Olflex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLFREX (OLFREX)

Composition:

Active substance: olanzapine;

1 film-coated tablet contains olanzapine 5 mg or 10 mg;

Excipients: lactose monohydrate, hydroxypropylcellulose, crospovidone, microcrystalline cellulose, magnesium stearate, Opadry AMB White OY-B-28920 coating*;

*Composition of Opadry AMB White OY-B-28920 coating: polyvinyl alcohol, titanium dioxide (E 171), talc, lecithin, xanthan gum.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg and 10 mg: white, oval-shaped, film-coated tablets.

Pharmacotherapeutic group. Antipsychotic agents. ATC code N05A H03.

Pharmacological Properties.

Pharmacodynamics.

Olanzapine is an antipsychotic, antimanic, and mood-stabilizing medicinal product with 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, adrenergic α1 receptor, and histamine H1 receptor. In animal behavioral studies, olanzapine demonstrated antagonism both at serotonin 5-HT and dopamine and cholinergic receptors. Olanzapine exhibits higher binding affinity to serotonin 5-HT2 receptors than to dopamine D2 receptors, as shown in both in vitro and in vivo models. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, while exerting minimal effects on striatal (A9) pathways associated with motor function. Olanzapine inhibits conditioned avoidance response, indicating its 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.

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

Clinical Efficacy.

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

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

In patients with manic or mixed episodes of bipolar disorder, olanzapine demonstrated high efficacy in reducing manic symptoms over 3 weeks compared to placebo and divalproex. Olanzapine also showed comparable efficacy 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 the addition of 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 of manic episodes in patients who achieved remission with olanzapine and were subsequently randomized to receive olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo in the primary endpoint of bipolar disorder relapse assessment. Olanzapine also showed statistically significant advantages over placebo in preventing recurrence of mania or depression.

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

In an 18-month study of combined treatment of manic or mixed episodes, where patients' conditions were stabilized with olanzapine and then continued on lithium or valproate as mood stabilizers, long-term combination therapy with olanzapine plus lithium or valproate did not demonstrate statistically significant superiority over monotherapy with lithium or valproate in delaying relapses of bipolar disorders, as defined by syndromal (diagnostic) criteria.

Children.

Experience in pediatric use (ages 13 to 17 years) is limited, based on data from short-term treatment studies of schizophrenia (6 weeks) and bipolar disorder-related mania (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 total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin levels were observed in adolescents compared to adults (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects"). Data on maintenance of therapeutic effect and long-term outcomes are limited and derived from open-label, uncontrolled clinical trials (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

Pharmacokinetics.

Absorption.

The drug is well absorbed after oral administration; Cmax in plasma is reached within 5–8 hours. Food intake does not affect the absorption of olanzapine. Absolute bioavailability of the oral formulation compared to intravenous administration has not been established.

Distribution.

Plasma protein binding of olanzapine is approximately 93% across concentrations ranging from 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-CYP1A2 and P450-CYP2D6 mediate the formation of N-desmethyl and 2-hydroxymethyl metabolites, which exhibit significantly lower pharmacological activity in vivo than olanzapine in animal studies. The predominant 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. Pharmacokinetic variations observed in elderly volunteers remain within the range observed in younger individuals. In 44 patients with schizophrenia 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, olanzapine (5–20 mg) showed a comparable safety profile in 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, no significant differences were observed in mean elimination half-life (37.7 vs. 32.4 hours) or plasma clearance (21.2 vs. 25.0 L/h). Studies indicate that approximately 57% of radiolabeled olanzapine is excreted in urine, primarily as metabolites.

Patients with Hepatic Impairment.

A study evaluating the effect of hepatic impairment in 6 patients with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)) showed minimal impact on the pharmacokinetics of orally administered olanzapine (single dose 2.5–7.5 mg). Patients with mild to moderate hepatic impairment had slightly increased systemic clearance and faster elimination compared to patients without hepatic impairment (n = 3). Among patients with cirrhosis, more were smokers (4/6; 67%) compared to those without hepatic impairment (0/3; 0%).

Smoking Patients.

In non-smokers compared to smokers (both men and women), the mean elimination half-life was prolonged (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 individuals compared to younger ones, in women compared to men, and in non-smokers compared to smokers. However, the extent of influence of age, sex, or smoking on olanzapine plasma clearance and elimination half-life is minor compared to overall inter-individual variability.

Pharmacokinetic studies in European, Japanese, and Chinese patients revealed no differences in olanzapine pharmacokinetics.

Children.

