olanzapine: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Zypadhera

4.1 Therapeutic indications

Maintenance treatment of adult patients with schizophrenia sufficiently stabilised during acute treatment with oral olanzapine.

4.2 Posology and method of administration

ZYPADHERA 210 mg, 300 mg or 405 mg powder and solvent for prolonged release suspension for injection must not be confused with olanzapine 10 mg powder for solution for injection.

Posology

Patients should be treated initially with oral olanzapine before administering ZYPADHERA, to establish tolerability and response.

In order to identify the first ZYPADHERA dose for all patients the scheme in Table 1 should be considered.

Table 1
Recommended dose scheme between oral olanzapine and ZYPADHERA

Target oral olanzapine dose Recommended starting dose of
ZYPADHERA
Maintenance dose after 2 months of
ZYPADHERA treatment
10 mg/day
210 mg/2 weeks or 405 mg/4 weeks
150 mg/2 weeks or 300 mg/4 weeks
15 mg/day
300 mg/2 weeks
210 mg/2 weeks or 405 mg/4 weeks
20 mg/day
300 mg/2 weeks
300 mg/2 weeks

Dose adjustment
Patients should be monitored carefully for signs of relapse during the first one to two months of treatment. During antipsychotic treatment, improvement in the patient’s clinical condition may take several days to some weeks. Patients should be closely monitored during this period. During treatment dose may subsequently be adjusted on the basis of individual clinical status. After clinical reassessment dose may be adjusted within the range 150 mg to 300 mg every 2 weeks or 300 to 405 mg every 4 weeks. (Table 1)

Supplementation
Supplementation with oral olanzapine was not authorised in double-blind clinical studies. If oral olanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from both formulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day.

Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from ZYPADHERA to other antipsychotic medicinal products. Due to the slow dissolution of the olanzapine pamoate salt which provides a slow continuous release of olanzapine that is complete approximately six to eight months after the last injection, supervision by a clinician, especially during the first 2 months after discontinuation of ZYPADHERA, is needed when switching to another antipsychotic product and is considered medically appropriate.

Special populations

Elderly
ZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA is not recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not routinely indicated, but should be considered for those 65 and over when clinical factors warrant.
ZYPADHERA is not recommended to be started in patients >75 years (see section 4.4).

Renal and/or hepatic impairment
Unless a well-tolerated and effective dose regimen using oral olanzapine has been established in such patients, ZYPADHERA should not be used. A lower starting dose (150 mg every 4 weeks) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 150 mg every 4 weeks and only increased with caution.

Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.5).

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the dose. When indicated, dose escalation should be performed with caution in these patients.

Paediatric population
The safety and efficacy of ZYPADHERA in children and adolescents below 18 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Method of administration

FOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR
SUBCUTANEOUSLY (See section 4.4)

ZYPADHERA should only be administered by deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique and in locations where post-injection observation and access to appropriate medical care in the case of overdose can be assured.

After each injection, patients should be observed in a health care facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.
Immediately prior to leaving the health care facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved (see section 4.4.). The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.

For instructions for use, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known risk of narrow-angle glaucoma.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions seen with olanzapine pamoate
Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistent with olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion.

Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen with oral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statistically significantly higher rate in the ZYPADHERA group than in the placebo group was sedation (ZYPADHERA 8.2%, placebo 2.0%). Among all ZYPADHERA treated patients, sedation was reported by 4.7% of patients.

In clinical trials with ZYPADHERA the incidence of injection site related adverse reactions was approximately 8%. The most commonly reported injection site related adverse reaction was pain (5%);
some other injection site adverse reactions reported were (in decreasing frequency): nodule type reactions, erythema type reactions, non-specific injection site reactions, irritation, oedema type reactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% of patients.

In a review of safety data from clinical trials and spontaneous postmarketing reports, injection site abscess was rarely (≥ 1/10,000 to < 1/1,000) reported.

Adverse reactions seen with olanzapine
The undesirable effects listed below have been observed following administration of olanzapine.

Adults
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.

Tabulated list of adverse reactions
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).

