Olanzapine Apotex

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: Each film-coated tablet contains 63.17 mg lactose.

For a 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

4.1 Therapeutic indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in

patients who have shown an initial treatment response.

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

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated

for the prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology and method of administration

Adults

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

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily

in combination therapy (see section 5.1).

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.

2

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.

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).

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.

Gender

The starting dose and dose range need not be routinely altered for female patients relative to

male patients.

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to

smokers.

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)

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Patients with known risk for narrow-angle glaucoma.

4.4 Special 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 approved for the treatment of dementia-related psychosis and/or behavioural

disturbances and is not recommended for use in this particular group of patients 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.

3

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 product.

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 rarely, 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.

Patients treated with any antipsychotic agents, 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.

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 agents, including Olanzapine Apotex,

should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

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

4

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 very rarely (<0.01%) 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, as with other

antipsychotics, 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 very rarely (<

0.01%) been reported. 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 rarely 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.

5

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As

with other antipsychotics, 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. Long-term outcomes associated with

these events have not been studied and remain unknown (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.

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

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 C max following fluvoxamine was 54

% in female nonsmokers 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.

6

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine

have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19,

3A4). Thus no particular interaction is expected as verified through in vivo studies where no

inhibition of metabolism of the following active substances was found: tricyclic antidepressant

(representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or

diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage

adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that

can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with

Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

Caution should be used if olanzapine is being administered concomitantly with medicinal

products known to increase QTc interval (see section 4.4).

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be

advised to notify their physician if they become pregnant or intend to become pregnant during

treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine

should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and

sleepiness, in infants born to mothers who had used olanzapine during the 3rd trimester.

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.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Because

olanzapine may cause somnolence and dizziness, patients should be cautioned about operating

machinery, including motor vehicles.

4.8

Undesirable effects

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

7

appetite, dizziness, akathisia, parkinsonism (see section 4.4), dyskinesia, orthostatic

hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic

aminotransferases (see section 4.4), rash, asthenia, fatigue and oedema.

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

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions

are presented in order of decreasing seriousness. The frequency terms listed are defined as

follows:

Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥

1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the

available data).

Very common

Common

Uncommon

Not known

Blood and the lymphatic system disorders

Eosinophilia

Leucopenia

Neutropenia

Thrombocytopenia

Immune system disorders

Allergic reaction

Metabolism and nutrition disorders

Weight gain 1

Elevated

cholesterol

levels 2,3

Elevated glucose

levels 4

Elevated

triglyceride

levels 2,5

Glucosuria

Increased appetite

Development or

exacerbation of

diabetes

occasionally

associated with

ketoacidosis or

coma, including

some fatal cases

(see section 4.4)

Hypothermia

Nervous system disorders

Somnolence

Dizziness

Akathisia 6

Parkinsonism 6

Dyskinesia 6

Seizures where in

most cases a

history of seizures

or risk factors for

seizures were

reported

Neuroleptic

malignant

syndrome (see

section 4.4)

Dystonia

(including

oculogyration)

Tardive dyskinesia

Discontinuation

symptoms 7

Cardiac disorders

Bradycardia

QTc prolongation

(see section 4.4)

Ventricular

tachycardia/fibrilla

tion, sudden death

(see section 4.4)

Vascular disorders

Orthostatic

hypotension

Thromboembolism

(including

pulmonary

embolism and

deep vein

8

thrombosis)

Gastro-intestinal disorders

Mild, transient

anticholinergic

effects including

constipation and

dry mouth

Pancreatitis

Hepato-biliary disorders

Transient,

asymptomatic

elevations of

hepatic

aminotransferases

(ALT, AST),

especially in early

treatment (see

section 4.4)

Hepatitis

(including

hepatocellular,

cholestatic or

mixed liver injury)

Skin and subcutaneous tissue disorders

Rash

Photosensitivity

reaction

Alopecia

Musculoskeletal and connective tissue disorders

Rhabdomyolysis

Renal and urinary disorders

Urinary

incontinence

Urinary hesitation

Reproductive system and breast disorders

Priapism

General disorders and administration site conditions

Asthenia

Fatigue

Oedema

Investigations

Elevated plasma

prolactin levels 8

High creatine

phosphokinase

Increased total

bilirubin

Increased alkaline

phosphatase

1 Clinically significant weight gain was observed across all baseline Body Mass Index

(BMI)categories. Following short term treatment (median duration 47 days), weight gain ≥ 7 %

of baseline body weight was very common (22.2 %), ≥ 15% was common (4.2 %) and ≥ 25 %

was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body

weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and

12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides)

were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 -

< 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7

mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥

7 mmol/l) were very common.

