Zyprexa Im 10.0 mg Powder for solution for injection

ZYPREXA IM injection is indicated for the control of agitation and disturbed behaviour in patients with schizophrenia and related psychoses and in patients with acute mania associated with Bipolar I disorder when oral therapy is not appropriate. Treatment with ZYPREXA IM should be discontinued and replaced with oral therapy as soon as clinically appropriate.

Posology
ZYPREXA IM is for intramuscular use only. ZYPREXA IM should not be administered intravenously or subcutaneously.
The recommended dose for ZYPREXA IM injection is 10 mg administered as a single intramuscular injection. On the basis of individual clinical status, a second injection of up to 10 mg may be administered as early as 2 hours after the first injection, and a third injection of up to 10 mg may be administered as early as 4 hours after the second injection. The safety of total daily doses greater than 30 mg has not been evaluated in clinical trials. Treatment with ZYPREXA IM for injection should be discontinued and oral ZYPREXA therapy, in a range of 5 - 20 mg/day, should be initiated as soon as clinically appropriate.
Elderly patients: A lower starting dose of 2,5 - 5 mg per injection should be considered for elderly patients.
Method of administration
Reconstitution of ZYPREXA IM (powder for injection) with sterile water for injection (see section 6.6):
u2022 Reconstitute using 2,1 ml sterile water for injection.
u2022 The following table provides injection volumes for delivering various doses of ZYPREXA IM:
Dose, mg ZYPREXA IM Volume of Injection, ml
10,0 Withdraw total contents of vial
7,5 1,5
5,0 1,0
2,5 0,5
Major reconstitution incompatibilities:
u2022 ZYPREXA IM should be reconstituted with sterile water for injection only.
u2022 ZYPREXA IM should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed.
u2022 Lorazepam injection should not be used to reconstitute ZYPREXA IM as this combination results in a delayed reconstitution time.
u2022 ZYPREXA IM should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.

ZYPREXA is contraindicated in:
u2022 patients who are hypersensitive to the active substance, olanzapine, or to any of the excipients listed in section 6.1.
u2022 patients with known risk of narrow-angle glaucoma.
Paediatric use: Safety and effectiveness in patients under 18 years of age have not been established.

