film coating: hypromellose, Opadry White 13B28444 (hypromellose, titanium dioxide (E 171), macrogol, polysorbate 80), carnauba wax: beeswax (60:40).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets, with a biconvex surface, coated with a white or almost white film coating.
Pharmacotherapeutic group
Antipsychotics. ATX code N05A H03.
Pharmacological properties
Pharmacodynamics.
Olanzapine is an antipsychotic, antimanic, mood-stabilizing drug with a broad pharmacological profile across multiple receptor systems. In preclinical studies, olanzapine has been shown to have affinity for a range of receptors (Ki; < 100 nM) including serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic M1-M5 receptors; α1-adrenergic; and histamine H1 receptors. Animal behavioral studies have demonstrated 5HT, dopamine, and cholinergic antagonism, consistent with the binding profile of olanzapine to these receptors. Olanzapine has demonstrated greater affinity for serotonin 5HT2 than dopamine D2 receptors in vitro and greater 5HT2 activity than D2 in vivo. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, while showing little effect on striatal (A9) pathways involved in motor function. Olanzapine inhibits the conditioned avoidance reflex, which indicates its antipsychotic activity at doses lower than those that cause catalepsy, which is a sign of motor side effects. Unlike some other antipsychotic drugs, olanzapine increases responses to stimuli in an anxiolytic test.
A single oral dose of 10 mg olanzapine was found to have higher binding to 5-HT2A receptors than to dopamine D2 receptors in healthy volunteers using positron emission tomography (PET). In addition, analysis of single-photon emission computed tomography (SPECT) images from schizophrenia patients showed that olanzapine-responsive patients had lower levels of striatal D2 receptor binding than other antipsychotic- and risperidone-responsive patients, and comparable to clozapine-responsive patients.
Clinical efficacy.
In two of two placebo-controlled and two of three comparator-controlled studies involving over 2,900 patients with schizophrenia with positive and negative symptoms, olanzapine showed statistically significant improvements in patients' condition.
In an international double-blind comparative study of 1484 patients with schizophrenia, schizoaffective disorder, and related disorders of varying severity associated with depressive symptoms (16.6 points on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to end-of-life mood changes showed a statistically significant improvement (p = 0.001) after olanzapine treatment (–6.0) compared with haloperidol treatment (–3.1).
In patients with manic or mixed episodes in bipolar disorder, olanzapine was superior to placebo and divalproex in reducing manic symptoms over 3 weeks. Olanzapine was comparable to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks of treatment. In a study, olanzapine 10 mg added to lithium or valproate for 2 weeks resulted in a significant reduction in manic symptoms compared with lithium or valproate alone after 6 weeks.
In a 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with olanzapine and were then randomized to olanzapine or placebo, olanzapine demonstrated a statistically significant advantage over placebo on the endpoint of recurrence of bipolar disorder. Olanzapine also demonstrated a statistically significant advantage over placebo in preventing recurrence of mania and depression.
In an 18-month study of patients stabilized with olanzapine as adjunctive treatment for manic or mixed episodes, lithium or valproate were used as mood stabilizers. There was no statistically significant advantage over lithium or valproate monotherapy in delaying relapse of bipolar disorder defined by syndromic (diagnostic) criteria.
Children.
Experience in adolescents (aged 13 to 17 years) is limited. There are studies of the efficacy of short-term treatment of schizophrenia (6 weeks) and mania associated with bipolar disorder (3 weeks) in less than 200 adolescents. The starting dose of olanzapine was 2.5 mg and was increased to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight than adults. In adolescents, increases in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin were observed compared to adults. Data on maintenance of treatment effect and long-term use are limited.
Pharmacokinetics.
Absorption.
The drug is well absorbed after oral administration, with Cmax in plasma reached after 5–8 hours. Food intake does not affect the absorption of olanzapine. The absolute bioavailability of olanzapine when administered orally compared to intravenous administration has not been established.
