Zyprexa 2.5 mg, 5mg, 7.5 mg,10 mg, 15 mg, 20 mg coated Tablets

Changes

Added (underline) deleted (strikethrough)

Formatting changes throughout the document.

 

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipient with known effect: Each orodispersible tablet contains

0.60 mg aspartame (E951)

0.1125 mg sodium methyl parahydroxybenzoate (E219)

0.0375 mg sodium propyl parahydroxybenzoate (E217)

ZYPREXA VELOTAB 10 mg orodispersible tablets

Each orodispersible tablet contains 10 mg olanzapine.

Excipient with known effect:Each orodispersible tablet contains

0.80 mg aspartame (E951)

0.15 mg sodium methyl parahydroxybenzoate (E219)

0.05 mg sodium propyl parahydroxybenzoate (E217)

ZYPREXA VELOTAB 15 mg orodispersible tablets

Each orodispersible tablet contains 15 mg olanzapine.

Excipient with known effect: Each orodispersible tablet contains

1.20 mg aspartame (E951)

0.225 mg sodium methyl parahydroxybenzoate (E219)

0.075 mg sodium propyl parahydroxybenzoate (E217)

ZYPREXA VELOTAB 20 mg orodispersible tablets

Each orodispersible tablet contains 20 mg olanzapine.

Excipient with known effect: Each orodispersible tablet contains

1.60 mg aspartame (E951)

0.30 mg sodium methyl parahydroxybenzoate (E219)

0.10 mg sodium propyl parahydroxybenzoate (E217)

 

3.         PHARMACEUTICAL FORM

Coated Tablets

ZYPREXA 2.5 mg coated tablets

ZYPREXA 2.5 mg tablets: Round, white, coated tablets imprinted with ‘LILLY’ and a numeric identicode ‘4112’.

ZYPREXA 5 mg coated tablets

ZYPREXA 5 mg tablets: Round, white, coated tablets imprinted with ‘LILLY’ and a numeric identicode ‘4115’.

ZYPREXA 7.5 mg coated tablets

ZYPREXA 7.5 mg tablets: Round, white, coated tablets imprinted with ‘LILLY’ and a numeric identicode ‘4116’.

ZYPREXA 10 mg coated tablets

ZYPREXA 10 mg tablets: Round, white, coated tablets imprinted with ‘LILLY’ and a numeric identicode ‘4117’.

ZYPREXA 15 mg coated tablets

ZYPREXA 15 mg tablets: Elliptical, blue, coated tablets debossed with ‘LILLY’ and a numeric identicode ‘4415’.

ZYPREXA 20 mg coated tablets

ZYPREXA 20 mg tablets: Elliptical, pink, coated tablets debossed with ‘LILLY’ and a numeric identicode ‘4420’.

 

4.4       Special warnings and precautions for use

Lactose

ZYPREXA tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take this medicine.

Aspartame

ZYPREXA VELOTAB orodispersible tablet contains up to 1.6 mg aspartame in each tablet.

Aspartame is a source of phenylalanine. It may be harmful for people who have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Mannitol

ZYPREXA VELOTAB orodispersible tablet contains mannitol.

Sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate

Olanzapine orodispersible tablet contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate. , which may cause allergic reactions (possibly delayed). 

These preservatives are known to cause urticaria. Generally, delayed type reactions such as contact dermatitis may occur, but rarely, immediate reactions with bronchospasm may occur.

Sodium

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

 

MARKETING AUTHORISATION NUMBERS

ZYPREXA tablets:

