Zolafrin

I N S T R U C T I O N for medical use of the medicinal product ZOLAFREN (ZOLAFREN)

Composition:

Active substance: 1 tablet contains 5 mg or 10 mg of olanzapine;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate; coating: hypromellose (hydroxypropylmethylcellulose), polyethylene glycol (Macrogol) 400, colorant Yellow No.6 Al-Lake (E 110), titanium dioxide (E 171), yellow iron oxide (E 172), lactose monohydrate.

Medicinal form. Film-coated tablets.

Main physicochemical properties: 5 mg tablets: beige-colored, film-coated, biconvex tablets with a break line on one side, 7 mm in diameter;

10 mg tablets: beige-colored, film-coated, biconvex tablets, 7 mm in diameter.

Pharmacotherapeutic group. Antipsychotic agents. ATC code: N05A H03.

Pharmacological Properties.

Pharmacodynamics.

Olanzapine is an antipsychotic and antimanic agent with mood-stabilizing properties, exhibiting a broad spectrum of pharmacological activity due to its effects on various receptors. Binding has been demonstrated to serotonin receptors 5-HT2A/2C, 5-HT3, 5-HT6, dopamine receptors D1, D2, D3, D4, D5, muscarinic receptors M1–M5, the α1-adrenergic receptor, and the histamine H1 receptor. In animal behavioral studies, olanzapine demonstrated antagonism at both serotonin 5-HT and dopamine as well as cholinergic receptors. Olanzapine exhibits higher binding affinity to serotonin 5-HT2 receptors than to dopamine D2 receptors in both in vitro and in vivo models. 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 suppresses conditioned avoidance response, indicating antipsychotic activity at doses lower than those causing catalepsy—a sign of motor side effects. Unlike some other antipsychotics, olanzapine enhances responses to stimuli in anxiety tests.

In positron emission tomography (PET) studies with healthy volunteers after a single 10 mg dose, olanzapine showed greater binding to 5-HT2A receptors than to dopamine D2 receptors. Furthermore, analysis of single-photon emission computed tomography (SPECT) images from patients with schizophrenia revealed that patients responsive to olanzapine had lower striatal D2 receptor binding compared to patients responsive to other antipsychotics and risperidone, and similar 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 and both 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 showed statistically significant improvement (p = 0.001) with olanzapine (–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 weeks 6 and 12 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 after 6 weeks.

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

In a subsequent 12-month relapse prevention study in patients who achieved remission with combination therapy of olanzapine and lithium and were then randomized to continue olanzapine or lithium alone, olanzapine did not show statistically significant superiority over lithium in the primary endpoint of bipolar disorder relapse (olanzapine 30%, lithium 38.3%; p = 0.055).

In an 18-month study, patients with manic or mixed episodes were stabilized with olanzapine and then continued on lithium or valproate as mood stabilizers. No statistically significant advantage was demonstrated over monotherapy with lithium or valproate in delaying bipolar disorder relapses defined by syndromal (diagnostic) criteria.

Children.

Experience in adolescents (aged 13 to 17 years) is limited. Data are available from studies on 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. Increases in fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin were observed in adolescents compared to adults (see sections "Special Warnings and Precautions for Use," "Adverse Reactions"). There are no controlled data on maintenance of effect or long-term safety (see sections "Special Warnings and Precautions for Use," "Adverse Reactions"). Information on long-term safety is mainly limited to data from open-label, uncontrolled studies.

Pharmacokinetics.

Absorption.

Olanzapine is well absorbed after oral administration; peak plasma concentration (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. Cytochrome P450 enzymes CYP1A2 and 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 lower (17.5 vs. 18.2 L/h) compared to younger volunteers. Pharmacokinetic variations observed in elderly volunteers were within the range observed 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 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.

Hepatic Impairment.

A small study in 6 subjects with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)) showed minimal impact on the pharmacokinetics of oral olanzapine (single dose 2.5–7.5 mg): subjects with mild to moderate hepatic dysfunction had slightly increased systemic clearance and shorter elimination half-life compared to subjects without hepatic dysfunction (n = 3). Among subjects with cirrhosis, there were more smokers (4/6; 67%) than among those without hepatic dysfunction (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 limited influence on plasma clearance and elimination half-life of olanzapine compared to inter-individual variability.

Pharmacokinetic studies in Japanese and Chinese populations showed no significant differences between these and other populations.

