Jubrexa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT JUBREXA

Composition:

Active substance: olanzapine;

1 tablet contains 5 mg, 10 mg, 15 mg or 20 mg of olanzapine;

Excipients: mannitol (E 421), aspartame (E 951), hydroxypropylcellulose, strawberry flavor, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Orally disintegrating tablets.

Main physicochemical properties: yellow, round, flat tablets with beveled edges, with characteristic odor, marked with “D5”, “D10”, “D15” or “D20” on one side and “CO” on the other side.

Pharmacotherapeutic group. Antipsychotic agents. ATC code: N05AH03.

Pharmacological Properties

Pharmacodynamics

Zubrex is an antipsychotic and antimanic agent with mood-stabilizing properties, exhibiting a broad spectrum of pharmacological activity due to its effects on various receptors. Clinical studies have demonstrated that olanzapine binds to serotonin receptors 5HT2A/2C, 5HT3, 5HT6, dopamine receptors D1, D2, D3, D4, D5, muscarinic receptors M1–M5, adrenergic receptors α1, and histamine H1 receptors. In animal behavioral studies, olanzapine demonstrated antagonism at both serotonin 5HT and dopamine as well as cholinergic receptors. Olanzapine exhibits higher affinity for serotonin 5HT2 receptors than for dopamine D2 receptors, both in in vitro and in vivo models. Electrophysiological studies have shown 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 responses, 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.

After single 10 mg doses of olanzapine in positron emission tomography (PET) studies involving healthy volunteers, olanzapine demonstrated greater binding to 5HT2A receptors than to dopamine D2 receptors. Furthermore, analysis of single-photon emission computed tomography (SPECT) images from schizophrenia patients revealed that olanzapine-responsive patients showed lower striatal D2 receptor binding compared to other antipsychotic- and risperidone-responsive patients, but higher than clozapine-responsive patients.

Clinical Efficacy

In two out of two placebo-controlled and two out of three comparator-controlled trials involving over 2900 patients with schizophrenia exhibiting 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 related 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 demonstrated statistically significant improvement (p = 0.001) with olanzapine treatment (–6.0) compared to haloperidol (–3.1).

In patients with manic or mixed episodes associated with 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 olanzapine 10 mg for 2 weeks, significant reduction in manic symptoms was observed compared to monotherapy with lithium or valproate alone after 6 weeks.

In a 12-month relapse prevention study 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 assessing relapse in bipolar disorder. 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 olanzapine or lithium monotherapy, olanzapine did not demonstrate statistically significant superiority over lithium in the primary endpoint assessing relapse in bipolar disorder (olanzapine 30%, lithium 38.3%; p = 0.055).

In an 18-month study evaluating combination therapy for manic or mixed episodes, where patients were initially stabilized with olanzapine and then maintained 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 relapse of bipolar disorder as defined by syndromal (diagnostic) criteria.

Children

Experience in adolescents (aged 13 to 17 years) is limited, based on data from short-term treatment studies of schizophrenia (6 weeks) and bipolar mania (3 weeks) involving fewer than 200 adolescents. The initial dose of olanzapine was 2.5 mg, titrated up to 20 mg daily. 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. Data on maintenance of therapeutic effect and long-term outcomes are limited.

Pharmacokinetics

Absorption

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

Distribution

Plasma protein binding of olanzapine is approximately 93% across 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 isoenzymes CYP1A2 and CYP2D6 are involved in 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 according to age and sex.

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

In women compared to men, the mean elimination half-life was longer (36.7 vs. 32.3 hours) and plasma clearance lower (18.9 vs. 27.3 L/h). However, olanzapine (5–20 mg) demonstrated 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, 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 is excreted in urine, primarily as metabolites.

Patients with Hepatic Impairment

In a study assessing the impact of hepatic impairment involving 6 patients with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)), minimal effects on the pharmacokinetics of orally administered olanzapine (single dose 2.5–7.5 mg) were observed. Patients with mild to moderate hepatic impairment showed slightly increased systemic clearance and faster elimination compared to patients without hepatic dysfunction (n = 3). In smoking patients with mild hepatic impairment, the mean elimination half-life was longer (4/6; 67%) compared to non-smoking patients without hepatic impairment (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 lower (18.6 vs. 27.7 L/h).

