ZEVALIN 1.6 mg/ml, REACTIVE KIT FOR THE PREPARATION OF A RADIOPHARMACEUTICAL FOR PERFUSION

Introduction

PACKAGE LEAFLET: INFORMATION FOR THE USER

Zevalin 1.6 mg/ml, kit for the preparation of a radiopharmaceutical for infusion

Ibritumomab tiuxetan (90Y)

Read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.

• If you have any further questions, ask your doctor or pharmacist.
• If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is Zevalin and what is it used for
2. What you need to know before you are given Zevalin
3. How to use Zevalin

1. Possible side effects
2. Storage of Zevalin

1. Contents of the pack and other information

1. WHAT IS ZEVALIN AND WHAT IS IT USED FOR

This medicine is a radiopharmaceutical for therapeutic use only.

Zevalin is a kit for the preparation of the active substance ibritumomab tiuxetan (90Y), a monoclonal antibody labeled with the radioactive substance yttrium-90 (90Y). Zevalin binds to a protein (CD20) on the surface of certain white blood cells (B lymphocytes) and eliminates them by irradiation.

Zevalin is used to treat patients with specific types of non-Hodgkin's lymphoma of B cells (indolent CD20+ B cell or transformed B cell non-Hodgkin's lymphoma) if previous treatment with rituximab, another monoclonal antibody, has not worked or has stopped working (refractory or relapsed disease).

Zevalin is also used in patients with follicular lymphoma who have not received previous treatment. It is used as consolidation treatment to improve the reduction in the number of lymphoma cells (remission) achieved with the initial chemotherapy regimen.

The use of Zevalin involves exposure to small amounts of radioactivity. Your doctor and the nuclear medicine doctor have considered that the clinical benefit you will gain from the procedure with the radiopharmaceutical outweighs the risk due to radiation.

2. WHAT YOU NEED TO KNOW BEFORE YOU ARE GIVEN ZEVALIN

You should not be given Zevalin:

• If you are allergic(hypersensitive) to any of the following substances:

• Ibritumomab tiuxetan, yttrium chloride, or any of the other components of Zevalin (listed in section 6 "Composition of Zevalin").
• Rituximab or other murine-derived proteins.
• If you are pregnant or breastfeeding (see also the section "Pregnancy and breastfeeding").

Be cautious with Zevalin

In the following cases, the use of Zevalin is not recommended, as its safety and efficacy have not been established:

• More than a quarterof your bone marrow is infiltrated by abnormal malignant cells.
• If you have received external beam radiation(a type of radiotherapy) that affects more than a quarter of your bone marrow.

• If you are going to receive Zevalin alone and your platelet count is less than 100,000/mm3.
• If your platelet count is less than 150,000/mm3after chemotherapy.
• If your white blood cell count is less than 1,500/mm3.

• If you have undergone a bone marrow transplant or stem cell transfusion in the past.

If you have received treatment with other proteins(especially murine-derived) before treatment with Zevalin, you may have a higher probability of suffering an allergic reaction. Therefore, you may need to undergo tests to determine specific antibodies.

Additionally, the use of Zevalin is not recommended in patients with non-Hodgkin's lymphoma that affects the brain, spinal cord, or both, as these patients were not included in clinical trials.

Children

The use of Zevalin is not recommended in children under 18 years of age, as safety and efficacy have not been established.

Elderly patients

There is limited data available in elderly patients (65 years and older). Overall, no differences in safety or efficacy were observed between these patients and younger patients.

Use of Zevalin with other medicines

Tell your doctor or pharmacist if you are using or have recently used any other medicines, including those obtained without a prescription.

In particular, your doctor should interrupt treatment with growth factors, such as filgrastim, for a period of three weeks before administering Zevalin and up to two weeks after treatment with Zevalin.

If you receive treatment with Zevalin before four months after receiving chemotherapy with the active substance fludarabine, you may have a higher risk of decreased blood cells. Please inform your doctor that you have been given Zevalin if you are going to be vaccinated after using this medicine.

Pregnancy and breastfeeding

Zevalin should not be used during pregnancy. Your doctor will perform tests to rule out pregnancy before starting treatment. Women of childbearing age and male patients should use effective contraceptive methods during treatment with Zevalin and for up to one year after treatment.

