ZYPADHERA 300 mg powder and solvent for prolonged releasesuspension for injection

ZYPADHERA belongs to a group of medicines called antipsychotics and is used to treat schizophrenia - a disease with symptoms such as hearing, seeing or sensing things which are not there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. People with this disease may also feel depressed, anxious or tense.

You should not be given ZYPADHERA if you have:

• an allergy (hypersensitivity) to olanzapine or any of the other ingredients of ZYPADHERA. An allergic reaction may be recognised as a rash, itching, a swollen face, swollen lips or shortness of breath. If this has happened to you, tell your nurse or doctor.
• been previously diagnosed with eye problems such as certain kinds of glaucoma (increased pressure in the eye).

Take special care with ZYPADHERA

• Prior to giving ZYPADHERA, your doctor or nurse should determine that you will not travel alone to your destination after each injection.
• An uncommon but serious reaction might occur after you receive each injection. ZYPADHERA can sometimes enter the bloodstream too quickly. If this happens, you may have the symptoms listed below after your injection. In some cases, these symptoms can lead to unconsciousness.
• excessive sleepiness ? dizziness
• confusion ? disorientation
• irritability ? anxiety
• aggression ? increase in blood pressure
• difficulty talking ? weakness
• difficulty walking ? muscle stiffness or shaking
• convulsions

These symptoms typically resolve within 24 to 72 hours after your injection. After each injection you will be observed in your healthcare facility for at least 3 hours for the symptoms listed above.

Although unlikely, you may get the symptoms more than 3 hours after the injection. If this happens, contact your doctor or nurse immediately. Because of this risk, do not drive or operate machinery for the remainder of the day after each injection.

• Tell the doctor or nurse if you feel dizzy or faint after the injection. You will probably need to lie down until you feel better. The doctor or nurse may also want to measure your blood pressure and pulse.
• Very rarely, medicines of this type may cause unusual movements mainly of the face or tongue or a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness. If this happens after you have been given ZYPADHERA, tell your doctor or nurse immediately.
• The use of ZYPADHERA in elderlypatientswithdementia is not recommended as it may have serious side effects.

Tell your doctor as soon as possible if any of the following applies to you:

• a recent heart attack, heart disease, sick sinus syndrome, (abnormal heart rhythms), unstable angina or low blood pressure
• diabetes
• liver or kidney disease
• Parkinson?s disease
• epilepsy
• prostate problems
• a blocked intestine (paralytic ileus)
• blood disorders
• stroke or ?mini? stroke (temporary symptoms of stroke)

ZYPADHERA is not for patients who are under 18 years.

As a routine precaution, if you are over 65 years your doctor may monitor your blood pressure.

Taking other medicines

Please tell your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription.

In particular, tell your doctor if you are taking:

• medicines for Parkinson?s disease.
• fluvoxamine (an antidepressant) or ciprofloxacin (an antibiotic) - it may be necessary to change your ZYPADHERA dose.

If you are already taking antidepressants, medicines for anxiety or to help you sleep (tranquillisers), you may feel drowsy if ZYPADHERA is given.

Using ZYPADHERA with food and drink

Do not drink any alcohol if you have been given ZYPADHERA as together with alcohol it may make you feel drowsy.

Pregnancy and breast-feeding

Tell your doctor as soon as possible if you are pregnant or think you may be pregnant.

You should not be given this injection if you are breast-feeding as small amounts of olanzapine can pass into breast milk.

Driving and using machines

Do not drive or operate machinery for the remainder of the day after each injection.

Your doctor will decide how much ZYPADHERA you need and how often you need to be given an injection. ZYPADHERA is given in doses of 150 to 300 mg every 2 weeks or 300 to 405 mg every 4 weeks.

ZYPADHERA comes as a powder which your doctor or nurse will make into a suspension that will then be injected into the muscle in your buttock.

If you are given more ZYPADHERA than needed

This medicine will be given to you under medical supervision, it is therefore unlikely that you will be given too much.

Patients who have been given too much olanzapine have also experienced the following symptoms:

• rapid beating of the heart, agitation/aggressiveness, problems with speech, unusual movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms may include:
• acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, muscle stiffness, and drowsiness or sleepiness; slower breathing, aspiration, high or low blood pressure, abnormal rhythms of the heart.

Contact your doctor or hospital straight away if you experience any of the above.