EU/1/96/022/002:             ZYPREXA 2.5 mg coated tablets - 28 tablets per box

EU/1/96/022/019:             ZYPREXA 2.5 mg coated tablets - 56 tablets per box

EU/1/96/022/023:             ZYPREXA 2.5 mg coated tablets - 35 tablets per box

EU/1/96/022/029:             ZYPREXA 2.5 mg coated tablets - 70 tablets per box

EU/1/96/022/035:             ZYPREXA 2.5 mg coated tablets - 98 tablets per box

EU/1/96/022/004:             ZYPREXA 5 mg coated tablets - 28 tablets per box

EU/1/96/022/020:             ZYPREXA 5 mg coated tablets - 56 tablets per box

EU/1/96/022/024:             ZYPREXA 5 mg coated tablets - 35 tablets per box

EU/1/96/022/030:             ZYPREXA 5 mg coated tablets - 70 tablets per box

EU/1/96/022/036:             ZYPREXA 5 mg coated tablets - 98 tablets per box

EU/1/96/022/011:             ZYPREXA 7.5 mg coated tablets - 28 tablets per box

EU/1/96/022/006:             ZYPREXA 7.5 mg coated tablets - 56 tablets per box

EU/1/96/022/025:             ZYPREXA 7.5 mg coated tablets - 35 tablets per box

EU/1/96/022/031:             ZYPREXA 7.5 mg coated tablets - 70 tablets per box

EU/1/96/022/037:             ZYPREXA 7.5 mg coated tablets - 98 tablets per box

EU/1/96/022/009:             ZYPREXA 10 mg coated tablets - 28 tablets per box

EU/1/96/022/010:             ZYPREXA 10 mg coated tablets - 56 tablets per box

EU/1/96/022/026:             ZYPREXA 10 mg coated tablets - 35 tablets per box

EU/1/96/022/032:             ZYPREXA 10 mg coated tablets - 70 tablets per box

EU/1/96/022/038:             ZYPREXA 10 mg coated tablets - 98 tablets per box

EU/1/96/022/012:             ZYPREXA 15 mg coated tablets - 28 tablets per box

EU/1/96/022/021:             ZYPREXA 15 mg coated tablets - 56 tablets per box

EU/1/96/022/027:             ZYPREXA 15 mg coated tablets - 35 tablets per box

EU/1/96/022/033:             ZYPREXA 15 mg coated tablets - 70 tablets per box

EU/1/96/022/039:             ZYPREXA 15 mg coated tablets - 98 tablets per box

EU/1/96/022/014:             ZYPREXA 20 mg coated tablets - 28 tablets per box

EU/1/96/022/022:             ZYPREXA 20 mg coated tablets - 56 tablets per box

EU/1/96/022/028:             ZYPREXA 20 mg coated tablets - 35 tablets per box

EU/1/96/022/034:             ZYPREXA 20 mg coated tablets - 70 tablets per box

EU/1/96/022/040:             ZYPREXA 20 mg coated tablets - 98 tablets per box

 

ZYPREXA VELOTABS:

 

EU/1/99/125/001:             5 mg x 28 Velotabs

EU/1/99/125/005:             5 mg x 56 Velotabs

EU/1/99/125/009:             5 mg x 35 Velotabs

EU/1/99/125/013:             5 mg x 70 Velotabs

EU/1/99/125/017:             5 mg x 98 Velotabs

EU/1/99/125/002:             10 mg x 28 Velotabs

EU/1/99/125/006:             10 mg x 56 Velotabs

EU/1/99/125/010:             10 mg x 35 Velotabs

EU/1/99/125/014:             10 mg x 70 Velotabs

EU/1/99/125/018:             10 mg x 98 Velotabs

EU/1/99/125/003:             15 mg x 28 Velotabs

EU/1/99/125/007:             15 mg x 56 Velotabs

EU/1/99/125/011:             15 mg x 35 Velotabs

EU/1/99/125/015:             15 mg x 70 Velotabs

EU/1/99/125/019:             15 mg x 98 Velotabs

EU/1/99/125/004:             20 mg x 28 Velotabs

EU/1/99/125/008:             20 mg x 56 Velotabs

EU/1/99/125/012:             20 mg x 35 Velotabs

EU/1/99/125/016:             20 mg x 70 Velotabs

EU/1/99/125/020:             20 mg x 98 Velotabs

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

ZYPREXA tablets 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg ZYPREXA tablets:

Date of first authorisation:                               27 September 1996

Date of latest renewal:                                     12 September 2006

ZYPREXA VELOTABS 5 mg, 7.5 mg, 10 mg, 15 mg, and 20 mg:

Date of first authorisation:                               3 February 2000

Date of latest renewal:                                     12 September 2006

 

10.       DATE OF REVISION OF THE TEXT

21 February19 November 2020

 

4.8          Undesirable effects

 

Nervous system disorders
Somnolence	Dizziness Akathisia6 Parkinsonism6  Dyskinesia6	Seizures where in most cases a history of seizures or risk factors for seizures were reported 11 Dystonia (including oculogyration) 11 Tardive dyskinesia11 Amnesia 9 Dysarthria Stuttering11 Restless Legs Syndrome11	Neuroleptic malignant syndrome (see section 4.4) 12 Discontinuation symptoms7, 12
Gastrointestinal disorders
	Mild, transient anticholinergic effects including constipation and dry mouth	Abdominal distension9 Salivary hypersecretion11	Pancreatitis11

 

 

 

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

 

Very common	Common	Uncommon	Rare	Not known
…
Nervous system disorders
Somnolence	Dizziness Akathisia6 Parkinsonism6 Dyskinesia6	Seizures where in most cases a history of seizures or risk factors for seizures were reported11 Dystonia (including oculogyration)11 Tardive dyskinesia11 Amnesia 9 Dysarthria Restless Legs Syndrome	Neuroleptic malignant syndrome (see section 4.4)12 Discontinuation symptoms7, 12

 

 

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

 

25 April 201401 January 2015

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.

 

Added:

 

Fertility

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

 

4.8     Undesirable effects

 

Added:

Summary of the safety profile

 

Note:Table re-formatted/re-ordered & ‘Not Known’ column added

 

Added:

 

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 UK: www.mhra.gov.uk/yellowcard or Ireland: IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, www.imb.ie, imbpharmacovigilance@imb.ie.