There is a potential risk that the ionizing radiation from Zevalin may damage your ovaries and testicles. Consult your doctor about how this may affect you, especially if you plan to have children in the future.

Women should not breastfeed during treatment and for 12 months after treatment.

Driving and using machines

Zevalin may affect your ability to drive and use machines, as dizziness is a very common side effect. Be cautious until you are sure you are not affected.

Zevalin contains sodium

This medicine contains up to 28 mg of sodium per dose, depending on the concentration of radioactivity. Patients on low-sodium diets should take this into account.

3. HOW TO USE ZEVALIN

There are strict rules for the use, handling, and disposal of radiopharmaceuticals. Zevalin will only be used in specially controlled areas. This medicine will only be handled and administered by trained and qualified personnel to use it safely. These people will take special care in the safe use of this product and will inform you of their actions.

The dose of Zevalin depends on your body weight, the number of platelets in your blood, and what Zevalin is used for (indication). The maximum dose should not exceed 1200 MBq ("megabecquerel", a unit to measure radioactivity).

Zevalin is used with another medicine that contains the active substance rituximab.

You will receive a total of three infusions, over the course of two visits to a medical center, with an interval of 7 to 9 days.

• On day 1, you will receive an infusion of rituximab
• On days 7, 8, or 9, you will be given an infusion of rituximab followed by an infusion of Zevalin immediately after (within four hours).

The recommended dose is:

For consolidation treatment in patients with follicular lymphoma

• The usual dose is 15 MBq/kg body weight.

For the treatment of patients with non-Hodgkin's lymphoma in relapse or refractory to rituximab

• The usual dose is 11 or 15 MBq per kg of body weight, depending on the number of platelets in the blood.

Preparation of Zevalin

Zevalin is not used directly, but first must be prepared by a healthcare professional. The kit allows the coupling of the antibody ibritumomab tiuxetan with the radioactive isotope yttrium-90 (90Y) (radioactively labeled).

How Zevalin is administered

Zevalin is administered by intravenous infusion (drip into a vein), which usually lasts approximately 10 minutes.

After you are given Zevalin

The amount of radiation to which your body will be exposed due to Zevalin is less than that received with radiotherapy. Most of the radioactivity will decay within your body, but a small part will be eliminated through urine. Therefore, during the week following the infusion of Zevalin, every time you urinate, you should wash your hands well after urinating.

After treatment, your doctor will perform blood tests at regular intervals to check your platelet and white blood cell counts. These usually decrease approximately two months after the start of treatment.

If your doctor plans to treat you with another antibody after treatment with Zevalin, you may need to undergo tests to determine specific antibodies. Your doctor will inform you if this applies to you.

If you have received more Zevalin than you should

Your doctor will give you the appropriate treatment if you experience any side effects. This may involve stopping treatment with Zevalin and treatment with growth factors with your own stem cells.

4. POSSIBLE SIDE EFFECTS

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

Tell your doctor immediatelyif you notice symptoms of the following conditions:

• Infection:fever, chills.
• Blood infection (sepsis):fever and chills, changes in mental status, rapid breathing, increased heart rate, decreased urine production, low blood pressure, shock, bleeding or coagulation problems.
• Lung infections (pneumonia):difficulty breathing.
• Low blood cell count:bruising, petechiae or unusual bleeding after injury, more bleeding than usual, fever or if you feel abnormally tired or have difficulty breathing.
• Severe mucosal reactionsthat can occur days or months after administration of Zevalin, rituximab, or both. Your doctor will immediately stop treatment.
• Extravasation(leakage of the infusion into the surrounding tissues): pain, burning, itching, or other reaction at the infusion site during administration. Your doctor will immediately stop the infusion and restart it in another vein.
• Allergic reactions(hypersensitivity) / infusion reactions: symptoms of allergic reactions or infusion reactions may be skin reactions, difficulty breathing, swelling, itching, flushing, chills, dizziness (as a possible sign of low blood pressure). Depending on the type or severity of the reaction, your doctor will decide whether treatment should be stopped immediately.

Side effects marked with an asterisk (*) have caused death in some cases, either in clinical trials or during the marketing of the product.

Side effects marked with two asterisks (**) were also observed with consolidation treatment.

