Rebif 44 micrograms/0.5 ml solution for injection in cartridge

Patient Information Leaflet

Introduction

Patient Information Leaflet

Rebif 44 micrograms/0.5 ml solution for injection in cartridge

interferon beta-1a

Read this entire leaflet carefully before you start using this medicine, because it contains important information for you.

• Keep this leaflet, as 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 they have the same symptoms as you, because it could harm them.
• If you experience any adverse reactions, consult your doctor, pharmacist, or nurse, even if they are adverse reactions not listed in this leaflet. 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 by the human body.

Rebif is used for the treatment of multiple sclerosis. It has been shown to reduce the frequency and severity of relapses and to delay the progression of disability. Its use is also approved in patients who have experienced a single clinical episode with a high likelihood of being the 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 starting to use Rebif.

• Rebif should only be used under the supervision of your doctor.
• Before starting treatment with Rebif, carefully read and follow the recommendations given in the section “How to use Rebif” to minimize the risk of necrosis at the injection site (skin breakdown and tissue destruction), which has been reported in patients treated with Rebif. If you notice bothersome local reactions, contact your doctor.
• Consult your doctor or pharmacist before starting Rebif if you have an allergy (hypersensitivity) to any other medicine.
• During treatment, blood clots may form in small blood vessels. These clots could affect your kidneys. This may occur several weeks or years after starting treatment with Rebif. Your doctor may want to monitor your blood pressure, blood (platelet count), and kidney function.

Inform your doctor if you have any disease of the

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

so that your doctor can closely monitor your treatment and any possible worsening of these conditions.

Other medicines and Rebif

Inform your doctor or pharmacist if you are taking, have recently taken, or might need to take any other medicines.

In particular, you must inform your doctor if you are taking antiepileptic drugs or antidepressants.

Pregnancy and breastfeeding

If you are pregnant, think you might be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

No harmful effects are expected in breastfed infants. Rebif may be used during breastfeeding.

Driving and using machines

The effects of the disease itself or of its treatment may affect your ability to drive or operate machinery. If this applies to you, discuss it with your doctor.

Rebif contains sodium and benzyl alcohol

This medicine contains less than 1 mmol of sodium (23 mg) 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 children.

This product should not be used for more than one week in children under 3 years of age unless directed 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 your body and cause adverse effects (metabolic acidosis).

3. How to use Rebif

This medicine is for multi-dose use.

Always follow exactly the instructions for administering this medicine as given by your doctor. If in doubt, consult your doctor again.

Dosage

Patients who have experienced a single clinical episode

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 cannot 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, and Friday);
• at the same time of day (preferably in the afternoon).

Use in children and adolescents (2 to 17 years of age)

Formal clinical trials have not been conducted in children or adolescents. However, clinical data are available suggesting that the safety profile in children and adolescents receiving 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)

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

Method of administration

• Rebif must be injected subcutaneously (under the skin).
• The first injection(s) should be administered under the supervision of a suitably qualified healthcare professional. After receiving appropriate training, you, a family member, friend, or caregiver may use Rebif cartridges with your device to administer the medicine at home.
• The cartridge must be used with the RebiSmart electronic injection device.
• Complete instructions for use are included with the device; follow them carefully.
• Brief instructions on how to use Rebif cartridges are provided below.

Before starting

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

Where to inject Rebif

How to inject Rebif

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

After injecting Rebif with RebiSmart

• Remove and dispose of the needle according to the instructions provided with your device.
• Gently massage the injection site with a dry cotton ball or gauze.
• Store the device containing the Rebif cartridge as indicated in section 5, "Storage of 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 an injection, continue injecting on the day scheduled for your next dose. Do not use a double dose to make up for missed doses.

If you stop using Rebif

The effects of Rebif may not be immediately noticeable. Therefore, do not interrupt the use of Rebif, but continue using it regularly to achieve the desired outcome. If you are unsure about the benefits, consult your doctor.

Do not stop treatment without first talking to your doctor.

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

4. Possible adverse effects

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

Tell your doctor immediately and stop treatment with Rebif if you experience any of the following adverse effects:

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

• Inform 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. Severe liver problems may be associated with other symptoms such as difficulty concentrating, drowsiness, and confusion.

• Depression is common (may affect up to 1 in 10 people) in patients with multiple sclerosis. If you feel depressed or have suicidal thoughts, inform your doctor immediately.

