Product Information for the User

Rebif 22micrograms/0.5ml Injectable Solution in Cartridge

Interferon beta-1a

Read this entire product information carefully before starting to use this medication, because it contains important information for you.

• Keep this product information, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribed only for you, and you should not give it to other people even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this product information. See section 4.

1.What is Rebif and how is it used

2.What you need to know before starting to use Rebif

3.How to use Rebif

4.Possible adverse effects

5.Storage of Rebif

6.Contents of the package and additional information

Rebif belongs to a class of medications known as interferons. They are natural substances that transmit messages between cells. Interferons are produced by the body and play an essential role in the immune system. Through mechanisms that are not fully understood, interferons help to limit the 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 by the human body.

Rebif is used for the treatment of multiple sclerosis. It has been shown to decrease the number and severity of relapses and to delay the progression of disability.

No use Rebif

• If you are allergic to natural or recombinant interferon beta or to any of the other components of this medication (listed in section 6).
• If you currently have a severe depression.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Rebif.

• Rebif should only be used under the supervision of your doctor.
• Before starting treatment with Rebif, read carefully and follow the recommendations given in the section “How to use Rebif” to minimize the risk of necrosis in the injection area (skin rupture and tissue destruction) that have been reported in patients treated with Rebif. If you notice local reactions, contact your doctor.
• Consult your doctor or pharmacist before starting to take Rebif if you are allergic (hypersensitive) to any other medication.
• During treatment, blood clots may form in small blood vessels. These clots could affect your kidneys. This may occur after several weeks orseveral yearsafter starting treatment with Rebif.Your doctor may want to perform checks on your blood pressure, blood (platelet count) and kidney function.

Inform your doctor if you have any diseases of

• the bone marrow,
• kidney,
• liver,
• heart,
• thyroid,
• or if you have had depression,
• or if you have a history of epileptic seizures,

so that your doctor can strictly control your treatment and any possible worsening of these diseases.

Other medications and Rebif

Inform your doctor or pharmacist if you are using, have used recentlyor may have to useany other medication.

In particular, inform your doctor if you are using antiepileptic or antidepressant medications.

Pregnancy and breastfeeding

If you are pregnant, think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before using this medication.

No adverse effects are anticipated in children/newborns. Rebif may be used during breastfeeding.

Driving and operating machinery

The effects of your own disease or treatment may affect your ability to drive or operate machinery. If this affects you, discuss it with your doctor.

Rebif contains sodium and benzyl alcohol

This medication contains less than 1mmol of sodium (23mg) per dose; this is essentially “sodium-free”.

This medication contains 2.5mg of benzyl alcohol per dose.Benzyl alcohol may cause allergic reactions.

Benzyl alcohol has been associated with the risk of severe adverse effects that include respiratory problems (“breathing difficulty”) in children.

This product should not be used for more than one week in children under 3years of age unless instructed by your doctor or pharmacist.

Consult your doctor or pharmacist if you are pregnant or breastfeeding or if you have liver or kidney diseases.This is because large amounts of benzyl alcohol may accumulate in your body and cause adverse effects (metabolic acidosis).

This medicine is for multiple-dose use.

Follow exactly the administration instructions for this medicine as indicated by your doctor.In case of doubt,consult your doctor again.

Dose

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

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

• on the same three days of each week (separated by at least 48hours; for example, Monday, Wednesday, and Friday);
• at the same time of day (preferably in the afternoon).

Use in children and adolescents (2 to 17years)

No formal clinical trials have been conducted in children or adolescents.However, there are clinical data suggesting that the safety profile in children and adolescents who received Rebif 22micrograms or Rebif 44micrograms three times a week is similar to that observed in adults.

Use in children (less than 2years of age)

Rebif is not recommended for use in children under 2years of age.

Administration form

• Rebif must be injected subcutaneously (under the skin).
• The first injection(s) must be administered under the supervision of a qualified healthcare professional.After receiving proper training, you, a family member, friend, or caregiver can use Rebif cartridges with the injection device to administer the medicine at home.
• The cartridge must be used with the RebiSmart electronic injection device.
• The device includes complete instructions for use; follow them carefully.
• Below are brief instructions on how to use Rebif cartridges.