Children.

Adolescents (aged 13 to 17 years): The pharmacokinetics of olanzapine in adolescents is similar to that in adults. 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.

Preclinical Safety Data

Acute (Single-Dose) Toxicity

Signs of oral toxicity in rodents were typical of potent neuroleptic compounds: hypoactivity, coma, tremor, clonic convulsions, salivation, and reduced weight gain. Median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without fatal outcomes. Clinical signs included sedation, ataxia, tremor, tachycardia, labored breathing, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg caused prostration, and higher doses led to a semiconscious state.

Repeated-Dose Toxicity

In studies lasting up to 3 months (in mice) and up to 1 year (in rats and dogs), the main effects were central nervous system (CNS) depression, anticholinergic effects, and peripheral hematological disorders. Tolerance to CNS depression developed over time. Growth parameters were reduced at high doses. Reversible effects related to elevated prolactin levels in rats included reduced ovarian and uterine weight and morphological changes in vaginal epithelium and mammary glands.

Hematological Toxicity

Effects on hematological parameters were observed in all species, including dose-dependent reduction in circulating leukocytes in mice and non-specific reduction in circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anemia developed in several dogs receiving 8 or 10 mg/kg/day (total olanzapine exposure [AUC] 12–15 times higher than in humans receiving a 12 mg dose). In dogs with cytopenia, no adverse effects on precursor and proliferating cells in the bone marrow were observed.

Reproductive Toxicity

Olanzapine showed no teratogenic effects. Sedation affected mating performance in male rats. Doses of 1.1 mg/kg (3 times the maximum human dose) affected the estrous cycle in rats, and doses of 3 mg/kg (9 times the maximum human dose) affected reproductive parameters. Offspring of rats treated with olanzapine showed delayed intrauterine development and transiently reduced activity levels.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, including bacterial mutagenicity tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on studies in mice and rats, olanzapine was concluded not to be carcinogenic.

Clinical Characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical response achieved 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; known risk of angle-closure glaucoma.

Interaction with other medicinal products and other forms of interactions.

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 influence the pharmacokinetics of olanzapine.

CYP1A2 inducers.

The metabolism of olanzapine may be induced by smoking and by the use of carbamazepine, leading to reduced olanzapine concentrations. A weak or moderate increase in olanzapine clearance has been observed. Clinical conclusions are limited, but clinical monitoring is recommended and, if necessary, an increase in the olanzapine dose (see section "Dosage and administration").

CYP1A2 inhibitors.

Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. 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, such as ciprofloxacin, reduced doses of olanzapine should be prescribed. Consideration should be given to reducing the olanzapine dose when initiating treatment with a CYP1A2 inhibitor.

Reduction of bioavailability.

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

Fluoxetine (a CYP2D6 inhibitor), a single dose of antacids containing aluminium and magnesium, or cimetidine did not significantly affect the pharmacokinetics of olanzapine.

Effect of olanzapine on other medicinal products.

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

Olanzapine did not inhibit the major CYP450 isoenzymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, significant interactions are not expected, which is 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 of olanzapine was observed when 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 CNS activity.

Olanzapine should be used with caution in patients taking ethanol or medicinal products that may cause central nervous system (CNS) depression.

Concomitant use of olanzapine with antiparkinsonian agents in patients with Parkinson's disease and dementia is not recommended (see section "Special precautions").

QTc interval.

Olanzapine should be administered with caution together with other agents that may prolong the QTc interval (see section "Special precautions").

CYP2D6 inhibitors. Fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) caused a mean increase in the maximum concentration of olanzapine by 16% and a mean decrease in olanzapine clearance by 16%. The clinical significance of these effects is small compared to inter-individual variability; therefore, dosage adjustments are generally not recommended.

Potential of olanzapine to interact with other medicinal products.

Antihypertensive agents. Olanzapine, due to its potential to lower blood pressure, 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.

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 disorders 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 disorders, 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 related to the dose of olanzapine used (mean daily dose 4.4 mg) or duration of treatment. Risk factors for increased mortality include age ≥65 years, dysphagia, sedation, poor nutrition, dehydration, pulmonary conditions (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 (e.g., stroke, transient ischemic attack), including fatal events, were observed in clinical trials. The incidence of cerebrovascular adverse reactions was three times higher in patients receiving olanzapine compared to 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 were identified as risk factors for cerebrovascular adverse reactions 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 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 continue using the lowest effective dose of anti-Parkinson medications (dopamine agonists) and to maintain the same anti-Parkinson medications and doses 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). Neuroleptic malignant syndrome (NMS) is a potentially fatal condition associated with antipsychotic drugs. Rare cases of NMS have been reported with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, 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 onset of NMS or hyperthermia without other clinical manifestations of NMS requires immediate discontinuation of all antipsychotic agents, including olanzapine.

