Rebif

Package leaflet: Information for the user

Rebif 22 micrograms solution for injection in pre-filled syringe

interferon beta-1a
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may be harmful to people even if their symptoms are the same as yours.
• If you experience any side effects, including any not listed in this leaflet, inform your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit signals between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not fully understood, interferons help limit damage to the central nervous system associated with multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown effective in reducing the frequency and severity of relapses, and in slowing the progression of disability.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you are currently severely depressed.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, carefully read and follow the instructions described in "How to use Rebif" to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction), which has been reported in patients treated with Rebif. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots (thrombi) may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any of the following conditions:

• bone marrow disorders,
• kidney disease,
• liver disease,
• heart disease,
• thyroid disorders,
• a history of depression,
• a history of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other
medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor
or pharmacist before taking this medicine.
No harmful effects are expected in newborns/infants breastfed with maternal milk. Rebif may be
used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the
treatment. This issue should be discussed with your doctor if it applies to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially 'sodium-free'.
This medicine contains 2.5 mg of benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems
(gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise
recommended by your doctor or pharmacist.
Consult your doctor or pharmacist if you are pregnant or breastfeeding, or if you have liver or kidney
disease. This is because large amounts of benzyl alcohol may accumulate in the body and
cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Use this medicine exactly as prescribed by your doctor. If you have any doubts, consult your doctor.

Dose
The usual dose is 44 micrograms (12 million IU) administered three times a week. Your doctor has prescribed a lower dose of 22 micrograms (6 million IU), also administered three times a week. This lower dose is recommended for patients who do not tolerate the higher dosage.

Rebif should be administered three times a week and, if possible:

• on the same three days each week (with at least 48 hours between doses, for example, Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (from 2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.

Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.

Method of administration
Rebif must be administered subcutaneously (under the skin).
The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a family member, a friend, or a caregiver using the Rebif syringe. The product may also be administered with a compatible auto-injector.

For administering Rebif, please read the following instructions carefully:
This medicine is for single use only.
Use only a solution that is clear to opalescent, free from particles, and shows no visible signs of deterioration.

How to inject Rebif

• Choosing the injection site. Your doctor will inform you about the possible areas where the injection can be given (suitable areas are the upper thigh and the lower abdominal area). Hold the syringe like a pencil or a dart. It is recommended to keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize the risk of injection site necrosis. NOTE: do not choose an area that is hardened, lumpy, or tender; for any clarification, consult your doctor or a qualified healthcare professional.
• Wash your hands with soap and water.
• Take the Rebif syringe out of the box by lifting the plastic wrapper cover.
• Before injecting, use an alcohol swab to clean the injection site. Make sure the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

Pinch a fold of skin between your fingers at the injection site and lift it slightly.

• Rest your wrist against the skin near the injection site. Insert the needle into the skin at a right angle with a quick, firm motion.

Inject the medicine slowly and steadily (push the plunger until the syringe is completely empty).

• Place a swab over 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 materials: after completing the injection, immediately discard the syringe into a designated sharps container.

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 treatment on the day the next dose is scheduled. Do not use a double dose to make up for the missed dose.

If you stop using Rebif
The effects of Rebif may not be immediate. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first consulting your doctor.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately contact your doctor and stop treatment with Rebif if you experience any of the following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after administration of Rebif, you experience sudden difficulty breathing, which may occur together with swelling of the face, lips, tongue or throat, skin rashes, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency room. These reactions are rare (may affect up to 1 in 1,000 people).
• Immediately contact your doctor if you experience any of the following possible symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Severe liver problems may also present with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10) in patients being treated for multiple sclerosis. If you feel depressed or develop suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild in intensity and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain and skin lesions, are very common. Injection site reactions usually decrease over time. Tissue damage (necrosis), abscess and nodules at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations under "Warnings and precautions". The injection site may become infected (uncommon); the skin may become swollen, tender and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are generally not noticeable by the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells or platelets may decrease individually (very common) or all values may decrease simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be impaired (very common). Inflammation of the liver (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms such as nausea, vomiting or jaundice, contact your doctor immediately (see "Immediately contact your doctor...").
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by patients as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to those of a multiple sclerosis relapse. For example, your muscles may become very stiff or very weak, making it difficult to move as desired. Sometimes these symptoms are associated with fever or the flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10):

• Headache

Common (may affect up to 1 in 10):

• Insomnia (difficulty sleeping)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100):

• Hives (urticaria)
• Seizures
• Inflammation of the liver (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), including inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness or a feeling of emptiness in the head. Your doctor is likely to detect blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may include fever, weight loss and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or all of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a condition causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly lead to red, painful patches or nodules.

Do not stop or alter your prescribed treatment without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, contact your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in the refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental
freezing.)
The Rebif pack currently in use may be stored outside the refrigerator at a temperature not
exceeding 25°C for a single period of up to 14 days.
After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the
solution is no longer clear or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how
to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each pre-filled syringe contains 22 micrograms, equivalent to 6 million International Units (IU) of interferon beta-1a.
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and contents of the pack
Rebif is available as an injectable solution in a pre-filled syringe with a fixed needle for self-administration. The Rebif solution ranges from clear to opalescent. The pre-filled syringe is ready for use and contains 0.5 mL of solution.
Rebif is available in packs containing 1, 3, 12 and 36 pre-filled syringes. Not all pack sizes may be marketed.

Marketing Authorization Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands

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

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

Package leaflet: information for the user

Rebif 44 micrograms solution for injection in pre-filled syringe

interferon beta-1a
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances
that transmit signals between cells. Interferons are produced by the body and play an
essential role in the immune system. Through mechanisms that are not fully understood,
interferons help limit damage to the central nervous system associated with
multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural interferon beta produced
in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in
reducing the number and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first sign of multiple sclerosis.

2. What you should know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, carefully read and follow the instructions provided in "How to use Rebif" to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction), which has been reported in patients receiving Rebif. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots (thrombi) may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any of the following conditions:

• bone marrow disorders,
• kidney disease,
• liver disease,
• heart disease,
• thyroid disorders,
• a history of depression,
• a history of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on infants breastfed with maternal milk are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease or by the therapy. This issue should be discussed with your doctor if relevant to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 'sodium-free'.
This medicine contains 2.5 mg of benzyl alcohol per dose. It must not be administered to premature infants or newborns. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (less than 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Consult your doctor or pharmacist if you are pregnant, breastfeeding, or have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.

Dose

Patients who have experienced a single clinical event
The usual dose is 44 micrograms (12 million IU) administered three times a week.

Patients with multiple sclerosis
The usual dose is 44 micrograms (12 million IU) administered three times a week.
A lower dose of 22 micrograms (6 million IU), also administered three times a week, is recommended for patients who do not tolerate the higher dose.

Rebif should be administered three times a week, and if possible:

• on the same three days each week (at least 48 hours apart, e.g., Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (aged 2 to 17 years)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.

Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.

Method of administration
Rebif is administered by subcutaneous injection (under the skin).

The first injection (or first few injections) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a family member, a friend, or a caregiver using the Rebif syringe. The product may also be administered with a compatible autoinjector.

For administering Rebif, carefully read the following instructions:
This medicine is for single use only.

Only use a solution that is clear to opalescent, free from particles, and shows no visible signs of deterioration.

How to inject Rebif

• Choosing the injection site. Your doctor will inform you about the possible injection areas (suitable sites are the upper thigh and the lower abdominal area). Hold the syringe like a pencil or dart. It is recommended to keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize the risk of injection site necrosis. NOTE: do not choose an area that is hardened, lumpy, or tender; for any clarification, consult your doctor or a qualified healthcare professional.
• Wash your hands with soap and water.
• Remove the Rebif syringe from the box by lifting off the plastic wrapper cover.
• Before injecting, clean the injection site with an alcohol swab. Make sure the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

Pinch a fold of skin at the injection site between your thumb and forefinger and lift it slightly.

• Place your wrist against the skin near the injection site. Insert the needle quickly and firmly at a 90-degree angle.

Inject the medicine slowly and steadily (press the plunger until the syringe is completely empty).

• Apply a swab to 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 materials: immediately after the injection, discard the syringe into a dedicated sharps container.

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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the missed dose.