The efficacy of ZYPREXA IM has not been established in patients with agitation and disturbed behaviours related to conditions other than schizophrenia or manic episode.
Unstable medical conditions
ZYPREXA IM 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 patientu2019s 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.
Concomitant use of benzodiazepines and other medicines
Special caution is necessary in patients who have received treatment with other medicines having haemodynamic properties similar to those of intramuscular olanzapine including other antipsychotics (oral and/or intramuscular) and benzodiazepines (see section 4.5). Serious/severe bradycardia and syncope may occur. In clinical studies there were cases with serious symptomatic hypotension, apnoea, and ventricular tachydysrythmias including fatalities. In most of the serious cases, there was a temporal relationship with the use of benzodiazepines.
Simultaneous injection of intramuscular ZYPREXA IM and parenteral benzodiazepines has not been studied and is therefore not recommended (see section 4.5). If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least 1 hour after ZYPREXA IM administration. If the patient has received parenteral benzodiazepines, ZYPREXA IM administration should only be considered after careful evaluation of clinical status and the patient should be closely monitored for excessive sedation and cardiorespiratory depression.
Hypotension
Hypotension and/or bradycardia after ZYPREXA IM administration may occur and patients should be closely observed, particularly for the first 4 hours following injection, and close observation after that 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 drowsy or dizzy after injection, until examination has indicated that they are not experiencing hypotension, postural hypotension, bradycardia and/or hypoventilation. In view of the possibility of bradycardia and/or hypotension with ZYPREXA IM caution should be considered in patients with serious cardiovascular disease where the occurrence of syncope or hypotension and/or bradycardia might put the patient at increased medical risk.
Discontinuation of treatment
Discontinuation reactions may occur, usually within a week of discontinuing ZYPREXA. These reactions may consist of a cholinergic syndrome (diaphoresis, diarrhoea, sialorrhoea, nausea and vomiting, anxiety, agitation, insomnia and tremor). ZYPREXA should therefore be gradually discontinued.
Hyperprolactinaemia
ZYPREXA elevates prolactin levels and elevation persists during chronic administration.
Neuroleptic malignant syndrome (NMS)
NMS has occurred in association with ZYPREXA. NMS is a potentially fatal symptom complex. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. ZYPREXA should be discontinued, as well as all antipsychotic medicines, should any of the clinical manifestations of NMS or unexplained high fever without additional clinical manifestations of NMS be observed.
Seizures
ZYPREXA should be used cautiously in patients who have a history of seizures or are subject to factors which may lower seizure threshold as seizures have been reported to occur in patients treated with ZYPREXA.
Tardive dyskinesia
ZYPREXA was associated with dyskinesia. If signs or symptoms of tardive dyskinesia appear in a patient on ZYPREXA, a dose reduction or discontinuation of treatment should be considered. The risk of tardive dyskinesia increases with long-term exposure. Symptoms of tardive dyskinesia can temporarily deteriorate or even arise after discontinuation of treatment.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with ZYPREXA exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. Discontinue ZYPREXA if DRESS is suspected.
Hepatic impairment
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised 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. Periodic assessment of transaminases is recommended in patients with significant hepatic disease. A 5 mg starting dose should be considered for patients with moderate hepatic impairment. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, ZYPREXA treatment should be discontinued.
Safety experience in elderly patients with Dementia-related psychosis
In elderly patients with dementia-related psychosis, the efficacy of ZYPREXA has not been established. In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in ZYPREXA-treated patients was significantly greater than placebo-treated patients (3,5 % vs 1,5 % respectively). Abnormal gait and falls were very common (> 10 %), urinary incontinence and respiratory infection were common, and there was an increased incidence in cerebrovascular incidents, including stroke. Risk factors that may predispose this patient population to increased mortality when treated with ZYPREXA include age u2265 65 years, dysphagia, sedation, malnutrition and dehydration, concomitant use of benzodiazepines, or presence of pulmonary conditions (e.g. pneumonia, with or without aspiration). ZYPREXA is not indicated for the treatment of patients with dementia-related psychosis.
Cerebrovascular adverse events (CVAE), including stroke, in elderly patients with dementia
Cerebrovascular adverse events (e.g. stroke, transient ischemic attack), including fatalities, were reported in trials of ZYPREXA in elderly patients with dementia-related psychosis. In placebo-controlled studies, there was a higher incidence of CVAE in patients treated with ZYPREXA compared to patients treated with placebo (1,3 % vs 0,4 %, respectively). All patients who experienced a cerebrovascular event had pre-existing risk factors known to be associated with an increased risk for a CVAE (e.g. history of previous CVAE or transient ischemic attack, hypertension, cigarette smoking) and presented with concurrent medical conditions and/or concomitant medications having a temporal association with CVAE.
Parkinson's disease
The use of ZYPREXA 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 medicines (dopamine agonist) and to remain on the same anti-Parkinsonian medicines 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.
Hyperglycaemia and diabetes mellitus
Hyperglycaemia and diabetes mellitus, which may be associated with ketoacidosis or hyperosmolar coma or death due to exacerbation of pre-existing diabetes, have been reported in patients treated with ZYPREXA. Patients with an established diagnosis of diabetes mellitus who are started on ZYPREXA should be monitored regularly for worsening of glucose control (measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter). Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes), who are starting treatment with ZYPREXA should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with ZYPREXA should undergo fasting blood glucose testing. Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting ZYPREXA treatment and quarterly thereafter. Continuation of anti-diabetic treatment may be needed even after discontinuation of ZYPREXA.
Anticholinergic activity
Clinical experience with ZYPREXA in patients with concomitant illness is limited. ZYPREXA demonstrated anticholinergic activity in vitro. Caution is advised when prescribing for patients with symptomatic prostatic enlargement, narrow-angle glaucoma or paralytic ileus and related conditions (see section 4.3).
Lipid Alterations
Increases in total cholesterol, LDL cholesterol and triglycerides are very common in patients treated with ZYPREXA. Appropriate clinical monitoring is recommended. 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.
QT interval
In clinical trials with oral administration, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] u2265 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 ZYPREXA, with no significant differences in associated cardiac events compared to placebo. However, caution should be exercised when ZYPREXA 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.
Thromboembolism
Temporal association of ZYPREXA treatment and venous thromboembolism has been reported uncommonly (u2265 0,1 % and < 1 %). A causal relationship between the occurrence of venous thromboembolism and treatment with ZYPREXA 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.
General CNS activity
Given the primary CNS effects of ZYPREXA, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, ZYPREXA may antagonize the effects of direct and indirect dopamine agonists.
Sudden cardiac death
In a retrospective observational study, patients treated with atypical antipsychotics (including ZYPREXA) or typical antipsychotics had a similar dose-related increase of presumed sudden cardiac death (SCD) compared to non-users of antipsychotics (almost twice the risk than that for non-users). In postmarketing reports with ZYPREXA, the event of SCD has been reported very rarely.
Geriatric use
Caution should be exercised in dosing the elderly, especially if there are other factors that might additively influence medicine metabolism and/or pharmacodynamic sensitivity. A lower starting dose of ZYPREXA should be used in the elderly. As postural hypotension may occur especially in the elderly, it is recommended that blood pressure is measured periodically in patients over 65 years.
Smokers
Plasma clearance of ZYPREXA is higher in smokers. The combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in population. The clearance in young smoking males is 3 times higher than that in elderly non-smoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of ZYPREXA.
Orthostatic hypotension
ZYPREXA may induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. ZYPREXA has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from pre-marketing clinical studies. Because of the risk of orthostatic hypotension with ZYPREXA, caution should be observed in cardiac patients.
Neutropenia
Caution should be exercised when using ZYPREXA in the following types of patients:
- In patients with low leucocyte and/or neutrophil counts due to any reason.
- In patients with a history of medicine-induced bone marrow depression/toxicity.
- In patients with bone marrow depression caused by concomitant illness, radiation therapy or chemotherapy.
- In patients with hypereosinophilic conditions or with myeloproliferative disease.
- In patients using concomitant valproate (see section 4.8).
Body temperature regulation
Disruption of the bodyu2019s ability to reduce core body temperature, pyrexia and malignant hyperpyrexia may occur during ZYPREXA therapy.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with antipsychotic medicines such as ZYPREXA. ZYPREXA should be used with caution in patients at risk for aspiration pneumonia.
Suicide
The possibility of suicide attempt is inherent in schizophrenia and close supervision of patients at risk should accompany ZYPREXA treatment.
ZYPREXA IM contains lactose
Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take ZYPREXA IM.