Distribution.
The level of binding of olanzapine to plasma proteins was approximately 93% at 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 by conjugation and oxidation. The major circulating metabolite is the 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, which have shown significantly less pharmacological activity in vivo than olanzapine in animal studies. The major pharmacological activity is due to the parent olanzapine.
Breeding.
After oral administration, the mean elimination half-life of olanzapine in volunteers varied depending on age and gender.
In healthy elderly volunteers (65 years of age 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. The pharmacokinetic variability observed in elderly volunteers is within the range of younger volunteers. In 44 schizophrenic patients >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinctive adverse event profile.
In women, the mean half-life was longer (36.7 vs. 32.3 hours) and plasma clearance was reduced (18.9 vs. 27.3 L/h) compared to men. However, the safety profile of olanzapine (5–20 mg) was comparable in women (N = 467) and men (N = 869).
Patients with renal failure.
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 have shown that approximately 57% of radiolabeled olanzapine is present in the urine, primarily as metabolites.
Patients with impaired liver function.
A small study of the effect of hepatic impairment in 6 patients with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)) found little effect on the pharmacokinetics of oral olanzapine (2.5–7.5 mg). Patients with mild to moderate hepatic dysfunction had slightly increased systemic clearance and a shorter half-life compared with patients without hepatic impairment (n = 3). There were more smokers in the group of patients with cirrhosis (4/6; 67%) than in the group of patients without hepatic impairment (0/3; 0%).
Patients who smoke.
In non-smokers compared to smokers (men and women), the mean half-life was longer (38.6 vs. 30.4 hours) and plasma clearance was reduced (18.6 vs. 27.7 L/h).
Olanzapine plasma clearance is lower in elderly patients compared to young patients, in women compared to men, and in non-smokers compared to smokers. However, factors such as age, gender, and smoking status may have little effect on olanzapine plasma clearance and half-life compared to the variability in these parameters between individuals.
No differences in the pharmacokinetics of olanzapine were found in studies involving European, Japanese, and Chinese patients.
Children.
The pharmacokinetics of olanzapine are similar in adolescents and adults. 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.
Indication
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the achieved clinical effect during long-term therapy in patients who have responded to initial therapy.
Olanzapine is indicated for the prevention of recurrent attacks in patients with bipolar disorder who have responded to olanzapine treatment of mania.
Contraindication
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 types of interactions
Drug interaction studies have only been conducted in adults.
Substances that potentially affect olanzapine.
Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
CYP1A2 inducers.
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may result in decreased olanzapine concentrations. Only a slight to moderate increase in olanzapine clearance has been observed. Its clinical consequences are likely to be limited, but clinical monitoring and, if necessary, an increase in the olanzapine dose are recommended.
CYP1A2 inhibitors.
Fluoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in a mean increase in Cmax after fluoxamine of 54% in non-smoking women and 77% in smoking men. The mean increase in olanzapine AUC is 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients taking fluoxamine or any other CYP1A2 inhibitor, such as ciprofloxacin. A dose reduction of olanzapine should be considered if treatment with a CYP1A2 inhibitor is considered.
Reduced bioavailability.
Activated charcoal reduced the oral bioavailability of olanzapine by 50–60% and should be administered at least 2 hours before or 2 hours after olanzapine.
Fluoxetine (CYP2D6 inhibitor), single doses of antacids (aluminum, magnesium), or cimetidine did not significantly affect the pharmacokinetics of olanzapine.
Olanzapine may affect the effects of other medicines.
Olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Olanzapine did not inhibit most CYP450 isoenzymes (e.g. 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, no specific interactions are expected, as confirmed by in vivo studies, where no inhibition of olanzapine metabolism was observed with the following active substances: tricyclic antidepressants (mainly represented by the CYP2D6 isoenzyme), warfarin (CYP2C9), theophylline (CYP 1A2) or diazepam (CYP 3A4 and 2C19).
