), which increased to high levels (≥ 7 mmol/L). Rapid increase in fasting glucose from baseline levels (≥ 5.56 to < 7 mmol/L) to high levels (≥ 7 mmol/L) was reported very commonly.

5 Observed in patients with normal baseline fasting levels (< 1.69 mmol/L), which increased to high levels (≥ 2.26 mmol/L). Rapid increase in fasting triglycerides from baseline levels (≥ 1.69 to < 2.26 mmol/L) to high levels (≥ 2.26 mmol/L) was reported very commonly.

6 During clinical trials, the incidence of parkinsonism and dystonia in patients treated with olanzapine was numerically higher than with 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 were reported: increased sweating, insomnia, tremor, anxiety, nausea, and vomiting.

8 In clinical trials (up to 12 weeks), plasma prolactin concentrations exceeded 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 values identified in 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 of 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 / HDL [high-density lipoproteins] or triglycerides, 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 therapy 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 % with olanzapine in combination with valproate; this may be due to increased plasma valproate levels.

With olanzapine used 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, within short-term treatment (up to 6 weeks), weight gain of ≥ 7 % from baseline was observed in 17.4 % of patients. Long-term olanzapine therapy (up to 12 weeks) for prevention of relapse in patients with bipolar disorders led to weight gain of ≥ 7 % from baseline in 39.9 % of patients.

Children

Olanzapine is not indicated for treatment in 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 %) occurred 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 order of decreasing 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 and gastrointestinal disorders

Very common: weight gain¹³, increased triglyceride levels¹⁴, increased appetite.

Common: increased cholesterol levels¹⁵.

Nervous system disorders

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

Gastrointestinal disorders

Common: dry mouth.

Hepatobiliary disorders

Very common: increased liver transaminase levels (ALT and AST).

Investigations

Very common: decreased total bilirubin levels, increased gamma-glutamyltransferase levels, increased plasma prolactin levels¹⁶.

¹³ With short-term treatment (mean duration 22 days), weight gain of ≥ 7 % was very common (40.6 % of cases), ≥ 15 % was common (7.1 % of cases), and ≥ 25 % occurred in 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), which increased to high levels (≥ 1.467 mmol/L). Rapid increase in fasting triglycerides from baseline levels (≥ 1.016 to < 1.467 mmol/L) to high levels (≥ 1.467 mmol/L) was reported very commonly.

¹⁵ Observed in patients with normal baseline fasting cholesterol levels (< 4.39 mmol/L), which increased to high levels (≥ 5.17 mmol/L). Rapid increase in fasting total cholesterol from baseline levels (≥ 4.39 to < 5.17 mmol/L) to high levels (≥ 5.17 mmol/L) was reported very commonly.

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

Suspected adverse reactions reporting

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required.

Keep out of reach of children.

Packaging. 10 tablets per blister. 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's location and address of its business activity.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.