Extavia 250 microgram/ml powder and solvent for solution forinjection

What Extavia is
Extavia is a type of medicine known as interferon used to treat multiple sclerosis. Interferons are proteins produced by the body that help it fight against attacks on the immune system such as viral infections.

How Extavia worksMultiple sclerosis (MS) is a long-term condition that affects the central nervous system (CNS), particularly the functioning of the brain and spinal cord. In MS inflammation destroys the protective sheath (called myelin) around the nerves of the CNS and stops the nerves from working properly. This is called demyelination.

The exact cause of MS is unknown. An abnormal response by the body?s immune system is thought to play an important part in the process which damages the CNS.

The damage to the CNS can occur within an MS attack (relapse). It can cause disability temporarily, such as difficulty walking. Symptoms may disappear completely or partly.

Interferon beta-1b has been shown to change the response of the immune system and to help to reduce disease activity.

How Extavia helps fight your diseaseSingle clinical event indicating a high risk of developing multiple sclerosis: Extavia has been shown to delay progression to definite multiple sclerosis.

Relapsing-remitting multiple sclerosis: People with relapsing-remitting MS have occasional attacks or relapses during which symptoms become noticeably worse. Extavia has been shown to cut down the number of attacks and make them less severe. It reduces the number of hospital stays due to the disease and prolongs the time without relapses.

Secondary progressive multiple sclerosis: In some cases people with relapsing-remitting MS find that their symptoms increase and they progress to another form of MS called secondary progressive MS. With this, people find themselves becoming increasingly impaired, whether or not they have relapses. Extavia can reduce the number and severity of the attacks, and slow the progression of disability.

What Extavia is used for
Extavia is for use in patients
- who have experienced for the first time symptoms which indicate a high risk of developing multiple sclerosis. Your doctor will rule out any other reasons which could explain these symptoms before you are treated.
- who suffer from relapsing-remitting multiple sclerosis, withat least two relapseswithin the last two years.
- who suffer from secondary progressive multiple sclerosis with active disease shown by relapses.

Do not use Extavia

• if you are pregnant. You should not start treatment with Extavia (see ?Pregnancy?).
• if you are allergic(hypersensitive) to natural or recombinant interferon beta, human albumin or any of the other ingredients of Extavia.
• if you currently suffer from severe depression and/or suicidal thoughts (see ?Take special care? and section 4, ?Possible side effects?).
• if you have a severe liver disease (see ?Take special care?, ?Using other medicines? and section 4, ?Possible side effects?).

Tell your doctor, if any of the above applies to you.

Take special care with Extavia

Your doctor also needs to know the following before you are given Extavia:

• If you havemonoclonal gammopathy. This is a disorder of the immune system where an abnormal protein is found in the blood. Problems with your small blood vessels (capillaries) may develop when using medicines like Extavia (systemic capillary leak syndrome). This can lead to shock (collapse) and even be fatal.
• If you have had depression or are depressed or previously had thoughts of suicide. Your doctor will closely monitor you during treatment. If your depression and/or suicidal thoughts are severe, you will not be prescribed Extavia (see also ?Do not use Extavia?).
• If you have ever had seizures or if you are taking medicines to treat epilepsy(anti-epileptics) (see also ?Using other medicines? and section 4, ?Possible side effects?), you doctor will monitor your treatment carefully.
• If you havesevere kidney problems, your doctor may monitor your kidney function during treatment.

Tell your doctor if any of these applies to you.

