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Olanzapine Apotex (olanzapine) – Summary of product characteristics - N05AH03

Updated on site: 08-Oct-2017

Medication nameOlanzapine Apotex
ATC CodeN05AH03
Substanceolanzapine
ManufacturerApotex Europe B.V.  

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 2.5 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2.5 mg olanzapine.

Excipient with known effect: Each film-coated tablet contains 63.17 mg lactose.

For the full list of excipients, see section 6.1

3.PHARMACEUTICAL FORM

Film-coated tablet

White, round, biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘2.5’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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 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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

Lactose

Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Very common

Common

Uncommon

Rare

Not

 

 

 

 

 

known

Blood and lymphatic system disorders

 

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and

nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

 

cholesterol

exacerbation of

 

 

 

 

levels2,3

diabetes occasionally

 

 

 

 

Elevated glucose

associated with

 

 

 

 

levels4

ketoacidosis or coma,

 

 

 

 

Elevated

including some fatal

 

 

 

 

triglyceride

cases (see section 4.4)

 

 

 

 

levels2,5

 

 

 

 

Glucosuria

 

 

 

 

 

Increased appetite

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic

 

 

 

Akathisia6

cases a history of

malignant syndrome

 

 

 

Parkinsonism6

seizures or risk factors

(see section 4.4)

 

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

 

reported 11

symptoms7, 12

 

 

 

 

Dystonia (including

 

 

 

 

 

oculogyration) 11

 

 

 

 

 

Tardive dyskinesia11

 

 

 

 

 

Amnesia 9

 

 

 

 

 

Dysarthria

 

 

 

 

 

Restless legs syndrome

 

 

Cardiac disorders

 

 

 

 

 

 

 

Bradycardia

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillatio

 

 

 

 

section 4.4)

n, sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

Orthostatic

 

 

 

Thromboembolism

 

 

hypotension10

 

 

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Epistaxis9

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

Pancreatitis11

 

 

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

Hepatitis (including

 

 

 

 

asymptomatic

 

hepatocellular,

 

 

 

 

elevations of

 

cholestatic or mixed

 

 

 

 

hepatic

 

liver injury) 11

 

 

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

 

Rash

Photosensitivity

 

Drug

 

 

 

 

reaction

 

Reaction

 

 

 

 

Alopecia

 

with

 

 

 

 

 

 

Eosinophil

 

 

 

 

 

 

ia 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

Amenorrhea

Priapism12

 

 

 

 

dysfunction in

Breast enlargement

 

 

 

 

 

males

Galactorrhea in

 

 

 

 

 

Decreased libido

females

 

 

 

 

 

in males and

Gynaecomastia/breast

 

 

 

 

 

females

enlargement in males

 

 

General disorders

and administration

site conditions

 

 

 

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

 

 

 

 

 

 

Pyrexia10

 

 

 

Investigations

 

 

 

 

Elevated plasma

Increased alkaline

Increased total

 

 

prolactin levels8

phosphatase10

bilirubin

 

 

 

High creatine

 

 

 

 

phosphokinase11

 

 

 

 

High Gamma

 

 

 

 

Glutamyltransfera

 

 

 

 

se10

 

 

 

 

High uric acid 10

 

 

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

13Following 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.

14Observed 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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with

olanzapine indicated 5 HT, 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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or

valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Maize starch

Magnesium stearate

Tablet coat

Hypromellose

Hydroxypropylcellulose

Macrogol 8000

Titanium dioxide (E171)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28 film-coated tablets per carton.

Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/001

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 5 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg olanzapine.

