Zalasta®

INSTRUCTIONS for medical use of the medicinal product Zalasta® (Zalasta®)

Composition:

Active substance: 1 tablet contains olanzapine 2.5 mg or 5 mg, or 7.5 mg, or 10 mg, or 15 mg, or 20 mg;

Excipients: Celactose (contains lactose monohydrate), pregelatinized starch, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate.

Dosage form. Tablets.

Main physicochemical properties:

tablets of 2.5 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks;

tablets of 5 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks and the imprint «5»;

tablets of 7.5 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks and the imprint «7.5»;

tablets of 10 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks and the imprint «10»;

tablets of 15 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks and the imprint «15»;

tablets of 20 mg: round, slightly biconvex, light yellow in color with possible separate yellow specks and the imprint «20».

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05A H03.

Pharmacological properties.

Pharmacodynamics.

Olanzapine is a neuroleptic, antimanic agent that stabilizes mood and also demonstrates a broad pharmacological profile across multiple receptor systems.

Olanzapine has affinity for receptors (Ki; < 100 nM) including serotonin 5-HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; muscarinic cholinergic receptors m1–m5; α1-adrenergic receptors; and histamine H1 receptors. In vitro, olanzapine demonstrated greater affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors, and greater in vivo activity at 5-HT2 receptors than at D2 receptors.

Pharmacokinetics.

Olanzapine is well absorbed after oral administration, reaching peak plasma concentration within 5–8 hours. Food intake does not affect absorption. Absolute oral bioavailability relative to intravenous administration has not been determined.

Olanzapine is metabolized in the liver via conjugative and oxidative pathways. The primary circulating metabolite is 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochrome P450 enzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites. Both metabolites exhibit significantly lower pharmacological activity in vivo compared to olanzapine. The predominant pharmacological activity is attributed to the parent olanzapine compound. After oral administration, the mean terminal elimination half-life of olanzapine in healthy volunteers varies depending on age and gender.

Plasma clearance of olanzapine is lower in elderly individuals compared to younger individuals, in women compared to men, and in non-smokers compared to smokers. However, the magnitude of the effects of age, gender, or smoking status on olanzapine clearance and elimination half-life is small relative to the overall inter-individual variability.

Olanzapine is approximately 93% bound to plasma proteins over the entire concentration range of about 7 to 1000 ng/mL. It binds primarily to albumin and α1-acid glycoprotein.

Clinical characteristics.

Indications.

Treatment of schizophrenia.

The medicinal product Zalasta® is effective for maintaining the achieved clinical response during long-term therapy in patients who have shown a response to initial treatment.

Treatment of moderate to severe manic episodes.

For prevention of recurrent manic episodes in patients with bipolar disorders who have responded to olanzapine treatment.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product. Risk of developing angle-closure glaucoma.

Interaction with other medicinal products and other forms of interaction.

Metabolism of olanzapine may be affected by inhibitors or inducers of cytochrome P450 isoenzymes, particularly CYP1A2 activity. Smoking or concomitant use of carbamazepine increases olanzapine metabolism, which may lead to reduced olanzapine concentrations. Known inhibitors of CYP1A2 activity may decrease olanzapine clearance. No inhibition of olanzapine metabolism was observed when administered with tricyclic antidepressants (CYP2D6), warfarin (CYP2C19), theophylline (CYP1A2), or diazepam (CYP3A4, CYP2C19). No interaction of olanzapine was observed when used 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. Concomitant use of ethanol with olanzapine may result in additional pharmacological effects, such as increased sedation. Fluoxetine, a single dose of antacids containing aluminium and magnesium, or cimetidine did not affect the oral bioavailability of olanzapine. Olanzapine may antagonize the effects of direct and indirect dopamine agonists. Concomitant administration of activated charcoal reduces the oral bioavailability of olanzapine by 50–60%; therefore, activated charcoal should not be administered within 2 hours before or 2 hours after olanzapine intake. Fluvoxamine, a CYP1A2 inhibitor, decreases olanzapine metabolism. This results in an average increase in maximum plasma concentration (Cmax) of olanzapine by 54% in non-smoking women and by 77% in smoking men. The average increase in area under the concentration-time curve (AUC) of olanzapine is 52% and 108%, respectively. For patients receiving fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, reduced doses of olanzapine should be prescribed. A dose reduction of olanzapine should be considered when initiating treatment with a CYP1A2 inhibitor.