Before starting

• Wash your hands thoroughly with water and soap.
• Remove the Rebif cartridge from its blister pack, removing the plastic cover.
• Check (just after removing it from the refrigerator) that the cartridge is not accidentally frozen in the packaging or inside the device.Only clear to opalescent solutions, without particles, and without visible signs of deterioration should be used.
• To place the cartridge in the device and administer the injection, follow the user manual (User Instructions) provided with your device.

Where to inject Rebif

How to inject Rebif

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

After the Rebif injection with RebiSmart

• Remove and dispose of the needle according to the user manual provided with your device.
• Gently massage the injection site with a cotton ball or dry gauze.
• Store the device containing a Rebif cartridge as indicated in the section5 “Storage of Rebif”.

If you have any doubts, ask your doctor, nurse, or pharmacist.

If you use more Rebif than you should

In case of overdose, contact your doctor immediately.

If you forgot to use Rebif

If you miss an injection, continue injecting from the day when your next dose is due.Do not use a double dose to compensate for the missed doses.

If you interrupt the treatment with Rebif

You may not notice the effects of Rebif immediately.Therefore, do not interrupt the use of Rebif but continue using it regularly to achieve the desired result.If you are unsure of the benefits, consult your doctor.

Do not interrupt treatment without first consulting your doctor.

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Inform your doctor immediately and discontinue treatment with Rebif if you experience any of the following side effects:

• Severe allergic reactions (hypersensitivity).Contact your doctor immediately or seek urgent medical attention if you experience difficulty breathing immediately after receiving Rebif, which may be accompanied by swelling of the face, lips, tongue, and throat, urticaria, itching all over the body, and a feeling of weakness and fatigue. These reactions arerarer(may affect up to 1 in 1,000people).

• Inform your doctor immediately if you experience any of the following possible symptoms of aliver problem: jaundice (yellowing of the skin or white parts of the eyes), generalized itching, loss of appetite accompanied by nausea and vomiting, and easy bruising of the skin. Severe liver problems may be associated with other symptoms such as difficulty concentrating, drowsiness, and confusion.

• Depressionis frequent(may affect up to 1 in 10people) in patients treated for multiple sclerosis. If you feeldepressed or experience suicidal thoughts, inform your doctor immediately.

Consult your doctor if you experience any of the following side effects:

• Symptoms similar to the flu,such as headache, fever, chills, muscle and joint pain, fatigue, and nausea arevery frequent(may affect more than 1 in 10people).

These symptoms are usually mild and more frequent at the beginning of treatment, decreasing with continued use.

To help reduce these symptoms, your doctor may recommend taking a pain reliever before each dose of Rebif and 24 hours after each injection.

• Reactions at the injection site,including redness, swelling, discoloration, inflammation, pain, and skin fragility arevery frequent.

The appearance of reactions at the injection site usually decreases over time.

Tissue destruction (necrosis), the appearance of abscesses, and masses at the injection site areinfrequent(may affect up to 1 in 100people).

See the recommendations in “Warnings and precautions” to minimize the risk of reactions at the injection site.

The injection site may become infected(infrequent); the skin may become inflamed, painful, and hardened, and the area may be very painful. If you experience any of these symptoms, contact your doctor.

• Sometest resultsmay be altered. These changes are usually not perceived by the patient (no symptoms), are generally reversible, and mild, and many of them do not require specific treatment.

The number of red blood cells, white blood cells, or platelets may decrease individually(very frequent)or all at once(rare). Possible symptoms associated with these changes may include fatigue, decreased ability to respond to infections, bruises or bleeding of unknown cause. Liver function may be altered(very frequent). Cases of liver inflammation(infrequent) have been reported. If you experience any symptoms that suggest a liver disorder, such as loss of appetite accompanied by other symptoms such as nausea, vomiting, jaundice, contact your doctor immediately (see above “Inform your doctor immediately”).

• Hypothyroidismisinfrequent. The thyroid gland may function both excessively and insufficiently. These changes in thyroid activity are not perceived by patients as symptoms of a disorder, but your doctor may recommend a test if they consider it appropriate.