The pharmacokinetics of olanzapine in adolescents (13–17 years) 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 mean body weight and fewer smokers among adolescent patients. These factors likely contribute to the higher mean exposure to olanzapine observed in adolescents.

Clinical characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical response during long-term therapy in patients who have 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 adult patients.

Interactions that may affect olanzapine

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

CYP1A2 inducers

Metabolism of olanzapine may be induced by smoking and by the use of carbamazepine, leading to decreased 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 an average increase in maximum concentration (Cmax) of 54% in non-smoking women and 77% in smoking men after fluvoxamine administration. The average increase in the area under the concentration-time curve (AUC) of olanzapine is 52% and 108%, respectively. For patients taking fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, reduced doses of olanzapine should be prescribed. Dose reduction of olanzapine should be considered if treatment with a CYP1A2 inhibitor is initiated.

Reduced bioavailability

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

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

Potential of olanzapine to interact with other medicinal products

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

Olanzapine did not inhibit major CYP450 isoenzymes (e.g., 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, no specific 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 (primarily metabolized via CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4, 2C19).

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

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

General central nervous system (CNS) activity

Olanzapine should be used with caution in patients taking ethanol or medicinal products that may cause CNS depression.

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

QTc interval

Olanzapine should be used with caution when co-administered with other medicinal products known to prolong the QTc interval (see section "Special precautions").

Special precautions for use.

During antipsychotic treatment, clinical improvement in patients may take from several days to several weeks. Close monitoring of patients is required during this period.

Psychosis associated with dementia and/or behavioral disorders.

Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioral disturbances and is not recommended for use in these patients due to increased mortality and risk of cerebrovascular events. In placebo-controlled clinical trials (6–12 weeks duration) involving elderly patients (mean age 78 years) with psychosis associated with dementia and/or behavioral 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 related to the dose of olanzapine (mean daily dose 4.4 mg) or duration of treatment. Risk factors potentially contributing to increased mortality include age ≥65 years, dysphagia, sedation, malnutrition, dehydration, pulmonary conditions (pneumonia with or without aspiration), and concomitant use of benzodiazepines. However, mortality rates were higher with olanzapine therapy than with placebo regardless of risk factors.

Cerebrovascular adverse reactions (including stroke and transient ischemic attack), some fatal, were observed during clinical trials. The incidence of cerebrovascular adverse reactions was three times higher in patients receiving olanzapine compared to placebo (1.3% vs. 0.4%, respectively). 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 studies.

Parkinson’s disease. Olanzapine is not recommended for the treatment of psychosis associated with dopamine agonists in patients with Parkinson’s disease. In clinical trials, worsening of Parkinson’s disease symptoms and hallucinations occurred very frequently and more often than with placebo (see section "Adverse reactions"). In these trials, patients were required from the beginning to maintain the lowest effective dose of anti-Parkinson medications (dopamine agonists) and to continue the same anti-Parkinson drugs and doses throughout the study. Olanzapine therapy was initiated at a dose of 2.5 mg/day, titrated upward to a maximum of 15 mg/day.

Neuroleptic Malignant Syndrome (NMS). NMS is a potentially fatal syndrome described in association 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 cardiovascular instability (irregular pulse or blood pressure changes, tachycardia, diaphoresis, and cardiac arrhythmia). Additional features may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. The onset of NMS or the presence of hyperthermia without full clinical expression of NMS requires immediate discontinuation of all antipsychotic agents, including olanzapine.

Hyperglycemia and diabetes mellitus.

Cases of hyperglycemia and/or development or worsening of pre-existing diabetes mellitus, sometimes associated with ketoacidosis or diabetic coma, and even fatal outcomes, have been reported infrequently. Prior weight gain, which may be a risk factor, has sometimes been reported.

Appropriate clinical monitoring of patients with diabetes mellitus and those with risk factors for developing diabetes is recommended, including measurement of blood glucose levels at the beginning of treatment, at 12 weeks, and annually thereafter. Patients receiving antipsychotic medications, including olanzapine, should be monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes or at risk for diabetes should be regularly monitored for worsening glycemic control. Body weight should be monitored regularly, e.g., at the beginning of treatment, at 4 weeks, 8 weeks, 12 weeks, and quarterly thereafter.

Changes in lipid levels. Unfavorable changes in lipid levels were observed in patients receiving olanzapine in placebo-controlled clinical trials. Lipid level changes should be appropriately managed in patients with dyslipidemia and in those with risk factors for lipid metabolism disorders. Patients receiving antipsychotic medications, including olanzapine, should have regular monitoring of blood lipid levels, e.g., at the beginning of treatment, at 12 weeks, and every 5 years thereafter.