If you stop using Rebif
The effects of Rebif may not be immediately apparent. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first consulting your doctor.

If you have any doubts about how to use this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately and stop treatment with Rebif if you experience any of the
following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after administration of Rebif, you experience sudden difficulty breathing, possibly accompanied by swelling of the face, lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, contact your doctor or go immediately to a medical emergency center. These reactions are rare (may affect up to 1 in 1,000 people).

• Contact your doctor immediately if you experience any of the following possible symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.

• Depression is common (may affect up to 1 in 10 people) in patients being treated for multiple sclerosis. If you feel depressed or develop suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are generally mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. Injection site reactions usually decrease over time. Tissue destruction (necrosis), abscess, and nodule at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations under “Warnings and precautions.” The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are generally not noticeable by the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all values may decrease simultaneously (rare). Possible symptoms due to these changes may include tiredness, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be impaired (very common). Inflammation of the liver (hepatitis) has also been reported (uncommon). However, if you experience symptoms that may suggest liver problems, such as loss of appetite associated with other symptoms like nausea, vomiting, or jaundice, contact your doctor immediately (see “Contact your doctor immediately...”).
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by the patient as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to those of a multiple sclerosis relapse. For example, your muscles may become very stiff or very weak, preventing you from moving as you wish. Sometimes these symptoms are associated with fever or the flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty sleeping)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Inflammation of the liver (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor is likely to find abnormalities in your blood and kidney function.
• Drug-induced lupus erythematosus: a side effect of long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may also appear, such as fever, weight loss, and fatigue. Symptoms usually disappear within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a condition causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause a hardened skin sensation and possibly lead to red, painful patches or nodules.

Do not stop or change your prescribed treatment without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after Exp.
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental
freezing.)
The pack of Rebif in use may be stored outside the refrigerator at a temperature not exceeding 25°C
for a single period of up to 14 days.
After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution is no
longer clear or contains particles.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each pre-filled syringe 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.

Description of the appearance of Rebif and contents of the pack
Rebif is available as an injectable solution in a pre-filled syringe with a fixed needle for self-administration. The Rebif solution ranges from clear to opalescent. The pre-filled syringe is ready for use and contains 0.5 mL of solution.
Rebif is available in packs containing 1, 3, 12 and 36 pre-filled syringes. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu .

Package leaflet: Information for the user

Rebif 8.8 micrograms solution for injection in pre-filled syringe, 22 micrograms solution for injection in pre-filled syringe

interferon beta-1a
Starting Treatment Pack
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit signals between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not fully understood, interferons help limit damage to the central nervous system associated with multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown effective in reducing the frequency and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first sign of multiple sclerosis.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.

• Before starting treatment with Rebif, carefully read and follow the instructions provided in “How to use Rebif” to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction) which has been reported in patients receiving Rebif. If you have experienced problems with local reactions, contact your doctor.

• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.

• During treatment, blood clots may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any diseases of the

• bone marrow,
• kidneys,
• liver,
• heart,
• thyroid,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on infants breastfed with maternal milk are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the treatment. This issue should be discussed with your doctor if it applies to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 'sodium-free'.
This medicine contains 1.0 mg of benzyl alcohol per 0.2 mL dose and 2.5 mg of benzyl alcohol per 0.5 mL dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with a risk of serious adverse effects, including respiratory problems (gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Ask your doctor or pharmacist for advice if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor.
Starting treatment
Treatment begins with a gradual dose increase (so-called "dose titration") over 4 weeks to reduce certain unwanted effects. It is recommended:

• During weeks one and two, inject Rebif 8.8 micrograms three times a week.
• During weeks three and four, inject Rebif 22 micrograms three times a week.

From week five onwards, after completing the initial phase, you should follow the usual dosing regimen prescribed by your doctor.
Dose
The usual dose is 44 micrograms (12 million IU) three times a week.
A lower dose of 22 micrograms (6 million IU) three times a week is recommended for patients with multiple sclerosis who do not tolerate the higher dose.
Rebif should be administered three times a week, and, if possible:

• on the same three days each week (with at least 48 hours between doses, e.g., Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (aged 2 to 17 years)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration
Rebif is administered by subcutaneous injection (under the skin).
The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a family member, a friend, or a caregiver using the Rebif syringe. The product may also be administered using a compatible autoinjector.
For administering Rebif, please read the following instructions carefully:
This medicine is for single use only.
Use only a solution that is clear to opalescent, free from particles, and without visible signs of deterioration.
How to inject Rebif

Choosing the injection site. Your doctor will inform you about possible injection sites (suitable areas are the upper thigh and lower abdomen). Hold the syringe like a pencil or dart. It is recommended to keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize the risk of injection site necrosis.
NOTE: Do not choose an area that is hardened, lumpy, or tender; for any clarification, consult your doctor or a qualified healthcare professional.

• Wash your hands with soap and water.
• Take the Rebif syringe out of the box by lifting the plastic wrapper cover.
• Before injecting, use an alcohol swab to clean the injection site. Make sure the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

Pinch the skin at the injection site between your fingers and lift it
slightly.

• Place your wrist against the skin near the injection site, insert the needle into the skin at a right angle with a quick, firm motion.

• Inject the medicine slowly and steadily (press the plunger until the syringe is completely empty).
• Place a swab over 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 materials: after completing the injection, immediately discard the syringe into a designated sharps container.

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 your treatment on the day the next dose is scheduled. Do not use a double dose to make up for the missed dose.
If you stop using Rebif
The effects of Rebif may not be immediate. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first contacting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately contact your doctor and stop treatment with Rebif if you experience any of the following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after administration of Rebif, you experience sudden difficulty breathing, possibly accompanied by facial, lip, tongue or throat swelling, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency room. These reactions are rare (may affect up to 1 in 1,000 people).
• Immediately contact your doctor if you experience any of the following possible symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Severe liver problems may also present with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 people) in patients with multiple sclerosis receiving treatment. If you feel depressed or have suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.

• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. These reactions usually decrease over time. Tissue destruction (necrosis), abscess, and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations under "Warnings and precautions". The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.

• Some laboratory tests may show abnormalities. These changes are generally not noticeable to the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all values simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be altered (very common). Liver inflammation (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms such as nausea, vomiting, or jaundice, contact your doctor immediately (see "Immediately contact your doctor...").

• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by the patient as symptoms, but your doctor may recommend appropriate blood tests.

• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to a relapse of multiple sclerosis. For example, your muscles may become very stiff or very weak, making it difficult to move as desired. Sometimes these symptoms occur together with fever or flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10):

• Headache

Common (may affect up to 1 in 10):

• Insomnia (difficulty falling asleep)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100):

• Hives (urticaria)
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels, which may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor is likely to detect blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, skin rash. Other signs may include fever, weight loss, and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain
    contact your doctor, as these may be signs of possible kidney problems.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a disease causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, including several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly the formation of red, painful patches or nodules.

Do not stop or change your prescribed treatment without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental freezing.)
The Rebif pack in use may be stored outside the refrigerator at a temperature not exceeding 25°C for a single period not longer than 14 days.
After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution is no longer clear or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a.
  • Each 8.8 microgram syringe contains 8.8 micrograms of interferon beta-1a (2.4 million IU).
  • Each 22 microgram syringe contains 22 micrograms of interferon beta-1a (6 million IU).
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and contents of the pack
Rebif 8.8 micrograms is available as an injectable solution in a pre-filled syringe with a fixed needle for self-administration. The pre-filled syringe is ready to use and contains 0.2 mL of solution.
Rebif 22 micrograms is available as an injectable solution in a pre-filled syringe with a fixed needle for self-administration. The pre-filled syringe is ready to use and contains 0.5 mL of solution.
Rebif solution ranges from clear to opalescent.
Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in a starter pack, designed for use during the first 4 weeks of treatment, during which a gradual dose escalation of Rebif is recommended.
The monthly starter pack contains six pre-filled syringes of Rebif 8.8 micrograms and six pre-filled syringes of Rebif 22 micrograms.
Marketing Authorisation Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Further information
More detailed information on this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

Package leaflet: information for the user

Rebif 22 micrograms/0.5 mL solution for injection in cartridge

interferon beta-1a
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances
that transmit signals between cells. Interferons are produced by the body and play an
essential role in the immune system. Through mechanisms that are not fully
understood, interferons help limit damage to the central nervous system associated with
multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced
in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in
reducing the number and severity of relapses, and in slowing the progression of disability.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, carefully read and follow the instructions described in "How to use Rebif" to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction), which has been reported in patients treated with Rebif. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood (platelet count), and kidney function.

