4.8          Undesirable effects

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 Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; website: www.hpra.ie; e-mail: medsafety@hpra.ie, or United Kingdom: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

10.          DATE OF REVISION OF THE TEXT

21 February 2020 22 November 2018

ZY69MZY70M

ZYPREXA^®

olanzapine

1.             NAME OF THE MEDICINAL PRODUCT

ZYPREXA * 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg coated tablets.

ZYPREXA VELOTAB  * 5 mg, 10 mg, 15 mg, and 20 mg orodispersible tablets.

4.8          Undesirable effects

Tabulated list of adverse reactions, Nervous system disorder

Stuttering¹¹added as an uncommon side effect

Reporting of suspected adverse reactions

UK reporting details updated

5.2          Pharmacokinetic properties

Hepatic impairment

A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %).

Smokers

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

Smoking

In non-smoking […] 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal: 27 12 September 2006

ZYPREXA VELOTABS:

Date of latest renewal: 27 12 September 2006

10.          DATE OF REVISION OF THE TEXT

22 November 2018 23 February 2017

Changes

Added (bold), Deleted (strikethrough)

4.8     Undesirable effects

Tabulated list of adverse reactions

10.     DATE OF REVISION OF THE TEXT

15 September 201623 February 2017

In Section 2 (Qualitative and Quantitative Composition), formatting change only.
In Section 3 (Pharmaceutical Form), formatting change only.
In Section 4.2 (Posology and method of administration), formatting change only.
In Section 4.8 (Undesirable effects), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been added to Skin and subcutaneous tissue disorders with an unknown frequency.
In Section 6.1 (List of excipients), formatting change only.

In Section 6.3 (Shelf life), formatting change only.

In Section 10 (Date of revision of text), amended to 15 September 2016.

Changes

Added (bold), Deleted (strikethrough):

7.       MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V.

Grootslag 1‑5

NL‑3991 RA, Houten

Papendorpseweg 83

3528 BJ Utrecht

The Netherlands

10.     DATE OF REVISION OF THE TEXT

4.       CLINICAL PARTICULARS

4.2     Posology and method of administration

Section re-ordered:

Paragraph moved to end of section:

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).

Added subheading:

Special populations

Deleted (strikethrough):

Gender

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

Added (bold):

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).

4.4     Special warnings and precautions for use

Added (bold), Deleted (strikethrough):

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 with dementia-related psychosis and/or behavioural disturbances because of an increase in mortality and the risk of cerebrovascular accident.

Hyperglycaemia and diabetes

Patients treated with any antipsychotic agentsmedicines, including ZYPREXA, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control.

Lipid alterations

Patients treated with any antipsychotic agentsmedicines, including ZYPREXA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

QT interval

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.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, iIt is recommended that blood pressure is measured periodically in patients over 65 years.

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).

4.5     Interaction with other medicinal products and other forms of interaction

Deleted (strikethrough):

Paediatric population

Interaction studies have only been performed in adults.

4.6     Fertility, pregnancy and lactation

Added (bold), Deleted (strikethrough):

NeonatesNew born infants exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery.

In Section 4.4, Special warnings and precautions for use –

In 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).’ is replaced with ‘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 Discontinuation of treatment, ‘Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported very rarely (<0.01%) when oral olanzapine is stopped abruptly.’ Is replaced with ‘Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported rarely (≥0.01% and <0.1%) when oral olanzapine is stopped abruptly.’

In Seizures, ‘Seizures have been reported to occur rarely in patients when treated with olanzapine.’ Is replaced with ‘Seizures have been reported to occur uncommonly in patients when treated with olanzapine.’

In Section 4.8, Undesirable effects –

Frequency of occurrence of many side effects has been updated, and a few side effects have been added. Foot notes have also been added to cite the source of supporting data for these updates.

In Section 10, Date of revision of the text, the date of revision is updated.

In Section 4.8, Undesirable effects - 'Urinary retention' is added as an uncommon event in the category 'Renal and Urinary disorders'. 