Hyperglycemia and diabetes mellitus. Hyperglycemia and new-onset diabetes mellitus or worsening of pre-existing diabetes, sometimes associated with ketoacidosis or diabetic coma, have been reported infrequently, including fatal cases. Weight gain, which may be a risk factor, has sometimes preceded these events.

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 beginning of treatment, after 12 weeks, and annually thereafter. Patients receiving antipsychotic agents, including olanzapine, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus and those with risk factors for developing diabetes should be regularly monitored for worsening glycemic control. Body weight should be monitored regularly, e.g., at the beginning of treatment, after 4 weeks, 8 weeks, 12 weeks, and quarterly thereafter.

Anticholinergic activity. Low incidence of anticholinergic effects has been observed in clinical trials. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, caution is advised when prescribing olanzapine 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 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 levels, signs or symptoms of hepatic dysfunction, conditions associated with hepatic insufficiency, or those receiving potentially hepatotoxic drugs. Olanzapine should be discontinued if hepatitis (including hepatocellular, cholestatic, or mixed liver injury) is detected.

Neutropenia. Olanzapine should be used with caution in patients with low white blood cell or neutrophil counts for any reason, patients receiving medications 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 is a common adverse effect when valproate and olanzapine are used concomitantly.

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

QT interval. Clinically significant prolongation of the QTc interval has been observed in patients receiving olanzapine in clinical trials (QTcF [Fridericia-corrected] ≥500 milliseconds [ms] at any time after baseline in patients with QTcF <500 ms at baseline occurred infrequently—0.1% to <1%). No significant differences in cardiac adverse events were observed compared to placebo. However, caution is advised when olanzapine is used concomitantly with other drugs that prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, left ventricular hypertrophy, or low serum potassium or magnesium levels.

Thromboembolism. Venous thromboembolism has been reported infrequently (≥0.1% to <1%) during olanzapine treatment. A causal relationship between olanzapine and venous thromboembolism has not been established. However, considering that patients with schizophrenia are at increased risk for thromboembolic events, all possible risk factors (e.g., patient immobilization) should be considered, and appropriate preventive measures taken.

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 cautiously in patients with a history of seizures or conditions that lower the seizure threshold. Seizures have been reported infrequently during olanzapine treatment. In most cases, patients had a history of seizures or were at increased risk of seizures.

Tardive dyskinesia. In clinical trials of up to one year duration, olanzapine was associated with a statistically significant reduction in the incidence of treatment-emergent dyskinesia. 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 signs or 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. As with other antipsychotics, periodic blood pressure monitoring is recommended for patients aged 65 years and older during olanzapine treatment.

Sudden cardiac death. Post-marketing reports have described cases of sudden cardiac death. According to a retrospective observational cohort study, the risk of sudden cardiac death in patients receiving olanzapine was nearly doubled compared to patients not using antipsychotics. The risk with olanzapine is comparable to that of other atypical antipsychotics included in a combined analysis.

Lactose. This medicinal product contains lactose and should not be administered to patients with hereditary lactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Dopaminergic antagonism. Olanzapine exhibits in vitro dopamine antagonism and may theoretically antagonize the effects of levodopa and dopamine agonists, as do other antipsychotic agents.

Glucose. In clinical trials (up to 52 weeks), olanzapine caused 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 progressively increased over time.

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

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

In clinical trials longer 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 lipids (total cholesterol, LDL, triglycerides) occurred more frequently in patients without a history of lipid disorders.

No statistically significant differences were observed in high-density lipoprotein (HDL) increases between olanzapine and placebo groups.

The 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 higher 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 behavior is a risk in patients with schizophrenia and bipolar I disorder, necessitating careful monitoring of patients at high risk for suicide receiving olanzapine therapy. To reduce the risk 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 undergo regular body weight monitoring.