Inform your doctor if you have any of the following conditions:

• bone marrow disorders,
• kidney disease,
• liver disease,
• heart disease,
• thyroid disorders,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on newborns/infants breastfed are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the treatment. This should be discussed with your doctor if relevant to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 'sodium-free'.
This medicine contains 2.5 mg of benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with a risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Consult your doctor or pharmacist if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

This medicine is for multi-dose use.
Always use this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor.
Dose
The usual dose is 44 micrograms (12 million IU) administered three times a week. Your doctor has
prescribed a lower dose of 22 micrograms (6 million IU), also administered three times a week. This
lower dose is recommended for patients who do not tolerate the higher dose.
Rebif should be administered three times a week and, if possible:

• on the same three days each week (at least 48 hours apart, for example, Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (from 2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical
data are available suggesting that the safety profile in children and adolescents treated with Rebif 22
micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration

• Rebif is administered by subcutaneous injection (under the skin).
• The first administration (or first administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a family member, a friend, or a caregiver using Rebif cartridges with the provided device.
• The cartridge must be used with the RebiSmart electronic injection device.
• Detailed instructions for use are provided with the device. Follow these instructions carefully.
• Below are brief instructions for using the Rebif cartridge.

Before starting

• Wash your hands thoroughly with water and soap.
• Remove the Rebif cartridge from its blister pack by removing the plastic cover.
• Check (immediately after removing the cartridge from the refrigerator) that the cartridge has not accidentally frozen inside the packaging or within the device. Only use solutions that are clear or opalescent, free from particles, and without visible signs of deterioration.
• To insert the cartridge into the device and perform the injection, follow the instruction manual (Instructions for Use) provided with the device.

Where to inject Rebif

• Choosing the injection site. Your doctor will inform you about suitable areas for injection (appropriate sites include the upper thigh and lower abdomen). It is recommended to keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize the risk of injection site necrosis.
• NOTE: do not choose an area that is hardened, lumpy, or painful; for any clarification, consult your doctor or a qualified healthcare professional.
• Before injection, use an alcohol swab to clean the skin at the injection site. Wait until the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

How to inject Rebif

• Your doctor will advise you on how to select the correct dose of 22 micrograms. Also read the instructions provided in the manual supplied with the device (RebiSmart).

RebiSmart • Before injection, check that the dose displayed on the device screen corresponds to the prescribed dose of 22 micrograms.

• Position RebiSmart at a right angle (90°) to the skin.
• Press the injection button. During injection, the button emits a flashing light.
• Wait for the light to go off. This indicates that the injection is complete.
• Remove RebiSmart from the injection site.

After injecting Rebif with RebiSmart

• Remove and dispose of the needle according to the instructions in the manual provided with the device.
• Gently massage the injection site with a dry cotton ball or gauze.
• Store the device containing a Rebif cartridge as indicated in section 5 “How to store Rebif”.

If you have any doubts, consult your doctor, nurse, or pharmacist.
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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the missed dose.
If you stop using Rebif
The effects of Rebif may not be immediate. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first contacting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
Contact your doctor immediately and stop treatment with Rebif if you experience any of the
following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after receiving Rebif, you experience sudden difficulty breathing, possibly accompanied by swelling of the face, lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical help or go to the nearest emergency medical centre. These reactions are rare (may affect up to 1 in 1,000 people).
• Contact your doctor immediately if you experience any of the following symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and increased tendency to bruise. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 people) in patients being treated for multiple sclerosis. If you feel depressed or have thoughts of suicide, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administering a dose of Rebif and 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. These reactions usually decrease over time. Tissue damage (necrosis), abscess, and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations in “Warnings and precautions”. The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are usually not noticeable by the patient (no symptoms), are generally reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all values may decrease simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be altered (very common). Inflammation of the liver (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms like nausea, vomiting, or jaundice, contact your doctor immediately (see “Contact your doctor immediately...”).
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by patients as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to a relapse of multiple sclerosis. For example, your muscles may become very stiff or very weak, making it difficult to move as you wish. Sometimes these symptoms are associated with fever or flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty falling asleep)
• Diarrhoea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Inflammation of the liver (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor is likely to find blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may include fever, weight loss, and fatigue. Symptoms usually disappear within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a disease causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly lead to the formation of red, painful patches or nodules.

Do not stop or change your prescribed dose without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in the refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment to avoid accidental freezing.)
Use within 28 days of the first injection.
The device (RebiSmart) containing a prefilled Rebif cartridge must be stored in its carrying case in the refrigerator (2°C–8°C). The used Rebif pack may be kept outside the refrigerator at a temperature not exceeding 25°C for one single period not exceeding 14 days. After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution in the cartridge is no longer clear and colourless or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each cartridge contains 66 micrograms, corresponding to 18 million International Units (IU) of interferon beta-1a.
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and contents of the pack
Pre-filled cartridge (type 1 glass), with a plunger stopper (rubber) and a crimp-sealed cap (aluminium and bromobutyl rubber), containing 1.5 mL of injectable solution. Packs of 4 or 12 cartridges. Not all pack sizes may be marketed.
The cartridge must be used with the RebiSmart electronic injection device. This device is supplied separately.
Marketing Authorization Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu .

Package leaflet: information for the user

Rebif 44 micrograms/0.5 mL solution for injection in cartridge

interferon beta-1a
Please read this entire leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances
that transmit signals between cells. Interferons are produced by the body and play an
essential role in the immune system. Through mechanisms that are not fully
understood, interferons help limit damage to the central nervous system associated with
multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural interferon beta produced
in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in
reducing the number and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first sign of multiple sclerosis.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, carefully read and follow the instructions described in "How to use Rebif" to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction), which has been reported in patients receiving Rebif. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any of the following conditions:

• bone marrow disorders,
• kidney disease,
• liver disease,
• heart disease,
• thyroid disorders,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
No harmful effects on newborns/infants breastfed with maternal milk are expected. Rebif may be
used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the therapy. This should be discussed with your doctor if relevant to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially 'sodium-free'.
This medicine contains 2.5 mg of benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (less than 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Ask your doctor or pharmacist for advice if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

This medicine is for multi-dose use.
Always use this medicine exactly as your doctor has instructed. If you have any doubts, consult your
doctor.
Dose
Patients who have experienced a single clinical event
The usual dose is 44 micrograms (12 million IU) administered three times a week.
Patients with multiple sclerosis
The usual dose is 44 micrograms (12 million IU) administered three times a week.
A lower dose of 22 micrograms (6 million IU), also administered three times a week, is recommended for
patients who do not tolerate the higher dose.
Rebif should be administered three times a week, and, if possible:

• on the same three days each week (at least 48 hours apart, for example, Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data
are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration

• Rebif is to be administered subcutaneously (under the skin).
• The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a relative, a friend, or a caregiver using Rebif cartridges with the supplied device.
• The cartridge must be used with the RebiSmart electronic injection device.
• Detailed instructions for use are provided with the device. Follow these instructions carefully.
• Below are brief instructions on how to use the Rebif cartridge.

Before starting

• Wash your hands thoroughly with soap and water.
• Remove the Rebif cartridge from its blister pack by peeling off the plastic cover.
• Check (immediately after removing the cartridge from the refrigerator) that the cartridge has not accidentally frozen either in the packaging or inside the device. Only use solutions that are clear or opalescent, free from particles, and show no visible signs of deterioration.
• To insert the cartridge and administer the injection, follow the instructions manual (Instructions for Use) provided with the device.

Where to inject Rebif

Selection of injection site. Your doctor will inform you about
possible injection sites (suitable areas include the upper thigh and lower abdomen). It is
recommended to keep a record and rotate injection sites so that the same area is not used too
frequently, in order to minimize the risk of injection site necrosis.