Your doctor also needs to know the following whilst you are using Extavia:

• If you experience symptoms such as itching all over your body, swelling of your face and/or your tongue or sudden shortness of breath. These may be symptoms of a serious allergic reaction (hypersensitivity), which may become life threatening.
• If you feel noticeably more sad or hopeless than before the treatment with Extavia, or if you develop thoughts of suicide. If you become depressed while you are on Extavia, you may need special treatment and your doctor will closely monitor you and may also consider stopping your treatment. If you suffer from severe depression and/or suicidal thoughts, you will not be treated with Extavia (see also ?Do not use Extavia?).
• If you notice any unusual bruising, excessive bleeding after injury or if you seem to be catching a lot of infections. These may be symptoms of a fall in your blood cell count or in the number of platelets in your blood (cells, which help the blood to clot). You may need extra monitoring by your doctor.
• If you have loss of appetite, fatigue, feeling sick(nausea), repeated vomiting, especially if you notice widespread itching, yellowing of the skin or of the whites of the eyes, or easy bruising. These symptoms may suggest problems with your liver. Changes to liver function values occurred in patients treated with Extavia during clinical studies. As for other beta interferons, severe liver damage, including cases of liver failure, have been reported rarely in patients taking Extavia. The most serious were reported in patients taking other medicines or who were suffering from diseases that can affect the liver (e.g. alcohol abuse, severe infection).
• If you experience symptoms such as irregular heart beat, swelling such as of the ankles or legs, or shortness of breath. This may suggest a disease of the heart muscle (cardiomyopathy) which has been reported rarely in patients using Extavia.
• If you notice pain in your belly which is radiating to your back , and/or you feel sick or have a fever. This may suggest an inflammation of the pancreas (pancreatitis), which has been reported with Extavia use. This is often associated with an increase of certain blood fats (triglycerides).

Stop using Extavia and tell your doctor immediately if any of these happens to you.

Other things to consider when using Extavia:

• You will need blood tests to determine your blood cell count, blood chemistry and your liver enzymes. These will be performed before you start using Extavia, regularly after treatment with Extavia has been initiated and periodically whilst you are on it, even if you have no particular symptoms . These blood tests will be in addition to the tests which are normally done to monitor your MS.
• If you have a heart disease, the flu-like symptoms which often occur at the start of treatment may prove stressful to you. Extavia must be used with caution, and your doctor will monitor you for worsening of your heart condition, particularly at the start of treatment. Extavia itself does not affect the heart directly.
• The functioning of your thyroid gland will be checked regularly or whenever thought necessary by your doctor for other reasons.
• Extavia contains human albumin and therefore carriesa potential risk for transmission of viral diseases. A risk of transmission of Creutzfeld-Jacob disease (CJD) cannot be ruled out.
• During treatment with Extaviayour body may produce substances calledneutralising antibodies, which may react with Extavia (neutralising activity). It is not yet clear whether these neutralising antibodies reduce the effectiveness of the treatment. Neutralising antibodies are not produced in all patients. Currently it is not possible to predict which patients belong to this group.

Injection site reactions:During Extavia treatment you are likely to experience injection site reactions. Symptoms include redness, swelling, change in the skin colour, inflammation, pain, and hypersensitivity. Dead skin and tissue around the injection site (necrosis) are reported less frequently. Injection site reactions usually become less frequent over time.

Injection site skin and tissue breakdown can result in scars forming. If this is severe a doctor may have to remove foreign matter and dead tissue (debridement) and, less often, skin grafting is required and healing may take up to 6 months.

To reduce the risk of getting injection site reaction you must:

• use a sterile (aseptic) injection technique,
• rotate the injection sites with each injection (see Annex Self-Injection procedure).

Injection site reactions may occur less frequently if you use an auto-injector device. Your doctor can tell you more about this.

If you experience any break in the skin, which may be associated with swelling or fluid leaking out from the injection site:

Stop injections with Extavia and talk to your doctor.

If you have only one sore injection site lesion and the tissue damage necrosis is not too extensive you may continue using Extavia.

If you have more than one sore injection sites multiple lesions you must stop using Extavia until your skin has healed.

Your doctor will regularly check the way you inject yourself, particularly if you have experienced injection site reactions.

Children and adolescents
There have been no formal clinical trials undertaken in children or adolescents.

