Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known risk of narrow-angle glaucoma.
The efficacy of IM olanzapine has not been established in patients with agitation and disturbed behaviours related to conditions other than schizophrenia or manic episode.
IM olanzapine should not be administered to patients with unstable medical conditions, such as acute myocardial infarction, unstable angina pectoris, severe hypotension and/or bradycardia, sick sinus syndrome, or following heart surgery. If the patient’s medical history with regard to these unstable medical conditions cannot be determined, the risks and benefits of IM olanzapine should be considered in relation to other alternative treatments.
Special caution is necessary in patients who have received treatment with other medicinal products having haemodynamic properties similar to those of intramuscular olanzapine including other antipsychotics (oral and/or intramuscular) and benzodiazepines (see section 4.5). Temporal association of treatment with IM olanzapine with hypotension, bradycardia, respiratory depression and death has been very rarely (<0.01%) reported particularly in patients who have received benzodiazepines and/or other antipsychotics (see section 4.8).
Simultaneous injection of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation, cardiorespiratory depression and in very rare cases, death (see sections 4.5 and 6.2). If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least one hour after IM olanzapine administration. If the patient has received parenteral benzodiazepine, IM olanzapine administration should only be considered after careful evaluation of clinical status and the patient should be closely monitored for excessive sedation and cardiorespiratory depression.
It is extremely important that patients receiving intramuscular olanzapine should be closely observed for hypotension including postural hypotension, bradyarrhythmia and/or hypoventilation, particularly for the first 4 hours following injection and close observation should be continued after this period if clinically indicated. Blood pressure, pulse, respiratory rate and level of consciousness should be observed regularly and remedial treatment provided if required. Patients should remain recumbent if dizzy or drowsy after injection until examination indicates that they are not experiencing hypotension including postural hypotension, bradyarrhythmia and/or hypoventilation.
The safety and efficacy of IM olanzapine has not been evaluated in patients with alcohol or drug intoxication (either with prescribed or illicit drugs) (see section 4.5).
Olanzapine is not recommended for use in patients with dementia-related psychosis and/or behavioural disturbances because of an increase in mortality and the risk of cerebrovascular accident. In placebo- controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age >65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g. pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g. stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age >75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson’s disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic medicines, including ZYPREXA, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders. Patients treated with any antipsychotic medicines, including ZYPREXA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.
While olanzapine demonstrated anticholinergic activity in vitro, experience during oral clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see section 4.8). Discontinuation of treatment Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely (≥0.01% and <0.1%) when olanzapine is stopped abruptly.
In clinical trials with oral administration, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥500 milliseconds [msec] at any time post baseline in patients with baseline QTcF <500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. In clinical trials with ZYPREXA powder for solution for injection, olanzapine was not associated with a persistent increase in absolute QT or in QTc intervals. However, caution should be exercised when olanzapine is prescribed with medicines known to increase QTc interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or hypomagnesaemia.
Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥0.1% and <1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients with schizophrenia often present with acquired risk factors for venous thromboembolism all possible risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures undertaken.
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.
In comparator oral studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension was infrequently observed in the elderly in oral olanzapine clinical trials. It is recommended that blood pressure is measured periodically in patients over 65 years.
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.
Interaction studies have only been performed in adults.
IM olanzapine has not been studied in patients with alcohol or drug intoxication (see section 4.4).
Caution should be exercised in patients who consume alcohol or receive medicinal products that can induce hypotension, bradycardia, respiratory or central nervous system depression (see section 4.4).
In a single dose intramuscular study of olanzapine 5 mg, administered 1 hour before intramuscular lorazepam 2 mg (metabolised by glucuronidation), the pharmacokinetics of both medicines were unchanged. However, the combination added to the somnolence observed with either medicines alone. Concomitant injection of olanzapine and parenteral benzodiazepine is not recommended (see sections 4.4 and 6.2).
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female non-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108% respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.
Olanzapine may antagonise the effects of direct and indirect dopamine agonists (see section 6.2).
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson’s disease and dementia is not recommended (see section 4.4).
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
New born infant exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine.
Effects on fertility are unknown (see section 5.3 for preclinical information).
No studies on the effects on the ability to drive and use machines have been performed. Because olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.
A common (≥1/100 to <1/10) undesirable effect associated with the use of intramuscular olanzapine in clinical trials was somnolence.