• NOTE: do not select an area that is hardened, lumpy, or tender; for any clarification, consult your doctor or a qualified healthcare professional.
• Before injection, use an alcohol swab to clean the skin at the injection site. Wait until the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

How to inject Rebif

• Your doctor will instruct you on how to select the correct dose of 44 micrograms. Also read the instructions provided in the manual accompanying the device (RebiSmart).

RebiSmart • Before injection, check that the dose displayed on the device screen corresponds to the prescribed dose of 44 micrograms.

• Place RebiSmart at a right angle (90°) against the skin.
• Press the injection button. During injection, a light on the button will flash.
• Wait until the light turns off. This indicates that the injection is complete.
• Remove RebiSmart from the injection site.

After injecting Rebif with RebiSmart

• Remove and dispose of the needle according to the instructions manual provided with the device.
• Gently massage the injection site with a dry cotton ball or gauze.
• Store the device containing a Rebif cartridge as indicated in section 5 “How to store Rebif”.

If you have any doubts, consult your doctor, nurse, or pharmacist.
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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the missed dose.
If you stop using Rebif
The effects of Rebif may not be immediately apparent. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the treatment, consult your doctor.
Do not stop treatment without first contacting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately and stop treatment with Rebif if you experience any of the
following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after receiving Rebif, you experience sudden difficulty breathing, possibly accompanied by swelling of the face, lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, contact your doctor or go to a medical emergency centre immediately. These reactions are rare (may affect up to 1 in 1,000 people).
• Contact your doctor immediately if you experience any of the following possible symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 people) in patients with multiple sclerosis receiving treatment. If you feel depressed or have suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing as treatment continues. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.
• Injection site reactions such as redness, swelling, depigmentation, inflammation, pain and skin lesions are very common. These reactions usually decrease over time. Tissue damage (necrosis), abscess and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimise the risk of injection site reactions, read the recommendations in “Warnings and precautions”. The injection site may become infected (uncommon); the skin may become swollen, tender and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are generally not noticeable to the patient (no symptoms), are usually reversible and mild to moderate, and often do not require specific treatment. The number of red blood cells, white blood cells or platelets may decrease individually (very common) or all values may decrease simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be impaired (very common). Inflammation of the liver (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms such as nausea, vomiting or jaundice, contact your doctor immediately (see “Contact your doctor immediately...”).
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticeable to the patient as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to those of a multiple sclerosis relapse. For example, your muscles may become very stiff or very weak, preventing you from moving as you wish. Sometimes these symptoms are associated with fever or the flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty sleeping)
• Diarrhoea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Inflammation of the liver (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye) such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some involving mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness or a feeling of emptiness in the head. Your doctor may detect blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may include fever, weight loss and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a disease causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause a hardened skin sensation and possibly the formation of red, painful patches or nodules.

Do not stop or change your prescribed treatment without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment to avoid accidental
freezing.)
Use within 28 days after the first injection.
The device (RebiSmart) containing a prefilled cartridge of Rebif should be stored in its case in the
refrigerator (2°C–8°C). The Rebif pack in use may be kept outside the refrigerator at a temperature not
exceeding 25°C for a single period of up to 14 days. After this, Rebif must be returned to the
refrigerator and used before the expiry date.
Store in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution in
the cartridge is no longer clear and colourless or if it contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose
of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each pre-filled cartridge contains 132 micrograms, equivalent to 36 million International Units (IU) of interferon beta-1a.
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injectable preparations.

Description of the appearance of Rebif and package contents
Pre-filled cartridge (type 1 glass), with a rubber plunger stopper and an aluminium and bromobutyl rubber screw cap, containing 1.5 mL of injectable solution. Pack sizes of 4 or 12 cartridges. Not all pack sizes may be marketed.
The cartridge must be used with the RebiSmart electronic injection device. This device is supplied separately.

Marketing Authorization Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands

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

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

Patient Information Leaflet: Information for the User

Rebif 8.8 micrograms/0.1 mL solution for injection in cartridge, 22 micrograms/0.25 mL solution for injection in cartridge

interferon beta-1a
Starting pack
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit signals between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not fully understood, interferons help limit damage to the central nervous system associated with multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in reducing the frequency and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first manifestation of multiple sclerosis.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, carefully read and follow the instructions described in "How to use Rebif" to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction) which has been reported in patients receiving Rebif. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots (thrombi) may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count) and kidney function.

Inform your doctor if you have any diseases of the:

• bone marrow,
• kidneys,
• liver,
• heart,
• thyroid,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on infants breastfed with mother's milk are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the treatment. This should be discussed with your doctor if it affects you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially 'sodium-free'.
This medicine contains 0.5 mg of benzyl alcohol per 0.1 mL dose and 1.25 mg of benzyl alcohol per 0.25 mL dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Ask your doctor or pharmacist for advice if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

This medicinal product is for multi-dose use.
Always use this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor.
Starting treatment
Treatment begins with a gradual dose increase (so-called "dose titration") over 4 weeks to reduce certain side effects. It is recommended that:

• During weeks one and two, inject Rebif 8.8 micrograms three times a week.
• During weeks three and four, inject Rebif 22 micrograms three times a week.

From week five onwards, after completion of the initial period, follow the usual dosing regimen prescribed by your doctor.
Dosage
The usual dose is 44 micrograms (12 million IU) three times a week.
A lower dose of 22 micrograms (6 million IU) three times a week is recommended for patients with multiple sclerosis who do not tolerate the higher dose.
Rebif must be administered three times a week, and, if possible:

• on the same three days each week (with at least 48 hours between doses, e.g. Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration

• Rebif is to be administered subcutaneously (under the skin).
• The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, the medicine may be self-administered at home by you, a relative, a friend, or a caregiver using Rebif cartridges with the supplied device.
• The starter pack contains two identical Rebif cartridges: you may start treatment with either of these cartridges.
• The cartridge must be used with the RebiSmart electronic injection device.
• Detailed instructions for use are provided with the device. Follow these instructions carefully.
• Below are brief instructions for using the Rebif cartridge.

Before starting

• Wash your hands thoroughly with soap and water.

• Remove the Rebif cartridge from its blister pack by taking off the plastic cover.

• Check (immediately after removing the cartridge from the refrigerator) that the cartridge has not accidentally frozen either inside the packaging or within the device. Only use solutions that are clear or opalescent, free from particles, and show no visible signs of deterioration.

• To insert the cartridge into the device and administer the injection, follow the instruction manual (Instructions for Use) provided with the device.

Where to inject Rebif

Choosing the injection site. Your doctor will inform you about
possible injection sites (suitable areas include the upper thigh and lower abdomen). It is
recommended that you keep a record and rotate injection sites so that the same area is not used too
frequently, in order to minimize the risk of injection site necrosis.

• NOTE: do not select an area that is hardened, lumpy, or tender; consult your doctor or a qualified healthcare professional for any clarification.
• Before injection, clean the skin at the injection site with an alcohol swab. Wait until the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

How to inject Rebif

• Your doctor will instruct you on how to select the correct dose. Also read the instructions provided in the manual supplied with the device (RebiSmart).

RebiSmart • RebiSmart is programmed to guide you through the entire
initiation process and automatically increases the dose during the
initial phase. The device will also alert you when it is time to change the
cartridge.

• You or your doctor must set the prescribed dose using the RebiSmart menu so that the correct dose is recorded.
• To activate the "initial dose" menu, you or your doctor must first set the "cartridge" to "44 mcg", then select 'initial dose', set it to 'on', and confirm 'initial dose yes' by pressing 'ok'.
• The device will ensure that:
  • during weeks one and two, 8.8 micrograms of Rebif are injected three times a week.
  • during weeks three and four, 22 micrograms of Rebif are injected three times a week.
  • from week five onwards, RebiSmart will automatically switch to the usual dosing regimen.
• Position RebiSmart at a right angle (90°) against the skin.
• Press the injection button. During injection, the button will flash.
• Wait until the light turns off. This indicates that the injection is complete.
• Remove RebiSmart from the injection site.

After injecting Rebif with RebiSmart

• Remove and dispose of the needle according to the instructions provided in the device manual.
• Gently massage the injection site with a dry cotton ball or gauze.
• Store the device containing a Rebif cartridge as indicated in section 5, “How to store Rebif”.