Inhibitors of CYP2D6. Fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) causes an average increase in olanzapine Cmax by 16% and an average decrease in olanzapine clearance by 16%. The clinical significance of these effects is small compared to individual patient variability; therefore, dosage adjustment is usually not required.

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

Olanzapine should be used with caution when administered with other medicinal products known to prolong the QTc interval.

Potential ability of olanzapine to interact with other medicinal products

Antihypertensive agents. Olanzapine, due to its potential to cause orthostatic hypotension, may enhance the effects of certain antihypertensive agents.

Levodopa and dopamine agonists. Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Imipramine. Single doses of olanzapine do not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

Special precautions for use.

Psychosis associated with dementia and/or behavioral disorders

Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioral disorders and is therefore not recommended for use in such patients due to an increased risk of mortality and cerebrovascular events. Risk factors include age ≥65 years, dysphagia, sedation, malnutrition, dehydration, pulmonary conditions (pneumonia, with or without aspiration), and concomitant use of benzodiazepines. However, fatal events occurred more frequently with olanzapine treatment than with placebo, regardless of the presence of risk factors.

Cerebrovascular adverse reactions (including stroke and transient ischemic attack), some with fatal outcomes, have been reported. The incidence of cerebrovascular adverse reactions was three times higher in patients receiving olanzapine compared to those receiving placebo (1.3% vs. 0.4%). All patients who experienced cerebrovascular adverse reactions while receiving olanzapine or placebo had risk factors. Age ≥75 years and vascular/mixed-type dementia have been identified as risk factors for cerebrovascular adverse reactions during olanzapine therapy. The efficacy of olanzapine was not established in these studies.

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.

Neuroleptic Malignant Syndrome (NMS). NMS is a potentially fatal syndrome associated with antipsychotic drugs. Rare cases of NMS associated with olanzapine have been reported. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected or if hyperthermia occurs without full NMS presentation, all antipsychotic agents, including olanzapine, must be discontinued immediately.

Hyperglycemia and diabetes mellitus

Hyperglycemia and/or new-onset diabetes mellitus, or worsening of pre-existing diabetes, have been rarely reported, sometimes associated with ketoacidosis or hyperosmolar coma, and including fatal cases. In some cases, patients had increased body weight, which may have been a contributing risk factor.

Appropriate clinical monitoring is recommended for patients with diabetes and those with risk factors for developing diabetes, including measurement of blood glucose levels at the beginning of treatment, at 12 weeks, and annually thereafter. Patients receiving antipsychotic therapy, including olanzapine, should be monitored for symptoms of hyperglycemia (polydipsia, polyuria, polyphagia, and weakness). Blood glucose control should be regularly assessed in patients with diabetes or those at risk for developing diabetes. Body weight should also be monitored regularly, for example at the beginning of treatment, at 4, 8, and 12 weeks, and then quarterly.

Anticholinergic activity. Low incidence of anticholinergic effects has been reported. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, caution is advised when prescribing the drug to patients with benign prostatic hyperplasia, paralytic ileus, or similar conditions.

Liver function tests. Transient, asymptomatic elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are frequently observed during olanzapine therapy, particularly at the beginning of treatment.

Olanzapine should be used with caution in patients with elevated ALT and/or AST levels, symptoms of hepatic dysfunction, conditions associated with hepatic insufficiency, or those receiving potentially hepatotoxic drugs. Olanzapine must be discontinued if hepatitis (including hepatocellular, cholestatic, or mixed liver injury) is diagnosed.

Neutropenia. Olanzapine should be used with caution in patients with low leukocyte and/or neutrophil counts for any reason, patients receiving medications that may cause neutropenia, patients with a history of drug-induced bone marrow suppression or toxicity, patients with bone marrow suppression due to concomitant diseases, radiation, or chemotherapy, and patients with hypereosinophilia or myeloproliferative disorders. Neutropenia is a common adverse effect when valproate and olanzapine are used concomitantly.