Excipient with known effect: Each film-coated tablet contains 126.34 mg lactose.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘5’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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 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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

Lactose

Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Very common

Common

Uncommon

Rare

Not

 

 

 

 

 

known

Blood and lymphatic system disorders

 

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and

nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

 

cholesterol

exacerbation of

 

 

 

 

levels2,3

diabetes occasionally

 

 

 

 

Elevated glucose

associated with

 

 

 

 

levels4

ketoacidosis or coma,

 

 

 

 

Elevated

including some fatal

 

 

 

 

triglyceride

cases (see section 4.4)

 

 

 

 

levels2,5

 

 

 

 

Glucosuria

 

 

 

 

 

Increased appetite

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic

 

 

 

Akathisia6

cases a history of

malignant syndrome

 

 

 

Parkinsonism6

seizures or risk factors

(see section 4.4)

 

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

 

reported 11

symptoms7, 12

 

 

 

 

Dystonia (including

 

 

 

 

 

oculogyration) 11

 

 

 

 

 

Tardive dyskinesia11

 

 

 

 

 

Amnesia 9

 

 

 

 

 

Dysarthria

 

 

 

 

 

Restless legs syndrome

 

 

Cardiac disorders

 

 

 

 

 

 

 

Bradycardia

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillatio

 

 

 

 

section 4.4)

n, sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

Orthostatic

 

 

Thromboembolism

 

 

hypotension10

 

 

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Epistaxis9

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

Pancreatitis11

 

 

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

Hepatitis (including

 

 

 

 

asymptomatic

 

hepatocellular,

 

 

 

 

elevations of

 

cholestatic or mixed

 

 

 

 

hepatic

 

liver injury) 11

 

 

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

 

Rash

Photosensitivity

 

Drug

 

 

 

 

reaction

 

Reaction

 

 

 

 

Alopecia

 

with

 

 

 

 

 

 

Eosinophil

 

 

 

 

 

 

ia 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 sy

stem and breast disorders

 

 

 

 

 

Erectile

Amenorrhea

Priapism12

 

 

 

 

dysfunction in

Breast enlargement

 

 

 

 

 

males

Galactorrhea in

 

 

 

 

 

Decreased libido

females

 

 

 

 

 

in males and

Gynaecomastia/breast

 

 

 

 

 

females

enlargement in males

 

 

General disorders

and administration

site conditions

 

 

 

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

 

 

 

 

 

 

Pyrexia10

 

 

 

Investigations

 

 

 

 

Elevated plasma

Increased alkaline

Increased total

 

 

prolactin levels8

phosphatase10

bilirubin

 

 

 

High creatine

 

 

 

 

phosphokinase11

 

 

 

 

High Gamma

 

 

 

 

Glutamyltransfera

 

 

 

 

se10

 

 

 

 

High uric acid 10

 

 

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with

olanzapine indicated 5 HT, 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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Maize starch

Magnesium stearate

Tablet coat

Hypromellose

Hydroxypropylcellulose

Macrogol 8000

Titanium dioxide (E171)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28 ,56 and 98 film-coated tablets per carton. Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/002-003

EU/1/10/635/015

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 7.5 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 7.5 mg olanzapine.

Excipient with known effect: Each film-coated tablet contains 189.50 mg lactose.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘7.5’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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 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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

Lactose

Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Very common

Common

Uncommon

Rare

Not

 

 

 

 

 

known

Blood and lymphatic system disorders

 

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and

nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

 

cholesterol

exacerbation of

 

 

 

 

levels2,3

diabetes occasionally

 

 

 

 

Elevated glucose

associated with

 

 

 

 

levels4

ketoacidosis or coma,

 

 

 

 

Elevated

including some fatal

 

 

 

 

triglyceride

cases (see section 4.4)

 

 

 

 

levels2,5

 

 

 

 

Glucosuria

 

 

 

 

 

Increased appetite

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic

 

 

 

Akathisia6

cases a history of

malignant syndrome

 

 

 

Parkinsonism6

seizures or risk factors

(see section 4.4)

 

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

 

reported 11

symptoms7, 12

 

 

 

 

Dystonia (including

 

 

 

 

 

oculogyration) 11

 

 

 

 

 

Tardive dyskinesia11

 

 

 

 

 

Amnesia 9

 

 