If you have any doubts, consult your doctor, nurse, or pharmacist.
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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the missed dose.
If you stop using Rebif
The effects of Rebif may not be immediately apparent. Therefore, do not stop treatment with Rebif but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first consulting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
Contact your doctor immediately and stop treatment with Rebif if you experience any of the
following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after receiving Rebif, you experience sudden difficulty breathing, which may occur together with swelling of the face, lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency medical centre. These reactions are rare (may affect up to 1 in 1,000 people).
• Contact your doctor immediately if you experience any of the following possible symptoms of liver problems: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Serious liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 patients) in patients being treated for multiple sclerosis. If you feel depressed or have suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain and skin lesions, are very common. These reactions usually decrease over time. Tissue damage (necrosis), abscess and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people).

To minimise the risk of injection site reactions, read the recommendations in
"Warnings and precautions".
The injection site may become infected (uncommon); the skin may become swollen, tender and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.

• Some laboratory tests may show abnormalities. These changes are generally not noticeable by the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. There may be a decrease in the number of red blood cells, white blood cells or platelets individually (very common) or all values simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be altered (very common). Liver inflammation (hepatitis) has also been reported (uncommon). However, if you experience symptoms that may indicate liver problems, such as loss of appetite associated with other symptoms such as nausea, vomiting or jaundice, contact your doctor immediately (see "Contact your doctor immediately...").
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely experienced by the patient as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to a relapse of multiple sclerosis. For example, your muscles may become very stiff or very weak, preventing you from moving as you wish. Sometimes these symptoms are associated with fever or flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty sleeping)
• Diarrhoea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Urticaria (hives)
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye) such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels which may affect the kidneys (thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness or a feeling of emptiness in the head. Your doctor is likely to find blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may also occur, such as fever, weight loss and fatigue. Symptoms usually disappear within one or two weeks after stopping treatment.
• Kidney problems, including scarring, which may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain, contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a condition causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the blood vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fatty tissue (panniculitis), which may cause a hardened feeling of the skin and may lead to the formation of red, painful patches or nodules.

Do not stop or change your prescribed dose without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care to avoid placing the product near the freezer compartment to prevent accidental freezing.)
Use within 28 days of the first injection.
The device (RebiSmart) containing a prefilled cartridge of Rebif should be stored in its original case in the refrigerator (2°C–8°C). The Rebif pack in use may be kept outside the refrigerator at a temperature not exceeding 25°C, for one single period not exceeding 14 days. After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution in the cartridge is no longer clear and colourless or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each cartridge contains 132 micrograms, equivalent to 36 million International Units (IU) of interferon beta-1a.
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and contents of the pack
Prefilled cartridge (type 1 glass), with a plunger stopper (rubber) and a screw cap (aluminium and halobutyl rubber), containing 1.5 mL of injectable solution. Pack containing 2 cartridges.
The cartridge must be used with the RebiSmart electronic injection device. This device is supplied separately.
Marketing Authorization Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu .

Patient Information Leaflet: Information for the User

Rebif 22 micrograms solution for injection in a pre-filled pen

interferon beta-1a
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances
that transmit signals between cells. Interferons are produced by the body and play an
essential role in the immune system. Through mechanisms that are not fully
understood, interferons help limit damage to the central nervous system associated with
multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced
in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in
reducing the frequency and severity of relapses, and in slowing the progression of disability.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction) reported in patients treated with Rebif, carefully read and follow the instructions provided in the "RebiDose User Instructions" supplied separately. If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any of the following conditions:

• bone marrow disorders,
• kidney disease,
• liver disease,
• heart disease,
• thyroid disorders,
• a history of depression,
• a history of seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on newborns/infants breastfed are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease or by the treatment. Discuss this with your doctor if it affects you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially "sodium-free".
This medicine contains 2.5 mg of benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Ask your doctor or pharmacist for advice if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor.
Dose
The usual dose is 44 micrograms (12 million IU) administered three times a week. Your doctor has
prescribed you a lower dose of 22 micrograms (6 million IU), also administered three times a week. This
lower dose is recommended for patients who do not tolerate the higher dosage.
Rebif should be administered three times a week, and, if possible:

• on the same three days each week (at least 48 hours apart, for example, Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (from 2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data
are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration

• Rebif should be administered by subcutaneous injection (under the skin) using the prefilled pen called “RebiDose”.
• Each RebiDose is for single use only.
• The first administration (or first administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, you, a relative, a friend, or a caregiver may administer the medicine at home using the prefilled pen of Rebif.
• Before use, read carefully the instructions provided in the “RebiDose User Manual” supplied separately.

Use only a solution that is clear to opalescent, without particles or visible signs of deterioration.
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 treatment on the day the next dose is scheduled. Do not use a double dose to make up for the missed dose.
If you stop using Rebif
The effects of Rebif may not be immediate. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first contacting your doctor.
If you have any questions about the use of this medicine, ask your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately contact your doctor and stop treatment with Rebif if you experience any of the
following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after receiving Rebif, you experience sudden difficulty breathing, possibly accompanied by swelling of the face, lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency room. These reactions are rare (may affect up to 1 in 1,000 people).
• Immediately contact your doctor if you experience any of the following symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, or easy bruising. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 patients) in people with multiple sclerosis receiving treatment. If you feel depressed or have suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before each dose of Rebif and again 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. These reactions usually decrease over time. Tissue damage (necrosis), abscess, or nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, follow the recommendations in section “Warnings and precautions”. The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are generally asymptomatic (not noticeable to the patient), usually reversible and mild, and often do not require specific treatment. There may be a decrease in red blood cells, white blood cells, or platelets individually (very common) or all values simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising, or bleeding. Liver function may be altered (very common). Liver inflammation (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms like nausea, vomiting, or jaundice, contact your doctor immediately (see “Immediately contact your doctor...”).
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticeable to the patient as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to a relapse of multiple sclerosis. For example, your muscles may become very stiff or very weak, making it difficult to move as desired. Sometimes these symptoms are associated with fever or flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty sleeping)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), including inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some involving mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor is likely to detect blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs such as fever, weight loss, and fatigue may also occur. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a condition causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the blood vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, including several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly lead to painful red patches or nodules.

Do not stop or change your prescribed dose without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in the refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental freezing.)
The Rebif pack in use may be stored outside the refrigerator at a temperature not exceeding 25°C for a single period not exceeding 14 days.
After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution is no longer clear or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Rebif contains

• The active substance is interferon beta-1a. Each pre-filled pen contains 22 micrograms, equivalent to 6 million International Units (IU) of interferon beta-1a.
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and contents of the pack
Rebif is available as an injectable solution in a pre-filled pen for self-administration. The
Rebif solution ranges from clear to opalescent. The pre-filled pen is ready to use and contains
0.5 mL of solution.
Rebif is available in packs containing 1, 3 or 12 pre-filled pens (RebiDose). Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, http://www.ema.europa.eu .

Instructions for Use of RebiDose

HOW TO USE REBIF PREFILLED PEN (RebiDose)

• This section explains how to use RebiDose.
• Rebif must be administered by subcutaneous injection (under the skin).
• Each RebiDose is for single use only.
• The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, you, a family member, friend, or caregiver may administer the medication at home using RebiDose. If you have any questions about the injection, consult your doctor, nurse, or pharmacist.
• Read the instructions below carefully before using RebiDose.

Materials Needed
To perform the self-injection, you will need:

• a new RebiDose
• alcohol swabs or similar
• a dry cotton ball or gauze pad.

The following figure shows the components of RebiDose.
Before injection

After injection

A. Cap
B. Transparent window
C. Plunger
D. Label
E. Main body
F. Button
G. Protective cylinder
H. Needle

Before Starting

• Wash your hands thoroughly with soap and water.
• Remove RebiDose from its packaging after removing the plastic cover.
• Check the appearance of Rebif through the transparent window. The solution should be clear to opalescent, free from particles and any visible signs of deterioration. If particles or other visible signs of deterioration are present, do not use the solution and consult your doctor, nurse, or pharmacist.
• Check the expiration date printed on the RebiDose label or packaging (marked as “Exp.”). Do not use RebiDose if the expiration date has passed.