However, there is some data available in children and adolescents from 12 to 16 years. This data suggests that the safety profile from this age is the same as in adults for use of Extavia 8 million IU under the skin (subcutaneously) every other day. Extavia should not be used in children under 12 years of age as there is no information on this use.

Using other medicines

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

No formal interaction studies have been carried out to find out whether Extavia affects other medicines or is affected by them.

Using Extavia with other medicines that modify the immune system response is not recommended, except anti-inflammatory medicines called corticosteroids or the adrenocorticotropic hormone (ACTH).

Extavia should be used with caution with:

• medicines which need a certain liver enzyme system (known as cytochrome P450 system) for their removal from the body, for example medicines used to treat epilepsy (such as phenytoin).
• medicines which affect the production of blood cells.

Using Extavia with food and drink

Extavia is injected under the skin so any food or drink you consume is not thought to have any effect on Extavia.

Pregnancy
Women at risk of becoming pregnant should use contraception during treatment with Extavia.

If you are pregnant or you think you may be, tell your doctor. Extavia therapy should not be started if you are pregnant see also Do not use Extavia.

If you wish to become pregnant, discuss this with your doctor first.

If you become pregnant while using Extavia, stop your treatment and contact your doctor immediately. Your doctor will decide together with you whether your Extavia treatment will be continued or not.

Ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding
It is not known whether interferon beta-1b passes into human breast milk. However, it is theoretically possible that a breast-fed baby could experience serious side effects to Extavia.

Discuss it with your doctor first to decide whether to stop breast-feeding or to stop using Extavia.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving or using machines
Extavia may cause side effects in the central-nervous system (see section 4 Possible side effects). If you are especially sensitive, this might influence your ability to drive or use machines.

Treatment with Extavia should be started under the supervision of a doctor who is experienced in the treatment of multiple sclerosis.

Always use Extavia exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.

Dose
The usual dose is:

Every other day (once every two days), 1.0 ml of the prepared Extavia solution (see Annex) injected under the skin (subcutaneously). This equals 250 microgram (8 million IU) interferon beta-1b.

In general, treatment should be started at a low dose of 0.25 ml (62.5 micrograms). Your doses will then be increased gradually to the full dose of 1.0 ml (250 micrograms).
The dose should be increased at every fourth injection in four steps (0.25 ml, 0.5 ml, 0.75 ml, 1.0 ml). Your doctor may decide together with you to change the time intervals for dose increase depending on side effects you may experience at the start of treatment.

Preparing the injectionBefore injection, the Extavia solution has to be prepared from a vial of Extavia powder and 1.2 ml of liquid from the pre-filled solvent syringe. This will either be done by your doctor or his/her assistant or by yourself after you have been carefully trained.

Detailed instructions for self-injectionof Extavia under the skin are provided in the Annex at the back of this leaflet. These instructions also tell you how to prepare the Extavia solution for injection.

The injection site must be changed regularly. See ?Take special care with Extavia? and follow the instructions under ?Rotating injection sites? in the Annex at the back of this leaflet.

At present it is not known how long treatment with Extavia should last. The length of treatment will be decided by your doctor together with you.

If you use more Extavia than you should
Giving many times the dose of Extavia recommended for the treatment of multiple sclerosis has not led to life-threatening situations.

Talk to your doctor if you inject too much Extavia or injected too often.

If you forget to use Extavia

If you have forgotten to give yourself an injection at the right time do it as soon as you remember and then follow on with the next one 48 hours later.

Do not inject a double dose to make up for a forgotten individual dose.

If you stop using Extavia
Talk to your doctor if you stop or wish to stop treatment. Stopping Extavia is not known to cause acute withdrawal symptoms.

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

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

At the beginning of treatment side effects are common but in general they become less with further treatment.

The most common side effects are:

Flu-like symptoms such as fever, chills, painful joints, malaise, sweating, headache, or muscular pain. These symptoms may be reduced by taking paracetamol or non-steroidal anti-inflammatory medicines such as ibuprofen.

