Rebif 44 micrograms solution for injection in pre-filled pen

Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit messages between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not totally understood, interferons help to limit the damage of the central nervous system associated with multiple sclerosis.

Rebif is a highly purified soluble protein that is similar to the natural interferon beta that is produced in the human body.

Rebifis used for the treatment of multiple sclerosis. It has been shown to reduce the number and the severity of relapses and to slow the progression of disability.

Do not use Rebif

if you are allergic hypersensitive to natural or recombinant interferon beta or any of the other ingredients of Rebif, if you are pregnant see Pregnancy and breast-feeding, if you are severely depressed at present.

Take special care with Rebif

Rebif should only be used under the supervision of your doctor. Before treatment with Rebif, read carefully and follow the advice given under How to use Rebif in order to minimise the risk of injection site necrosis skin breakdown and tissue destruction that has been reported in patients treated with Rebif. If you experience troubling local reactions, contact your doctor. Before treatment with Rebif, advise your doctor if you have an allergy hypersensitivity to any other medicines.

Inform your doctor if you have a disease of the bone marrow, kidney, liver, heart, thyroid, or if you have experienced depression, or if you have any history of epileptic seizures, so that heshe can closely monitor your treatment and any worsening of these conditions.

Using other medicines

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.
In particular you should tell your doctor if you are using antiepileptics or antidepressants.

Pregnancy and breast-feeding

You must not start treatment with Rebif if you are pregnant. While taking Rebif, you must use effective methods of contraception if you are a woman of child-bearing potential. If you become pregnant or plan to become pregnant while using Rebif ask your doctor for advice.

Prior to taking the medicine, please inform your doctor if you are breast-feeding. The use of Rebif is not recommended if you are breast-feeding.

Driving and using machines

Effects of the disease itself or of its treatment might influence your ability to drive or to use machines. You should discuss this with your doctor if you are concerned.

Important information about some of the ingredients of Rebif

This medicinal product contains 2.5 mg benzyl alcohol per dose.
Must not be given to premature babies or neonates.
May cause toxic reactions and allergic reactions in infants and children up to 3 years old.

Always use Rebif exactly as your doctor has told you. You should check with your doctor if you are not sure.

Dose
The usual dose is 44 micrograms (12 million IU) given three times per week for adults and adolescents from 16 years of age. A lower dose of 22 micrograms (6 million IU) given three times per week is recommended for:
- patients who cannot tolerate the higher dose.
- adolescents from the age of 12 years.

Rebif should be administered, if possible:
- three times per week
- on the same three days (at least 48 hours apart)
- at the same time (preferably in the evening).

Method of administration

Rebif is intended for subcutaneous (under the skin) injection.
The first injection(s) must be performed under the supervision of an appropriately qualified healthcare professional. After receiving adequate training, you, a family member, friend or carer can use Rebif pre-filled pen to administer the medicine at home.

For instructions for handling of Rebif in pre-filled pen, please read the separate RebiDose user guide enclosed in the box.

This medicinal product is for single use.
Only clear to opalescent solution without particles and without visible signs of deterioration should be used.

If you use more Rebif than you should

In case of overdose, contact your doctor immediately.

If you forget to use Rebif

If you miss a dose, continue to inject from the day of the next scheduled dose. Do not take a double dose to make up for a forgotten dose.

If you stop using Rebif

The effects of Rebif may not be noticed immediately. Therefore you should not stop using Rebif but continue to use it regularly to achieve the desired result. If you are uncertain about the benefits, please consult your doctor.

You should not discontinue the treatment without first contacting your doctor.

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

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

Tell your doctor immediately and stop using Rebif if you experience any of the following serious side effects:

Serious allergic hypersensitivity reactions. If, immediately following Rebif administration you experience a sudden difficulty breathing, which may appear in association with swelling of face, lips, tongue or throat, nettle rash, itching all over the body, and a feeling of weakness or faintness, contact your doctor immediately or seek urgent medical attention.