Very common
Common
Uncommon
Rare
Not known
Blood and the lymphatic system disorders

Eosinophilia
Leukopenia10
Neutropenia10

Thrombocytopenia

Immune system disorders

Hypersensitivity11

Metabolism and nutrition disorders
Weight gain1
Elevated cholesterol levels2,3
Elevated glucose levels4
Elevated triglyceride levels2,5
Glucosuria
Increased appetite
Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4)11 Hypothermia12

Nervous system disorders
Somnolence
Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6
Seizures where in most cases a history of seizures or risk factors for seizures were reported11 Dystonia (including oculogyration)11 Tardive dyskinesia11 Amnesia 9 Dysarthria Stuttering11 Restless Legs Syndrome 11 Neuroleptic malignant syndrome (see section 4.4)12 Discontinuation symptoms7, 12

Cardiac disorders

Bradycardia
QTc prolongation
(see section 4.4)
Ventricular tachycardia/fibrill ation, sudden death (see section
4.4) 11

Vascular disorders
Orthostatic hypotension10

Thromboembolis m (including pulmonary embolism and deep vein thrombosis) (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Epistaxis9

Gastrointestinal disorders

Mild, transient anticholinergic effects including constipation and dry mouth
Abdominal distension9
Salivary hypersecretion11
Pancreatitis11

Hepatobiliary disorders

Transient, asymptomatic elevations of hepatic aminotransferases
(ALT, AST), especially in early treatment (see section 4.4)

Hepatitis
(including hepatocellular, cholestatic or mixed liver injury)11

Skin and subcutaneous tissue disorders

Rash
Photosensitivity reaction
Alopecia

Drug Reaction with Eosinophilia and Systemic
Symptoms
(DRESS)
Musculoskeletal and connective tissue disorders

Arthralgia9

Rhabdomyolysis11

Renal and urinary disorders

Urinary incontinence
Urinary retention
Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders

Erectile dysfunction in males
Decreased libido
Amenorrhea
Breast enlargement
Galactorrhea in
Priapism12

in males and females females
Gynaecomastia/ breast enlargement in males
General disorders and administration site conditions

Asthenia
Fatigue
Oedema
Pyrexia10
Injection site pain

Injection site abscess

Investigations
Elevated plasma prolactin levels8
Increased alkaline phosphatase10
High creatine phosphokinase11
High Gamma
Glutamyltransfera se 10
High uric acid 10
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.

Long-term exposure (at least 48 weeks)
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.

Additional information on special populations
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 also 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.

Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years.
Although no clinical studies designed to compare adolescents to adults have been conducted, data from the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure.

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).

Gastrointestinal disorders
Common: Dry mouth
Hepatobiliary disorders
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.

13 Following short term treatment (median duration 22 days), weight gain ≥ 7% of baseline body weight (kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥ 25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 15 % and 29.1 % gained ≥ 25% of their baseline body weight.

14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (≥ 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l - < 1.467 mmol/l) to high (≥ 1.467 mmol/l).

15 Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common.

16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.

Reporting of suspected adverse reactions
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.

4.4 Special warnings and precautions for use

Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular or subcutaneous injection (see section 6.6).

Use in patients who are in an acutely agitated or severely psychotic state
ZYPADHERA should not be used to treat patients with schizophrenia who are in an acutely agitated or severely psychotic state such that immediate symptom control is warranted.

Post-injection syndrome
During pre-marketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose, were reported in patients following an injection of ZYPADHERA. These reactions occurred in <0.1% of injections and approximately 2% of patients. Most of these patients have developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and convulsion. In most cases, initial signs and symptoms related to this reaction have appeared within 1 hour following injection, and in all cases full recovery was reported to have occurred within 24 – 72 hours after injection. Reactions occurred rarely (<1 in 1,000 injections) between 1 and 3 hours, and very rarely (<1 in 10,000 injections) after 3 hours. Patients should be advised about this potential risk and the need to be observed for 3 hours in a healthcare facility each time ZYPADHERA is administered. Post-marketing reports of post-injection syndrome since the marketing authorization of ZYPADHERA are generally consistent with the experience seen in clinical studies.