Anticholinergic activity. Low frequency of anticholinergic effects was observed in clinical trials. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, caution should be exercised when prescribing the drug to patients with prostatic hypertrophy, paralytic ileus, or similar conditions.

Liver function tests. Transient, asymptomatic elevations in liver transaminases (ALT and AST) were frequently observed with olanzapine use, particularly at the beginning of treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, signs or symptoms of hepatic dysfunction, pre-existing conditions associated with reduced hepatic functional reserve, or in patients 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 leukocyte and/or neutrophil counts from any cause, in patients receiving medications 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, and in patients with hypereosinophilia or myeloproliferative disorders. Neutropenia is a common adverse effect when valproate and olanzapine are used concomitantly (see section "Adverse reactions").

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

QT interval. Clinically significant prolongation of the QTc interval (corrected QT interval by Fridericia [QTcF] ≥500 milliseconds [ms] at any time after treatment initiation in patients with baseline QTcF <500 ms) was observed infrequently (0.1% to 1%) in patients treated with olanzapine during clinical trials. No significant difference in the frequency of cardiac adverse reactions was observed compared to placebo. However, as with other antipsychotics, olanzapine should be used cautiously in combination with drugs that may prolong the QTc interval, especially in elderly patients and in patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

Thromboembolism. A temporal association between olanzapine treatment and venous thromboembolism has been reported infrequently (≥0.1% to <1%). 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 possible risk factors, such as patient immobilization, should be taken into account, and appropriate preventive measures should be implemented.

General CNS effects. Given the predominant central nervous system (CNS) effects of olanzapine, additional precautions should be taken when olanzapine is used concomitantly with other centrally acting agents, including alcohol. In vitro, olanzapine exhibits dopamine antagonism and may counteract the effects of direct and indirect dopamine agonists.

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

Tardive dyskinesia. In comparative clinical trials up to one year in duration, olanzapine use was associated with a statistically significant reduction in the incidence of treatment-emergent dyskinesia. Due to the increasing risk of developing tardive dyskinesia with long-term use of antipsychotics, a gradual 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 were reported infrequently in elderly patients during clinical trials. Periodic blood pressure monitoring is recommended for patients aged 65 years and older during olanzapine use.

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 in patients receiving olanzapine 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.

Children and adolescents. Olanzapine is not recommended for use in children and adolescents. In studies involving patients aged 13–17 years, various adverse reactions were observed, including weight gain, changes in metabolic parameters, and increased prolactin levels (see sections "Pharmacological properties" and "Adverse reactions").

Lactose. The product contains lactose monohydrate and therefore should not be administered to patients with hereditary lactose intolerance, lactase deficiency (The Lapp lactase deficiency), or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

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 clinical 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 are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, the symptoms of which may vary in intensity and duration after birth. Symptoms such as agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, newborns should be closely monitored.

Lactation

Olanzapine has been detected in human breast milk in studies of healthy lactating women. 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.

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 about the potential hazards associated with 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 per day or 10 mg per day when used in combination therapy (see section "Pharmacological Properties").

Prevention of recurrent episodes in patients with bipolar disorder. The recommended initial dose is 10 mg per day. Patients with bipolar disorder who have been treated with olanzapine for manic episodes should continue receiving 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 bipolar disorder relapses. The daily dose should be individualized based on clinical status within a range of 5 to 20 mg per day. Increases from the recommended initial dose should be made at intervals of not less than 24 hours and only after clinical evaluation. Olanzapine can be administered regardless of food intake, as food does not affect drug absorption. When discontinuing the medication, therapy should be tapered gradually.

Elderly patients. A lower initial dose (5 mg per day) is generally not required. However, consideration should be given to initiating treatment with a lower dose (5 mg per day) in patients aged 65 years and older if clinically indicated (see section "Special Warnings and Precautions for Use").

Patients with renal and/or hepatic impairment. A lower initial dose (5 mg per day) may be prescribed for such patients. In patients with moderate hepatic impairment (cirrhosis, Child-Pugh class A or B), the initial dose should be 5 mg per day, and dose escalation should be performed cautiously.

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

Smoking may increase the metabolism of olanzapine. Clinical monitoring is recommended, and the olanzapine dose should be increased if necessary (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

A lower initial dose may be considered in patients with a combination of factors (female gender, advanced age, non-smoking status) that may reduce olanzapine metabolism. Dose increases in such patients, if indicated, should be performed gradually and cautiously (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Pharmacological Properties").

Children.