If you miss an injection of ZYPADHERA

Do not stop your treatment just because you feel better. It is important that you carry on receiving ZYPADHERA for as long as your doctor has told you to.

If you miss an injection, you should contact your doctor to arrange your next injection as soon as you can.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

Like all medicines, ZYPADHERA can cause side effects, although not everybody gets them.

Common side effects: affects 1 to 10 users in 100

• ZYPADHERA can sometimes enter the bloodstream too quickly and this may lead to thefollowing side effects: excessive sleepiness, dizziness, confusion, disorientation, difficulty talking, difficulty walking, muscle stiffness or shaking, weakness, irritability, aggression, anxiety, increase in blood pressure, or convulsions and can lead to unconsciousness.
• Sleepiness.
• Injection site pain.

The side effects listed below have been observed when oral olanzapine has been given but may occur following administration of ZYPADHERA.

Very common side effects: affects 1 user in 10

• Weight gain.
• Sleepiness.
• Increases in the levels of prolactin in the blood.

Common side effects: affects 1 to 10 users in 100

• Changes in the levels of some blood cells and circulating fats.
• Increases in the level of sugars in the blood and urine.
• Feeling more hungry.
• Dizziness.
• Restlessness.
• Tremor.
• Muscle stiffness or spasm (including eye movements).
• Problems with speech.
• Unusual movement (especially of the face or tongue).
• Constipation.
• Dry mouth.
• Rash.
• Loss of strength.
• Extreme tiredness.
• Water retention leading to swelling of the hands, ankles or feet.
• In the early stages of treatment, some people may feel dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. This will usually pass on its own but if it does not, tell your doctor.
• Sexual dysfunctions such as decreased libido in males and females or erectile dysfunction inmales.

Uncommon side effects: affects1 to 10 users in 1,000

• Slow heart rate.
• Make you sensitive to sunlight.
• Urinary incontinence.
• Hair loss.
• Absence or decrease in menstrual periods.
• Changes in breasts in males and females such as an abnormal production of breast milk or abnormal growth.

Other possible side effects: frequency cannot be estimated from the available data.

• Allergic reaction (e.g. swelling in the mouth and throat, itching, rash).
• Diabetes or the worsening of diabetes, occasionally associated with ketoacidosis (ketones in theblood and urine) or coma.
• Lowering of normal body temperature.
• Seizures, usually associated with a history of seizures (epilepsy).
• Combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness.
• Spasms of the muscle of the eye causing rolling movement of the eye.
• Abnormal rhythms of the heart.
• Sudden unexplained death.
• Blood clots such as deep venous thrombosis of the leg or blood clot on the lung.
• Inflammation of the pancreas causing severe stomach pain, fever and sickness.
• Liver disease appearing as yellowing of the skin and white parts of the eyes.
• Muscle disease presenting as unexplained aches and pains.
• Difficulty in passing urine.
• Prolonged and/or painful erection.

While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the skin and have trouble walking. Some fatal cases have been reported in this particular group of patients.

In patients with Parkinson's disease oral olanzapine may worsen the symptoms.

Rarely women taking medicines of this type for a long time have started to secrete milk and have missed periods or had irregular periods. If this persists tell your doctor as soon as possible. Very rarely babies born to mothers who have taken oral olanzapine in the last stage of pregnancy (3 rd trimester) may have tremors, be sleepy or drowsy.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Keep out of the reach and sight of children.

The injection must not be given after the expiry date which is stated on the ZYPADHERA carton.

Do not refrigerate or freeze.

After reconstitution in the vial the medicine is stable for 24 hours. If the medicine is not used right away, it should be shaken vigorously to re-suspend. Once withdrawn from vial into the syringe, the suspension should be used immediately.

Chemical and physical stability of the suspension in the vials has been demonstrated for 24 hours at 20-25 °C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 20-25°C

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What ZYPADHERA contains

The active substance is olanzapine. Each vial contains olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. Each vial contains olanzapine pamoate monohydrate equivalent to 300 mg olanzapine. Each vial contains olanzapine pamoate monohydrate equivalent to 405 mg olanzapine. After reconstitution: 1ml suspension contains 150 mg/ml olanzapine.

The solvent ingredients are croscarmellose sodium, mannitol, polysorbate 80, water for injections, hydrochloric acid and sodium hydroxide.