After each injection, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.

Immediately prior to leaving the health care facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved. The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.

For the remainder of the day after injection, patients should be advised to be vigilant for signs and symptoms of overdose secondary to post injection adverse reactions, be able to obtain assistance if needed and should not drive or operate machinery (see section 4.7).

If parenteral benzodiazepines are essential for management of post injection adverse reactions, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended (see section 4.5).

Injection site related adverse events
The most commonly reported injection site related adverse reaction was pain. The majority of these reactions was reported to be of “mild” to “moderate” severity. In the event of an injection site related adverse reaction occuring, appropriate measures to manage these events should be taken (see section 4.8).

Dementia-related psychosis and/or behavioural disturbances
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 oral 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 oral olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse reactions (CVAEvents e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with oral olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All oral 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.

Parkinson's disease
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 oral 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. Oral olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

(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 diabetes
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 antipsychoticmedicines, including ZYPADHERA, 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.

Lipid alterations
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 antipsychoticmedicines, including ZYPADHERA, 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.

Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the 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.

Hepatic function
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.

Neutropenia
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 oral olanzapine is stopped abruptly.

QT interval
In clinical trials with oral olanzapine, 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 olanzapine powder for solution for injection or ZYPADHERA, 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.

Thromboembolism
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.

Seizures
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.

Tardive dyskinesia
In comparator 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
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death
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.

Paediatric population
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels (see sections 4.8 and 5.1).

Use in elderly (>75 years)
No information on the use of ZYPADHERA in patients >75 years is available. Due to biochemical and physiological modification and reduction of muscular mass, this formulation is not recommended to be started in this sub-group of patients.

Excipients with known effect

Polysorbate
This medicinal product contains 1 mg of polysorbate 80 in each ml of solvent. After reconstitution ZYPADHERA 210 mg contains 1.3 mg, ZYPADHERA 300 mg contains 1.8 mg and ZYPADHERA 405 mg contains 2.3 mg of polysorbate 80. Polysorbates may cause hypersensitivity reactions.

Sodium
After reconstitution this medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially sodium-free.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Caution should be exercised in patients who receive medicinal products that can induce hypotension or sedation.

Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2
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).

Inhibition of CYP1A2
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.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

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.

General CNS activity
Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

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).

QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy
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 infants 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.

Breast-feeding
In a study of oral olanzapine 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.

Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information)

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. As olanzapine may cause somnolence and dizziness, patients should be cautioned about operating machinery, including motor vehicles.

Patients should be advised not to drive or operate machinery for the remainder of the day after each injection due to the possibility of a post-injection syndrome event leading to symptoms consistent with olanzapine overdose (see section 4.4).

4.9 Overdose

If signs and symptoms of overdose consistent with post injection syndrome are observed, appropriate supportive measures should be taken (see section 4.4).

While overdose is less likely with parenteral than oral medicinal products, reference information for oral olanzapine overdose is presented below:

Signs and symptoms
Very common symptoms in overdose (>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 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 oral overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management
There is no specific antidote for olanzapine. Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity since beta stimulation may worsen hypotension.
Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC code N05A H03.

Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nM) for serotonin 5- HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α-1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5- HT2 than D2 activity in vivo, models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an “anxiolytic” test.

In a Positron Emission Tomography (PET) study in patients treated with ZYPADHERA (300 mg/4 weeks), mean D2 receptor occupancy was 60% or higher at the end of a 6 month period, a level consistent with that found during treatment with oral olanzapine.

Clinical efficacy
The effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia is consistent with the established effectiveness of the oral formulation of olanzapine.

A total of 1469 patients with schizophrenia were included in 2 pivotal trials:

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Absorption
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine.

After a single IM injection with ZYPADHERA the slow dissolution of the olanzapine pamoate salt in muscle tissue begins immediately and provides a slow continuous release of olanzapine for more than four weeks. The release becomes diminishingly smaller within eight to twelve weeks. Antipsychotic supplementation is not required at the initiation of ZYPADHERA treatment (see section 4.2).