Where to Inject RebiDose

Choosing the injection site. Your doctor will inform you of
the possible areas for injection (suitable areas are the upper
thigh and lower abdomen).

• Keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize skin damage (necrosis).
• NOTE: Do not select an area that is hardened, lumpy, or tender; consult your doctor or a qualified healthcare professional for any clarification.

How to Inject RebiDose

• Do not remove the cap until you are ready to administer the injection.
• Before injection, use an alcohol swab to clean the injection site. Ensure the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

• Hold RebiDose in one hand, gripping the main body, and with the other hand remove the cap.
• Place RebiDose at the injection site at a right angle (90 degrees). Push the pen against the skin until you feel resistance. This action unlocks the button.

While maintaining adequate pressure on the skin, press the
button with your thumb. You will hear a click indicating the
start of the injection, and the plunger will begin to move.
Keep RebiDose pressed against the skin for at least 10 seconds
to ensure the full dose is delivered.
After the injection has started, it is no longer necessary to
keep pressing the button with your thumb.

Remove RebiDose from the injection site.
The protective cylinder will automatically cover the needle and
lock into place, protecting you from needlestick injury.
After Injection

Check through the transparent window to make sure
the plunger has moved downward, as shown in the figure.

• Check whether any liquid remains. If liquid is visible, not all the medication has been injected; in this case, consult your doctor or nurse.
• Gently massage the injection site with a dry cotton ball or gauze pad.
• Never replace the protective needle cap on a used RebiDose. The needle is covered by the protective cylinder. Never insert your fingers into the protective cylinder.
• RebiDose is for single use only and must never be reused.
• After completing the injection, dispose of RebiDose immediately. Ask your pharmacist how to properly dispose of RebiDose.

For further information, consult your doctor, nurse, or pharmacist.
These Instructions for Use were last updated on:

Package leaflet: information for the user

Rebif 44 micrograms solution for injection in pre-filled pen

interferon beta-1a
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances that transmit signals between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not fully understood, interferons help limit damage to the central nervous system associated with multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural beta interferon produced in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in reducing the number and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first sign of multiple sclerosis.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Rebif.

• Rebif must only be used under the supervision of a doctor.
• Before starting treatment with Rebif, to reduce the risk of necrosis at the injection site (skin lesions and tissue destruction) reported in patients treated with Rebif, carefully read and follow the instructions provided in the separate "RebiDose User Instructions". If you have experienced problems with local reactions, contact your doctor.
• Talk to your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.
• During treatment, blood clots may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any diseases of the:

• bone marrow,
• kidneys,
• liver,
• heart,
• thyroid,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on newborns/infants breastfed are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease itself or by the therapy. Discuss this with your doctor if it applies to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially 'sodium-free'.
This medicine contains 2.5 mg of benzyl alcohol per dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects, including breathing problems (gasping syndrome), in young children.
Do not use for more than one week in young children (under 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Ask your doctor or pharmacist for advice if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your
doctor.
Dose
Patients who have experienced a single clinical event
The usual dose is 44 micrograms (12 million IU) administered three times a week.
Patients with multiple sclerosis
The usual dose is 44 micrograms (12 million IU) administered three times a week.
A lower dose of 22 micrograms (6 million IU), also administered three times a week, is recommended for
patients who do not tolerate the higher dose.
Rebif should be administered three times a week and, if possible:

• on the same three days each week (at least 48 hours apart, for example Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (from 2 to 17 years of age)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data
are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.
Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.
Method of administration

• Rebif should be administered by subcutaneous injection (under the skin) using the pre-filled pen called “RebiDose”.
• Each RebiDose is for single use only.
• The first administration (or first administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, you, a relative, a friend, or a caregiver may administer the medicine at home using the pre-filled pen of Rebif.
• Before use, read carefully the instructions provided in the “RebiDose User Instructions” supplied separately.

Only use a solution that is clear to opalescent, without visible particles or signs of deterioration.
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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the forgotten dose.
If you stop using Rebif
The effects of Rebif may not be immediately apparent. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of the therapy, consult your doctor.
Do not stop treatment without first contacting your doctor.
If you have any questions about the use of this medicine, consult your doctor, pharmacist, or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will get them.
Immediately contact your doctor and stop treatment with Rebif if you experience any of the following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after receiving Rebif, you experience sudden difficulty breathing, possibly accompanied by facial, lip, tongue or throat swelling, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency medical center. These reactions are rare (may affect up to 1 in 1,000 people).
• Immediately contact your doctor if you experience any of the following possible symptoms indicating a liver problem: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, or easy bruising. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 people) in patients with multiple sclerosis receiving treatment. If you feel depressed or develop suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.

• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. These reactions usually decrease over time. Tissue damage (necrosis), abscess, and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations under "Warnings and precautions." The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.

• Some laboratory tests may show abnormalities. These changes are generally not noticeable to the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all values simultaneously (rare). Possible symptoms related to these changes may include fatigue, reduced ability to fight infections, unexplained bruising, or bleeding. Liver function may be altered (very common). Liver inflammation (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms like nausea, vomiting, or jaundice, contact your doctor immediately (see "Contact your doctor immediately...").

• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by patients as symptoms, but your doctor may recommend appropriate blood tests.

• Pseudo relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to a relapse of multiple sclerosis. For example, your muscles may become very stiff or very weak, making it difficult to move as desired. Sometimes these symptoms are associated with fever or flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty falling asleep)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some involving mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor may detect blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may include fever, weight loss, and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • foamy urine
  • fatigue
  • swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for beta interferon (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a condition causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the blood vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, including several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly lead to red, painful patches or nodules.

Do not stop or change your prescribed dose without first consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental freezing.)
The Rebif pack in use may be kept outside the refrigerator at a temperature not exceeding 25°C for a single period of up to 14 days.
After this period, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example, if the solution is no longer clear or contains particles.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Rebif contains

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

Description of the appearance of Rebif and contents of the pack
Rebif is available as an injectable solution in a pre-filled pen for self-administration.
The Rebif solution ranges from clear to opalescent. The pre-filled pen is ready for use and contains 0.5 mL of solution.
Rebif is available in packs containing 1, 3 or 12 pre-filled pens (RebiDose). Not all pack sizes may be marketed.
Marketing Authorization Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands
Manufacturer
Merck Serono S.p.A.
Via delle Magnolie 15
I-70026 Modugno (Bari)
Italy
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

Instructions for Use of RebiDose

HOW TO USE REBIF PRE-FILLED PEN (RebiDose)

• This section explains how to use RebiDose.
• Rebif must be administered by subcutaneous injection (under the skin).
• Each RebiDose is for single use only.
• The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, you, a family member, friend, or caregiver may administer the medication at home using RebiDose. If you have any questions about the injection, consult your doctor, nurse, or pharmacist.
• Read carefully the instructions below before using RebiDose.

Materials Needed
To perform the self-injection, you will need:

• a new RebiDose
• alcohol swabs or similar
• a dry cotton ball or gauze.

The following figure shows the components of RebiDose.
Before injection

After injection

A. Cap
B. Transparent window
C. Plunger
D. Label
E. Main body
F. Button
G. Protective sleeve
H. Needle

Before Starting

• Wash your hands thoroughly with soap and water.
• Remove RebiDose from its packaging after removing the plastic cover.
• Check the appearance of Rebif through the transparent window. The solution should be clear to opalescent, free from particles and any visible signs of deterioration. If particles or other visible signs of deterioration are present, do not use the solution and consult your doctor, nurse, or pharmacist.
• Check the expiration date printed on the RebiDose label or packaging (indicated as “Exp.”). Do not use RebiDose if the expiration date has passed.

Where to Inject RebiDose

Choosing the injection site. Your doctor will inform you about
possible injection sites (suitable areas are the upper thigh and lower abdomen).

• Keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize skin damage (necrosis).
• NOTE: do not select an area that is hardened, lumpy, or tender; consult your doctor or a qualified healthcare professional for any clarification.

How to Inject RebiDose

• Do not remove the cap until you are ready to perform the injection.
• Before injection, use an alcohol swab to clean the injection site. Make sure the skin is dry. If some alcohol remains on the skin, you may feel a stinging sensation.

• Hold RebiDose in one hand, gripping the main body, and with the other hand remove the cap.
• Place RebiDose against the injection site at a right angle (90 degrees). Push the pen against the skin until you feel resistance. This action unlocks the button.