In post marketing reports, temporal association of treatment with IM olanzapine with cases of respiratory depression, hypotension or bradycardia and death have been very rarely reported, mostly in patients who concomitantly received benzodiazepines, and/or other antipsychotic medicinal products or who were treated in excess of olanzapine recommended daily doses (see sections 4.4 and 4.5).
The following table is based on the undesirable effects and laboratory investigations from clinical trials with ZYPREXA powder for solution for injection rather than oral olanzapine.
Common (≥1/100 to <1/10): Bradycardia with or without hypotension or syncope, tachycardia.
Uncommon (≥1/1,000 to <1/100): Sinus pause.
__Common (≥1/100 to <1/10): __Postural hypotension, hypotension.
Uncommon (≥1/1,000 to <1/100): Hypoventilation.
Common (≥1/100 to <1/10): Injection site discomfort.
The most frequently (seen in ≥1% of patients) reported adverse reactions associated with the use of olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.
The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the data available).
Common: Eosinophilia, Leukopenia10, Neutropenia10
Rare: Thrombocytopenia11
Uncommon: Hypersensitivity11
Very common: Weight gain1
Common: Elevated cholesterol levels2,3, Elevated glucose levels4, Elevated triglyceride levels2,5, Glucosuria, Increased appetite
Uncommon: Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4)11
Rare: Hypothermia12
Very common: Somnolence
Common: Dizziness, Akathisia6, Parkinsonism6, Dyskinesia6
Uncommon: Seizures where in most cases a history of seizures or risk factors for seizures were reported11, Dystonia (including oculogyration)11, Tardive dyskinesia11, Amnesia9, Dysarthria, Stuttering11,13, Restless Legs Syndrome
Rare: Neuroleptic malignant syndrome (see section 4.4)12, Discontinuation symptoms7,12
Uncommon: Bradycardia QTc prolongation (see section 4.4)
Rare: Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11
Very common: Orthostatic hypotension10
Uncommon: Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4)
Uncommon: Epistaxis9
Common: Mild, transient anticholinergic effects including constipation and dry mouth
Uncommon: Abdominal distension9
Rare: Pancreatitis11
Common: Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4)
Rare: Hepatitis (including hepatocellular, cholestatic or mixed liver injury)11
Common: Rash
Uncommon: Photosensitivity reaction, Alopecia
Not known: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Common: Arthralgia9
Rare: Rhabdomyolysis11
Uncommon: Urinary incontinence, urinary retention, Urinary hesitation11
Not known: Drug withdrawal syndrome neonatal (see section 4.6)
Common: Erectile dysfunction in males, Decreased libido in males and females
Uncommon: Amenorrhea, Breast enlargement, Galactorrhea in females, Gynaecomastia/breast enlargement in males
Rare: Priapism12
Common: Asthenia, Fatigue, Oedema, Pyrexia10
Very common: Elevated plasma prolactin levels8
Common: Increased alkaline phosphatase10, High creatine phosphokinase11, High Gamma Glutamyltransferase10, High uric acid10
Uncommon: Increased total bilirubin
1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥7% of baseline body weight was very common (22.2%), ≥15% was common (4.2%) and ≥25% was uncommon (0.8%). Patients gaining ≥7%, ≥15% and ≥25% of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4%, 31.7% and 12.3% respectively).
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.
3 Observed for fasting normal levels at baseline (<5.17 mmol/l) which increased to high (≥6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥5.17 - <6.2 mmol/l) to high (≥6.2 mmol/l) were very common.
4 Observed for fasting normal levels at baseline (<5.56 mmol/l) which increased to high (≥7 mmol/l). Changes in fasting glucose from borderline at baseline (≥5.56 - <7 mmol/l) to high (≥7 mmol/l) were very common.
5 Observed for fasting normal levels at baseline (<1.69 mmol/l) which increased to high (≥2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥1.69 mmol/l - <2.26 mmol/l) to high (≥2.26 mmol/l) were very common.
6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the majority of these patients the elevations were generally mild, and remained below two times the upper limit of normal range.
9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.
10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database.
11 Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.
12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.
13 Undesirable effects listed and observed following administration of oral and LAIM olanzapine, which may also occur following administration of RAIM olanzapine.
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher incidence of death and cerebrovascular adverse reactions compared to placebo (see section 4.4). Very common adverse reactions associated with the use of olanzapine in this patient group were abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson’s disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (≥10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of ≥7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar disorder was associated with an increase of ≥7% from baseline body weight in 39.9% of patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Olanzapine for injection should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed.
Lorazepam injection should not be used to reconstitute olanzapine for injection as this combination results in a delayed reconstitution time.
Olanzapine for injection should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.
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