Injection site reactions. Symptoms can be redness, swelling, discolouration, inflammation, pain, hypersensitivity, necrosis. See Take special care in section 2 for more information and what to do if you experience an injection site reaction. These may be reduced by the use of an auto-injector device. Please talk to your doctor for further information.

To reduce side effects at the start of treatment, your doctor should start you on a low dose of Extavia and increase it gradually (see section 3, ?How to use Extavia?).

Extavia may also cause serious side effects. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Tell your doctor immediately and stop using Extavia

• if you experiencesymptoms such as itching all over your body, swelling of your face and/or your tongue or sudden shortness of breath.
• if you feel noticeably more sad or hopeless than before the treatment with Extavia, or if you develop thoughts of suicide.
• if you notice any unusual bruising, excessive bleeding after injury or if you seem to be catching a lot of infections.
• if you have loss of appetite, fatigue, feeling sick(nausea), repeated vomiting, especially if you notice widespread itching, yellowing of the skin, or of the whites of the eyes or easy bruising.
• if you experience symptoms like irregular heart beat, swelling such as of the ankles or legs, or shortness of breath.
• if you notice pain in your belly which is radiating to your back , and/or you feel sick or have a fever.

The following side effects listing is based on reports from clinical trials with Extavia (List 1)and from side effects reported on the marketed product (List 2).

List 1 Side effects which have occurred in clinical trials with Extavia very commonly 1 or more in every 10 patients and at a higher percentage than those observed with placebo. The list also includes side effects which occur in less than 1 in 10 patients but were significantly associated with the treatment

• infection, abscess
• reduced number of white blood cells, swollen lymph glands
• decrease of sugar in the blood
• depression, anxiety
• headache, dizziness, sleeplessness, migraine, numbness or tingling feeling(paresthesia)
• conjunctivitis, abnormal vision
• ear pain
• irregular, rapid beating or pulsation of the heart(palpitation)
• redness and/or facial flushing due to widening of blood vessels, increased blood pressure
• runny nose, cough, hoarseness due to infection of the upper respiratory tract, sinusitis, cough increased, shortness of breath
• diarrhoea, constipation, nausea, vomiting, abdominal pain
• rises in the blood levels of liver enzymes (will show up in blood tests)
• skin disorder, rash
• muscle stiffness (hypertonia), painful muscles (myalgia), muscular debility (myasthenia), back pain, pain in extremities such as fingers and toes
• holding urine (urine retention), protein in the urine (will show up in urine tests), urinary frequency, urinary incontinence, urinary urgency
• painful periods (menstruation), menstrual disorder, heavy uterine bleeding especially between menstrual periods, impotence
• injection site reaction (including redness, swelling, discoloration, inflammation, pain, allergic reaction (hypersensitivity), see ?Take special care with Extavia?), skin breakdown and tissue destruction (necrosis) at injection site (see ?Take special care with Extavia?), flu-like symptoms, fever, pain, chest pain, accumulation of fluid in arm, leg or face, lack/loss of strength, chills, sweating, malaise

List 2 Side effects reports on the marketed product from spontaneous reporting

Very common side effects means 1 or more in every 10 patients are likely to get these flu-like symptoms, chills, fever, injection site reaction, injection site inflammation, injection site pain. frequencies based on clinical trials

Common side effects means between 1 and 10 in every 100 patients are likely to get these skin breakdown and tissue destruction necrosis at injection site frequencies based on clinical trials

Uncommon side effects means between 1 and 10 in every 1,000 patients are likely to get these the number of white cells and red cells in the blood may fall, the number of platelets which help the blood to clot may fall, depression, increase in blood pressure, nausea, vomiting, change in the results of liver tests increase in the blood levels of enzymes produced by the liver, swollen and usually itching patches of skin or mucous membranes urticaria, rash, itching pruritus, loss of scalp hair, painful muscles, muscle stiffness.