While maintaining sufficient pressure on the skin, press the
button with your thumb. You will hear a click, indicating the start
of the injection, and the plunger will begin to move. Keep
RebiDose pressed against the skin for at least 10 seconds to
ensure the full dose is delivered.
After the injection has started, it is no longer necessary to keep
the button pressed with your thumb.

Remove RebiDose from the injection site.
The protective sleeve will automatically cover the needle and
lock into place to protect you from needlestick injury.
After Injection

Check through the transparent window to make sure that the
plunger has moved downward, as shown in the figure.

• Check that no liquid remains. If liquid is visible, the full dose has not been administered; in this case, consult your doctor or nurse.
• Gently massage the injection site with a dry cotton ball or gauze.
• Never recap the needle by replacing the protective cap on a used RebiDose. The needle is covered by the protective sleeve. Never insert your fingers into the protective sleeve.
• RebiDose is for single use only and must never be reused.
• After completing the injection, dispose of RebiDose immediately. Ask your pharmacist how to properly dispose of RebiDose.

For further information, consult your doctor, nurse, or pharmacist.
These Instructions for Use were last updated in:

Patient Information Leaflet: Information for the User

Rebif 8.8 micrograms injectable solution in pre-filled pen, 22 micrograms injectable solution in pre-filled pen

interferon beta-1a
Starting treatment pack
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Rebif is and what it is used for
2. What you need to know before using Rebif
3. How to use Rebif
4. Possible side effects
5. How to store Rebif
6. Contents of the pack and other information

1. What Rebif is and what it is used for

Rebif belongs to a class of medicines known as interferons. These are natural substances
that transmit signals between cells. Interferons are produced by the body and play an
essential role in the immune system. Through mechanisms that are not fully
understood, interferons help to limit damage to the central nervous system associated with
multiple sclerosis.
Rebif is a highly purified, soluble protein that is similar to the natural interferon beta produced
in the human body.
Rebif is indicated for the treatment of multiple sclerosis. Treatment has been shown to be effective in
reducing the number and severity of relapses, and in slowing the progression of disability. Its use is also approved in patients who have experienced a single clinical event considered to be a probable first sign of multiple sclerosis.

2. What you need to know before using Rebif

Do not use Rebif

• if you are allergic to natural or recombinant interferon beta or to any of the other ingredients of this medicine (listed in section 6),
• if you currently have severe depression.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Rebif.

• Rebif must only be used under medical supervision.

• Before starting treatment with Rebif, to reduce the risk of injection site necrosis (skin lesions and tissue destruction) reported in patients treated with Rebif, carefully read and follow the instructions provided in the separately supplied “RebiDose User Manual”. If you have experienced problems with local reactions, contact your doctor.

• Consult your doctor or pharmacist before taking Rebif if you are allergic (hypersensitive) to any other medicine.

• During treatment, blood clots (thrombi) may form within small blood vessels. These clots could affect the kidneys. Clot formation may occur from several weeks to several years after starting treatment with Rebif. Your doctor may decide to monitor your blood pressure, blood counts (platelet count), and kidney function.

Inform your doctor if you have any diseases of the

• bone marrow,
• kidneys,
• liver,
• heart,
• thyroid,
• if you have had episodes of depression,
• if you have had episodes of epileptic seizures, so that your doctor can closely monitor your treatment and any worsening of these conditions.

Other medicines and Rebif
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
In particular, you must inform your doctor if you are taking antiepileptic or antidepressant medicines.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
No harmful effects on infants breastfed with maternal milk are expected. Rebif may be used during breastfeeding.

Driving and using machines
Your ability to drive or operate machinery may be impaired either by the underlying disease or by the treatment. This issue should be discussed with your doctor if relevant to you.

Rebif contains sodium and benzyl alcohol
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially 'sodium-free'.
This medicine contains 1.0 mg of benzyl alcohol per 0.2 mL dose and 2.5 mg of benzyl alcohol per 0.5 mL dose. Benzyl alcohol may cause allergic reactions.
Benzyl alcohol has been associated with the risk of serious adverse effects including breathing problems (gasping syndrome) in young children.
Do not use for more than one week in young children (less than 3 years of age) unless otherwise recommended by your doctor or pharmacist.
Consult your doctor or pharmacist if you are pregnant or breastfeeding, or if you have liver or kidney disease. This is because large amounts of benzyl alcohol may accumulate in the body and cause adverse effects (such as metabolic acidosis).

3. How to use Rebif

Always use this medicine exactly as instructed by your doctor. If you have any doubts, please consult your doctor.

Starting treatment
Treatment begins with a gradual increase in dose (the so-called "dose titration") over 4 weeks in order to reduce certain unwanted effects. It is recommended that:

• During weeks one and two, Rebif 8.8 micrograms is injected three times a week.
• During weeks three and four, Rebif 22 micrograms is injected three times a week.

From week five onwards, after completing the initial phase, you should follow the usual dosing regimen.

Dosage
The usual dose is 44 micrograms (12 million IU) three times a week.
A lower dose of 22 micrograms (6 million IU), three times a week, is recommended for patients with multiple sclerosis who do not tolerate the higher dose.
Rebif should be administered three times a week, and, if possible:

• on the same three days each week (at least 48 hours apart, e.g. Monday, Wednesday, Friday)
• at the same time of day (preferably in the evening).

Use in children and adolescents (aged 2 to 17 years)
Formal clinical studies have not been conducted in children or adolescents. However, some clinical data are available suggesting that the safety profile in children and adolescents treated with Rebif 22 micrograms or Rebif 44 micrograms three times a week is similar to that observed in adults.

Use in children (under 2 years of age)
The use of Rebif is not recommended in children under 2 years of age.

Method of administration

• Rebif should be administered by subcutaneous injection (under the skin) using the pre-filled pen called "RebiDose".
• Each RebiDose is for single use only.
• The first administration (or first few administrations) should be performed under the supervision of a qualified healthcare professional. After adequate training, you yourself, a relative, a friend, or a caregiver may administer the medicine at home using the pre-filled pen.
• Before use, read carefully the instructions provided in the "RebiDose Instructions for Use", supplied separately.

Only use a solution that is clear to opalescent, without particles or visible signs of deterioration.

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 treatment on the day when the next dose is scheduled. Do not use a double dose to make up for the missed dose.

If you stop treatment with Rebif
The effects of Rebif may not be immediate. Therefore, do not stop treatment with Rebif, but continue regularly to achieve the desired results. If you have any doubts about the benefits of your therapy, consult your doctor.
Do not stop treatment without first contacting your doctor.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Immediately contact your doctor and stop treatment with Rebif if you experience any of the following serious side effects:

• Severe allergic reactions (hypersensitivity). If, shortly after administration of Rebif, you experience sudden difficulty breathing, possibly associated with facial swelling, swelling of the lips, tongue or throat, skin rash, itching all over the body, or a feeling of weakness or fainting, seek immediate medical attention or go to the nearest emergency medical center. These reactions are rare (may affect up to 1 in 1,000 people).
• Immediately contact your doctor if you experience any of the following possible symptoms of liver problems: jaundice (yellowing of the skin or whites of the eyes), widespread itching, loss of appetite accompanied by nausea and vomiting, and easy bruising. Severe liver problems may also be associated with additional signs such as difficulty concentrating, drowsiness, and confusion.
• Depression is common (may affect up to 1 in 10 people) in patients being treated for multiple sclerosis. If you feel depressed or develop suicidal thoughts, contact your doctor immediately.