• Pseudo-relapse (or false relapse) of multiple sclerosis(unknown frequency): it is possible that at the beginning of treatment with Rebif you may experience symptoms similar to a relapse of multiple sclerosis. For example, you may notice that your muscles are tense or very weak, preventing free movement. In some cases, these symptoms are associated with fever or symptoms similar to the flu, as described above. If you notice any of these side effects, consult your doctor.

Other possible side effects may include:

Very frequent (may affect more than 1 in 10people):

• Headache.

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

• Insomnia (difficulty sleeping)
• Diarhea, nausea, vomiting
• Jaundice, urticaria (skin eruptions)
• Muscle and joint pain

• Fatigue, fever, and chills
• Hair loss.

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

• Urticaria
• Seizures
• Liver inflammation (hepatitis)
• Difficulty breathing
• Clots such as deep vein thrombosis
• Alterations of the retina (eye fundus) such as inflammation, blood clots with resulting vision disorders (vision disturbances, loss of vision)
• Increased sweating.

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

• Attempted suicide
• Severe skin reactions, some with mucosal damage
• Clots 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 disorientation. Your doctor may find changes in your blood and kidney function.
• Drug-induced lupus erythematosus: aside effectof long-term use of Rebif. Your symptoms may include muscle pain, joint pain and swelling, and skin eruptions.You may also present other signs such as fever, weight loss, and fatigue.Symptoms usually disappear within one or two weeks after discontinuing treatment.
• Kidney problems, including scarring that may reduce kidney function.

If you experience any of these symptoms or all of them:

-Foamy urine

-Fatigue

-Swelling, especially of ankles and eyelids, and weight gain.

Inform your doctor, as they may be signs of a possible kidney problem.

The following side effects were reported for interferon beta (unknown frequency)

• Dizziness
• Nervousness
• Loss of appetite
• vasodilation and palpitations
• Irregularities and/or changes in menstrual flow.
• Pulmonary hypertension is a disease in which a great narrowing of the blood vessels in the lungs causes an increase in pressure in the blood vessels that transport blood from the heart to the lungs. Pulmonary hypertension was reported at different times, even several years after starting treatment with Rebif.
• Subcutaneous fat inflammation (panniculitis), which may appear hardened and may have red, painful lumps or spots.

Do not interrupt or change treatment without consulting your doctor.

Children and adolescents

Side effects in children and adolescents aresimilarto those observed in adults.

Reporting side effects

If you experienceany type of side effect, consult your doctor, pharmacist, or nurse, even if it is apossibleside effect that does not appear in this prospectus.You can also report them directly through theSpanish System for Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es.

By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the label after CAD.

Store in the refrigerator (between 2°C and 8°C).

Do not freeze. (To avoid accidental freezing, do not place near the freezer).

Use within 28 days after the first injection.

The device (RebiSmart) with a Rebif cartridge inside must be stored in its protective case in the refrigerator (between 2°C and 8°C). For outpatient use, you can remove Rebif from the refrigerator and store it at a temperature not exceeding 25°C for a maximum period of 14 days. After that, Rebif must be returned to the refrigerator and used before the expiration date.

Store in the original packaging to protect it from light.

Do not use this medication if you observe any visible signs of deterioration, such as if the solution in the cartridge is no longer clear and colorless or if it contains particles.

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of Rebif

• The active ingredient is interferon beta‑1a. Each cartridge contains 66micrograms corresponding to 18million International Units (UI) of interferon beta‑1a.
• The other components are mannitol, poloxamer188, L‑methionine, benzyl alcohol, sodium acetate, acetic acid, sodium hydroxide, and water for injection.

Appearance of the product and content of the container

Pre-filled cartridge (type1 glass), with stopper (rubber) and closure cap (aluminum with halobutilo rubber) containing 1.5ml of solution. Container size of 4or 12 cartridges. Only some container sizes may be commercially available.

The cartridge must be used with the RebiSmart electronic injection device. The device is supplied separately.

Marketing authorization holder

Merck Europe B.V.

Gustav Mahlerplein 102

1082 MA Amsterdam

Netherlands

Responsible for manufacturing

Merck Serono S.p.A.

Via delle Magnolie 15

I-70026 Modugno (Bari)

Italy

Last review date ofthis leaflet: 01/2023

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency website:http://www.ema.europa.eu/.