Discontinuation of therapy. Very rare cases of acute symptoms following abrupt discontinuation of therapy have been reported, including excessive sweating, insomnia, tremor, agitation, nausea, or vomiting.

QT interval. Data indicate that olanzapine does not cause prolonged absolute QT or QTc intervals. However, as with other antipsychotics, caution is advised when olanzapine is used concomitantly with drugs that may prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

Thromboembolism. Rare associations between olanzapine treatment and venous thromboembolism (≥0.1%–<1%) have been reported. A causal relationship between olanzapine treatment and venous thromboembolism has not been established. However, considering that patients with schizophrenia are often predisposed to thromboembolic events, all potential risk factors, such as patient immobilization, should be taken into account, and appropriate preventive measures should be implemented.

General central nervous system (CNS) effects. Given the predominant CNS effects of olanzapine, additional precautions should be taken when olanzapine is used concomitantly with other CNS-acting agents, including alcohol consumption.

Seizures. Olanzapine should be used with caution in patients with a history of seizures or those at risk of lowered seizure threshold. Seizures have been rarely reported during olanzapine treatment. In most of these cases, patients had a history of seizures or other risk factors for seizure occurrence.

Tardive dyskinesia. Olanzapine has been associated with a statistically significantly lower incidence of treatment-emergent dyskinesia. Due to the increased risk of developing tardive dyskinesia with long-term use of antipsychotics, the dose should be reduced or the drug discontinued 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. As with other antipsychotics, periodic blood pressure monitoring is recommended for patients aged 65 years and older during olanzapine therapy.

Sudden cardiac death. Cases of sudden cardiac death have been reported in post-marketing surveillance. According to a retrospective observational cohort study, the risk of sudden cardiac death was nearly doubled compared to patients not using antipsychotics. The risk associated with olanzapine use is consistent with that of other atypical antipsychotics included in the combined analysis.

Dopaminergic antagonism. Olanzapine exhibits in vitro antagonism at dopamine receptors and, like other antipsychotics, may theoretically antagonize the effects of levodopa and dopamine agonists.

Glucose. Olanzapine is known to cause greater changes in glucose levels compared to placebo. The difference in glucose changes between olanzapine and placebo was greater in patients with a history of glucose dysregulation (including patients with diabetes or hyperglycemia). 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 increased steadily over time.

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

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

Elevations in total cholesterol, low-density lipoprotein (LDL), and triglycerides have been observed in patients receiving olanzapine compared to placebo.

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

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

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

Suicide. Suicide risk is inherent in both schizophrenia and bipolar I disorder, necessitating careful monitoring of patients at risk during therapy. To reduce the risk of overdose, olanzapine should be prescribed in small quantities sufficient to ensure appropriate therapeutic effect.

Body weight. The potential consequences of weight gain should be considered before initiating olanzapine therapy. Patients receiving olanzapine should undergo regular body weight monitoring.

Olanzapine monotherapy in adults. Weight gain has been observed in patients receiving olanzapine, with an average increase of 2.6 kg compared to an average weight loss of 0.3 kg in the placebo group over a median treatment duration of 6 weeks; 22.2% of patients receiving olanzapine experienced weight gain of at least 7% from baseline weight compared to 3% in the placebo group over a median treatment duration of 8 weeks; 4.2% of patients experienced weight gain of at least 15% from baseline weight compared to 0.3% in the placebo group over a median treatment duration of 12 weeks. Clinically significant increases in body mass index were observed across all patient categories. Discontinuation due to weight gain occurred in 0.2% of patients receiving olanzapine compared to 0% in the placebo group.