No interactions of olanzapine were observed when administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not reveal the need for valproate dose adjustment when co-administered with olanzapine.
General activity regarding the central nervous system.
Caution should be exercised in patients who consume alcohol or are taking medications that may cause central nervous system depression.
Concomitant use of olanzapine with antiparkinsonian drugs is not recommended in patients with Parkinson's disease and dementia.
QTc interval.
Caution should be exercised when prescribing olanzapine with other drugs that may prolong the QTc interval.
Application features
During treatment with antipsychotics, clinical improvement may take from a few days to a few weeks. During this period, patients should be closely monitored.
Psychosis associated with dementia and/or behavioural disturbances. Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioural 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) in elderly patients (mean age 78 years) with psychosis associated with dementia and/or behavioural disturbances, the rate of deaths was 2-fold higher in patients treated with olanzapine compared to placebo (3.5% vs. 1.5%, respectively). The higher mortality was not related to the dose of olanzapine used (mean daily dose was 4.4 mg) or to the duration of treatment. Risk factors for increased mortality include age 65 years or older, dysphagia, sedation, malnutrition and dehydration, the presence of pulmonary pathology (e.g., pneumonia with or without aspiration), and concomitant use of benzodiazepines. However, mortality was higher with olanzapine than with placebo, regardless of risk factors.
Parkinson's disease. Olanzapine is not recommended for the treatment of psychosis associated with dopamine agonists. Concomitant use of olanzapine and antiparkinsonian medicinal products is not recommended in patients with Parkinson's disease and dementia. In clinical trials, worsening of Parkinson's disease symptoms and hallucinations were very common, more common than with placebo; olanzapine was not more effective than placebo in the treatment of psychotic symptoms. From the outset of these studies, patients were required to continue on the lowest effective dose of antiparkinsonian medicinal products (dopamine agonists) and to continue on the same antiparkinsonian medicinal products and doses throughout the study. Olanzapine was initiated at a dose of 2.5 mg/day and titrated to a maximum of 15 mg/day.
Neuroleptic malignant syndrome. Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom complex associated with antipsychotic drugs. Rare cases of NMS have been reported with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, loss of consciousness, and symptoms of cardiac instability (irregular pulse or blood pressure changes, tachycardia, increased sweating, and cardiac arrhythmia). Additional features may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of NMS or the presence of hyperthermia without clinical manifestations of NMS require immediate discontinuation of all antipsychotic drugs, including olanzapine.
Hyperglycemia and diabetes mellitus: Hyperglycemia and/or development of diabetes mellitus or worsening of pre-existing diabetes mellitus associated with ketoacidosis or diabetic coma, as well as fatal cases, have been reported uncommonly. Pre-existing weight gain has occasionally been reported, which may be a risk factor.
Appropriate clinical monitoring is recommended in patients with diabetes mellitus and those at risk for diabetes mellitus, including measurement of blood glucose at baseline, 12 weeks, and annually thereafter. Patients treated with antipsychotics, including olanzapine, should be observed for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus and those at risk for diabetes should have their glucose levels monitored regularly. Weight should be monitored regularly, e.g. at baseline, 4 weeks, 8 weeks, and 12 weeks, and quarterly thereafter.
Anticholinergic Activity: While olanzapine has demonstrated anticholinergic activity in vitro, clinical experience has shown a low incidence of anticholinergic events. However, due to limited clinical experience with olanzapine in patients with comorbid conditions, caution should be exercised when prescribing olanzapine to patients with prostatic hypertrophy, paralytic ileus, or conditions associated with these conditions.
Liver function: Transient, asymptomatic elevations of hepatic aminotransferases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), have been commonly observed with olanzapine, especially early in treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, symptoms of liver dysfunction, conditions associated with hepatic insufficiency, and patients receiving potentially hepatotoxic drugs. If hepatitis (including hepatocellular, cholestatic, or mixed liver injury) is diagnosed, olanzapine should be discontinued.