Plasma clearance of olanzapine is lower in elderly patients compared to younger individuals, in women compared to men, and in non-smokers compared to smokers. However, the influence of factors such as age, sex, and smoking on olanzapine plasma clearance and elimination half-life is small relative to overall inter-individual variability.

In studies involving European, Japanese, and Chinese patients, no differences in olanzapine pharmacokinetics were observed.

Children

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

Clinical characteristics.

Indications.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical response during long-term therapy in patients who have 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 developing angle-closure glaucoma.

Interaction with other medicinal products and other forms of interaction.

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

Interactions potentially affecting olanzapine

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

CYP1A2 inducers

The metabolism of olanzapine may be induced by smoking and by concomitant use of carbamazepine, leading to reduced olanzapine concentrations. A weak or moderate increase in olanzapine clearance has been observed. Clinical conclusions are limited; however, clinical monitoring is recommended, and if necessary, an increase in the olanzapine dose.

CYP1A2 inhibitors

Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in an average increase in Cmax of olanzapine by 54% in non-smoking women and by 77% in smoking men. The average increase in the area under the plasma concentration-time curve (AUC) of olanzapine is 52% and 108%, respectively. For patients receiving fluvoxamine or other CYP1A2 inhibitors (e.g., ciprofloxacin), reduced doses of olanzapine should be administered. Dose reduction of olanzapine should be considered when initiating treatment with a CYP1A2 inhibitor.

Reduced bioavailability

Administration of activated charcoal reduces the oral bioavailability of olanzapine by 50–60%; therefore, it should be administered at least 2 hours before or 2 hours after olanzapine.

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

Potential effect of olanzapine on other medicinal products

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

Olanzapine did not inhibit the major cytochrome P450 isoenzymes (e.g., CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4) in vitro. Therefore, no significant interactions are expected, as confirmed by in vivo studies, where no inhibition of olanzapine metabolism was observed when co-administered with the following active substances: tricyclic antidepressants (mainly metabolized by CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and CYP2C19).

No interaction between olanzapine and lithium or biperiden was observed.

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

General central nervous system (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 antiparkinsonian agents is not recommended in patients with Parkinson's disease and dementia.

QTc interval

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

Special precautions for use.

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

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 an increased risk of mortality and cerebrovascular events. In placebo-controlled clinical trials (6–12 weeks duration) involving elderly patients (mean age 78 years) suffering from psychosis associated with dementia and/or behavioral disturbances, the mortality rate 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 administered (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 (stroke, transient ischemic attack), including fatal cases, 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 trials.

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

Malignant neuroleptic syndrome (MNS). MNS is a potentially fatal condition described in association with antipsychotic drugs. Cases of MNS related to olanzapine use have been rarely reported. Clinical manifestations of MNS include hyperpyrexia, muscle rigidity, altered consciousness, and signs of cardiovascular instability (irregular pulse or changes in blood pressure, tachycardia, excessive sweating, and cardiac arrhythmia). Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. The clinical presentation of MNS or the presence of hyperthermia without full MNS symptoms requires immediate discontinuation of all antipsychotic agents, including olanzapine.

Hyperglycemia and diabetes mellitus. Hyperglycemia and/or onset or worsening of pre-existing diabetes mellitus, sometimes associated with ketoacidosis or diabetic coma, have been reported infrequently, including fatal cases. Weight gain has sometimes been reported as a preceding factor, which may contribute to risk.

Appropriate clinical monitoring is recommended for patients with diabetes mellitus and those with risk factors for developing diabetes, 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 signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes or those at risk for developing diabetes should be regularly monitored for worsening glycemic control. Body weight should be monitored regularly, for example at the beginning of treatment, at weeks 4, 8, and 12, and then quarterly thereafter.