The combination of the release profile and the dosage regimen (IM injection every two or four weeks) result in sustained olanzapine plasma concentrations. Plasma concentrations remain measurable for several months after each ZYPADHERA injection. The half-life of olanzapine after ZYPADHERA is 30 days compared to 30 hours following oral administration. The absorption and elimination are complete approximately six to eight months after the last injection.

Distribution
Oral olanzapine is rapidly distributed. The plasma protein binding of olanzapine is about 93% over the concentration range of 7 to about 1000 ng/mL. In plasma, olanzapine is bound to albumin and α1-acid glycoprotein.

After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10th to 90th percentile of steady-state plasma concentrations of olanzapine were between 4.2 and 73.2 ng/ml. The plasma concentrations of olanzapine observed across the dose range of 150mg every 4 weeks to 300mg every 2 weeks illustrate increased systemic olanzapine exposure with increased ZYPADHERA doses.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT {MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu

Zyprexa

4.1 Therapeutic indications

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Adults
Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

Applies to: ZYPREXA 10 mg powder for solution for injection

Adults
ZYPREXA powder for solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or manic episode, when oral therapy is not appropriate. Treatment with ZYPREXA powder for solution for injection should be discontinued and the use of oral olanzapine should be initiated as soon as clinically appropriate.

4.2 Posology and method of administration

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Adults
Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1).

Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with dose optimisation as needed), with supplementary therapy to treat mood symptoms, as clinically indicated.

During treatment for schizophrenia, manic episode and recurrence prevention in bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual clinical status within the range 5- 20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours.
Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.

Special populations

Elderly
A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see section 4.4).

Renal and/or hepatic impairment
A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5 mg and only increased with caution.

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.

(See sections 4.5 and 5.2)

Paediatric population
Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations has been reported in short term studies of adolescent patients than in studies of adult patients (see sections 4.4, 4.8, 5.1 and 5.2).

Applies to: ZYPREXA 10 mg powder for solution for injection

Adults
For intramuscular use. Do not administer intravenously or subcutaneously. ZYPREXA powder for solution for injection is intended for short term use only, for up to a maximum of three consecutive days.

The maximum daily dose of olanzapine (including all formulations of olanzapine) is 20 mg.

The recommended initial dose for olanzapine injection is 10 mg, administered as a single intramuscular injection. A lower dose (5 mg or 7.5 mg) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.4). A second injection, 5-10 mg, may be administered 2 hours after the first injection on the basis of individual clinical status. Not more than three injections should be given in any 24 hour period and the maximum daily dose of olanzapine of 20 mg (including all formulations) should not be exceeded.

ZYPREXA powder for solution for injection should be reconstituted in accordance with the recommendation in section 6.6.

For further information on continued treatment with oral olanzapine (5 to 20 mg daily), see the Summary of Product Characteristics for ZYPREXA coated tablets or ZYPREXA VELOTAB orodispersible tablets.

Special populations

Elderly
The recommended starting dose in elderly patients (> 60 years) is 2.5 - 5 mg. Depending on the patient's clinical status (see section 4.4), a second injection, 2.5 - 5 mg, may be administered 2 hours after the first injection. Not more than 3 injections should be given in any 24 hour period and the maximum daily dose of 20 mg (including all formulations) of olanzapine should not be exceeded.

Smokers
The dose and dose range need not be routinely altered for non-smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.5).

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the dose. Additional injections, when indicated, should be conservative in such patients.

(See sections 4.5 and 5.2)

Paediatric population
There is no experience in children. ZYPREXA powder for solution for injection is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

4.3 Contraindications

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets · ZYPREXA 10 mg powder for solution for injection

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known risk of narrow-angle glaucoma.

4.8 Undesirable effects

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Summary of the safety profile

Adults
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.