Caution should be exercised when ZYPREXA is taken in combination with other centrally acting medicines (especially those that can cause CNS depression) and alcohol. ZYPREXA may antagonise the effects of levodopa and dopamine agonists. Because of the potential for inducing hypotension, ZYPREXA may enhance the effects of certain antihypertensive medicines. Hypotension and/or bradycardia have been observed after administration of ZYPREXA for injection. ZYPREXA has u03b1 - 1 adrenergic antagonist activity. Caution should be exercised in patients who receive treatment with other medicines that can lower blood pressure.
Potential for other medicines to affect ZYPREXA
Administration of intramuscular lorazepam (2 mg) one hour after intramuscular ZYPREXA IM (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular ZYPREXA IM increased the somnolence observed with either medicine alone and is associated with hypotension, which may be symptomatic and severe. Temporal association of treatment with ZYPREXA IM 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.
Simultaneous injection of intramuscular ZYPREXA IM and parenteral benzodiazepine is not recommended due to the potential for excessive sedation, cardiorespiratory depression and in very rare cases, death (see sections 4.2 and 4.4). If the patient is considered to need parenteral benzodiazepine treatment, this should not be given until at least one hour after ZYPREXA IM administration. If the patient has received parenteral benzodiazepines, ZYPREXA IM administration should only be considered after careful evaluation of clinical status and the patient should be closely monitored for excessive sedation and cardiorespiratory depression.
Potential interactions affecting ZYPREXA
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of ZYPREXA.
Induction of CYP1A2
The metabolism of olanzapine may be induced by concomitant smoking or carbamazepine therapy causing subsequent lower olanzapine plasma levels. Clinical monitoring is recommended and an increase of the ZYPREXA dose may be considered.
Inhibition of CYP1A2
Known potent inhibitors of CYP1A2 activity may decrease ZYPREXA clearance. Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of ZYPREXA. The mean increase in olanzapine C max 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 or ketoconazole.

Pregnancy
Safety of ZYPREXA during pregnancy has not been established. 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 ZYPREXA. New born infants exposed to antipsychotics (including ZYPREXA) 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, new borns should be monitored carefully.
Breastfeeding
Safety of ZYPREXA during lactation has not been established. In a study in breastfeeding, healthy women, ZYPREXA 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 ZYPREXA.
Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information).

ZYPREXA may cause somnolence. Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely.

Summary of the safety profile
A common (u2265 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 medicines 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 IM powder for solution for injection rather than oral olanzapine.
Cardiac disorders
Common (u2265 1/100 to < 1/10): Bradycardia with or without hypotension or syncope, tachycardia.
Uncommon (u2265 1/1 000 to < 1/100): Sinus pause.
Vascular Disorders
Common (u2265 1/100 to < 1/10): Postural hypotension, hypotension.
Respiratory disorders
Uncommon (u2265 1/1 000 to < 1/100): Hypoventilation.
General disorders and administration site conditions
Common (u2265 1/100 to < 1/10): Injection site discomfort.
The undesirable effects listed below have been observed following administration of oral and prolonged release intramuscular injection olanzapine, but may also occur following administration of ZYPREXA IM powder for solution for injection.
Adults
The most frequently (seen in u2265 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.

Signs and symptoms
Very common symptoms reported in ZYPREXA overdose (u2265 10 % incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma. Other medically significant sequelae of ZYPREXA overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (< 2 % of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg of oral ZYPREXA but survival has also been reported following acute overdose of 2 g of oral ZYPREXA.
Treatment
The possibility of multiple medicine involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose, may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. There is no specific antidote to ZYPREXA; therefore appropriate symptomatic and supportive measures should be initiated. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic medicines. Induction of emesis is not recommended. Do not use epinephrine, dopamine or other sympathomimetics with u03b2 - agonist activity, since u03b2 -stimulation may worsen hypotension in the setting of ZYPREXA-induced u03b1 - blockade. Close medical supervision and monitoring should continue until the patient recovers.