 

 

 

Dysarthria

 

 

 

 

 

Restless legs syndrome

 

 

Cardiac disorders

 

 

 

 

 

 

 

Bradycardia

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillatio

 

 

 

 

section 4.4)

n, sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

Orthostatic

 

 

Thromboembolism

 

 

hypotension10

 

 

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Epistaxis9

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

Pancreatitis11

 

 

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

Hepatitis (including

 

 

 

 

asymptomatic

 

hepatocellular,

 

 

 

 

elevations of

 

cholestatic or mixed

 

 

 

 

hepatic

 

liver injury) 11

 

 

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

 

Rash

Photosensitivity

 

Drug

 

 

 

 

reaction

 

Reaction

 

 

 

 

Alopecia

 

with

 

 

 

 

 

 

Eosinophil

 

 

 

 

 

 

ia 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 sy

stem and breast disorders

 

 

 

 

 

Erectile

Amenorrhea

Priapism12

 

 

 

 

dysfunction in

Breast enlargement

 

 

 

 

 

males

Galactorrhea in

 

 

 

 

 

Decreased libido

females

 

 

 

 

 

in males and

Gynaecomastia/breast

 

 

 

 

 

females

enlargement in males

 

 

General disorders

and administration

site conditions

 

 

 

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

 

 

 

 

 

 

Pyrexia10

 

 

 

Investigations

 

 

 

 

Elevated plasma

Increased alkaline

Increased total

 

 

prolactin levels8

phosphatase10

bilirubin

 

 

 

High creatine

 

 

 

 

phosphokinase11

 

 

 

 

High Gamma

 

 

 

 

Glutamyltransfera

 

 

 

 

se10

 

 

 

 

High uric acid 10

 

 

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with

olanzapine indicated 5 HT, 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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Maize starch

Magnesium stearate

Tablet coat

Hypromellose

Hydroxypropylcellulose

Macrogol 8000

Titanium dioxide (E171)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28 and 56 film-coated tablets per carton. Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/004-005

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 10 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg olanzapine.

Excipient with known effect: Each film-coated tablet contains 252.70 mg lactose.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Film-coated tablet

White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘10’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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 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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

Lactose

Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Very common

Common

Uncommon

Rare

Not

 

 

 

 

 

known

Blood and lymphatic system disorders

 

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and

nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

 

cholesterol

exacerbation of

 

 

 

 

levels2,3

diabetes occasionally

 

 

 

 

Elevated glucose

associated with

 

 

 

 

levels4

ketoacidosis or coma,

 

 

 

 

Elevated

including some fatal

 

 

 

 

triglyceride

cases (see section 4.4)

 

 

 

 

levels2,5

 

 

 

 

Glucosuria

 

 

 

 

 

Increased appetite

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic

 

 

 

Akathisia6

cases a history of

malignant syndrome

 

 

 

Parkinsonism6

seizures or risk factors

(see section 4.4)

 

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

 

reported 11

symptoms7, 12

 

 

 

 

Dystonia (including

 

 

 

 

 

oculogyration) 11

 

 

 

 

 

Tardive dyskinesia11

 

 

 

 

 

Amnesia 9

 

 

 

 

 

Dysarthria

 

 

 

 

 

Restless legs syndrome

 

 

Cardiac disorders

 

 

 

 

 

 

 

Bradycardia

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillatio

 

 

 

 

section 4.4)

n, sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

Orthostatic

 

 

Thromboembolism

 

 

hypotension10

 

 

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Epistaxis9

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

Pancreatitis11

 

 

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

Hepatitis (including

 

 

 

 

asymptomatic

 

hepatocellular,

 

 

 

 

elevations of

 

cholestatic or mixed

 

 

 

 

hepatic

 

liver injury) 11

 

 

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

 

Rash

Photosensitivity

 

Drug

 

 

 

 

reaction

 

Reaction

 

 

 

 

Alopecia

 

with

 

 

 