Very common
Common
Uncommon
Rare
Not known
Blood and the lymphatic system disorders

Eosinophilia
Leukopenia10
Neutropenia10

Thrombocytopenia11

Immune system disorders

Hypersensitivity11

Metabolism and nutrition disorders

Weight gain1
Elevated cholesterol levels2,3
Elevated glucose levels4
Elevated triglyceride levels2,5
Glucosuria
Increased appetite
Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4) 11 Hypothermia12

Nervous system disorders

Somnolence Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6
Seizures where in most cases a history of seizures or risk factors for seizures were reported 11 Dystonia (including oculogyration) 11 Tardive dyskinesia11 Amnesia 9 Dysarthria Stuttering11 Restless Legs Syndrome11 Neuroleptic malignant syndrome (see section 4.4)12 Discontinuation symptoms7, 12

Cardiac disorders

Bradycardia
QTc prolongation (see section 4.4)
Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11

Vascular disorders

Orthostatic hypotension10

Thromboembolism
(including pulmonary embolism and deep vein thrombosis) (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Epistaxis9

Gastrointestinal disorders

Mild, transient anticholinergic effects including constipation and dry mouth
Abdominal distension9
Salivary hypersecretion11
Pancreatitis11

Hepatobiliary disorders

Transient, asymptomatic elevations of hepatic aminotransferases
(ALT, AST), especially in early treatment (see section 4.4)

Hepatitis (including hepatocellular, cholestatic or mixed liver injury) 11

Skin and subcutaneous tissue disorders

Rash
Photosensitivity reaction
Alopecia

Drug
Reaction with
Eosinophilia and Systemic
Symptoms
(DRESS)
Musculoskeletal and connective tissue disorders

Arthralgia9

Rhabdomyolysis11

Renal and urinary disorders

Urinary incontinence, urinary retention
Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal
(see section
4.6)
Reproductive system and breast disorders

Erectile dysfunction in males
Decreased libido in males and females
Amenorrhea
Breast enlargement
Galactorrhea in females
Gynaecomastia/breast enlargement in males
Priapism12

General disorders and administration site conditions

Asthenia
Fatigue
Oedema
Pyrexia10

Investigations

Elevated plasma prolactin levels8
Increased alkaline phosphatase10
High creatine phosphokinase11
High Gamma
Glutamyltransferase10
High uric acid 10
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.

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.

Long-term exposure (at least 48 weeks)
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.

Additional information on special populations
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 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.

The following table summarises the adverse reactions reported with a greater frequency in adolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term clinical trials in adolescent patients. Clinically significant weight gain (≥ 7 %) appears to occur more frequently in the adolescent population compared to adults with comparable exposures. The magnitude of weight gain and the proportion of adolescent patients who had clinically significant weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure.

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).

Metabolism and nutrition disorders
Very common: Weight gain13, elevated triglyceride levels14, increased appetite.
Common: Elevated cholesterol levels15
Nervous system disorders
Very common: Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common: Dry mouth
Hepatobiliary disorders
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.

13 Following short term treatment (median duration 22 days), weight gain ≥ 7 % of baseline body weight (kg) was very common (40.6 %), ≥ 15 % of baseline body weight was common (7.1 %) and ≥ 25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 15 % and 29.1 % gained ≥ 25 % of their baseline body weight.

16 Elevated plasma prolactin levels were reported in 47.4 % of adolescent patients.

Applies to: ZYPREXA 10 mg powder for solution for injection

Summary of the safety profile
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.

Cardiac disorders
Common ( ≥ 1/100 to < 1/10): Bradycardia with or without hypotension or syncope, tachycardia.
Uncommon (≥ 1/1,000 to < 1/100): Sinus pause.
Vascular Disorders
Common (≥ 1/100 to < 1/10): Postural hypotension, hypotension.
Respiratory disorders
Uncommon (≥ 1/1,000 to < 1/100): Hypoventilation.
General disorders and administration site conditions
Common (≥ 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 powder for solution for injection.

Adults
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.