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

Anticholinergic activity. In vitro clinical studies have shown a low incidence of anticholinergic effects. However, due to limited clinical experience with olanzapine in patients with concomitant diseases, caution should be exercised when prescribing the drug to patients with benign prostatic hyperplasia, paralytic ileus, or similar conditions.

Liver function tests. Transient, asymptomatic elevations in hepatic transaminases (ALT and AST) have frequently been observed with olanzapine use, particularly at the beginning of treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST levels, signs and 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 cautiously in patients with low leukocyte and/or neutrophil counts for any reason, patients receiving drugs that may cause neutropenia, patients with a history of drug-induced bone marrow suppression or toxicity, patients with bone marrow suppression due to concomitant diseases, radiation, or chemotherapy, and patients with hypereosinophilia or myeloproliferative disorders. Neutropenia is a common adverse effect when valproate is used concomitantly with olanzapine.

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. In clinical trials, olanzapine did not cause prolonged prolongation of absolute QT and QTc intervals. However, as with other antipsychotics, olanzapine should be used with caution when co-administered with drugs that may prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.

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

General CNS effects. Given the predominant central nervous system (CNS) effects of olanzapine, additional precautions should be taken when olanzapine is used concomitantly with other CNS-acting drugs, including alcohol consumption. In vitro, olanzapine exhibits dopamine antagonism and may theoretically counteract the effects of levodopa and dopamine agonists, as do other antipsychotic agents.

Seizures. Olanzapine should be used cautiously in patients with a history of seizures or those sensitive to seizure threshold-lowering factors. 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 clinical trials lasting 1 year or less, a statistically significant lower incidence of treatment-emergent dyskinesia was observed with olanzapine. 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 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 receiving antipsychotics. The risk associated with olanzapine use corresponds to that of other atypical antipsychotics included in the combined analysis.

Children.

Olanzapine is not recommended for use in children and adolescents.

Studies in patients aged 13–17 years have shown various adverse reactions, including weight gain, metabolic parameter changes, and increased prolactin levels. The long-term consequences of these adverse effects have not been studied and remain unknown.

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

The medicinal product contains aspartame, a source of phenylalanine. It is harmful for individuals with phenylketonuria.

The medicinal product contains mannitol.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

Breastfeeding period

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

Fertility

The effect on fertility is unknown.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect of olanzapine on reaction speed during driving or operating machinery have been conducted. Since olanzapine may cause somnolence and dizziness, patients should be warned of the potential danger associated with operating machinery, including motor vehicles.

Dosage and Administration

Adults

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

Manic episodes. The 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 dosage 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, if clinically indicated.

Treatment of schizophrenia, manic episodes, and prevention of bipolar disorder relapse. 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 not less than 24 hours and only after clinical evaluation.

Jubrex should be administered regardless of food intake, as food does not affect the absorption of the drug. When discontinuing the medication, therapy should be tapered gradually.

Jubrex orally disintegrating tablets should be placed in the mouth, where they rapidly disperse in saliva and can be easily swallowed. It is difficult to remove the entire tablet from the mouth once placed. Since orally disintegrating tablets are fragile, they should be taken immediately after opening the blister pack. Alternatively, they can be dispersed in a glass of water or another suitable beverage (orange juice, apple juice, milk, or coffee) immediately before administration.

Jubrex orally disintegrating tablets are bioequivalent to coated olanzapine tablets and have the same rate and extent of absorption. Jubrex orally disintegrating tablets can be used as an alternative to coated olanzapine tablets.

Special patient populations

Elderly patients. A lower initial dose (5 mg daily) is generally not required. However, consideration should be given to initiating treatment with a lower dose (5 mg daily) in patients aged 65 years and older 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.

Smokers. Dose adjustment based on smoking status is not required. Smoking may induce olanzapine metabolism. Clinical monitoring is recommended, and dose increase may be considered if necessary.

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

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.

Overdose.

