ZYPADHERA 210 mg, 300 mg, and 405 mg, powder and solvent for prolonged release suspension for injection

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4.4     Special warnings and precautions for use

[…]

Sodium

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

10.        DATE OF REVISION OF THE TEXT

18 February November 2020

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2.       What you need to know before you are given ZYPADHERA

ZYPADHERA contains sodium

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

6.       Contents of the pack and other information

February November 2020

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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

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2.         What you need to know before you take ZYPREXA VELOTAB

[…]

ZYPREXA VELOTAB contains aspartame, mannitol and sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate

Patients who cannot take phenylalanine should note that ZYPREXA VELOTAB contains aspartame, which is a source of phenylalanine. May be harmful for people with phenylketonuria.

Patients who cannot take mannitol should note that ZYPREXA VELOTAB contains mannitol.

This medicine contains up to 1.6 mg aspartame in each tablet.

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

This medicineZYPREXA VELOTAB contains sodium methyl parahydroxybenzoate and sodium propyl parahydroxybenzoate, which may cause an allergic reactions in some people (possibly delayed). An allergic reaction may be recognised as a rash, itching or shortness of breath. This may occur immediately or some time after you take ZYPREXA VELOTAB.

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

[…]

6.         Contents of the pack and other information

[…]

This leaflet was last revised in February 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

 

18 February 202022 November 2018

 

 

ZYA18MZYA19M

ZYPADHERA^®                                             

olanzapine 

1.             NAME OF THE MEDICINAL PRODUCT 

ZYPADHERA * 210 mg, 300 mg, and 405 mg, powder and solvent for prolonged release suspension for injection.

4.8          Undesirable effects

Tabulated list of adverse reactions, Nervous system disorders

Stuttering¹¹  introduced as an uncommon side effect

Reporting of suspected adverse reactions

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. United Kingdom: www.mhra.gov.uk/yellowcard or 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

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). 

10.  22 November 2018 23 February 2017

Removed from Patient Information Leaflet and created separate document.

Updated picture of syringes.

Changes

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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 4.2 (Posology and method of administration), formatting change only.
In Section 4.4 (Special warnings and precautions for use), 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 6.6 (Special precautions for disposal and other handling), formatting change only.

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

 

Changes

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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

 

01 September 201501 January 2016

6.       PHARMACEUTICAL PARTICULARS

 

6.5     Nature and contents of container

 

210 mg powder: Type I glass vial. Bromobutyl stopper with rust-colour seal.

 

300 mg powder: Type I glass vial. Bromobutyl stopper with olive-colour seal.

 

405 mg powder: Type I glass vial. Bromobutyl stopper with steel blue-colour seal.

 

3 ml solvent: Type I glass vial. Butyl stopper with purple seal.

 

One carton contains one vial of powder and one vial of solvent, one Hypodermic 3ml syringe with pre-attached 19-gauge, 38 mm safety needle, one 19-gauge, 38 mm Hypodermic safety needle and one two 19-gauge, 50 mm Hypodermic safety needles.

 

6.6         Special precautions for disposal and other handling

 

. . . . .

Administration

STEP 1: Injecting ZYPADHERA

This table confirms the final ZYPADHERA suspension volume to inject.  Suspension concentration is 150 mg/ml olanzapine.

 

 

1.    Determine which needle will be used to administer the injection to the patient. For obese patients, the 50 mm needle is recommended for injection:

§   If the 50 mm needle is to be used for injection, attach the 38 mm safety needle to the syringe to withdraw the required suspension volume.

§   If the 38 mm needle is to be used for the injection, attach the 50 mm safety needle to withdraw the required suspension volume.

2.    Slowly withdraw the desired amount. Some excess product will remain in the vial.

3.    Engage the needle safety device and remove needle from syringe.

4.    Attach the remaining selected 50 mm or 38 mm safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

5.    Select and prepare a site for injection in the gluteal area. DO NOT INJECT INTRAVENOUSLY OR SUBCUTANEOUSLY.

6.    After insertion of the needle, aspirate for several seconds to ensure no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin reconstitution and administration procedure again. The injection should be performed with steady, continuous pressure.

DO NOT MASSAGE THE INJECTION SITE.

7.   Engage the needle safety device (Fig. 1 and 2).

8.   Discard the vials, syringe, used needles, extra needle and any unused solvent in accordance with appropriate clinical procedures. The vial is for single use only.