Neutropenia: Olanzapine should be used with caution in patients with low white blood cell 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 underlying disease, radiation or chemotherapy, in patients with hypereosinophilia or myeloproliferative disease. Neutropenia has been commonly reported with the concomitant use of olanzapine and valproate.
Discontinuation of therapy: Acute symptoms, including excessive sweating, insomnia, tremor, irritability, nausea, or vomiting, have been reported rarely (≥ 0.01% and < 0.1%) upon abrupt discontinuation of therapy.
Thromboembolism: Venous thromboembolism has been reported uncommonly (≥ 0.1% - < 1%) with olanzapine treatment. A causal relationship between olanzapine treatment and the development of venous thromboembolism has not been established. However, given that patients with schizophrenia are often predisposed to thromboembolism, all possible risk factors, such as immobilization of the patient, should be considered and all necessary precautions taken.
General effects on the central nervous system (CNS). Given the primary CNS effects of olanzapine, caution should be exercised when it is taken in combination with other centrally acting drugs and alcohol. Olanzapine exhibits dopamine antagonism in vitro and may antagonize the effects of direct and indirect dopamine agonists.
Seizures: Olanzapine should be used with caution in patients with a history of seizures or in patients with factors that lower the seizure threshold. Seizures have been reported uncommonly with olanzapine. In most of these cases, patients had a history of seizures or were at increased risk of seizures.
Tardive dyskinesia: In clinical trials of 1 year or less duration, olanzapine was associated with a statistically significant reduction in the incidence of treatment-emergent dyskinesia. Because of the increased risk of tardive dyskinesia with long-term use of antipsychotics, appropriate dose reduction or discontinuation of the drug is recommended if a patient develops symptoms of tardive dyskinesia. These symptoms may worsen over time or even reappear after treatment is discontinued.
Orthostatic hypotension: Orthostatic hypotension has been reported uncommonly in elderly patients in clinical trials. Periodic blood pressure monitoring is recommended in patients aged 65 years and older.
Sudden cardiac death. Cases of sudden cardiac arrest have been reported in postmarketing studies with olanzapine. In a retrospective observational cohort study, the risk of sudden cardiac arrest in patients treated with olanzapine was approximately twice that in patients not taking antipsychotics. In this study, the risk with olanzapine was comparable to the risk with atypical antipsychotics included in the pooled analysis.
Lipid changes. Undesirable changes in lipid levels may occur in patients treated with olanzapine. Lipid changes should be managed appropriately in patients with dyslipidemia and in patients with risk factors for lipid disorders. Patients treated with antipsychotics, including olanzapine, should have their blood lipid levels monitored regularly, for example: at baseline, after 12 weeks, and every 5 years thereafter.
This medicinal product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate and well-controlled studies of olanzapine in pregnant women. Patients receiving olanzapine should inform their physician if they are pregnant or intend to become pregnant. Because experience with olanzapine in pregnant women is limited, olanzapine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. Agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, close monitoring of the neonate is necessary.
Breast-feeding
In a study of healthy lactating women, olanzapine was detected in breast milk. The mean infant exposure (mg/kg) at steady state was approximately 1.8% of the maternal olanzapine dose (mg/kg).
Patients should be advised not to breastfeed if they are taking olanzapine.
Fertility
The effect on fertility is unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effects of olanzapine on the ability to drive or use machines. Since olanzapine may cause drowsiness and dizziness, patients should be warned about the dangers associated with operating machinery, including motor vehicles.
Method of administration and doses
Adults.
Schizophrenia: The recommended starting dose of olanzapine is 10 mg once daily.
Prevention of recurrence in bipolar disorder. The recommended starting dose is 10 mg daily. Patients already receiving olanzapine for the treatment of manic episodes are advised to continue treatment at the same dose to prevent recurrence. If new manic, mixed or depressive episodes occur, olanzapine treatment should be continued (with dose adjustments as necessary) with additional treatment for mood changes as clinically indicated.
