Eli Lilly and Company Limited

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

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Hepatic function

4.         CLINICAL PARTICULARS

4.4       Special warnings and precautions for use

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             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):

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

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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)

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

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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

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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

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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