Olanzapine monotherapy in adults. Analysis of 13 placebo-controlled clinical trials showed that patients receiving olanzapine therapy had a mean body weight increase of 2.6 kg compared to a mean weight loss of 0.3 kg in the placebo group, with a median treatment duration of 6 weeks; 22.2% of patients receiving olanzapine had a weight gain of at least 7% of baseline body weight compared to 3% in the placebo group, with a median treatment duration of 8 weeks; 4.2% of patients had a weight gain of at least 15% compared to 0.3% in the placebo group, with a median treatment duration of 12 weeks. Clinically significant weight gain occurred across all BMI categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine-treated patients compared to 0% in the placebo group.

In long-term clinical trials (≥48 weeks), mean body weight increase was 5.6 kg (median duration 573 days; N = 2021). The proportion of patients with weight gain ≥7%, ≥15%, or ≥25% of baseline weight during long-term olanzapine treatment 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 to reduce body temperature has been observed with antipsychotic use. This should be considered when prescribing olanzapine to patients exposed to conditions that may increase body temperature, such as strenuous exercise, extreme environmental 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 exhibits 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 required discontinuation of olanzapine, but caution is advised when using olanzapine in patients with clinically significant benign prostatic hyperplasia, narrow-angle glaucoma, paralytic ileus, or related conditions due to cholinergic antagonism that may be exacerbated by olanzapine. In five placebo-controlled trials in elderly patients with dementia-related psychosis (n = 1184), treatment-related adverse reactions occurring in ≥2% of patients and significantly more frequently 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. 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 placebo. Olanzapine is not indicated for the treatment of elderly patients with dementia-related psychosis. Olanzapine has not been used in sufficient numbers of patients with recent myocardial infarction or unstable cardiac disease. Patients with these conditions were excluded from premarketing clinical trials. Olanzapine should be used with caution in patients with cardiovascular disease 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 treatment.

Hyperprolactinemia. Like other agents with dopamine D2 receptor antagonist properties, olanzapine increases serum prolactin levels, and this elevation persists with long-term use. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in 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 prolactin-elevating agents. Long-term hyperprolactinemia 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 leukopenia associated with olanzapine were observed in some animal studies (see "Toxicological studies in animals" below), hematological parameters were evaluated with particular attention in premarketing olanzapine trials. No risk of clinically significant treatment-related neutropenia was identified in these studies.

Post-marketing reports.

Post-marketing adverse reaction reports temporally associated (but not necessarily caused) by olanzapine therapy include neutropenia.

Toxicological studies in animals.

In animal studies with olanzapine, the main hematological findings 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 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 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 basis) for 3 months or 16 mg/kg (8 times the maximum recommended daily oral dose for humans on a mg/m² basis) for 6 or 12 months. No evidence of bone marrow cytotoxicity was found in any species studied. Bone marrow cells were normocellular or hypercellular, suggesting that reduced circulating blood cells were likely related to peripheral (non-bone marrow) factors.

The medicinal product Zolafren, film-coated tablets 5 mg and 10 mg, contains the excipient Yellow No.6 Al-Lake (E 110), which may cause allergic reactions.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

There are no adequate and well-controlled studies of olanzapine use in pregnant women. Patients receiving olanzapine should inform their physician if they become pregnant or intend to become pregnant. Because experience with olanzapine use during pregnancy is limited, olanzapine 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 for adverse reactions, including extrapyramidal and/or withdrawal symptoms, which may vary in severity and duration after birth. Reports include agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders. Therefore, newborns should be carefully monitored.

In a study of healthy breastfeeding women, olanzapine was detected in breast milk. The average infant dose (mg/kg) without risk was estimated to be 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 (see "Non-clinical safety data" above).

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Adults.

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

Manic episodes. The recommended initial dose of olanzapine as monotherapy is 15 mg daily or 10 mg daily when used in combination therapy.

Prevention of recurrent episodes in patients with bipolar disorder. The recommended initial dose is 10 mg daily. Patients with bipolar disorder who have been treated with olanzapine for manic episodes should continue olanzapine at the same dose for prevention of recurrent episodes. If a new manic, depressive, or mixed episode occurs, treatment should be continued (with dose optimization if necessary) along with supportive therapy to manage mood disorder symptoms, as clinically indicated.

Treatment of schizophrenia, manic episodes, and prevention of relapse in bipolar disorder. The daily dose should be individualized based on clinical status, within a range of 5 to 20 mg daily. Increases from the recommended initial dose should be made at intervals of no less than 24 hours and only after clinical evaluation. Olanzapine may be administered regardless of food intake, as food does not affect drug absorption. When discontinuing the medication, therapy should be tapered gradually.