Very common
Common
Uncommon
Rare
Not known
Blood and the lymphatic system disorders

Eosinophilia
Leukopenia10
Neutropenia10

Thrombocytopenia11

Immune system disorders

Hypersensitivity11

Metabolism and nutrition disorders

Nervous system disorders

Somnolence
Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6
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
Syndrome11
Neuroleptic malignant syndrome (see section
4.4)12
Discontinuation symptoms7,12

Cardiac disorders

Bradycardia
QTc prolongation (see section 4.4)
Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11

Vascular disorders

Orthostatic hypotension10

Thromboembolism
(including pulmonary embolism and deep vein thrombosis) (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Epistaxis9

Gastrointestinal disorders

Mild, transient anticholinergic effects including constipation and dry mouth
Abdominal distension9
Salivary hypersecretion11
Pancreatitis11

Hepatobiliary disorders

Transient, asymptomatic elevations of hepatic aminotransferases
(ALT, AST), especially in early treatment (see section 4.4)

Hepatitis (including hepatocellular, cholestatic or mixed liver injury)11

Skin and subcutaneous tissue disorders

Rash
Photosensitivity reaction
Alopecia

Drug
Reaction with
Eosinophilia and
Systemic
Symptoms
(DRESS)

Musculoskeletal and connective tissue disorders

Arthralgia9

Rhabdomyolysis11

Renal and urinary disorders

Urinary incontinence, urinary retention
Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal
(see section
4.6)
Reproductive system and breast disorders

Erectile dysfunction in males
Decreased libido in males and females
Amenorrhea
Breast enlargement
Galactorrhea in females
Gynaecomastia/breast enlargement in males
Priapism12

General disorders and administration site conditions

Asthenia
Fatigue
Oedema
Pyrexia10

Investigations

Elevated plasma prolactin levels8
Increased alkaline phosphatase10
High creatine phosphokinase11
High Gamma
Glutamyltransferase
High Uric acid 10
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.

7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported when olanzapine is stopped abruptly.

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.

13Undesirable effects listed and observed following administration of oral and LAIM olanzapine, which may also occur following administration of RAIM olanzapine.

Additional information on special populations
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 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.

4.4 Special warnings and precautions for use

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances
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.

Parkinson's disease
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.

Hyperglycaemia and diabetes
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.

Lipid alterations
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.

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.

QT interval
In clinical trials, 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. 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.

Thromboembolism
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.

Tardive Dyskinesia
In comparator 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.

Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Applies to: ZYPREXA 10 mg powder for solution for injection

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.

Unstable medical conditions
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.

Concomitant use of benzodiazepines and other medicinal products
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.

Hypotension
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).

Dementia-related psychosis and/or behavioural disturbances
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.

Parkinson's disease
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.

Hyperglycaemia and diabetes
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.

Lipid alterations
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.

Anticholinergic activity
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.

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.

QT interval
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.

Thromboembolism
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.

Tardive Dyskinesia
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
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.

Sudden cardiac death:
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.

Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Decreased bioavailability
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.

Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

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.

General CNS activity
Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

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).

QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

Applies to: ZYPREXA 10 mg powder for solution for injection

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).

Potential for interaction following intramuscular injection
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).

Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Decreased bioavailability
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.

Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists (see section 6.2).

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).

QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products known to increase QTc interval (see section 4.4).

4.6 Fertility, pregnancy and lactation

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Pregnancy

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 infants 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.

Breast-feeding
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.

Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information).

Applies to: ZYPREXA 10 mg powder for solution for injection

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.

Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information).

4.7 Effects on ability to drive and use machines

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets · ZYPREXA 10 mg powder for solution for injection

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.

4.9 Overdose

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Signs and symptoms
Very common symptoms in overdose (> 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 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 but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management
There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60 %.

Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta- agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

5.
PHARMACOLOGICAL PROPERTIES

Applies to: ZYPREXA 10 mg powder for solution for injection

Signs and symptoms
Very common symptoms in overdose (> 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 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 but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management
There is no specific antidote for olanzapine.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC code N05A H03.

Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki < 100 nM) for serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity in vivo models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding in an “anxiolytic” test.

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced a higher 5 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy
In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p = 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: ZYPREXA 10 mg powder for solution for injection

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC code N05A H03.

Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologic profile across a number of receptor systems.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: ZYPREXA 2.5 mg coated tablets / ZYPREXA 5 mg coated tablets / ZYPREXA 7.5 mg coated tablets

Absorption
Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined.

Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.

Biotransformation
Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450- CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine.

Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44 patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.

In female versus male subjects the mean elimination half life was somewhat prolonged (36.7 versus 32.3 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).

Renal impairment

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: ZYPREXA 10 mg powder for solution for injection

In a pharmacokinetic study in healthy volunteers, a dose of 5 mg of ZYPREXA powder for solution for injection produced a maximum plasma concentration (Cmax) approximately 5 times higher than that seen with the same dose of olanzapine administered orally. The Cmax occurs earlier after intramuscular compared to oral use (15 to 45 minutes versus 5 to 8 hours). As with oral use, Cmax and area under the curve after intramuscular use are directly proportional to the dose administered. For the same dose of olanzapine administered intramuscularly and orally, the associated area under the curve, half-life, clearance and volume of distribution are similar. The metabolic profiles following intramuscular and oral use are similar.

In non-smoking versus smoking subjects (males and females) administered olanzapine intramuscularly the mean elimination half-life was prolonged (38.6 versus 30.4 hr) and the clearance was reduced (18.6 versus 27.7 l/hr).

Additional pharmacokinetic data following administration of oral olanzapine are described below.

Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1,000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.

Biotransformation
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450- CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine.

Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT {MM/YYYY} Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu

Zyprexa Velotab

4.1 Therapeutic indications

Adults
Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology and method of administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in combination therapy (see section 5.1).

ZYPREXA VELOTAB orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before administration.

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. It has the same dosage and frequency of administration as olanzapine coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine coated tablets.

Special populations

Elderly
A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and over when clinical factors warrant (see section 4.4).

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, ZYPREXA coated tablets should be used.

(See sections 4.5 and 5.2.)

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients with known risk of narrow-angle glaucoma.

4.8 Undesirable effects

Summary of the safety profile

Very common
Common
Uncommon
Rare
Not known
Blood and the lymphatic system disorders

Eosinophilia
Leukopenia10
Neutropenia10

Thrombocytopenia11

Immune system disorders

Hypersensitivity11

Metabolism and nutrition disorders

Nervous system disorders

Somnolence
Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6
Seizures where in most cases a history of seizures or risk factors for seizures were reported11

Dystonia (including oculogyration) 11
Tardive dyskinesia11

Amnesia 9

Dysarthria
Stuttering11
Restless Legs
Syndrome11
Neuroleptic malignant syndrome (see section
4.4)12

Discontinuation symptoms7, 12

Cardiac disorders

Bradycardia
QTc prolongation (see section 4.4)
Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11

Vascular disorders

Orthostatic hypotension10

Thromboembolism
(including pulmonary embolism and deep vein thrombosis) (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Epistaxis9

Gastrointestinal disorders

Mild, transient anticholinergic effects including constipation and dry mouth
Abdominal distension9
Salivary hypersecretion11
Pancreatitis11

Hepatobiliary disorders

Transient, asymptomatic elevations of hepatic aminotransferases
(ALT, AST), especially in early treatment (see section 4.4)

Hepatitis (including hepatocellular, cholestatic or mixed liver injury)11

Skin and subcutaneous tissue disorders

Rash
Photosensitivity reaction
Alopecia

Drug
Reaction with
Eosinophilia and
Systemic
Symptoms
(DRESS)
Musculoskeletal and connective tissue disorders

Arthralgia9

Rhabdomyolysis11

Renal and urinary disorders

Urinary incontinence, urinary retention
Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders

Erectile dysfunction in males
Decreased libido in males and females
Amenorrhea
Breast enlargement
Galactorrhea in females
Gynaecomastia/breast enlargement in males
Priapism12

General disorders and administration site conditions

Asthenia
Fatigue
Oedema
Pyrexia10

Investigations

Elevated plasma prolactin levels8
Increased alkaline phosphatase10
High creatine phosphokinase11
High Gamma
Glutamyltransferase
High uric acid 10

Increased total bilirubin