The mean weight gain in patients was 5.6 kg (median treatment duration 573 days; N = 2021). The proportion of patients with weight gain of at least 7%, 15%, or 25% from baseline weight during long-term olanzapine therapy was 64%, 32%, and 12%, respectively. 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 is 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 in the presence of factors that may lead to increased body temperature, such as strenuous exercise, exposure to extreme temperatures, concomitant use of drugs with anticholinergic activity, 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. Constipation, dry mouth, tachycardia, and other adverse effects possibly related to cholinergic antagonism have been reported with olanzapine use. Such adverse reactions rarely led to discontinuation of olanzapine, but caution is advised when using olanzapine in patients with clinically significant benign prostatic hyperplasia, narrow-angle glaucoma, history of paralytic ileus, or related conditions that may be exacerbated by cholinergic antagonism. In elderly patients with dementia-related psychosis (N = 1184) treated with olanzapine, treatment-related adverse reactions occurring at a frequency of ≥2% and significantly higher than in the placebo group included falls, somnolence, peripheral edema, gait disturbance, urinary incontinence, lethargy, weight gain, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse events was higher in the olanzapine group compared to placebo (13% vs. 7%). Elderly patients with dementia-related psychosis treated with olanzapine had 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. Such patients were excluded from pre-marketing clinical trials. Olanzapine should be used with caution in patients with cardiovascular diseases due to the risk of orthostatic hypotension.

Laboratory tests

Fasting glucose and lipid profile should be monitored at the beginning of treatment and periodically during therapy.

Hyperprolactinemia

Like other drugs with dopamine D2 receptor antagonist properties, olanzapine increases serum prolactin levels, and this elevation persists during long-term use. Hyperprolactinemia may suppress hypothalamic GnRH, leading to reduced pituitary gonadotropin secretion. This, in turn, may impair reproductive function by disrupting gonadal spermatogenesis in both men and women. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving drugs that elevate prolactin levels. Long-term hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both men and women.

Additional studies/laboratory data

Animal studies have reported neutropenia associated with other psychotropic components and leukopenia associated with olanzapine (see "Toxicological studies in animals"). Hematological parameters were evaluated with particular attention in pre-marketing olanzapine studies. There were no signs of clinically significant treatment-related neutropenia risk in the pre-marketing olanzapine database.

Post-marketing reports

Adverse reactions reported since olanzapine was marketed, which were temporally associated with olanzapine therapy (but not necessarily caused by it), included neutropenia.

Toxicological studies in animals

Animal studies with olanzapine have shown that the main hematological findings included reversible peripheral cytopenia in some 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 hemolytic anemia developed in several dogs receiving 10 mg/kg between 1 and 10 months of treatment. Dose-dependent decreases in lymphocyte and neutrophil counts were observed in mice receiving 10 mg/kg (twice the maximum recommended daily oral dose for humans on a mg/m² body surface area basis) during 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, suggesting that the reduction in circulating blood cells was likely related to peripheral (non-bone marrow) factors.

Lactose. Zalasta® tablets contain lactose and therefore should not be administered to patients with hereditary lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Adequate and well-controlled studies on the effects of olanzapine in pregnant women are lacking. Since human experience with olanzapine is limited, the drug should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Newborns exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy may be at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, with symptoms varying in intensity and duration. Symptoms reported include agitation, hypertension, hypotonia, tremor, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns should be closely monitored.

Olanzapine has been detected in human breast milk in healthy women. The average infant dose (mg/kg) without risk was estimated to be 1.8% of the maternal dose (mg/kg). Breastfeeding is not recommended for patients taking olanzapine.

Fertility. The effect on fertility is unknown.

Ability to affect reaction speed when driving or operating machinery.

Since olanzapine may cause somnolence and dizziness, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Adults

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

Manic episode: the initial dose is 15 mg as a single daily dose when used as monotherapy, or 10 mg daily as part of combination therapy.

Prevention of relapse in bipolar disorder: the recommended initial dose is 10 mg once daily. For patients who have been receiving olanzapine for treatment of a manic episode, continuation of therapy for relapse prevention should be carried out at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimization if necessary), and, based on clinical indication, adjunctive therapy should be added to improve mood symptoms.

During treatment of schizophrenia, manic episodes, and prevention of relapse in bipolar disorder, daily doses may be gradually adjusted according to individual clinical response within the range of 5–20 mg once daily. Dose increases above the recommended initial dose are advised only after appropriate clinical reassessment and should be performed at intervals of no less than 24 hours. Olanzapine may be taken regardless of food intake, as food does not affect absorption. Discontinuation of olanzapine should be performed by gradually reducing the dose.