 

 

10.     DATE OF REVISION OF THE TEXT

 

25 April 2014 01 September 2015

4.       CLINICAL PARTICULARS

4.4     Special warnings and precautions for use

 

Paediatric population

 

Deleted (strikethrough):

 

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).

 

 

 

5.             PHARMACOLOGICAL PROPERTIES

 

5.1          Pharmacodynamic properties

 

Added (bold):

 

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

 

Paediatric population

 

Added (bold):

 

ZYPADHERA has not been studied in the paediatric population. The experience Controlled efficacy data in adolescents (ages 13 to 17 years) isare limited to short term oral olanzapine efficacy datastudies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents. Oral olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. During treatment with oral 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 on long term safety (see sections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.

 

6.       PHARMACEUTICAL PARTICULARS

 

6.1     List of excipients

 

Added (bold), Deleted (strikethrough):

 

CrosCarmellose sodium

 

 

6.6         Special precautions for disposal and other handling

 

STEP 3: Reconstituting ZYPADHERA

Added (bold), Deleted (strikethrough):

 

1.      Open the pre-packaged Hypodermic syringe and needle with needle protection device. Peel blister pouch and remove device. Attach a syringe (if not already attached) to the Luer connection of Ensure needle is firmly seated on the device with an easy twisting motion. Seat the needle firmly on the device with a push and a clockwise twist, then pull the needle cap straight away from the needle. Failure to follow these instructions may result in a needlestick injury.

 

7.        Engage the needle safety device. Press the needle into the sheath using a one-handed technique.  Perform a one-handed technique by GENTLY pressing the sheath against a flat surface.  AS THE SHEATH IS PRESSED (Fig. 1), THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (Fig.ure 1 and 2)

 

8.      Visually confirm that the needle is fully engaged into the needle protection sheath. (Figure 3)Only remove the device with the engaged needle from the syringe when required by a specific medical procedure. Remove by grasping the Luer hub of the needle protection device with thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle point (Fig. 3).

 

 

 

10.     DATE OF REVISION OF THE TEXT

 

Added (bold) Deleted (strikethrough):

 

26 August 2013 25 April 2014

In Section 4.2, Posology and method of administration - changes have been made to compy with the QRD template, and an extra statement has been added in the sub section - smokers.

In Sections 4.4, 4.5 and 4.6 - Special warnings and precautions for use - changes have been made to compy with the QRD template

In Section 4.8, Undesirable effects - a section on 'Reporting of suspected adverse reactions' is added.

In Section 5.1, Pharmaodynamic properties - 'psycholeptics' is added as a Pharmacotherapeutic group.

In Section 9, Date of first authorisation/ renewal of authorisation - date of last renewal is added.

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

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 4.2, Posology and method of administration - 'It should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose' has been amended to 'Immediately prior to leaving the healthcare facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose.' and the statement 'The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.' has been added.

In Section 4.4, Special warnings and precautions for use - The statements 'Post-marketing reports of post-injection syndrome since the marketing authorization of ZYPADHERA are generally consistent with the experince seen in clinical studies.' and 'The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.' have been added; 'It should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose' has been amended to 'Immediately prior to leaving the healthcare facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose.' The statement 'Prior to giving the injection, the healthcare professional should determine that the patient will not travel alone to their destination' has been removed'

In Section 10, Date of revision of the text, the date of revision has been 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 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 ZYPADHERA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines’ is amended to ‘Patients treated with any antipsychotic agents, including ZYPADHERA, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.’

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.

*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:

 

01 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 (bold) and deleted (strikethrough):

 

             Post-injection syndrome

During pre-marketing clinical studies, reactions that presented with signs and symptoms consistent with olanzapine overdose, were reported in patients following an injection of ZYPADHERA. These reactions occurred in <0.1% of injections and approximately 1.42% of patients

 

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

SPC typos corrected and re-formatted throughout:

 

Events changed to reactions throughout SPC,

 

 

 

4.         CLINICAL PARTICULARS

4.8       Undesirable effects

 

Added (bold) deleted (strikethrough):

 

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 %). and ≥ 15% 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):

 

the rate of increase in mean blood glucose slowed after approximately  4 6 months.