The following adverse events are moved from footnote to table and frequency defined

Reproductive system and breast disorders – Common - Erectile dysfunction in males, decreased libido in males and females

Reproductive system and breast disorders – Uncommon

Amenorrhea, Breast enlargement, Galactorrhea in females, Gynaecomastia/ breast enlargement in males

In Sections 2, 4.2, 4.3, 4.8, 4.9, 5.1, 5.2 - Changes are made to align with the qrd template.

In Section 4.4, Special warnings and precautions for use-

In subsection ‘Hyperglycemia and diabetes’ –

The statement ‘Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines’ is amended to ‘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’

The statement ‘Weight should be monitored regularly’ is amended to ‘Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.’

In subsection ‘Lipid alterations’ –

The statement ‘Patients treated with any antipsychotic agents, including ZYPREXA/ZYPREXA VELOTAB, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines’ is amended to ‘Patients treated with any antipsychotic agents, including ZYPREXA/ZYPREXA VELOTAB, 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.’

In subsection ‘Thromboembolism’ –

The statement ‘Temporal association of olanzapine treatment and venous thromboembolism has very rarely (<0.01%) been reported’ Is amended to ‘Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%).’

In Section 4.8, Undesirable effects – in ‘’vascular disorders’, the frequency of ‘Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4)’ is changed from ‘not known’ to ‘uncommon’

In Section 10, Date of revision of the text, the date of revision is updated

In Section 4.6, Pregnancy and lactation, the following text has been added - 'Neonates 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.' and the following text has been deleted - 'Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in infants born to mothers who had used olanzapine during the 3^rd trimester.'

In Section 4.8, Undesirable effects - 'Drug withdrawal syndrome neonatal (see section 4.6)' is added under the 'Pregnancy, puerperium and perinatal conditions'

In Section 10, Date of revision of the text, the revision date is updated.

6.             PHARMACEUTICAL PARTICULARS

6.5           Nature and contents of container

Re-formatted in its entirety due to addition of 98’s pack size.

8.             MARKETING AUTHORISATION NUMBERS

Re-formatted in its entirety due to addition of 98’s pack size.

10.          DATE OF REVISION OF THE TEXT

New date:

18 November 2010

4.         CLINICAL PARTICULARS

4.4       Special warnings and precautions for use

Added:

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.

4.8       Undesirable effects

             Added (bold):

Added:

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. In patients with schizophrenia, mean prolactin level changes decreased with continued treatment, whereas mean increases were seen in patients with other diagnoses.  The mean changes were modest.  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.

Deleted:

⁸ Associated clinical manifestations (e.g., gynaecomastia, galactorrhoea, and breast enlargement) were rare. In most patients, levels returned to normal ranges without cessation of treatment.

10.          DATE OF REVISION OF THE TEXT

New date:

21 December 2009

4.         CLINICAL PARTICULARS

4.4       Special warnings and precautions for use

Neuroleptic Malignant Syndrome (NMS)

Added(bold) deleted(strikethrough):

Additional signs may include elevated creatinecreatinine phosphokinase

4.8       Undesirable effects

¹ Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), wWeight gain ≥ 7 % of baseline body weight  was very common and (22.2 %), ≥ 15% was common (4.2 %) and ≥ 25 % was uncommon (0.8 %)of baseline body weight was common. 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).

Long-term exposure (at least 48 weeks)

Added(bold) deleted(strikethrough):

In adult patients who completed 9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately  4- 6 months.

10.          DATE OF REVISION OF THE TEXT

New date:

4.         CLINICAL PARTICULARS

4.4       Special warnings and precautions for use

Hyperglycaemia and diabetes

Added (bold) Deleted (strikethrough):

Appropriate clinical monitoring is advisable particularly in diabetic patients and in patients with risk factors for the development of diabetes mellitus for which regular glucose control is recommended.in accordance with utilised antipsychotic guidelines.  Patients treated with any antipsychotic agents, including ZYPREXA, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.