 

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Added (bold) Deleted (strikethrough):

 

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

 

Paediatric population

The experienceControlled efficacy data in adolescents (ages 13 to 17 years) isare limited to short term efficacy datastudies 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 and limited data onlong term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

 

 

10.          DATE OF REVISION OF THE TEXT

 

Added (bold) Deleted (strikethrough):

 

27th May 2013 25 April 2014

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 10, the date of revision of text is updated.

In Section 6.5 Nature and contents of container, pack size 56 is added to 7.5mg coated tablets and 15mg coated tablets. This has been erroneously missed in the previous version.

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



 

*This SPC has been re-formatted in its entirety due to QRD changes.

 

4.         CLINICAL PARTICULARS

 

4.4       Special warnings and precautions for use

 

Added (bold) Deleted (strikethrough):

 

Hepatic function

Transient, asymptomatic elevations of hepatic transaminasesaminotransferases, ALT, AST have been seen commonly, especially in early treatment. Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic medicines. In the event of elevated ALT and/or AST during treatment, follow-up should be organised and dose reduction should be considered. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued.

 

4.8       Undesirable effects

 

Adults

 

Added (bold) Deleted (strikethrough):

 

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 (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic transaminasesaminotransferases (see section 4.4), rash, asthenia, fatigue and oedema.

 

Added (bold) Deleted (strikethrough):

 

Hepato-biliary disorders
	Transient, asymptomatic elevations of hepatic transaminases aminotransferases (ALT, AST), especially in early treatment (see section 4.4)		Hepatitis (including hepatocellular, cholestatic or mixed liver injury)

 

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 levels 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.

 

 

Added (bold) Deleted (strikethrough):

 

Hepato-biliary disorders Very common: Elevations of hepatic transaminases aminotransferases (ALT/AST; see section 4.4).

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

 

06 September 2010

 

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

 

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):

 

 

Very common	Common		Uncommon		Not known
Renal and urinary disorders
				Urinary incontinence		Urinary hesitation

 

 

 

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:

                ZYPREXA tablets: 03 July 2009

 

ZYPREXA VELOTABS: 07 July 2009

 

 

 

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

Please Note: This SPC has been Re-formatted in its entirety

4. CLINICAL PARTICULARS

4.2 Posology and method of administration

Added:

Children and adolescents

Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack

of data on long term 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).

4.4 Special warnings and precautions for use

Added:

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.

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 creatinine 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.

Lipid alterations

Deleted:

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

very rarely (<0.01%) when olanzapine is stopped abruptly. Gradual dose reduction should be

considered when discontinuing olanzapine.

Anticholinergic activity

Deleted:

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 also 4.8

Undesirable effects), 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 medications (dopamine agonist) and to remain on the same anti-Parkinsonian

medications 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.

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.

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.

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.

Added:

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] ¡Ý 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.

Deleted:

There are limited data on co-medication with lithium and valproate (see section 5.1). There are no

clinical data available on olanzapine and carbamazepine co-therapy, however a pharmacokinetic study

has been conducted (see section 4.5).

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

with antipsychotic medication. 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 creatinine 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.

Tardive Dyskinesia

Deleted:

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.

Postural hypotension

Deleted:

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

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.

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.

Added:

Use in children and adolescents under 18 years of age

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

Added:

Interaction studies have only been performed in adults.

CNS medicinal products

Caution should be exercised in patients who 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).

4.8 Undesirable effects

Changed in its entirety:

Adults

The most frequently (seen in ¡Ý 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 (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient

asymptomatic elevations of hepatic transaminases (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 (¡Ý10%), common (¡Ý 1% and < 10%), uncommon (¡Ý 0.1% and < 1%), rare (¡Ý 0.01% and

< 0.1%), very rare (< 0.01%), not known (cannot be estimated from the data available).

TABLE

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

common.

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 (¡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.

4

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

very common.

5

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

(¡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

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.

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

when olanzapine is stopped abruptly.

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

rare. In most patients, levels returned to normal ranges without cessation of treatment.

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 (¡Ý10%)

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 ¡Ý7% from baseline body weight in 39.9% of patients.

Children and adolescents

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 clinical

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

in the adolescent population.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

TABLE

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

was common.

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Added:

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

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.

6. PHARMACEUTICAL PARTICULARS

6.4 Special precautions for storage

Changed:

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

10. DATE OF REVISION OF THE TEXT

New date:

22 April 2008

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)

 

Metabolism and nutrition disorders Very common (>10%): Weight gain1. Common (1-10%): Increased appetite. Elevated glucose levels (see note 2 below). Elevated triglyceride levels3,4. Elevated cholesterol levels3,5 Glycosuria.

Nervous system disorders Very common (>10%): Somnolence. Common (1-10%): Dizziness, akathisia, parkinsonism, dyskinesia. (See also note 6 below).

 

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

Metabolism and nutrition disorders Rare (0.01-0.1%): Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been spontaneously reported rarely, including some fatal cases (see section 4.4). Very rare (<0.01%): Hypertriglyceridaemia, hypercholesterolaemia and hypothermia.

 

 

10.          DATE OF REVISION OF THE TEXT

 

New date:

 

17 January 2008

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