Geriatric Patients

A lower initial dose (5 mg daily) is not routinely required; however, such a dose may be appropriate for patients aged 65 years and older if clinical factors raise concerns.

Renal and/or Hepatic Impairment

A lower initial dose (5 mg) should be considered for such patients. In patients with moderate hepatic impairment (cirrhosis, Child–Pugh class A or B), the initial dose should be 5 mg, and dose increases should be made cautiously.

A lower initial dose may be considered for patients with a combination of factors that may reduce olanzapine metabolism (female gender, advanced age, non-smoking status). Dose increases in these patients, if indicated, should be gradual and cautious.

Patients with a combination of the above-mentioned factors should initially receive the lowest dose (5 mg), with monitoring of their condition over the following several days. If no improvement is observed, the dose may be increased to 10 mg, provided that the patient's condition is monitored for several days after the dose increase. Dose escalation may continue as described above, up to the maximum dose of 20 mg.

Children

Olanzapine is not recommended for use in children due to insufficient data on safety and efficacy.

Overdose

Symptoms

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

Other medically significant consequences of overdose include delirium, seizures, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, arterial hypertension or hypotension, cardiac arrhythmias (< 2% of overdose cases), and cardiopulmonary shock. Fatal outcomes have been reported following acute overdose at a low dose of 450 mg, as well as survival after acute overdose with a dose of 1500 mg.

Treatment

There is no specific antidote for olanzapine. Agents that induce vomiting are not recommended. Standard procedures for overdose management may be employed (gastric lavage, administration of activated charcoal). Concomitant administration of activated charcoal has been shown to reduce the oral bioavailability of olanzapine by 50–60%.

Symptomatic treatment and monitoring of vital organ functions should be initiated according to the clinical condition, including management of arterial hypotension and collapse, and support of respiratory function. Epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity should not be used, as beta-stimulation may exacerbate arterial hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

Adverse Reactions

Adverse reactions associated with olanzapine use are classified by organ systems.

The most frequently reported adverse reactions (observed in ≥1% of patients) related to olanzapine use during clinical trials include: somnolence, weight gain, eosinophilia, increased levels of prolactin, cholesterol, glucose, and triglycerides, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section "Special Warnings and Precautions for Use"), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of liver transaminases (see section "Special Warnings and Precautions for Use"), rash, asthenia, fatigue, hyperthermia, arthralgia, increased levels of alkaline phosphatase, gamma-glutamyl transferase, uric acid, creatine phosphokinase, and edema.

Blood and lymphatic system disorders

Eosinophilia, leukopenia¹⁰, neutropenia¹⁰, thrombocytopenia¹¹.

Immune system disorders

Hypersensitivity¹¹.

Metabolism and nutrition disorders

Weight gain¹, increased cholesterol levels^2,3, increased glucose levels⁴, increased triglyceride levels^2,5, glucosuria, increased appetite, onset or worsening of diabetes, rarely associated with ketoacidosis or coma, including some fatal cases¹¹; hypothermia¹².

Nervous system disorders

Somnolence, dizziness, akathisia⁶, parkinsonism⁶, dyskinesia⁶, amnesia⁹, seizures (in patients with history or risk factors)¹¹; neuroleptic malignant syndrome¹²; dystonia (including ocular symptoms)¹¹; tardive dyskinesia¹¹; withdrawal syndrome^7,12, dysarthria, stuttering¹¹, restless legs syndrome¹¹.

Cardiac disorders

Bradycardia, QTc interval prolongation, ventricular tachycardia/fibrillation, sudden death¹¹.

Vascular disorders

Orthostatic hypotension¹⁰, thromboembolism (including pulmonary embolism and deep vein thrombosis).

Respiratory, thoracic and mediastinal disorders

Epistaxis⁹.

Gastrointestinal disorders

Mild, transient anticholinergic effects including constipation and dry mouth, abdominal distension⁹, hypersalivation, pancreatitis¹¹.