 

 

 

Eosinophil

 

 

 

 

 

 

ia 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 sy

stem and breast disorders

 

 

 

 

 

Erectile

Amenorrhea

Priapism12

 

 

 

 

dysfunction in

Breast enlargement

 

 

 

 

 

males

Galactorrhea in

 

 

 

 

 

Decreased libido

females

 

 

 

 

 

in males and

Gynaecomastia/breast

 

 

 

 

 

females

enlargement in males

 

 

General disorders

and administration

site conditions

 

 

 

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

 

 

 

 

 

 

Pyrexia10

 

 

 

Investigations

 

 

 

 

Elevated plasma

Increased alkaline

Increased total

 

 

prolactin levels8

phosphatase10

bilirubin

 

 

 

High creatine

 

 

 

 

phosphokinase11

 

 

 

 

High Gamma

 

 

 

 

Glutamyltransfera

 

 

 

 

se10

 

 

 

 

High uric acid 10

 

 

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with

olanzapine indicated 5 HT, 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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Maize starch

Magnesium stearate

Tablet coat

Hypromellose

Hydroxypropylcellulose

Macrogol 8000

Titanium dioxide (E171)

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28, 56 and 98 film-coated tablets per carton. Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/006-007

EU/1/10/635/016

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 5 mg orodispersible tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 5 mg olanzapine.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Orodispersible tablet

Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘5’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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

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.

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 starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated tablets should be used.

(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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Bradycardia

Ventricular

QTc prolongation (see

tachycardia/fibrillation,

Tabulated list of adverse reactions

 

The following table lists the adverse reactions and laboratory investigations observed from spontaneous

Very

Common

Uncommon

Rare

Not known

common

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

Leukopenia10

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

cholesterol levels2,3

exacerbation of

 

 

 

Elevated glucose

diabetes occasionally

 

 

 

levels4

associated with

 

 

 

Elevated

ketoacidosis or coma,

 

 

 

triglyceride levels2,5

including some fatal

 

 

 

Glucosuria

cases (see section 4.4)

 

 

 

Increased appetite

 

 

 

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic malignant

 

 

Akathisia6

cases a history of

syndrome (see

 

 

Parkinsonism6

seizures or risk factors

section 4.4)12

 

 

Dyskinesia6

for seizures were

 

 

 

 

reported 11

Discontinuation

 

 

 

 

symptoms7, 12

 

 

 

 

 

 

Cardiac disorders

 

 

 

Dystonia (including oculogyration) 11 Tardive dyskinesia11

Amnesia 9

Dysarthria

Restless legs syndrome

 

 

section 4.4)

 

sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

 

 

Orthostatic

 

Thromboembolism

 

 

 

 

hypotension10

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

Epistaxis9

 

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

 

Pancreatitis11

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

 

 

Hepatitis (including

 

 

asymptomatic

 

 

 

hepatocellular,

 

 

elevations of

 

 

 

cholestatic or mixed

 

 

hepatic

 

 

 

liver injury) 11

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

Rash

Photosensitivity

 

 

Drug

 

 

reaction

 

 

Reaction

 

 

Alopecia

 

 

with

 

 

 

 

 

 

Eosinophili

 

 

 

 

 

 

a 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

Amenorrhea

 

Priapism12

 

 

dysfunction in

Breast enlargement

 

 

 

 

males

Galactorrhea in females

 

 

 

 

Decreased libido in

Gynaecomastia/breast

 

 

 

 

males and females

enlargement in males

 

 

 

General disorders and administration site conditions

 

 

 

 

Asthenia

 

 

 

 

 

Fatigue

Oedema

Pyrexia10

Investigations

Elevated

Increased alkaline

Increased total bilirubin

 

plasma

phosphatase10

 

 

prolactin

High creatine

 

 

levels8

phosphokinase11

 

 

 

High Gamma

 

 

 

Glutamyltransferase

 

 

 

 

 

 

High uric acid 10

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

13Following 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.