 

Added (bold) deleted (strikethrough):

 

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 approximately half of adolescent patients gained ≥ 15% and almost a third gained ≥ 25% of their baseline body weight. Among adolescent patients, mean weight gain was greatest in patients who were overweight or obese at baseline.

 

4.9       Overdose

 

Added (bold) deleted (strikethrough):

 

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

 

 

 

 

6.         PHARMACEUTICAL PARTICULARS

6.5       Nature and contents of container

 

Added (bold):

 

One carton contains one vial of powder and one vial of solvent, one Hypodermic Needle-Pro  3ml syringe with pre-attached 19-gauge, 38 mm safety needle,one 19-gauge, 38 mm Hypodermic Needle-Pro  safety needle and one 19-gauge, 50 mm Hypodermic Needle-Pro  safety needle.

 

6.6           Special precautions for disposal and other handling

 

Added (DEEP):

 

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY.  DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY.

 

Deleted:

 

Each ZYPADHERA pack is provided with a card that fully describes the reconstitution and administration instructions.  Please refer to the card for instructions on how to reconstitute and administer this product.

 

Added:

Reconstitution

STEP 1: Preparing materials

 

It is recommended that gloves are used as ZYPADHERA may irritate the skin.

 

Reconstitute ZYPADHERA powder for prolonged release suspension for injection only with the solvent provided in the pack using standard aseptic techniques for reconstitution of parenteral products.

 

STEP 2: Determining solvent volume for reconstitution

This table provides the amount of solvent required to reconstitute ZYPADHERA powder for prolonged release suspension for injection.

 

 

 

It is important to note that there is more solvent in the vial than is needed to reconstitute.

 

STEP 3: Reconstituting ZYPADHERA

1.                        Loosen the powder by lightly tapping the vial.

2.                        Open the pre-packaged Hypodermic Needle-Pro syringe and needle with needle protection device. Peel blister pouch and remove device. Insure needle is firmly seated on the Needle-Pro device with a push and a clockwise twist, then pull the needle cap straight away from the needle. Failure to follow these instructions may result in a needlestick injury.

3.                        Withdraw the pre-determined solvent volume (Step 2) into the syringe.

4.                        Inject the solvent volume into the powder vial.

5.                        Withdraw air to equalize the pressure in the vial.

6.                        Remove the needle, holding the vial upright to prevent any loss of solvent.

7.                        Engage the needle safety device. Press the needle into the sheath using a one-handed technique.  Perform a one-handed technique by GENTLY pressing the sheath against a flat surface.  AS THE SHEATH IS PRESSED, THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (Figure 1 and 2)

8.Visually confirm that the needle is fully engaged into the needle protection sheath. (Figure 3) Only remove the Needle-Pro device with the engaged needle from the syringe when required by a specific medical procedure. Remove by grasping the Luer hub of the needle protection device with thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle point.

 

   

                                Figure 1                      Figure 2                                  Figure 3

9.Tap the vial firmly and repeatedly on a hard surface until no powder is visible. Protect the surface to cushion impact. (See Figure A)

Figure A: Tap firmly to mix

 

10. Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to the vial. Additional tapping may be required if clumps remain. (See Figure B)

   

Unsuspended: visible clumps     Suspended:  no clumps

Figure B: Check for unsuspended powder and repeat tapping if needed.

 

11. Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture. The suspended product will be yellow and opaque. (See Figure C)

Figure C: Vigorously shake vial

If foam forms, let vial stand to allow foam to dissipate. If the product is not used immediately, it should be shaken vigorously to re-suspend. Reconstituted ZYPADHERA remains stable for up to 24 hours in the vial.

 

Administration

STEP 1: Injecting ZYPADHERA

This table confirms the final ZYPADHERA suspension volume to inject.  Suspension concentration is 150 mg/ml olanzapine.

 

1.     Determine which needle will be used to administer the injection to the patient. For obese patients, the 50 mm needle is recommended for injection:

§    If the 50 mm needle is to be used for injection, attach the 38 mm safety needle to the syringe to withdraw the required suspension volume.

§    If the 38 mm needle is to be used for the injection, attach the 50 mm safety needle to withdraw the required suspension volume

2.     Slowly withdraw the desired amount. Some excess product will remain in the vial.

3.     Engage the needle safety device and remove needle from syringe.

4.     Attach the remaining safety needle to the syringe prior to injection. Once the suspension has been removed from the vial, it should be injected immediately.