Rare side effects means between 1 and 10 in every 10,000 patients are likely to get these swollen lymph glands, serious allergic hypersensitivity reactions, disturbance in the functioning of the thyroid gland too much or too little hormone is produced, a certain type of blood fats triglycerides may increase, see Take special care with Extavia this will show up in blood tests, severe loss of appetite leading to weight loss anorexia, confusion, anxiety, mood swings, suicide attempt, convulsion, disease of the heart muscle cardiomyopathy, faster heart beat, irregular, rapid beating or pulsation of the heart palpitation, sudden shortness of breath bronchospasm, shortness of breath dyspnoea, pancreatitis, see Take special care with Extavia, blood levels of a specific liver enzyme gamma GT and a reddish yellow pigment bilirubin, which is produced by your liver, may rise this will show up in blood tests,

• hepatitis,
• skin discoloration,
• menstrual disorders,
• chest pain,
• malaise,
• sweating,
• loss of weight.

Keep out of the reach and sight of children.

Do not use after the expiry date which is stated on the pack.

Do not store above 25°C. Do not freeze.

After preparing the solution you should use it immediately. However, if you are not able to do so, it will remain usable for a period of 3 hours, if kept at 2-8°C (in a refrigerator).

Do not use Extavia if you notice it contains particles or is discoloured.

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 Extavia contains

• The active substance is interferon beta-1b. Each vial contains 300 microgram (9.6 million IU) interferon beta-1b per vial. After reconstitution, each millilitre contains 250 microgram (8 million IU) interferon beta-1b.
• The other ingredients are
• in the powder: mannitol and human albumin.
• in the solvent: sodium chloride, water for injections.

What Extavia looks like and contents of the pack

Extavia is a powder and solvent for solution for injection.

The powder is white to off-white.
The Extavia powder is provided in a 3-millilitre vial.
The solvent for Extavia is provided in a 1.2 ml pre-filled syringe and contains 1.2 ml sodium chloride 5.4 mg/ml (0.54% (w/v)) solution for injection.

Extavia is available in pack sizes of:

• 5 vials of interferon beta-1b and 5 pre-filled syringes containing solvent.
• 14 vials of interferon beta-1b and 14 pre-filled syringes containing solvent.
• 15 vials of interferon beta-1b and 15 pre-filled syringes containing solvent.
• 3-month multipack containing 42 (3x14) vials of interferon beta-1b and 42 (3x14) pre-filled syringes containing solvent.
• 3-month multipack containing 45 (3x15) vials of interferon beta-1b and 45 (3x15) pre-filled syringes containing solvent.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom

Manufacturer

Novartis Pharmaceuticals UK, Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom

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

BelgiëBelgiqueBelgien Novartis Pharma N.V. TélTel 32 2 246 16 11 LuxembourgLuxemburg Novartis Pharma GmbH TélTel 49 911 273 0

Novartis Pharma Services Inc. . 359 2 489 98 28 Magyarország Novartis Hungária Kft. Pharma Tel. 36 1 457 65 00

eská republika Novartis s.r.o. Tel 420 225 775 111 Malta Novartis Pharma Services Inc. Tel 356 2298 3217

Danmark Novartis Healthcare AS Tlf 45 39 16 84 00 Nederland Novartis Pharma B.V. Tel 31 26 37 82 111

Deutschland Novartis Pharma GmbH Tel 49 911 273 0 Norge Novartis Norge AS Tlf 47 23 05 20 00

Eesti Novartis Pharma Services Inc. Tel 372 66 30 810 Österreich Novartis Pharma GmbH Tel 43 1 86 6570

Novartis Hellas A.E.B.E. 30 210 281 17 12 Polska Novartis Poland Sp. z o.o. Tel. 48 22 550 8888

España Novartis Farmacéutica, S.A. Tel 34 93 306 42 00 Portugal Novartis Farma - Produtos Farmacêuticos, S.A. Tel 351 21 000 8600