Inform your doctor immediately if you experience any of the following possible symptoms of a liver problem jaundice yellowing of the skin or of the whites of the eyes, widespread itching, loss of appetite accompanied by nausea and vomiting and easy bruising of the skin. Severe liver problems can be associated with additional signs, e.g. difficulty concentrating, sleepiness and confusion.

If you feel very depressed or develop thoughts of suicide, report it immediately to your doctor.

Side effects may occur with certain frequencies, which are defined as follows very common affects more than 1 user in 10 common affects 1 to 10 users in 100 uncommon affects 1 to 10 users in 1,000 rare affects 1 to 10 users in 10,000 very rare affects less than 1 user in 10,000 not known frequency cannot be estimated from the available data.

Flu-like symptoms, such as headache, fever, chills, muscle and joint pains, fatigue and nausea are very common. These symptoms are usually mild, are more common at the start of the treatment and decrease with continued use. To help reduce these symptoms your doctor may advise you to take a fever reducing painkiller before a dose of Rebif and then for 24 hours after each injection.

Injection site reactions including redness, swelling, discoloration, inflammation, pain and skin breakdown are very common. The occurrence of injection site reactions usually decreases over time. Tissue destruction necrosis, abscess and mass at injection site are uncommon. See recommendations in section Take special care with Rebif to minimise the risk of injection site reactions. The injection site can become infected frequency not known the skin may become swollen tender and hard and the whole area could be very painful. If you experience any of these symptoms, contact your doctor for advice.

Certain laboratory tests may change very common. These changes are generally not noticed by the patient no symptoms, are usually reversible and mild, and most often do not require particular treatment. The number of red blood cells, white blood cells or platelets may decrease. Possible symptoms resulting from these changes could include tiredness, reduced ability to fight infection, bruising or unexplained bleeding. Liver function tests may be disturbed. Inflammation of the liver has also been reported frequency not known. If you experience symptoms suggesting a liver disorder, such as loss of appetite accompanied by other symptoms such as nausea, vomiting, jaundice, please contact your doctor immediately see above Tell your doctor immediately....

Depression is common in treated patients with multiple sclerosis. If you feel depressed, please contact your doctor immediately.

Thyroid dysfunction is uncommon. The thyroid gland may function either excessively, or insufficiently. These changes in the thyroid activity are almost always not felt by the patient as symptoms, however your doctor may recommend testing as appropriate.

MS pseudo-relapse frequency not known There is a possibility that at the beginning of your treatment with Rebif you may experience symptoms that resemble those of a multiple sclerosis relapse. For example, your muscles may feel very tense or very weak, preventing you from moving as you want. In some cases such symptoms are associated with fever or flu-like symptoms described above. If you notice any of these side effects talk to your doctor.

Other possible side effects include:

Very common:
- Headache

Common Insomnia sleeping difficulty Diarrhoea, nausea, vomiting Itching, rash skin eruptions Muscle and joints pain Fatigue, fever, chills

Frequency not known Allergic hypersensitivity reactions Face swelling, hives Suicide attempt Epileptic seizures Serious skin reactions - some with mucosal lesions Liver inflammation hepatitis Hair loss Breathing difficulties Blood clots such as deep venous thrombosis Disorders of the retina back of the eye such as inflammation or blood clots with consequent vision disorders vision disturbances, loss of vision Thrombotic thrombocytopenic purpura Haemolytic uremic syndrome a disorder that may present with small blood clots, increased bruising, bleeding, decreased platelets, anaemia, extreme weakness, and renal disorders.

The following side effects were reported for interferon beta frequency not known Dizziness Nervousness Loss of appetite Dilatation of the blood vessels and palpitation Irregularities andor changes in menstrual flow.

You should not stop or alter the medication without your doctor?s advice.

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

Keep out of the reach and sight of children.

Do not use Rebif after the expiry date which is stated on the label after EXP.

Store in a refrigerator (2°C ? 8°C).

Do not freeze. (To prevent accidental freezing, avoid placing near the freezer compartment).

For the purpose of ambulatory use, you may remove Rebif from the refrigerator and store it not above 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used before the expiry date.
Store in the original package in order to protect from light.

Do not use Rebif if you notice any visible signs of deterioration such as if the solution is no longer clear or if it contains particles.

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 Rebif contains

The active substance is interferon beta-1a. Each pre-filled pen contains 44 micrograms, corresponding to 12 million International Units (IU) of interferon beta-1a.
The other ingredients are mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide and water for injections.

What Rebif looks like and contents of the pack

Rebif is available as a solution for injection in a pre-filled pen for self-administration. Rebif solution is clear to opalescent. The pre-filled pen is ready for use and contains 0.5 ml of solution. Rebif is available in packs of 1, 3 and 12 pre-filled pens (RebiDose). Not all pack sizes may be marketed.

Marketing Authorisation Holder

Merck Serono Europe Limited

56, Marsh Wall

London E14 9TP
United Kingdom

Manufacturer

Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

BelgiëBelgiqueBelgien MERCK NVSA Brusselsesteenweg 288 B-3090 Overijse TélTel 32-2-686 07 11 LuxembourgLuxemburg MERCK NVSA Brusselsesteenweg 288 B-3090 Overijse, BelgiqueBelgien TélTel 32-2-686 07 11

Magyarország Merck Kft. Bocskai út 134-146. H-1113 Budapest Tel 36-1-463-8100 . . 83 1582 Te 359 28075 111

eská republika Merck spol. s r.o. Na Hebenech II. 171810 CZ-140 00 Praha 4 Tel. 420 272084211 Malta Cherubino Ltd Delf Building Sliema Road MT-GZR 06 Gzira Malta Tel 356-21-3432701234

Danmark Merck AB Strandvejen 102 B, 4th DK-2900 Hellerup Tlf 45 35253550 Nederland Merck BV Tupolevlaan 41-61 NL-1119 NW Schiphol-Rijk Tel 31-20-6582800

Deutschland Merck Serono GmbH Alsfelder Straße 17 D-64289 Darmstadt Tel 49-6151-6285-0 Norge Merck Serono Norge Luhrtoppen 2 N-1470 Lørenskog Tlf 47 67 90 35 90

Eesti Merck Serono OÜ Tornimäe 7 - 132 EE-10145, Tallinn Tel 372 682 5882 Österreich Merck GesmbH. Zimbagasse 5 A-1147 Wien Tel 43 1 57600-0

Polska Merck Sp. z o.o. Al. Jerozolimskie 178 PL-02-486 Warszawa Tel. 48 22 53 59 700 Merck A.E. 41-45, GR-151 23 T 30-210-61 65 100

Portugal Merck, s.a. Rua Alfredo da Silva, 3-C P-1300-040 Lisboa Tel 351-21-361 35 00 España Merck S.L. María de Molina, 40 E-28006 Madrid Línea de Información 900 200 400 Tel 34-91-745 44 00

România MERCK d.o.o., Dunajska cesta 119 SI-1000 Lubliana, Slovenia Tel 386 1 560 3 800 France Merck Serono s.a.s. 37, rue Saint-Romain F-69379 Lyon cedex 08 Tél. 33-4-72 78 25 25 Numéro vert 0 800 888 024

Slovenija MERCK d.o.o. Dunajska cesta 119 SI-1000 Ljubljana Tel 386 1 560 3 800 Ireland Merck Serono Ltd Bedfont Cross, Stanwell Road Feltham, Middlesex TW14 8NX United Kingdom Tel 44-20 8818 7200

Ísland Icepharma hf Lynghálsi 13 IS-110 Reykjavík Tel 354 540 8000 Slovenská republika Merck spol. s r.o. Tuhovská 3 SK-831 06 Bratislava Tel 421 2 49 267 111

Italia Merck Serono S.p.A. Via Casilina 125 I-00176 Roma Tel 39-06-70 38 41 SuomiFinland Merck Oy Pihatörmä 1 C FIN-02240 Espoo PuhTel 358-9-8678 700

Sverige Merck AB S-195 87 Stockholm Tel 46-8-562 445 00 . . 35, CY-2234 , . 357 22490305

Latvija Merck Serono SIA Duntes iela 23A LV-1005, Rga Tel 371 67152500 United Kingdom Merck Serono Ltd Bedfont Cross, Stanwell Road Feltham, Middlesex TW14 8NX- UK Tel 44-20 8818 7200

Lietuva
Merck Serono UAB
Savanoriu pr. 192,
LT-44151 Kaunas
Tel: +370 37320603

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INSTRUCTIONS FOR HANDLING OF REBIF IN PRE-FILLED PEN (RebiDose)

This section contains information on how to properly use RebiDose. The first injection(s) must be performed under the supervision of an appropriately qualified healthcare professional. After receiving adequate training, you, a family member, friend or carer can use RebiDose to administer the medicine at home. If you have questions about how to inject, please ask your doctor, nurse or pharmacist for assistance.

How do you, or the person injecting you, use RebiDose

Your doctor has prescribed Rebif in the RebiDose for injection into the tissue just under the skin. Only use each RebiDose for one injection.

Read all the following instructions carefully before using RebiDose.

Equipment

To give yourself an injection you will need:
- A new RebiDose and
- Alcohol wipes or similar.
Below is a diagram that shows what RebiDose looks like.

Before the injection After the injection

A. Cap B. Transparent control area C. Plunger D. Label E. Main body F. Button G. Safety guard H. Needle

What to do before you give yourself a subcutaneous injection with RebiDose

Wash your hands thoroughly with soap and water. Remove RebiDose from the blister pack by peeling back the plastic covering. Check the appearance of Rebif through the transparent control area. It must be clear to opalescent, without particles and without any visible signs of deterioration. If there are particles or other visible signs of deteriorations, do not use it and contact your doctor, nurse or pharmacist for assistance. Check the expiry date on the RebiDose label as indicated as EXP. You can also check the expiry date on the RebiDose outer box. Do not use RebiDose if the expiry date has passed.

Where to inject with RebiDose

Choose an injection site. Your doctor will advise you on the possible injection sites good sites include the upper thighs and the lower abdomen. It is recommended that you keep track of and rotate your injection sites, so that one area is not injected too frequently in order to minimise the risk of injection site necrosis. NOTE do not use any areas in which you feel lumps, firm knots, or pain talk to your doctor or healthcare professional about anything you find.

How to inject with RebiDose

Do not remove the cap until you are ready to administer the injection. Before the injection use an alcohol wipe to clean the skin at the injection site. Let the skin dry. If a bit of alcohol is left on the skin, you may get a stinging sensation.

Hold RebiDose by the main body and use your other hand to remove the cap. Hold RebiDose at a right angle 90 dergees to the injection site. Push the pen down until you feel resistance. This action unlocks the button. Keep enough pressure on the skin and press the button with your thumb. You will hear a click which indicates the start of the injection and the plunger will start moving. Keep RebiDose pressed against the skin for at least 10 seconds in order to deliver the full medicinal product. It is not necessary to keep the button pressed down with your thumb after the injection has begun. Remove RebiDose from the injection site. The safety guard automatically surrounds the needle and locks into place to protect you from the needle.

Look through the transparent control area to make sure that the plunger has moved to the bottom as indicated in the figure. Visually check that there is no liquid left. If there is liquid left, not all of the medicinal product has been injected and you should consult your doctor or nurse for assistance.

Gently massage the injection site with a dry cotton ball or gauze.

In case of any difficulties while using RebiDose, please contact your doctor or nurse for assistance.

How to dispose of used RebiDose

RebiDose is for single use only and should never be reused. Never put the needle cap back on the used RebiDose. Once you have finished your injection, immediately discard RebiDose in an appropriate disposal unit. To avoid any injury, never insert your fingers in the opening of the safety guard covering the needle.