5.     Select and prepare a site for injection in the gluteal area. DO NOT INJECT INTRAVENOUSLY OR SUBCUTANEOUSLY.

6.     After insertion of the needle, aspirate for several seconds to ensure no blood appears. If any blood is drawn into the syringe, discard the syringe and the dose and begin reconstitution and administration procedure again. The injection should be performed with steady, continuous pressure.

DO NOT MASSAGE THE INJECTION SITE.

7.     Engage the needle safety device. (Figure 1 and 2)

8.     Discard the vials, syringe, needles and any unused solvent in accordance with appropriate clinical procedures. The vial is for single use only.

 

 

 

10.          DATE OF REVISION OF THE TEXT

 

27 July 2009

6.         PHARMACEUTICAL PARTICULARS

 

6.5           Nature and contents of container

 

Added (bold):

 

One carton contains one vial of powder and one vial of solvent, one Hypodermic Needle-Pro 3ml syringe with pre-attached 19-gauge, 38 mm safety needle and two 19-gauge, 38 mm Hypodermic Needle-Pro safety needles.

 

6.6         Special precautions for disposal and other handlings

 

Deleted:

 

RECONSTITUTION

STEP 1: Assembling and preparing materials

 

Other materials needed:

n     One 3 ml syringe

n     Three 19-gauge, 35 mm needles for injection (For obese patients, 19-gauge, 50 mm needles are recommended)

 

It is recommended that gloves are used as ZYPADHERA may irritate the skin.

 

Reconstitute ZYPADHERA powder for suspension for injection only with the solvent for parenteral use provided in the pack using standard aseptic techniques for reconstitution of parenteral products.

ZYPADHERA powder for suspension for injection must not be combined in the syringe with any substance other than the solvent for parenteral use.

 

STEP 2: Determining solvent volume for reconstitution

This table provides the amount of solvent required to reconstitute ZYPADHERA powder for suspension for injection.

 

 

It is important to note that there is more solvent in the vial to reconstitute than is needed.

 

STEP 3: Reconstituting ZYPADHERA

1.         Loosen the powder by lightly tapping the vial. Inject the required solvent volume into the ZYPADHERA powder vial.

2.         Withdraw air to equalize the pressure in the vial.

3.         Remove the needle, holding the vial upright to prevent any loss of solvent.

4.         Tap the vial firmly and repeatedly on a hard surface, protected to cushion impact, until no powder is visible.

Figure A: Tap firmly to mix

 

5.       The suspended product will be yellow and opaque. Visually check the vial for clumps. Unsuspended powder appears as light yellow, dry clumps clinging to the bottom of the vial. Additional tapping may be required if clumps remain.

Figure B: Check for unsuspended powder

 

6.       Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture.

Figure C: Vigorously shake vial

 

7.        If foam forms, let vial stand to allow foam to dissipate.

Reconstituted ZYPADHERA remains stable for up to 24 hours in the vial. If the product is not used right away, it should be shaken vigorously to re-suspend. This medicinal product does not require any special storage conditions. Do not refrigerate or freeze.

 

ADMINISTRATION

STEP 1: Injecting ZYPADHERA

This table confirms the final ZYPADHERA suspension volume to inject.  Suspension concentration is 150 mg/ml.

 

 

1.       Use a second needle and slowly withdraw the desired amount. Some excess product will remain in the vial.

2.       Remove air bubbles to ensure a full dose.

3.       Change to the third 19-gauge (35 mm or 50 mm) needle prior to injection.

4.       Once ZYPADHERA has been removed from the vial into the syringe, it should be injected immediately.

5.       Select and prepare a site for injection in the gluteal area. DO NOT INJECT INTRAVENOUSLY. Aspirate for several seconds to ensure no blood appears after insertion of the needle into the muscle. If any blood is drawn into the syringe, the syringe and the dose should be discarded and fresh drug prepared. The injection should be performed with steady, continuous pressure. Do not massage the injection site.

6.       Discard the syringe, needles and any unused solvent in accordance with appropriate clinical procedures. The vial is for single use only.

 

Added:

 

Each ZYPADHERA pack is provided with a card that fully describes the reconstitution and administration instructions.  Please refer to the card for instructions on how to reconstitute and administer this product.

 

Any unused product or waste material should be disposed of in accordance with local requirements.

 

 

10.          DATE OF REVISION OF THE TEXT

 

15 December 2008