14Observed 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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT,

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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 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 1-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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Mannitol (E421)

Microcrystalline cellulose

Carmellose calcium

Sucralose

Magnesium stearate

Colloidal anhydrous silica

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28, 56 and 98 orodispersible tablets per carton Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/008-009

EU/1/10/635/017

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 10 mg orodispersible tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 10 mg olanzapine.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Orodispersible tablet

Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘10’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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

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.

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 starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated tablets should be used.

(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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Bradycardia

Ventricular

QTc prolongation (see

tachycardia/fibrillation,

Tabulated list of adverse reactions

 

The following table lists the adverse reactions and laboratory investigations observed from spontaneous

Very

Common

Uncommon

Rare

Not known

common

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

Leukopenia10

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

cholesterol levels2,3

exacerbation of

 

 

 

Elevated glucose

diabetes occasionally

 

 

 

levels4

associated with

 

 

 

Elevated

ketoacidosis or coma,

 

 

 

triglyceride levels2,5

including some fatal

 

 

 

Glucosuria

cases (see section 4.4)

 

 

 

Increased appetite

 

 

 

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic malignant

 

 

Akathisia6

cases a history of

syndrome (see

 

 

Parkinsonism6

seizures or risk factors

section 4.4)

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

reported 11

symptoms7, 12

 

 

 

 

 

 

Cardiac disorders

 

 

 

Dystonia (including oculogyration) 11 Tardive dyskinesia11

Amnesia 9

Dysarthria

Restless legs syndrome

 

 

section 4.4)

 

sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

 

 

Orthostatic

 

Thromboembolism

 

 

 

 

hypotension10

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

Epistaxis9

 

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

 

Pancreatitis11

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

 

 

Hepatitis (including

 

 

asymptomatic

 

 

 

hepatocellular,

 

 

elevations of

 

 

 

cholestatic or mixed

 

 

hepatic

 

 

 

liver injury) 11

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

Rash

Photosensitivity

 

 

Drug

 

 

reaction

 

 

Reaction

 

 

Alopecia

 

 

with

 

 

 

 

 

 

Eosinophili

 

 

 

 

 

 

a 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

Amenorrhea

 

Priapism12

 

 

dysfunction in

Breast enlargement

 

 

 

 

males

Galactorrhea in females

 

 

 

 

Decreased libido in

Gynaecomastia/breast

 

 

 

 

males and females

enlargement in males

 

 

 

General disorders and administration site conditions

 

 

 

 

Asthenia

 

 

 

 

 

Fatigue

Oedema

Pyrexia10

Investigations

Elevated

Increased alkaline

Increased total bilirubin

 

plasma

phosphatase10

 

 

prolactin

High creatine

 

 

levels8

phosphokinase11

 

 

 

High Gamma

 

 

 

Glutamyltransferase

 

 

 

 

 

 

High uric acid 10

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

13Following 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.

14Observed 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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT,

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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 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 1-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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Mannitol (E421)

Microcrystalline cellulose

Carmellose calcium

Sucralose

Magnesium stearate

Colloidal anhydrous silica

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28, 56 and 98 orodispersible tablets per carton Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/010-011

EU/1/10/635/018

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 15 mg orodispersible tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 15 mg olanzapine.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Orodispersible tablet

Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘15’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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

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.

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 starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated tablets should be used.