France Novartis Pharma S.A.S. Tél 33 1 55 47 66 00 România Novartis Pharma Services Inc. Tel 40 21 31299 01

Ireland Novartis Ireland Limited Tel 353 1 260 12 55 Slovenija Novartis Pharma Services Inc. Tel 386 1 300 75 50

Ísland Vistor hf. Sími 354 535 7000 Slovenská republika Novartis Slovakia s.r.o. Tel 421 2 5542 5439

Italia Novartis Farma S.p.A. Tel 39 02 96 54 1 SuomiFinland Novartis Finland Oy PuhTel 358 010 6133 200

Novartis Pharma Services Inc. 357 22 690 690 Sverige Novartis Sverige AB Tel 46 8 732 32 00

Latvija Novartis Pharma Services Inc. Tel 371 67 887 070 United Kingdom Novartis Pharmaceuticals UK Ltd. Tel 44 1276 698370

Lietuva

Novartis Pharma Services Inc.
Tel: +370 5 269 16 50

This leaflet was last approved in

Annex: SELF-INJECTION PROCEDURE

The following instructions are intended to explain how to prepare Extavia for administration and how to inject Extavia yourself. Please read the instructions carefully and follow them step by step. Your doctor or his/her assistant will help you to learn the process of self-administration. Do not attempt to inject yourself until you are sure that you understand how to prepare the injection solution and give the injection to yourself.

PART I: STEP BY STEP INSTRUCTIONS

The instructions include the following main steps:

A) General advice

B) Getting ready to inject

C) Reconstituting the solution, step by step

D) Drawing up the injection

E) Making the injection manually (to make an injection with an auto-injector, refer to the instructions for use provided with the auto-injector)

F) Quick review of the process

A) General advice

• Getting off to a good start!

You will find that within a few weeks your treatment will become a natural part of your routine. As you get started, you may find the following tips helpful:

• Set up a permanent storage area in a convenient location out of the reach of children so that your Extavia and other supplies are always easy to find. For details on storage conditions see section 5 of the leaflet, ?How to store Extavia?.
• Try to give yourself the injection at the same time each day. This makes it easier to remember and easier to plan a block of time when you will not be interrupted. Please refer to section 3 of the leaflet, ?How to use Extavia?, for further details on how to use Extavia.
• Prepare each dose only when you are ready for an injection. After mixing Extavia, you should administer the injection immediately (if Extavia is not used immediately, see section 5 of the leaflet, ?How to store Extavia?).
• Important tips to keep in mind
• Be consistent - use Extavia as described in section 3 of the leaflet, ?How to use Extavia?. Always double-check your dosage.
• Keep your syringes and syringe disposal unit out of the reach of children; lock the supplies if possible.
• Never re-use syringes or needles.
• Always use a sterile (aseptic) technique as described in here.
• Always place the used syringes in the proper disposal unit.

B) Getting ready to inject

• Choosing an injection site

Before preparing your injection, decide where you are going to inject. You should inject Extavia into the fatty layer between the skin and muscle (that is, subcutaneously, about 8 to 12 mm under the skin). The best places for injections are where the skin is loose and soft, and away from joints, nerves, bones, for example the abdomen, arm, thigh or buttocks.

Important: Do not use any area where you can feel lumps, bumps, firm knots, pain or an area that is discoloured, indented, scabbed, or where the skin is broken. Talk to your doctor or healthcare professional about these or any other unusual conditions you may find.

You should rotate the injection site at every injection. If some areas are too difficult for you to reach, you may need a family member or friend to help you with these injections. Follow the sequence described in the schedule at the end of the Annex (see II) Rotating injection sites) and you will come back to your first injection site area after 8 injections (16 days). This will give each injection site a chance to fully recover before receiving another injection.

Please refer to the rotation schedule at the end of this Annex to learn how to choose an injection site. An example of a medication record is also included. This should give you an idea of how you can keep track of your injection sites and dates.