During the treatment of schizophrenia, manic episodes and prevention of relapse in bipolar disorders, the daily dose can be adjusted according to the clinical condition of the patient within the range of 5-20 mg/day. Increases in dose above the recommended initial dose are indicated only after appropriate clinical re-evaluation and should not occur at intervals of less than 24 hours.
Olanzapine should be used without regard to meals, as food intake does not affect the absorption of the drug. When discontinuing olanzapine, a gradual dose reduction should be used.
Elderly patients: If appropriate clinical factors are present, a lower starting dose (5 mg/day) should be considered in patients aged 65 years and older.
Impaired renal and/or hepatic function. A lower initial dose (5 mg) is appropriate for these patients. In cases of moderate hepatic impairment (Child-Pugh class A or B cirrhosis), the initial dose should be 5 mg. Dose increases should be made with caution.
Smokers: No dose adjustment is required depending on the presence/absence of a smoking habit.
Smoking may increase the metabolism of olanzapine. Clinical monitoring is recommended and consideration should be given to increasing the dose of olanzapine.
A lower starting dose may be considered in patients with a combination of factors (female gender, older age, non-smoking) that contribute to reduced metabolism of olanzapine. Dose increases in these patients, if indicated, should be made gradually and with caution.
Children.
Olanzapine is not recommended for use in children and adolescents due to insufficient data on safety and efficacy. In short-term studies in adolescents, greater weight gain and changes in lipid and prolactin levels were observed than in studies in adults.
Overdose
Symptoms: Very common symptoms of overdose (incidence > 10%) included tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and decreased level of consciousness ranging from sedation to coma.
Other clinically significant effects of overdose included delirium, convulsions, coma, neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmia (in < 2% of overdoses), and cardiopulmonary shock. Fatalities have been reported following acute overdoses of 450 mg, but there have been reports of survivors following acute overdoses of approximately 2 g of olanzapine orally.
Treatment. There is no specific antidote for olanzapine. Induction of vomiting is not recommended. Standard procedures for the treatment of overdose are indicated (including gastric lavage, administration of activated charcoal). Coadministration of activated charcoal reduced the bioavailability of oral olanzapine by 50–60%.
Symptomatic treatment and monitoring of vital organ functions are recommended as clinically indicated, including treatment of hypotension, vascular collapse, and support 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.
Side effects
The most common adverse reactions (occurring in ≥ 1% of patients) associated with the use of olanzapine in clinical trials were: somnolence, weight gain, eosinophilia, increases in blood prolactin, cholesterol, glucose and triglycerides, glycosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic transaminases, rash, asthenia, fatigue, hyperthermia, arthralgia, increases in alkaline phosphatase, gamma-glutamyltransferase, uric acid, creatine phosphokinase and oedema.
Table 1 summarizes the main adverse reactions and their frequencies identified during clinical trials and/or from post-marketing experience. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency is classified as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency unknown (frequency cannot be estimated from the available data).
Table 1.
Very often
Often
Infrequently
Rarely
Frequency unknown
Disorders of the hematopoietic and lymphatic systems
-
Eosinophilia Leukopenia10
Neutropenia10
-
Thrombocytopenia11
-
Immune system disorders
Hypersensitivity11
-
-
Metabolic and digestive disorders
Weight gain1
Increased cholesterol levels2,3,
level up
glucose4,
level up
triglycerides2.5,
glycosuria,
increased appetite
Development or exacerbation of diabetes associated with ketoacidosis or coma, including fatal outcomes11
Hypothermia12
-
Nervous system disorders
Drowsiness
Dizziness,
akathisia6,
parkinsonism6,
dyskinesia 6
Epileptic seizures (in most cases if there was a history or risk factors)11, dystonia (including oculogyric crisis)11, tardive dyskinesia11,
amnesia9, dysarthria, stuttering11, restless legs syndrome11