Consult your doctor if you experience any of the following adverse 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 with continued use.

To help reduce these symptoms, your doctor may recommend taking an analgesic before each dose of Rebif and again 24 hours after each injection.

• Injection site reactions, including redness, swelling, discoloration, inflammation, pain, and skin fragility, are very common.

Injection site reactions generally decrease over time.

Tissue destruction (necrosis), abscess formation, and masses at the injection site are uncommon (may affect up to 1 in 100 people).

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

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

• Results of certain laboratory tests may change. These changes are usually not noticeable to the patient (no symptoms), are generally mild and reversible, and many do not require specific treatment.

The number of red blood cells, white blood cells, or platelets may decrease individually (very common) or all together (rare). Possible symptoms associated with these changes may include fatigue, reduced ability to respond to infections, unexplained bruising, or bleeding. Liver function may be affected (very common). Cases of liver inflammation (hepatitis) have been reported (uncommon). If you experience any symptoms suggesting liver disorder, such as loss of appetite accompanied by other symptoms such as nausea, vomiting, or jaundice, contact your doctor immediately (see above “Tell your doctor immediately”).

• Thyroid dysfunction is uncommon. The thyroid gland may become either overactive or underactive. These changes in thyroid activity are not usually noticed by patients as symptoms of a disorder, but your doctor may recommend a blood test if considered appropriate.

• Pseudo-relapse (or false relapse) of multiple sclerosis (frequency not known): At the beginning of treatment with Rebif, you may experience symptoms resembling a multiple sclerosis relapse. For example, you may notice your muscles feel stiff or very weak, limiting free movement. In some cases, these symptoms are associated with fever or flu-like symptoms as described above. If you notice any of these adverse effects, consult your doctor.

Other possible adverse effects may include:

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
• Jaundice, rashes (skin eruptions)
• Muscle and joint pain
• Fatigue, fever, and chills
• Hair loss.

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

• Hives
• Seizures
• Liver inflammation (hepatitis)
• Breathing difficulties
• Blood clots such as deep vein thrombosis
• Retinal disorders (fundus changes), such as inflammation or blood clots, leading to vision disturbances (visual disturbances, vision loss)
• Increased sweating.

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

• Suicide attempt
• Severe skin reactions, some involving mucosal damage
• Blood 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 lightheadedness. Your doctor may detect abnormalities in blood tests and kidney function.
• Drug-induced lupus erythematosus: an adverse effect associated with long-term use of Rebif. Symptoms may include muscle pain, joint pain and swelling, and rashes. Other signs may include fever, weight loss, and fatigue. Symptoms usually resolve within one or two weeks after stopping treatment.
• Kidney problems, including scarring, which may reduce kidney function.

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

• Foamy urine
• Fatigue
• Swelling, especially in the ankles and eyelids, and weight gain

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

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

• Dizziness
• Nervousness
• Loss of appetite
• Blood vessel dilation and palpitations
• Irregularities and/or changes in menstrual flow
• Pulmonary arterial hypertension is a condition in which the blood vessels in the lungs become severely narrowed, leading to increased pressure in the blood vessels carrying blood from the heart to the lungs. Pulmonary arterial hypertension has been reported at various times, even several years after starting treatment with Rebif.
• Inflammation of the fatty tissue under the skin (panniculitis), which may feel hardened and may develop painful red lumps or patches.

Do not stop or change your treatment without consulting your doctor.

Children and adolescents

Adverse effects in children and adolescents are similar to those observed in adults.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You can also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaRAM.es.

By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of 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 (between 2°C and 8°C).

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

After the first injection, use within the following 28 days.

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, Rebif may be removed from the refrigerator and stored 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 from light.

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

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the container and other information

Composition of Rebif

• The active substance is interferon beta-1a. Each cartridge contains 132 micrograms corresponding 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.

Appearance of the product and contents of the container

Prefilled cartridge (type I glass), with a stopper (rubber) and a closure cap (aluminum with halobutyl rubber) containing 1.5 ml of solution. Pack sizes of 4 or 12 cartridges. Only certain pack sizes may be marketed.

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

The Netherlands

Manufacturer

Merck Serono S.p.A.

Via delle Magnolie 15

I-70026 Modugno (Bari)

Italy

Date of the most recent revision of this 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/.