• Medicine

You will need the medicine:

• 1 Extavia vial (with powder for solution for injection)
• 1 pre-filled syringe of solvent for Extavia (sodium chloride solution (0.54% (w/v))

To reconstitute and inject your medicine you will need the following components:

• a needle suitable for reconstitution
• 30-gauge needle for injection
• alcohol wipes You will also need a disposal unit for used syringes and needles.

Alternatively, you can use an application kit for the administration of Extavia (supplied separately from your medicine), which contains vial adapters for reconstituting your medicine, 30-gauge needles for injecting your medicine and alcohol wipes, as well as instructions on how to use these components.

The 30-gauge needles provided with the application kit for the administration of Extavia can be used either for manual injection OR with an ExtaviJect 30G auto-injector.

For skin disinfection use an appropriate disinfectant.

C) Reconstituting the solution, step by step

1 - Wash your hands thoroughly with soap and water before beginning this process.

2 - Open the Extavia vial and put it on the table. It is best to use your thumb rather than your nail as it could break.

3 - Clean the top of the vial with an alcohol wipe, moving the wipe in one direction only. Leave the wipe on top of the vial.

4 ? Take out the pre-filled solvent syringe from its package. Remove the tip cap from the pre-filled syringe by twisting it off. Be careful not to touch the exposed end of the syringe. Do not push the plunger.

5 - Take the needle suitable for reconstitution out of its wrapping and place it firmly onto the tip (nozzle) of the syringe. Remove the needle guard from the needle. Do not touch the needle.

6 - Holding the Extavia vial on a stable surface, slowly insert the needle of the syringe (containing 1.2 ml of liquid) all the way through the stopper of the vial.

7 - Push the plunger down slowly, directing the needle toward the side of the vial to allow the liquid to run down the inside of the vial.
Injecting solvent directly onto the powder will cause excess foaming.
Transfer all the solvent to the vial. Release the plunger.

8 - After the solvent in the syringe has been completely injected into the Extavia vial, hold the vial between your thumb, forefinger and middle finger with the needle and syringe resting against your hand and swirl the vial gently to completely dissolve the powder of Extavia.
Do not shake the vial.

9 - Examine the solution carefully. It should be clear and contain no particles. If the solution is discoloured or contains particles, discard it and start again with a syringe and vial out of your package.

If foam is present ?- which can happen if the vial is shaken or swirled too vigorously ? let the vial sit undisturbed until the foam settles.

D) Drawing up the solution for injection

10 - In order to redraw the solution back into the syringe, turn the syringe-vial-assembly, needle pointing upwards. Redraw the needle a little bit back within the vial so that the needle tip rests at the lowest point of the vial.

Keep the needle tip in the liquid, and slowly pull the plunger back all the way to withdraw the solution into the syringe.

11 - Any excessive air rises to the top of the solution. Remove the air bubbles by gently tapping the syringe and pushing the plunger to the 1 ml mark, or to the volume prescribed by your doctor.

If too much solution goes into the vial along with the air bubbles, pull the plunger back a little to withdraw the solution back from the vial into the syringe. Do this until all the air is gone and there is 1 ml of reconstituted solution in the syringe.

12 - Disconnect the syringe and the needle. Leave the needle in the vial.

13 - Take the 30-gauge needle out of its wrapping and place it firmly onto the tip (nozzle) of the syringe.

14 - Dispose of the vial and the remaining unused portion of the solution into the disposal unit.

15 - You are now ready to inject.

If, for some reason, you are not able to inject Extavia immediately, you can keep the reconstituted solution in the syringe in a refrigerator for up to 3 hours before using. Make sure the needle cap is fixed properly while the syringe is stored in the fridge. Do not freeze the solution, and do not wait longer than 3 hours to inject it. If more than 3 hours pass, discard the medicine and prepare a new injection. When you use the solution, warm it up in your hands before injecting to avoid pain.