What ZYPADHERA looks like and contents of the pack

ZYPADHERA is a powder and solvent for prolonged release suspension for injection. One carton contains one vial of powder for prolonged release suspension for injection, one vial of 3 ml solvent one syringe with safety needle attached and two separate safety needles.

ZYPADHERA powder for prolonged release suspension for injection comes as a yellow powder in a clear glass vial. Your doctor or nurse will make it into a suspension that will be given as an injection using the vial of solvent for ZYPADHERA that comes as a clear, colourless to slightly yellow solution in a clear glass vial.

Marketing Authorisation Holder and Manufacturer

Eli Lilly Nederland BV, Grootslag 1 ? 5, NL-3991 RA, Houten, The Netherlands.

Manufacturer:
Lilly Pharma Fertigung und Distribution GmbH & Co. KG, Teichweg 3, D-35396 Giessen, Germany.

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

BelgiëBelgiqueBelgien Eli Lilly Benelux S.A.N.V. TélTel 32 0 2 548 84 84 .. - 359 2 491 41 40 eská republika Eli Lilly R, s.r.o. Tel 420 234 664 111 Danmark Eli Lilly Danmark AS Tlf 45 45 26 60 00 Deutschland Lilly Deutschland GmbH Tel 49 0 6172 273 2222 Eesti Eli Lilly Holdings Limited Eesti filiaal Tel 372 6817 280 a - .... 30 210 629 4600 España Lilly S.A. Tel 34 91 663 50 00 France Lilly France SAS Tél 33 0 1 55 49 34 34 Ireland Eli Lilly and Company Ireland Limited Tel 353 0 1 661 4377 Ísland Icepharma hf. Sími 354 540 8000 Italia Eli Lilly Italia S.p.A. Tel 39 055 42571 Phadisco Ltd 357 22 715000 Latvija LuxembourgLuxemburg Eli Lilly Benelux S.A.N.V. TélTel 32 0 2 548 84 84 Magyarország Lilly Hungária Kft. Tel 36 1 328 5100 Malta Charles de Giorgio Ltd. Tel 356 25600 500 Nederland Eli Lilly Nederland B.V. Tel 310 30 6025800 Norge Eli Lilly Norge A.S Tlf 47 22 88 18 00 Österreich Eli Lilly Ges. m.b.H. Tel 43 0 1 711 780 Polska Eli Lilly Polska Sp. z o.o. Tel 48 0 22 440 33 00 Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel 351 21 412 66 00 România Eli Lilly România S.R.L. Tel 40 21 4023000 Slovenija Eli Lilly farmacevtska druba, d.o.o. Tel 386 0 1 580 00 10 Slovenská republika Eli Lilly Slovakia, s.r.o. Tel 421 220 663 111 SuomiFinland Oy Eli Lilly Finland Ab PuhTel 358 0 9 8545 250 Sverige Eli Lilly Sweden AB Tel 46 0 8 7378800 United Kingdom Eli Lilly Holdings Limited, prstvniecba Latvij Eli Lilly and Company Limited Tel 371 67364000 Tel 44 0 1256 315000 Lietuva Eli Lilly Holdings Limited atstovyb Tel 370 5 2649600

This leaflet was last approved in September 2010

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INSTRUCTIONS FOR HEALTH CARE PROFESSIONALS

RECONSTITUTION AND ADMINISTRATION INSTRUCTIONS

ZYPADHERA olanzapine powder and solvent for prolonged release suspension for injection

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

Reconstitution
STEP 1: Preparing materials
Pack includes:

• Vial of ZYPADHERA powder for prolonged release suspension for injection
• Vial of solvent for ZYPADHERA
• One Hypodermic Needle-Pro syringe and safety needle (Hypodermic Needle-Pro Device)
• One 19-gauge, 38 mm Hypodermic Needle-Pro safety needle
• One 19-gauge, 50 mm Hypodermic Needle-Pro safety needle
• Patient Information Leaflet
• Reconstitution and Administration card (this leaflet)
• Hypodermic Needle-Pro Device Safety Information and Instructions for Use leaflet

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.

ZYPADHERA vial strength mg Volume of solvent to add ml 210 1.3 300 1.8 405 2.3

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-Prosyringe 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 needle stick 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 mgml olanzapine. Dose mg Final volume to inject ml 150 1.0 210 1.4 300 2.0 405 2.7

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.