Hepatobiliary disorders

Transient, asymptomatic elevations of liver transaminases (alanine aminotransferase and aspartate aminotransferase), particularly at the beginning of treatment, peripheral edema, hepatitis (including hepatocellular, cholestatic, or mixed liver injury)¹¹.

Skin and subcutaneous tissue disorders

Rash, photosensitivity reactions, alopecia, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders

Arthralgia⁹, rhabdomyolysis¹¹.

Renal and urinary disorders

Urinary incontinence; urinary retention, difficulty in micturition¹¹.

Reproductive system and breast disorders

Erectile dysfunction in men; decreased libido in women and men, amenorrhea; breast enlargement; galactorrhea in women; gynecomastia/breast enlargement in men, priapism¹².

Pregnancy, postpartum and perinatal period

Withdrawal syndrome in newborns.

General disorders and administration site conditions

Asthenia, fatigue, edema, pyrexia¹⁰.

Investigations

Increased plasma prolactin levels⁸, increased creatine phosphokinase levels¹¹, increased total bilirubin levels, increased alkaline phosphatase levels¹⁰, increased gamma-glutamyl transferase levels¹⁰, increased uric acid levels¹⁰.

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

2 Mean increase in fasting lipid levels (total cholesterol, LDL-C, and triglycerides) was greater 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). Sudden increase in fasting total cholesterol (≥6.2 mmol/L) was reported very commonly.

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

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

6 The incidence of parkinsonism and dystonia in patients treated with olanzapine was higher than in placebo groups, but clinically insignificant. The incidence of parkinsonism, akathisia, and dystonia with olanzapine was lower than with titrated doses of haloperidol. Due to lack of information on prior history of acute or late extrapyramidal movement disorders, it cannot be established that olanzapine causes less tardive dyskinesia and/or other late extrapyramidal syndromes.

7 Acute symptoms such as excessive sweating, insomnia, tremor, agitation, nausea, and vomiting have been reported following abrupt discontinuation of olanzapine.

8 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 less than twice the upper normal limit.

9 Adverse reactions identified from clinical trials in the integrated olanzapine database.

10 Assessment based on measured values from clinical trials in the integrated olanzapine database.

11 Adverse reactions identified from spontaneous post-marketing reports, with frequency determined based on the integrated olanzapine database.

12 Adverse reactions identified from spontaneous post-marketing reports, with frequency estimated using the upper limit of the 95% confidence interval based on the integrated olanzapine database.

Use in Specific Patient Populations

Very common adverse reactions (≥10%) associated with olanzapine use in elderly patients with dementia-related psychosis include gait disturbance and falls; common adverse reactions (<10% and ≥1%) include urinary incontinence, elevated body temperature, erythema, visual hallucinations, and pneumonia.

Effects of Long-Term Use (≥48 weeks)

The proportion 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 completing 9–12 months of therapy, the rate of increase in fasting blood glucose slowed after approximately 6 months of treatment.

Adverse Reactions in Specific Populations

In elderly patients with dementia, olanzapine therapy has been associated with increased mortality and cerebrovascular adverse reactions. Very common adverse reactions in these patients include gait disturbance and falls. Pneumonia, elevated body temperature, lethargy, erythema, visual hallucinations, and urinary incontinence were commonly observed.

In 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.

Data indicate that neutropenia occurred in 4.1% of patients with bipolar mania treated with olanzapine in combination with valproate, possibly due to increased plasma valproate levels.

When olanzapine is used with lithium or valproate, tremor, dry mouth, weight gain, and increased appetite have been observed (≥10%). Speech disturbances have also been reported. During olanzapine therapy combined with lithium or divalproex, ≥7% body weight gain from BMI was observed in 17.4% of patients during intensive treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 weeks) for prevention of relapse in patients with bipolar disorders was associated with ≥7% body weight gain from BMI in 39.9% of patients.

Shelf life. 5 years.

Storage conditions.

Store in original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging.

7 tablets in a blister; 4 or 8 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

KRKA, d. d., Novo mesto, Slovenia.

Manufacturer's location and address of business activity.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.

Manufacturer.

KRKA Poland Sp. z o.o., Poland.

Manufacturer's location and address of business activity.

Równoległa 5, Warsaw, 02-235, Poland.