Lipid alterations

Added:

Patients treated with any antipsychotic agents, including ZYPREXA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

4.9       Overdose

Signs and symptoms

Deleted (strikethrough):

Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of 1,500 mg approximately 2 g of oral olanzapine.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Added (bold) Deleted (strikethrough):

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

10.          DATE OF REVISION OF THE TEXT

New date:

25 March 2009

4.         CLINICAL PARTICULARS

4.5          Interaction with other medicinal products and other forms of interaction

Changed:

General CNS activitymedicinal products

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

4.8           Undesirable effects

Adults

Added under table to footnote 1:

Patients gaining ¡Ý 25% of their baseline body weight with long-term exposure were very common.

Added:

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.

Children and adolescents

Changed:

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 (¡Ý 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.

Added under table to footnote 9:

With long-term exposure (at least 24 weeks), approximately half of adolescent patients gained ¡Ý 15% and almost a third gained ¡Ý 25% of their baseline body weight. Among adolescent patients, mean weight gain was greatest in patients who were overweight or obese at baseline.

10.          DATE OF REVISION OF THE TEXT

New date:

28 July 2008

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ¡Ý 500

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially life-threatening condition associated

with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism,

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ¡Ý500

been reported. . A causal relationship between the occurrence of venous thromboembolism and

The most frequently (seen in ¡Ý 1% of patients ) reported adverse reactions associated with the use of

common (¡Ý10%), common (¡Ý 1% and < 10%), uncommon (¡Ý 0.1% and < 1%), rare (¡Ý 0.01% and

1Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories.

Weight gain ¡Ý 7% of baseline body weight was very common and ¡Ý 15% of baseline body weight was

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

3Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (¡Ý 6.2 mmol/l).

Changes in total fasting cholesterol levels from borderline at baseline (¡Ý 5.17 - < 6.2 mmol) to high

(¡Ý 6.2 mmol) were common.

Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (¡Ý 7 mmol/l).

Changes in fasting glucose from borderline at baseline (¡Ý 5.56 - < 7 mmol/l) to high (¡Ý 7 mmol/l) were

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

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

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

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

8Associated clinical manifestations (e.g., gynaecomastia, galactorrhoea, and breast enlargement) were

valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (¡Ý10%)

disorder was associated with an increase of ¡Ý7% from baseline body weight in 39.9% of patients.

trials in adolescent patients. Clinically significant weight gain (¡Ý 7%) appears to occur more frequently

The frequency terms listed are defined as follows: Very common (¡Ý 10%), common (¡Ý 1% and < 10%).

9Weight gain > 7% of baseline body weight (kg) was very common and ¡Ý 15% of baseline body weight

10Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high

(¡Ý 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (¡Ý 1.016 mmol/l -

< 1.467 mmol/l) to high (¡Ý 1.467 mmol/l).

11Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high

(¡Ý 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline

at baseline (¡Ý 4.39 - < 5.17 mmol/l) to high (¡Ý 5.17 mmol/l) were very common.

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

ZYPREXA tablets: Store in the original package in order to protect from light and moisture.

4.             CLINICAL PARTICULARS

4.4          Special warnings and precautions for use

Delete:

Text in bold

Hyperglycaemia and/or development or exacerbation of diabetes, occasionally associated with ketoacidosis or coma, has been reported very rarely, including some fatal cases (see section 4.8).

Added:

Text in bold

particularly in diabetic patients and in patients with risk factors for the development of diabetes mellitus for which regular glucose control is recommended.

Added:

Text in bold

Lipid alterations should be managed as clinically appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development of lipids disorders.

4.8               Undesirable effects

Added:

Notes to Table (see Bold)

Added:

Corresponding notes under table

¹ Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Weight gain ¡Ý 7% of baseline body weight  was very common and ¡Ý 15% of baseline body weight was common.

²Observed for fasting normal levels at baseline (< 5.56mmol/l) which increased to high (¡Ý 7mmol/l). Changes in fasting glucose from borderline at baseline (¡Ý 5.56 - < 7mmol/l) to high (¡Ý 7mmol/l) were very common.

³ Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

⁴Observed for fasting normal levels at baseline (< 1.69mmol/l) which increased to high (¡Ý 2.26mmol/l). Changes in fasting triglycerides from borderline at baseline (¡Ý 1.69mmol/l - < 2.26mmol/l) to high (¡Ý 2.26mmol/l) were very common.