Symptoms

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

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

Treatment

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

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

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

Adverse reactions

During clinical studies, the following adverse reactions (observed in ≥1% of patients) were most frequently reported with olanzapine treatment: 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 elevation of liver transaminases, rash, asthenia, fatigue, hyperthermia, arthralgia, increased levels of alkaline phosphatase, gamma-glutamyl transferase, uric acid, creatine phosphokinase, and edema.

The table below summarizes the main adverse reactions identified during clinical studies and/or the post-marketing period.

The frequency categories are defined as follows: 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), and not known (frequency cannot be estimated from available data).

Very common		Common			Uncommon			Rare		Frequency unknown
Blood and lymphatic system disorders
		Eosinophilia, leukopenia10, neutropenia10						Thrombocytopenia11
Immune system disorders
					Hypersensitivity11
Metabolism and nutrition disorders
Weight gain1		Increased cholesterol2,3, increased glucose4, increased triglycerides2,5, glucosuria, increased appetite			Development or worsening of diabetes, rarely associated with ketoacidosis or coma, including some fatal cases11			Hypothermia12
Nervous system disorders
Somnolence		Dizziness, akathisia6, parkinsonism6, dyskinesia6			Seizures if there was a history or presence of risk factors11, dystonia (including ocular symptoms)11, tardive dyskinesia11, amnesia9, dysarthria, stuttering11,13, restless legs syndrome			Neuroleptic malignant syndrome12, withdrawal syndrome7,12
Cardiac disorders
					Bradycardia, QTc interval prolongation			Ventricular tachycardia/fibrillation, sudden death11
Vascular disorders
Orthostatic hypotension10				Thromboembolism (including pulmonary embolism and deep vein thrombosis)
Respiratory, thoracic and mediastinal disorders
				Nosebleed9
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.				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 micturition11
Pregnancy, postpartum and perinatal period
										Withdrawal syndrome in newborns
Reproductive system and breast disorders
		Erectile dysfunction in males, decreased libido in females and males	Amenorrhea, breast enlargement, galactorrhea in females, gynecomastia/breast enlargement in males				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 acid10	Increased total bilirubin

1 Clinically significant weight gain was observed in all BMI (body mass index) patient categories. With short-term treatment (mean duration of 47 days), weight gain of ≥7% occurred very commonly (22.2% of cases), ≥15% occurred commonly (4.2% of cases), and ≥25% occurred uncommonly (0.8% of cases). In patients receiving long-term therapy (for at least 48 weeks), weight gain of ≥7%, ≥15%, and ≥25% occurred 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) that 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) that 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) that increased to high levels (≥2.26 mmol/L). Rapid increases in fasting triglycerides 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 receiving olanzapine was lower than with titrated doses of haloperidol. Due to lack of information on the history of acute or tardive 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: 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 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 estimated using the upper limit of the 95% confidence interval based on the integrated olanzapine database.

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

Adverse reactions in specific populations. In clinical trials in elderly patients with dementia, olanzapine therapy was associated with increased mortality and cerebrovascular adverse reactions compared to placebo. Very common adverse reactions associated with olanzapine 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, more frequently than in the placebo group.

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

With olanzapine 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% BMI occurred in 17.4% of patients during intensive treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 weeks) for prevention of relapse in patients with bipolar disorders was associated with weight gain of ≥7% BMI in 39.9% of patients.

Children

Olanzapine is not indicated for use in children and adolescents. 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 than in 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 transaminases (ALT and AST).

Investigations

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

13 With short-term treatment (mean duration of 22 days), weight gain of ≥7% occurred very commonly (40.6% of cases), ≥15% occurred commonly (7.1% of cases), and ≥25% occurred in 2.5% of cases. During long-term treatment (at least 24 weeks), weight gain of ≥7% occurred 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 rapid increases 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 (<4.39 mmol/L) that 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.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25°C. Keep out of reach and sight of children.

Packaging. 10 tablets per blister. 1 or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's address and location of operations.

Village Sikandarpur, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, District Roorkee Haridwar, Uttarakhand, IN-247661, India.