Contact your doctor if you notice any of the following side effects:

• Flu-like symptoms, such as headache, fever, chills, muscle and joint pain, fatigue, and nausea, are very common (may affect more than 1 in 10 people). These symptoms are usually mild and occur more frequently at the beginning of treatment, decreasing over time. To reduce these symptoms, your doctor may prescribe an antipyretic before administration of a dose of Rebif and 24 hours after each injection.
• Injection site reactions, such as redness, swelling, depigmentation, inflammation, pain, and skin lesions, are very common. These reactions usually decrease over time. Tissue destruction (necrosis), abscess, and nodule formation at the injection site are uncommon (may affect up to 1 in 100 people). To minimize the risk of injection site reactions, read the recommendations in "Warnings and precautions." The injection site may become infected (uncommon); the skin may become swollen, tender, and hardened, and the entire area may be very painful. If you notice any of these symptoms, contact your doctor.
• Some laboratory tests may show abnormalities. These changes are generally not noticeable to the patient (no symptoms), are usually reversible and mild, and often do not require specific treatment. The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all values simultaneously (rare). Possible symptoms due to these changes may include fatigue, reduced ability to fight infections, unexplained bruising or bleeding. Liver function may be impaired (very common). Inflammation of the liver (hepatitis) has also been reported (uncommon). However, if you experience symptoms suggestive of liver problems, such as loss of appetite associated with other symptoms such as nausea, vomiting, or jaundice, contact your doctor immediately (see "Immediately contact your doctor...").
• Thyroid dysfunction is uncommon. The thyroid gland may become overactive or underactive. These changes in thyroid function are rarely noticed by the patient as symptoms, but your doctor may recommend appropriate blood tests.
• Pseudo-relapses of multiple sclerosis (frequency not known). At the beginning of treatment with Rebif, you may experience symptoms similar to those of a multiple sclerosis relapse. For example, your muscles may become very stiff or very weak, making it difficult to move as desired. Sometimes these symptoms are associated with fever or the flu-like symptoms described above. If you notice any of these symptoms, discuss them with your doctor.

Other possible side effects:
Very common (may affect more than 1 in 10 people):

• Headache

Common (may affect up to 1 in 10 people):

• Insomnia (difficulty falling asleep)
• Diarrhea, nausea, vomiting
• Itching, rash (skin eruption)
• Muscle and joint pain
• Fatigue, fever, chills
• Hair loss

Uncommon (may affect up to 1 in 100 people):

• Hives (urticaria)
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Blood clots such as deep vein thrombosis
• Retinal disorders (back of the eye), such as inflammation or blood clots, leading to vision problems (visual disturbances, vision loss)
• Increased sweating

Rare (may affect up to 1 in 1,000 people):

• Suicide attempt
• Severe skin reactions, some with mucosal lesions
• Blood clots (thrombi) in small blood vessels that may affect the kidneys (thrombotic thrombocytopenic purpura or hemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness, or a feeling of emptiness in the head. Your doctor is likely to find blood abnormalities and impaired kidney function.
• Drug-induced lupus erythematosus: a side effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and skin rash. Other signs may include fever, weight loss, and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring that may reduce kidney function. If you experience one or more of the following symptoms:
  • Foamy urine
  • Fatigue
  • Swelling, particularly in the ankles and eyelids, and weight gain contact your doctor, as these may be signs of a possible kidney problem.

The following side effects have been reported for interferon beta (frequency not known):

• Dizziness
• Nervousness
• Loss of appetite
• Vasodilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension – a disease causing severe narrowing of blood vessels in the lungs, leading to increased pressure in the blood vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been observed at various times during treatment, even several years after starting Rebif.
• Inflammation of subcutaneous fat tissue (panniculitis), which may cause hardened skin and possibly the formation of red, painful patches or nodules.

Do not stop or change your dose without consulting your doctor.
Children and adolescents
Side effects in children and adolescents are similar to those observed in adults.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Rebif

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label after "Exp".
Store in a refrigerator (2°C – 8°C).
Do not freeze. (Take care not to place the product near the freezer compartment, to avoid accidental freezing).
The Rebif pack in use may be stored outside the refrigerator at a temperature not exceeding 25°C for a single period of up to 14 days.
After this, Rebif must be returned to the refrigerator and used before the expiry date.
Keep in the original packaging to protect the medicine from light.
Do not use this medicine if you notice any visible signs of deterioration, for example if the solution is no longer clear or contains particles.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Rebif contains

• The active substance is interferon beta-1a.
  • Each 8.8 microgram pre-filled pen contains 8.8 micrograms of interferon beta-1a (2.4 million IU).
  • Each 22 microgram pre-filled pen contains 22 micrograms of interferon beta-1a (6 million IU).
• The other components are: mannitol, poloxamer 188, L-methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injections.

Description of the appearance of Rebif and pack contents
Rebif 8.8 micrograms is available as a solution for injection in a pre-filled pen for self-administration. The pre-filled pen is ready for use and contains 0.2 mL of solution.
Rebif 22 micrograms is available as a solution for injection in a pre-filled pen for self-administration. The pre-filled pen is ready for use and contains 0.5 mL of solution.
Rebif solution is from clear to opalescent.
Rebif 8.8 micrograms and Rebif 22 micrograms are supplied in a starter pack, designed for use during the initial 4 weeks of treatment, during which a gradual dose escalation of Rebif is recommended.
The monthly starter pack contains six pre-filled pens of Rebif 8.8 micrograms and six pre-filled pens of Rebif 22 micrograms.

Marketing Authorisation Holder
Merck Europe B.V.
Gustav Mahlerplein 102
1082 MA Amsterdam
The Netherlands

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

Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu .

Instructions for Use of RebiDose

HOW TO USE THE REBIF PRE-FILLED PEN (RebiDose)

• This section explains how to use RebiDose.
• Rebif must be administered by subcutaneous injection (under the skin).
• Each RebiDose is for single use only.
• The first injection (or first few injections) should be performed under the supervision of a qualified healthcare professional. After adequate training, you, a family member, friend, or caregiver may administer the medication at home using RebiDose. If you have any questions about the injection, consult your doctor, nurse, or pharmacist.
• Read the instructions below carefully before using RebiDose.

Materials Needed
To perform the self-injection, you will need:

• a new RebiDose
• alcohol swabs or similar
• a dry cotton ball or gauze pad.

The following figure shows the components of RebiDose.
Before injection

After injection

A. Cap
B. Transparent window
C. Plunger
D. Label
E. Main body
F. Button
G. Protective sleeve
H. Needle

Before You Begin

• Wash your hands thoroughly with soap and water.
• Remove RebiDose from its packaging after taking off the plastic cover.
• Check the appearance of Rebif through the transparent window. The solution should be clear to opalescent, free from particles and any visible signs of deterioration. If particles or other visible signs of deterioration are present, do not use the solution and consult your doctor, nurse, or pharmacist.
• Check the expiration date printed on the label or packaging of RebiDose (marked as “Exp.”). Do not use RebiDose if the expiration date has passed.

Where to Inject RebiDose

Choosing the injection site. Your doctor will inform you of the
possible areas for injection (suitable areas are the upper thigh and lower abdomen).

• Keep a record and rotate injection sites so that the same area is not used too frequently, in order to minimize skin damage (necrosis).
• NOTE: do not choose an area that is hardened, lumpy, or tender; consult your doctor or a qualified healthcare professional for any clarification.

How to Inject RebiDose

• Do not remove the cap until you are ready to perform the injection.
• Before injection, clean the injection site with an alcohol swab. Make sure the skin is completely dry. If any alcohol remains on the skin, you may feel a stinging sensation.

• Hold RebiDose in one hand, gripping the main body, and with the other hand remove the cap.
• Place RebiDose at the injection site at a right angle (90 degrees). Press the pen firmly against the skin until you feel resistance. This action unlocks the button.

While maintaining adequate pressure on the skin, press the
button with your thumb. You will hear a click indicating the start
of the injection, and the plunger will begin to move. Keep
RebiDose pressed against the skin for at least 10 seconds to
ensure the full dose is delivered.
After the injection starts, it is no longer necessary to keep
the button pressed with your thumb.

Remove RebiDose from the injection site.
The protective sleeve will automatically cover the needle and
lock into place, protecting you from needlestick injury.

After the Injection

Check through the transparent window to make sure
the plunger has moved downward, as shown in the figure.

• Check whether any liquid remains. If liquid is still present, the full dose has not been injected; in this case, consult your doctor or nurse.
• Gently massage the injection site with a dry cotton ball or gauze pad.
• Never replace the needle cap on a used RebiDose. The needle is already covered by the protective sleeve. Never insert your fingers into the protective sleeve.
• RebiDose is for single use only and must never be reused.
• After completing the injection, dispose of RebiDose immediately. Ask your pharmacist how to properly dispose of RebiDose.

For further information, consult your doctor, nurse, or pharmacist.
These Instructions for Use were last updated on: