What is it and how is it used?

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.

Rebif is 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.

Table of Contents
What do you have to consider before using it?
How is it used?
What are possible side effects?
How should it be stored?
Further information

What do you have to consider before using it?

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 1.0 mg benzyl alcohol per dose of 0.2 ml and 2.5 mg benzyl alcohol per dose of 0.5 ml. 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.

How is it used?

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

Initiating treatment

When treatment is started, in order to reduce some of the side effects, it is recommended that: - During weeks one and two, Rebif 8.8 micrograms should be injected three times per week. - During weeks three and four, Rebif 22 micrograms syringe should be injected three times per week.

From the fifth week onwards, 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
Rebifis 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 syringes to administer the medicine at home. It may also be administered with a suitable auto-injector.

For administration of Rebif, please read the following instructions carefully:

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

How to inject Rebif
- Choose an injection site. Your doctor will advise you on the possible injection sites (good sites include the upper thighs and the lower abdomen). Hold the syringe like a pencil or dart. 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.
- Wash your hands thoroughly with soap and water.
- Remove the Rebif syringe from the blister pack by peeling back the plastic covering. - 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.

Gently pinch the skin together around the site to lift it up a bit. Resting your wrist on the skin near the site, stick the needle at a right angle straight into the skin with a quick, firm motion. Inject the medicine by using a slow, steady push push the plunger all the way in until the syringe is empty. Hold a swab on the injection site. Remove the needle from the skin.

Gently massage the injection site with a dry cotton ball or gauze. Dispose of all used items once you have finished your injection, immediately discard the syringe in an appropriate disposal unit.

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.

What are possible side effects?

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.

How should it be stored?

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.

Further information

What Rebif contains

The active substance is interferon beta-1a.
- Each 8.8 micrograms syringe contains 8.8 micrograms of interferon beta-1a (2.4 million IU). - Each 22 micrograms syringe contains 22 micrograms of interferon beta-1a (6 million IU). 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 8.8 micrograms is a solution for injection in a pre-filled syringe with a fixed needle for self-administration. The pre-filled syringe is ready for use and contains 0.2 ml of solution.

Rebif 22 micrograms is a solution for injection in a pre-filled syringe with a fixed needle for self-administration. The pre-filled syringe is ready for use and contains 0.5 ml of solution.

Rebif solution is clear to opalescent.

Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in an initiation pack, that is intended for use during the initial 4 weeks of treatment, during which a gradual increase in Rebif dose is recommended.

One-month treatment pack contains six Rebif 8.8 micrograms pre-filled syringes and six Rebif 22 micrograms pre-filled syringes.

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

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Lietuva
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LT-44151 Kaunas
Tel: +370 37320603

This leaflet was last approved in

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