(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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Bradycardia

Ventricular

QTc prolongation (see

tachycardia/fibrillation,

Tabulated list of adverse reactions

 

The following table lists the adverse reactions and laboratory investigations observed from spontaneous

Very

Common

Uncommon

Rare

Not known

common

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

 

Thrombocytopenia11

 

 

Leukopenia10

 

 

 

 

Neutropenia10

 

 

 

Immune system

disorders

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

cholesterol levels2,3

exacerbation of

 

 

 

Elevated glucose

diabetes occasionally

 

 

 

levels4

associated with

 

 

 

Elevated

ketoacidosis or coma,

 

 

 

triglyceride levels2,5

including some fatal

 

 

 

Glucosuria

cases (see section 4.4)

 

 

 

Increased appetite

 

 

 

 

 

 

Nervous system

disorders

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic malignant

 

 

Akathisia6

cases a history of

syndrome (see

 

 

Parkinsonism6

seizures or risk factors

section 4.4)

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

reported 11

symptoms7, 12

 

 

 

 

 

 

Cardiac disorders

 

 

 

Dystonia (including oculogyration) 11 Tardive dyskinesia11

Amnesia 9

Dysarthria

Restless legs syndrome

 

 

section 4.4)

 

sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

 

 

Orthostatic

 

Thromboembolism

 

 

 

 

hypotension10

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

Epistaxis9

 

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

 

Pancreatitis11

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

 

 

Hepatitis (including

 

 

asymptomatic

 

 

 

hepatocellular,

 

 

elevations of

 

 

 

cholestatic or mixed

 

 

hepatic

 

 

 

liver injury) 11

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

Rash

Photosensitivity

 

 

Drug

 

 

reaction

 

 

Reaction

 

 

Alopecia

 

 

with

 

 

 

 

 

 

Eosinophili

 

 

 

 

 

 

a 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

Amenorrhea

 

Priapism12

 

 

dysfunction in

Breast enlargement

 

 

 

 

males

Galactorrhea in females

 

 

 

 

Decreased libido in

Gynaecomastia/breast

 

 

 

 

males and females

enlargement in males

 

 

 

General disorders and administration site conditions

 

 

 

 

Asthenia

 

 

 

 

 

Fatigue

Oedema

Pyrexia10

Investigations

Elevated

Increased alkaline

Increased total bilirubin

 

plasma

phosphatase10

 

 

prolactin

High creatine

 

 

levels8

phosphokinase11

 

 

 

High Gamma

 

 

 

Glutamyltransferase

 

 

 

 

 

 

High uric acid 10

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

13Following 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.

14Observed 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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT,

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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 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 1-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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Mannitol (E421)

Microcrystalline cellulose

Carmellose calcium

Sucralose

Magnesium stearate

Colloidal anhydrous silica

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28 orodispersible tablets per carton Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/012

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

1.NAME OF THE MEDICINAL PRODUCT

Olanzapine Apotex 20 mg orodispersible tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 20 mg olanzapine.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Orodispersible tablet

Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘20’ on the other side.

4.CLINICAL PARTICULARS

4.1Therapeutic 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).

4.2Posology 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).

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.

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

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.

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 starting dose. Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated tablets should be used.

(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).

4.3Contraindications

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

4.4Special warnings and precautions for use

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.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and 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 Olanzapine Apotex, 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 Olanzapine Apotex, 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, alanine transferase (ALT), aspartate transferase (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 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.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of direct and indirect dopamine agonists.

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).

4.5Interaction with other medicinal products and other forms of interaction

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.

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.

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 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).

4.6Fertility, 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.

Newborn 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, hypotonis, 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).

4.7Effects on ability to drive and use machines

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.

4.8Undesirable effects

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.

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 available data).

Very

Common

Uncommon

Rare

Not known

common

 

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

 

 

Thrombocytopenia11

 

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

 

Immune system

disorders

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

 

Weight gain1

Elevated

Development or

Hypothermia12

 

 

cholesterol levels2,3

exacerbation of

 

 

 

Elevated glucose

diabetes occasionally

 

 

 

levels4

associated with

 

 

 

Elevated

ketoacidosis or coma,

 

 

 

triglyceride levels2,5

including some fatal

 

 

 

Glucosuria

cases (see section 4.4)

 

 

 

Increased appetite

 

 

 

 

 

 

 

 

Nervous system

disorders

 

 

 

 

Somnolence

Dizziness

Seizures where in most

Neuroleptic malignant

 

 