9

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l -

< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was

numerically higher, but not statistically significantly different from placebo. Olanzapine-treated

patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated

doses of haloperidol. In the absence of detailed information on the pre-existing history of

individual acute and tardive extrapyramidal movement disorders, it can not be concluded at

present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal

syndromes.

7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been

reported when olanzapine is stopped abruptly.

8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of

normal range in approximately 30% of olanzapine treated patients with normal baseline prolactin

value. In the majority of these patients the elevations were generally mild, and remained below two

times the upper limit of normal range. Generally in olanzapine-treated patients potentially associated

breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,

galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially

associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased

libido in both genders) were commonly observed.

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 4-6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a

higher incidence of death and cerebrovascular adverse reactions compared to placebo (see also

section 4.4).

Very common adverse reactions associated with the use of olanzapine in this patient group were

abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual

hallucinations and urinary incontinence were observed commonly.

In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with

Parkinson’s disease, worsening of Parkinsonian symptomatology and hallucinations were

reported very commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with

olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could

be high plasma valproate levels. Olanzapine administered with lithium or valproate resulted in

increased levels (≥ 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech

disorder was also reported commonly. During treatment with olanzapine in combination with

lithium or divalproex, an increase of ≥ 7% from baseline body weight occurred in 17.4% of

patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to 12

months) for recurrence prevention in patients with bipolar disorder was associated with an

increase of ≥ 7% from baseline body weight in 39.9% of patients.

Paediatric population Olanzapine is not indicated for the treatment of children and adolescent

patients below 18 years.

Although no clinical studies designed to compare adolescents to adults have been conducted,

data from the adolescent trials were compared to those of the adult trials.

10

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 gain 9 , elevated triglyceride levels 10 , increased appetite.

Common: Elevated cholesterol levels 11

Nervous system disorders

Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastro-intestinal disorders

Common: Dry mouth

Hepato-biliary disorders

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Investigations

Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels 12 .

9 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.

10 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).

11 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.

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

4.9

Overdose

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 of overdose

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%.

11

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

betaagonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring

is necessary to detect possible arrhythmias. Close medical supervision and monitoring should

continue until the patient recovers.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antipsychotics: diazepines, oxazepines and thiazepines. ATC code:

N05AH03.

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 (K i < 100 nM) for

serotonin 5 HT 2A/2C , 5 HT 3 , 5 HT 6 ; dopamine D 1 , D 2 , D 3 , D 4 , D 5 ; cholinergic muscarinic

receptors M 1 -M 5 ; α 1 adrenergic; and histamine H 1 receptors. Animal behavioral 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 HT 2 than

dopamine D 2 receptors and greater 5 HT 2 than D 2 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 HT 2A than dopamine D 2 receptor occupancy. In addition, a

Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic

patients revealed that olanzapine-responsive patients had lower striatal D 2 occupancy than some

other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-

responsive patients.

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

12

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

The experience in adolescents (ages 13 to 17 years) is limited to short term efficacy data 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 data on maintenance of effect and limited data on long term safety (see sections 4.4

and 4.8) .

5.2

Pharmacokinetic properties

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.

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. 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).

13

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.

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.

The plasma protein binding of olanzapine was about 93 % over the concentration range of about

7 to about 1,000 ng/ml. Olanzapine is bound predominantly to albumin and α 1 -acid-

glycoprotein.

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.

5.3

Preclinical 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.

14

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 fetal 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

6.1

List of excipients

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Maize starch

Magnesium stearate

Tablet coat

Hypromellose

Hydroxypropylcellulose

Macrogol 8000

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

15

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.

16

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: Each film-coated tablet contains 126.34 mg lactose.

For a 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.