⁵Observed for fasting normal levels at baseline (< 5.17mmol/l) which increased to high (¡Ý 6.2mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (¡Ý 5.17-< 6.2mmol/l) to high (¡Ý 6.2mmol/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 can not be concluded at present that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

Changed:

In next table - All text under heading

10.          DATE OF REVISION OF THE TEXT

New date:

4.       CLINICAL PARTICULARS

4.8         Undesirable effects

Insert - fatigue:

General disorders and administration site conditions

Common (1-10%): Asthenia, fatigue, oedema.

10.          DATE OF REVISION OF THE TEXT

New date:

21 November 2007

4.             CLINICAL PARTICULARS

4.4          Special warnings and precautions for use

Added:

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.

4.8          Undesirable effects

Changes to table of undesirable effects based on adverse event reporting and laboratory investigations from clinical trials:

Added to ‘Metabolism and nutrition disorders’:

Common (1-10%): Elevated cholesterol levels.

Changes to table of undesirable effects based on post-marketing spontaneous reports:

Added (in bold text) to ‘Nervous system disorders:

Very rare (<0.01%): dystonia, (including oculogyration)

Added to ‘Skin and subcutaneous tissue disorders’:

Very rare (<0.01%): Alopecia.

10.          DATE OF REVISION OF THE TEXT

New date:

30 August 2007

Addition of 20mg oral tablets, which are expected to be launched in December 2006.

1.             NAME OF THE MEDICINAL PRODUCT

Addition of 20mg tablets.

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Addition of 20mg tablets.

Addition of amount of lactose/coated tablet.

Addition of amount of aspartame, sodium methyl parahydroxybenzoate or sodium propyl parahydroxybenzoate/orodispersible tablet.

3.             PHARMACEUTICAL FORM

Addition of 20mg tablets.

4.             CLINICAL PARTICULARS

4.2          Posology and method of administration

Deleted:

Children and adolescents: Olanzapine has not been studied in subjects under 18 years of age.

Replaced by:

There is no experience in children.

4.3                Contra-indications

Olanzapine replaced by active ingredient.

4.4          Special warnings and precautions for use

Added (new text in bold):

In cases where hepatitis (including hepatocellular, cholestatic, or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.

Statements on lactose, aspartame, sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate moved to end of section.

4.7          Effects on ability to drive and use machines

Added:

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

4.8          Undesirable effects

Changes to table of undesirable effects based on adverse event reporting and laboratory investigations from clinical trials:

Moved from ‘Investigations’ to ‘Cardiac disorders’:

QT prolongation (see also section 4.4).

Changes to table of undesirable effects based on post-marketing spontaneous reports:

Removed from ‘Hepatobiliary disorders’:

Very rare (<0.01%): Hepatitis.

Added to ‘Hepatobiliary disorders’:

Rare (0.01-0.1%): Hepatitis (including hepatocellular, cholestatic, or mixed liver injury).

Added:

Investigations

Increased transaminases.

Very rare (<0.01%): Increased alkaline phosphatase.  Increased total bilirubin.

Moved from ‘Vascular disorders’ to new ‘Cardiac disorders’ section:

QTc prolongation, ventricular tachycardia/fibrillation, and sudden death (see also section 4.4).

5.             PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Moved from section 4.1.1:

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).

6.             PHARMACEUTICAL PARTICULARS

6.1                List of excipients

Tablet core

Hydroxypropylcellulose replaced by Hyprolose.

Tablet coat

2.5mg, 5mg, 7.5mg, and 10mg tablet: Propylene glycol added.

Addition of 20mg tablet excipients.

6.3          Shelf-life

Shelf-life added for 20mg tablets.

6.5          Nature and contents of container

Addition of 20mg tablets.

8.             MARKETING AUTHORISATION NUMBERS

Addition of 20mg tablets.

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

New date of renewal:

12 September 2006

10.          DATE OF REVISION OF THE TEXT

New date:

13 September 2006