The use of olanzapine in children and adolescents (under 18 years of age) is not recommended due to insufficient data on safety and efficacy. In short-term studies in adolescent patients, increased body weight, changes in prolactin levels, and lipid alterations were observed compared to adults (see sections "Special Warnings and Precautions for Use", "Adverse Reactions", and "Pharmacological Properties").

Overdose.

Symptoms. Very common (> 10% of cases): 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, risk of 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; however, survival has also been documented after acute ingestion of up to 2 g of olanzapine orally.

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

Symptomatic treatment and monitoring of vital functions should be implemented according to 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 required to detect potential arrhythmias. Close medical supervision and monitoring should continue until full recovery of the patient.

Adverse reactions.

Short description of the safety profile

Adults

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

Tabulated list of adverse reactions

Table 1 summarizes the main adverse reactions and their frequency as observed in clinical trials and/or reported from post-marketing experience.

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from 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
Increased body weight1	Increased cholesterol levels2,3, increased glucose levels4, increased triglyceride levels2,5, glucosuria, increased appetite	Development or worsening of diabetes, rarely associated with ketoacidosis or coma, including some fatal cases (see section "Special precautions")11	Hypothermia12
Nervous system disorders
Somnolence	Dizziness, akathisia6, parkinsonism6, dyskinesia6	Epileptic seizures, previously reported or with existing risk factors11, dystonia (including ocular symptoms)11, tardive dyskinesia11, amnesia9, dysarthria, stuttering11, restless legs syndrome11	Neuroleptic malignant syndrome (see section "Special precautions")12, withdrawal syndrome7,12
Respiratory, thoracic and mediastinal disorders
		Nosebleeds9
Cardiac disorders
		Bradycardia, QTc interval prolongation (see section "Special precautions")	Ventricular tachycardia/fibrillation, sudden death (see section "Special precautions")11
Vascular disorders
Orthostatic hypotension10		Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section "Special precautions")
Gastrointestinal disorders
	Mild, transient anticholinergic effects, including constipation and dry mouth	Abdominal distension9, hypersalivation11	Pancreatitis11
Hepatobiliary disorders
	Transient, asymptomatic elevations in liver transaminases (ALT and AST), particularly at the beginning of treatment (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
		Incontinence; urinary retention, difficulty in urination11
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, fatigue, edema, pyrexia10
Investigations
Increased plasma prolactin levels8	Increased alkaline phosphatase10, increased creatine phosphokinase11, increased gamma-glutamyl transferase10, increased uric acid levels10	Increased total bilirubin
Pregnancy, postpartum and perinatal period
				Withdrawal syndrome in newborns (see section "Use in pregnancy or breastfeeding")

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

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

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

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

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

6 During clinical trials, the incidence of parkinsonism and dystonia in patients receiving olanzapine treatment was higher than in placebo-controlled trials, but clinically insignificant. The incidence of parkinsonism, akathisia, and dystonia in patients receiving 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 Upon abrupt discontinuation of olanzapine therapy, acute symptoms were reported, including increased sweating, insomnia, tremor, agitation, 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 normal limit.

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

10 Assessment of measured values was determined from clinical trials in the integrated olanzapine database.

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

12 Adverse reactions were identified from spontaneous post-marketing reports, with frequency assessed using the upper confidence limit (95%) 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 triglycerides 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 occurred very commonly and more frequently than in the placebo group.

In one clinical trial in patients with bipolar mania, neutropenia was observed in 4.1% of patients receiving olanzapine in combination with valproate; a possible cause may be elevated plasma valproate levels.

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

Children.

Olanzapine is not indicated for the treatment of children and adolescents (under 18 years of age). Clinical trials comparing olanzapine use in adolescents and adults have not been conducted.

Below are adverse reactions occurring more frequently in adolescents (aged 13–17 years) than in adults, or 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.

The frequency of the adverse reactions listed below is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders.

Very common: weight gain¹³, increased 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; (see section "Special precautions")).

Investigations.

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

¹³ After 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% (2.5% of cases). During long-term treatment (at least 24 weeks), weight gain of ≥ 7% was observed in 89.4% of patients, ≥ 15% in 55.3%, and ≥ 25% in 29.1%.

¹⁴ Observed in patients with normal baseline fasting levels (< 1.016 mmol/L) that increased to high levels (≥ 1.467 mmol/L), and a marked increase in fasting triglycerides from baseline levels (≥ 1.016 to < 1.467 mmol/L) to high levels (≥ 1.467 mmol/L).

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

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

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Nobel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskı Akcakoca Avenue, No: 299, 81100, Duzce, Turkey.