Children. The use of olanzapine in children and adolescents is not recommended due to insufficient data on safety and efficacy. In short-term studies in adolescent patients, increased body weight, and changes in prolactin and lipid levels were observed compared to adults.

Elderly patients. A lower initial dose (5 mg daily) is generally not required. However, a lower initial dose should be considered for patients over 65 years of age if clinically indicated.

Patients with renal and/or hepatic impairment. A lower initial dose (5 mg daily) may be considered for these patients. In patients with moderate hepatic impairment (cirrhosis, Child-Pugh classes A or B), the initial dose should be 5 mg, and dose escalation should be performed cautiously.

Sex. Dose adjustment based on patient sex is not required.

Smoking patients. The initial dose and dosage range for non-smoking patients do not require routine adjustment compared to doses used in smoking patients.

Smoking may induce olanzapine metabolism. Clinical monitoring is recommended. If necessary, consider increasing the olanzapine dose (see section "Special Warnings and Precautions for Use").

Children.

Olanzapine is not recommended for the treatment of children and adolescents (under 18 years of age) due to lack of data on safety and efficacy. In short-term studies involving adolescent patients, greater increases in body weight, and changes in lipid and prolactin levels were reported compared to adult patients (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", "Pharmacodynamics", "Pharmacokinetics").

Overdose.

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

Other significant complications of overdose include delirium, seizures, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, arterial hypertension or hypotension, cardiac arrhythmia (< 2% of overdose cases), and cardiopulmonary shock. Fatal outcomes have been reported following acute overdose at a dose of 450 mg, although survival has also been documented after acute ingestion of up to 2 g of olanzapine orally.

Treatment. There is no specific antidote. Induction of emesis is not recommended. Standard overdose management procedures are recommended (e.g., gastric lavage, activated charcoal). Concomitant administration of activated charcoal has been shown to reduce the bioavailability of orally administered olanzapine by 50–60%.

Symptomatic treatment and monitoring of vital functions should be implemented based on clinical manifestations, including management of arterial hypotension and circulatory failure, as well as respiratory support. Epinephrine, dopamine, and other sympathomimetics with beta-agonist activity should not be used, as beta-stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect potential arrhythmias. Close medical supervision and monitoring should continue until full recovery of the patient.

Adverse reactions.

The most commonly observed adverse reactions (occurring in ≥ 1% of patients) associated with olanzapine use during clinical trials 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 in liver transaminases (see section "Special precautions"), rash, asthenia, increased 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 as determined during clinical trials and/or based on post-marketing experience.

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 from the available data).

Table 1.

Very common	Common	Uncommon	Rare	Frequency not known
Blood and lymphatic system disorders
	Eosinophilia Leukopenia10 Neutropenia10		Thrombocytopenia11
Immune system disorders
		Hypersensitivity11
Metabolism and nutrition disorders
Weight gain1	Increase in cholesterol levels2,3 Increase in glucose levels4 Increase in triglyceride levels2,5, glucosuria, increased appetite	Development or worsening of diabetes, associated with ketoacidosis or coma, including fatal outcomes11	Hypothermia12
Nervous system disorders
Somnolence	Dizziness, akathisia6, parkinsonism6, dyskinesia6	Epileptic seizures if there was a history or risk factors present11, dystonia (including ocular symptoms)11, tardive dyskinesia11, amnesia9, dysarthria, restless legs syndrome	Neuroleptic malignant syndrome12 (see section "Special precautions"), withdrawal syndrome7,12
Respiratory, thoracic and mediastinal disorders
		Nosebleeds9
Cardiac disorders
		Bradycardia, prolongation of QTc interval (see section "Special precautions")	Ventricular tachycardia/fibrillation, sudden fatal outcome11 (see section "Special precautions")
Vascular disorders
Orthostatic hypotension10		Thromboembolism (including pulmonary artery embolism and deep vein thrombosis) (see section "Special precautions")
Gastrointestinal disorders
	Mild, transient anticholinergic effects including constipation and dry mouth	Abdominal distension9 Increased salivation11	Pancreatitis11
Hepatobiliary disorders
	Transient, asymptomatic fluctuations in liver transaminase levels (ALT and AST), especially at the beginning of treatment, peripheral edema (see section "Special precautions")		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
Pregnancy, postpartum and perinatal period
				Withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding")
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
General disorders and administration site conditions
	Asthenia, increased fatigue, edema, pyrexia10
Investigations
Increased plasma prolactin concentration8	Increased levels of alkaline phosphatase10, creatine phosphokinase1, gamma-glutamyl transferase10, uric acid10	Increased total bilirubin