Akathisia6

cases a history of

syndrome (see

 

 

Parkinsonism6

seizures or risk factors

section 4.4)

 

 

Dyskinesia6

for seizures were

12Discontinuation

 

 

 

reported 11

symptoms7, 12

 

 

 

Dystonia (including

 

 

 

 

oculogyration) 11

 

 

 

 

Tardive dyskinesia11

 

 

 

 

Amnesia 9

 

 

 

 

Dysarthria

 

 

 

 

Restless legs

 

 

 

 

syndrome

 

 

Cardiac disorders

 

 

 

 

 

 

Bradycardia

 

Ventricular

 

 

 

QTc prolongation (see

 

tachycardia/fibrillation,

 

 

 

section 4.4)

 

sudden death (see

 

 

 

 

 

section 4.4)11

 

Vascular disorders

 

 

 

 

Orthostatic

 

Thromboembolism

 

 

 

hypotension10

 

(including pulmonary

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

Epistaxis9

 

 

 

Gastrointestinal

disorders

 

 

 

 

 

 

Mild, transient

Abdominal distension9

 

Pancreatitis11

 

 

anticholinergic

 

 

 

 

 

 

effects including

 

 

 

 

 

 

constipation and

 

 

 

 

 

 

dry mouth

 

 

 

 

 

Hepatobiliary

disorders

 

 

 

 

 

 

Transient,

 

 

 

Hepatitis (including

 

 

asymptomatic

 

 

 

hepatocellular,

 

 

elevations of

 

 

 

cholestatic or mixed

 

 

hepatic

 

 

 

liver injury) 11

 

 

aminotransferases

 

 

 

 

 

 

(ALT, AST),

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

treatment (see

 

 

 

 

 

 

section 4.4)

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

Rash

Photosensitivity

 

 

Drug

 

 

reaction

 

 

Reaction

 

 

Alopecia

 

 

with

 

 

 

 

 

 

Eosinophili

 

 

 

 

 

 

a 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

Amenorrhea

 

Priapism12

 

 

dysfunction in

Breast enlargement

 

 

 

 

males

Galactorrhea in females

 

 

 

 

Decreased libido in

Gynaecomastia/breast

 

 

 

 

males and females

enlargement in males

 

 

 

General disorders and administration site conditions

 

 

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

 

 

 

 

 

 

Pyrexia10

 

 

 

 

 

Investigations

 

 

 

 

 

 

Elevated

Increased alkaline

Increased total bilirubin

 

 

plasma

phosphatase10

 

 

 

prolactin

High creatine

 

 

 

levels8

phosphokinase11

 

 

 

 

High Gamma

 

 

 

 

Glutamyltransferase

 

 

 

 

 

 

 

 

High uric acid 10

 

 

 

 

 

 

 

 

1Clinically 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).

2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3Observed 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.

4Observed 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.

5Observed 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.

6In 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.

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

8In 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.

9Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.

12Adverse 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 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).

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.

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.

4.9Overdose

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

5.1Pharmacodynamic 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; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT,

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 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).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also showed a statistically significant advantage over placebo in terms of preventing either recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remission with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria.

Paediatric population

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

5.2Pharmacokinetic properties

Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 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 1-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 hrs) 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 hrs) 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

In renally impaired patients (creatinine clearance <10 ml/min) versus healthy subjects, there was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared in urine, principally as metabolites.

Smokers

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hrs) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8 hrs and 14.1 l/hr, respectively).

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

The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

5.3Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in prostration and, at higher doses, semi-consciousness.

Repeated dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and morphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow.

Reproductive toxicity

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Mannitol (E421)

Microcrystalline cellulose

Carmellose calcium

Sucralose

Magnesium stearate

Colloidal anhydrous silica

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Aluminium/aluminium blister strips in cartons of 28 and 56 orodispersible tablets per carton Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20

2333 CR Leiden

The Netherlands

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/10/635/013-014

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10.06.2010

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

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