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

• Decreased number of platelets, white blood cells, and red blood cells in the blood (thrombocytopenia, leucopenia, neutropenia, anemia) *.
• Feeling of discomfort (nausea).

• Weakness, fever, chills.
• Infection*.

• Fatigue**.
• Small red spots under the skin (petechiae)**.

Common side effects(may affect up to 1 in 10 people)

• Blood infection (sepsis)*; lung infections (pneumonia)*, urinary tract infections, fungal infections in the mouth, such as oral thrush (oral candidiasis).
• Other types of blood cancer (myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML))*, **, tumor pain.
• Fever with decreased number of specific white blood cells (neutropenic fever), decreased counts of all blood cells (pancytopenia)*, decreased number of lymphocytes (lymphocytopenia).

• Allergic reactions (hypersensitivity).
• Severe loss of appetite (anorexia).

• Feeling of anxiety (anxiety), sleep problems (insomnia).
• Dizziness, headache.

• Bleeding due to decreased platelets in the blood*.
• Cough, runny nose.
• Vomiting, stomach pain (abdominal), diarrhea, indigestion, throat irritation, constipation.
• Skin rash, itching (pruritus).

• Pain in the joints (arthralgia), muscle pain (myalgia), back pain, neck pain.
• Pain, flu-like symptoms, feeling of general discomfort, swelling caused by fluid accumulation in the arms and legs, and in other tissues (peripheral edema), increased sweating.

• High blood pressure (hypertension)**.
• Low blood pressure (hypotension)**.
• Absence of menstruation (amenorrhea)**.

Uncommon side effects(may affect up to 1 in 100 people)

• Increased heart rate (tachycardia).

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

• Benign brain tumor (meningioma).
• Brain hemorrhage due to decreased platelets in the blood*.

Side effects with unknown frequency:

• Skin and mucous membrane reaction (including Stevens-Johnson syndrome)*.

• Leakage of the infusion into the surrounding tissues (extravasation), causing skin inflammation (infusion site dermatitis) and skin peeling at the infusion site or ulcers at the injection site.

• Damage to the tissues around lymphoma tumors and complications caused by swelling of such tumors.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. You can also report them directly through the national reporting system included in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. STORAGE OF ZEVALIN

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

Do not use this medicine after the expiry date stated on the packaging.

This medicine will be stored by a healthcare professional.

Store in a refrigerator (between 2°C and 8°C). Do not freeze.

Store the vials in the original packaging to protect them from light.

Storage procedures must comply with national regulations on radioactive materials.

After radioactive labeling, immediate use is recommended. Stability has been demonstrated for 8 hours at 2°C - 8°C and protected from light.

6. CONTENTS OF THE PACK AND OTHER INFORMATION

Composition of Zevalin

• The active substance is ibritumomab tiuxetan. Each vial contains 3.2 mg of ibritumomab tiuxetan in 2 ml of solution (1.6 mg per ml).
• The other components are:
• • Vial of ibritumomab tiuxetan: sodium chloride, water for injections.
  • Vial of sodium acetate: sodium acetate, water for injections.

• Vial of buffer solution: human albumin solution, sodium chloride, disodium phosphate dodecahydrate, sodium hydroxide, potassium dihydrogen phosphate, potassium chloride, pentetic acid, hydrochloric acid diluted for pH adjustment, water for injections.

The final formulation after radioactive labeling contains 2.08 mg of ibritumomab tiuxetan labeled with yttrium-90 (90Y) in a total volume of 10 ml.

Appearance and packaging

Zevalin is a kit for the preparation of radiopharmaceuticals for infusion that contains:

• A glass vial of ibritumomab tiuxetan, with 2 ml of clear and colorless solution.
• A glass vial of sodium acetate, with 2 ml of clear and colorless solution.

• A glass vial, buffer solution, with 10 ml of transparent yellow to amber solution.
• A glass vial for reaction (empty).

Marketing authorization holder

Ceft Biopharma s.r.o.

Trtinova 260/1

Cakovice, 196 00 Praha 9

Czech Republic

Manufacturer

CIS bio international

RN 306- Saclay

B.P. 32

91192 Gif-sur-Yvette Cedex

France

Date of last revision of this leaflet:

Other sources of information

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

The leaflet for this medicine can be found on the European Medicines Agency website in all languages of the European Union/European Economic Area.