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 observed very commonly (22.2% of cases), ≥ 15% was observed commonly (4.2% of cases), and ≥ 25% was observed uncommonly (0.8% of cases). In patients receiving long-term therapy (at least 48 weeks), weight gain of ≥ 7%, ≥ 15%, and ≥ 25% was observed very commonly (in 64.4%, 31.7%, and 12.3% of cases, respectively).

2 Mean increases in fasting lipid levels (total cholesterol, LDL-C, and triglycerides) were more pronounced in patients who initially did not have 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 increases in fasting total cholesterol from baseline levels (≥ 5.17 to < 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), which increased to high levels (≥ 7 mmol/L). Rapid increases in fasting glucose from baseline levels (≥ 5.56 to < 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), which increased to high levels (≥ 2.26 mmol/L). Rapid increases in fasting triglyceride levels from baseline levels (≥ 1.69 to < 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 higher than in placebo-controlled trials, but clinically insignificant. 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 less tardive dyskinesia and/or other late extrapyramidal syndromes.

7 Acute symptoms have been reported following abrupt discontinuation of olanzapine treatment: increased sweating, insomnia, tremor, agitation, nausea, and vomiting.

8 During clinical trials (up to 12 weeks), plasma prolactin concentrations exceeded the upper limit of normal in 30% of patients receiving 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, according to 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, established 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-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 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, lethargy, 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 were observed 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; this may be due to increased plasma valproate levels.

Tremor, dry mouth, weight gain, and increased appetite were observed (≥ 10%) with olanzapine use in combination with lithium or valproate. Speech disorder was also reported. Weight gain of ≥ 7% BMI (body mass index) was observed in 17.4% of patients during intensive treatment (up to 6 weeks) with olanzapine in combination with lithium or divalproex. Long-term olanzapine treatment (up to 12 weeks) for prevention of relapse in patients with bipolar disorders was associated with weight gain of ≥ 7% BMI in 39.9% of patients.

Children.

Olanzapine is not indicated for the treatment of children and adolescents. Clinical trials comparing olanzapine use in adolescents and adults have not been conducted.

Below are adverse reactions observed 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. During long-term treatment (at least 24 weeks), clinically significant weight gain was higher than during short-term treatment.

The frequency of 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 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 observed very commonly (40.6% of cases), ≥ 15% was observed commonly (7.1% of cases), and ≥ 25% was observed uncommonly (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 increases in fasting triglyceride levels from baseline levels (≥ 1.016 to < 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), which increased to high levels (≥ 5.17 mmol/L). Rapid increases in fasting total cholesterol from baseline levels (≥ 4.39 to < 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.

Other adverse reactions observed during clinical trials of oral olanzapine administration.

Nervous system disorders: uncommon (≥ 0.1%) – ataxia, dysarthria.

Withdrawal syndrome (including diarrhea, nausea, vomiting) has been reported very rarely.

Adverse reactions reported from post-marketing experience are listed below.

Hepatobiliary disorders: very rare (< 0.01%) – jaundice.

Skin and subcutaneous tissue disorders: rare (< 0.1% and > 0.01%) – rash.

Immune system disorders: allergic reactions, including: very rare (< 0.01%) – anaphylactic reactions, angioedema (< 0.01%), urticaria, or pruritus.

Other major adverse events characteristic of patients with bipolar mania receiving olanzapine in combination with lithium or valproate.

Tremor was reported very commonly (> 10%). Speech disorder was reported commonly (> 1% and < 10%).

Other major adverse events characteristic of patients with medication-induced (dopamine agonist) psychosis associated with Parkinson’s disease.

Hallucinations were reported very commonly (> 10%).

Other major adverse events characteristic of elderly patients with psychosis associated with dementia.

Gait disturbance was reported very commonly (> 10%).

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in the original packaging.

Keep out of reach of children.

Packaging. 30 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Adamed Pharma S.A., Poland.

Manufacturer’s address and place of business.

5 J. Pilsudski Marsz. St., 95-200 Pabianice, Poland.