E) Making the injection manually (to make an injection with an auto-injector, refer to the instructions for use provided with the auto-injector)

1 - Choose an area for the injection (see advice at the start and the diagrams at the end of this Annex), and make a note of it in your medication record.

2 - Use an alcohol swab to clean the skin at the injection site. Let the skin air-dry. Throw the swab away. For skin disinfection use an appropriate disinfectant. 3 - Remove the cap from the needle by pulling and not twisting it.

4 - Gently pinch the skin together around the disinfected injection site to raise it up a little. 5 - Holding the syringe like a pencil or a dart, push the needle straight into the skin at a 90 angle with a quick, firm motion. 6 - Inject the medicine using a slow, steady push on the plunger. Push the plunger all the way in until the syringe is empty.

7 - Discard the syringe in the disposal unit.

F) Quick review of the process

1. Take out the contents needed (1 vial, 1 pre-filled syringe, 2 alcohol wipes, needle suitable for reconstitution, 30-gauge needle for injection).

2. Take off the cap from the vial and clean the rubber stopper with an alcohol wipe.

3. Unwrap the needle suitable for reconstitution and fix it to the syringe from which you removed the tip cap before.

4. Transfer the solvent from the syringe to the vial by pushing the plunger in all the way.

5. Turn the syringe-vial-assembly over, then withdraw plunger to redraw the solution.

6. Disconnect syringe and needle, leave the needle in the vial and discard both.

7. Unwrap the 30-gauge needle and connect it to the syringe.

8. Remove needle cap just before injection - you are now ready to inject.

NOTE: The injection should be administered immediately after mixing (if the injection is delayed, refrigerate the solution and inject it within 3 hours). Do not freeze.

PART II ROTATING INJECTION SITES

You need to choose a new site for each injection to allow the area time to recover and help prevent infection. Advice on which areas to choose is given in the first part of this Annex. It is a good idea to know where you plan to inject before you prepare your syringe. The schedule shown in the diagram below will help you to vary the sites appropriately. For example, give the first injection into the right side of the abdomen, choose the left side for the second injection, then move to the right thigh for the third, and so on through the diagram until all suitable areas of the body have been used. Keep a record of where and when you last gave yourself an injection. One way to do that is to note the injection site on the enclosed medication record card.

By following this schedule, you will come back to your first area (e.g. the right side of the abdomen) after 8 injections (16 days). This is called a Rotation Cycle. On our example schedule each area is split again into 6 injection sites (which adds up to 48 injection sites altogether), left, right, upper, middle and lower part of each area. If you come back to an area after one Rotation Cycle choose the most distant injection site within this area. If an area becomes sore, talk to your doctor or nurse about choosing other injection sites.

Rotation Schedule
To help you rotate the injection sites appropriately we recommend that you keep a record of the date and location of your injection. You can use the following rotation schedule.

Work through each rotation cycle in turn. Each cycle will be 8 injections (16 days), given in area 1 through to area 8 in turn. By following this sequence, you will give each area a chance to recover before receiving another injection.

Rotation Cycle 1 Rotation Cycle 2 Rotation Cycle 3 Rotation Cycle 4 Rotation Cycle 5 Rotation Cycle 6 Upper left section of each area Lower right section of each area Middle left section of each area Upper right section of each area Lower left section of each area Middle right section of each area

PART III: EXTAVIAMedication record

Instructions for keeping track of your injection sites and dates

• Start with your first injection (or your last injection if you are not a new Extavia user).
• Select an injection site. If you have already been using Extavia start with the area that has not been used during the last rotation cycle, i.e. the past 16 days).
• After your injection, fill in the used injection site and date in the table in your injection record (See the example: Keeping track of your injection sites and dates).

ROTATION SCHEDULE:

AREA 1 AREA 2 AREA 3 AREA 4 10 15 cm from groin AREA 5 AREA 6 AREA 8 AREA 7

EXAMPLE OF A MEDICATION RECORD: