Zevalin 1.6 mg/ml, radiopharmaceutical preparation kit for infusion

Package leaflet: Information for the user

Introduction

PACKAGE LEAFLET: INFORMATION FOR THE USER

Zevalin 1.6 mg/ml, reagent 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, as you may need to read it again.

• If you have any questions, ask your doctor or pharmacist.

• If you experience any side effects, talk to your doctor or pharmacist, including any side effects not listed in this leaflet. See section 4.

Contents of the leaflet

1. What Zevalin is and what it is used for

2. What you need to know before you are given Zevalin

3. How to use Zevalin

4. Possible side effects

5. How to store Zevalin

6. Contents of the pack and other information

1. What Zevalin is and what it is used for

This medicine is a radiopharmaceutical intended solely for therapeutic use.

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 through irradiation.

Zevalin is used to treat patients with specific types of CD20-positive B-cell non-Hodgkin's lymphoma (indolent B-cell NHL or transformed B-cell NHL) when a previous treatment with rituximab, another monoclonal antibody, has failed or has stopped working (refractory or relapsed disease).

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

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

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

You must 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”).

Take special care with Zevalin

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

• If more than one quarter of your bone marrow is infiltrated by abnormal malignant cells.

• If you have received external beam radiation (a type of radiotherapy) affecting more than one quarter of your bone marrow.

• If you are to receive Zevalin alone and your platelet count is below 100,000/mm³.

• If your platelet count is below 150,000/mm³ after chemotherapy.

• If your white blood cell count is below 1,500/mm³.

• If you have previously undergone a bone marrow transplant or stem cell transfusion.

If you have previously received treatment with other proteins (especially mouse-derived ones) before treatment with Zevalin, you may have an increased risk of an allergic reaction. Therefore, you may need to undergo tests to detect specific antibodies.

In addition, the use of Zevalin is not recommended in patients with non-Hodgkin's lymphoma affecting the brain, spinal cord, or both, as such patients were not included in clinical studies.

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

Limited data are available in elderly patients (aged 65 years and older). Overall, no differences in safety or efficacy have been observed between these patients and younger patients.

Use of Zevalin with other medicines

Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those obtained without a prescription.

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

If you receive treatment with Zevalin within four months after chemotherapy containing the active substance fludarabine, you may have an increased risk of reduced blood cells. Please inform your doctor that you have been given Zevalin if you are to be vaccinated after using this medicine.

Pregnancy and breastfeeding

Zevalin must not be used during pregnancy. Your doctor will perform tests to rule out pregnancy before starting treatment. Women of childbearing potential and male patients must use effective contraception during treatment with Zevalin and for one year after the end of treatment.

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

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

Driving and use of machines

Zevalin may affect your ability to drive and use machines, as dizziness is a very common side effect. Exercise caution until you are certain that you are not affected.

Zevalin contains sodium

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

3. HOW TO USE ZEVALIN

There are strict regulations regarding 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 who are skilled in its safe use. These individuals 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 the indication for which Zevalin is being used. The maximum dose must not exceed 1200 MBq ("megabecquerel", a unit for measuring radioactivity).

Zevalin is used in combination with another medicinal product containing the active substance rituximab.

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

• On Day 1, you will receive an infusion of rituximab.
• On Day 7, 8, or 9, you will receive an infusion of rituximab followed immediately by an infusion of Zevalin (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 treatment of patients with relapsed or refractory non-Hodgkin's lymphoma who do not respond 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 must first be prepared by a healthcare professional. The kit allows for the conjugation of the antibody ibritumomab tiuxetan with the radioactive isotope yttrium-90Y (radioactive labelling).

How Zevalin is administered

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

After Zevalin has been administered

The amount of radiation your body will be exposed to due to Zevalin is lower than that received with radiotherapy. Most of the radioactivity will decay within the body, but a small portion will be eliminated in the urine. Therefore, for one week after the Zevalin infusion, you should thoroughly wash your hands after each urination.

After treatment, your doctor will perform regular blood tests to monitor your platelet and white blood cell counts. These counts usually decrease about two months after starting treatment.

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

If you have received more Zevalin than you should

Your doctor will provide appropriate treatment if you experience any adverse effects. This may include discontinuation of treatment with Zevalin and treatment with growth factors using your own stem cells.

4. Possible adverse effects

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

Inform your doctor immediately if 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 output, low blood pressure, shock, bleeding or coagulation problems.
• Lung infections (pneumonia): difficulty breathing.
• Low blood cell count: unusual bruising, discoloration, or bleeding, increased bleeding after injury, fever, or if you feel unusually tired or have difficulty breathing.
• Severe mucosal reactions, which may occur days or months after administration of Zevalin, rituximab, or both. Your doctor will immediately stop treatment.
• Extravasation (leakage of infusion into 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 or infusion reactions may include 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 must be immediately discontinued.

Adverse effects marked with an asterisk (*) have resulted in death in some cases, either during clinical trials or post-marketing experience.

Adverse effects marked with two asterisks (**) were additionally observed with consolidation treatment.

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

• Decrease in platelets, white blood cells, and red blood cells in the blood (thrombocytopenia, leukopenia, neutropenia, anemia)*.
• Feeling unwell (nausea).
• Weakness, fever, chills.
• Infection*.
• Fatigue**.
• Pinpoint red spots under the skin (petechiae)**.

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

• Blood infection (sepsis)*; lung infection (pneumonia)*, urinary tract infection, fungal infections in the mouth such as oral thrush (oral candidiasis).
• Other blood-related cancers (myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML))*, **, tumor pain.
• Fever with decreased specific white blood cells (febrile neutropenia), reduction in counts of all blood cells (pancytopenia)*, decreased lymphocyte count (lymphopenia).
• Allergic reactions (hypersensitivity).
• Severe loss of appetite (anorexia).
• Feeling of anxiety (anxiety), trouble sleeping (insomnia).
• Dizziness, headache.
• Bleeding due to reduced platelets in the blood*.
• Cough, runny nose.
• Vomiting, stomach pain (abdominal), diarrhea, indigestion, throat irritation, constipation.
• Skin rash, itching (pruritus).
• Joint pain (arthralgia), muscle pain (myalgia), back pain, neck pain.
• Pain, flu-like symptoms, general feeling of discomfort, swelling due to fluid accumulation in arms and legs and other tissues (peripheral edema), increased sweating.
• High blood pressure (hypertension)**.
• Low blood pressure (hypotension)**.
• Absence of menstruation (amenorrhea)**.

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

• Increased heart rate (tachycardia).

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

• Benign brain tumor (meningioma).
• Intracranial hemorrhage due to decreased platelet count in the blood*.

Adverse effects with unknown frequency:

• Skin and mucosal reactions (including Stevens-Johnson syndrome)*.
• Leakage of infusion into surrounding tissues (extravasation), causing skin inflammation (dermatitis at infusion site) and skin peeling or ulceration at the injection site.
• Injury to tissues surrounding lymphatic system tumors and complications caused by swelling of such tumors.

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor or pharmacist, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system detailed in Annex V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. ZEVALIN Storage

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

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

This medicine will be stored by a healthcare professional.

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

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

Storage procedures must comply with national regulations regarding radioactive materials.

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

6. PACKAGE CONTENTS AND ADDITIONAL 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:

  • Ibritumomab tiuxetan vial: sodium chloride, water for injections.
  • Sodium acetate vial: sodium acetate, water for injections.

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

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

Appearance of the product and contents of the pack

Zevalin is a reagent kit for the preparation of radiopharmaceuticals for infusion, containing:

• One glass vial of ibritumomab tiuxetan, with 2 ml of colourless, clear solution.

• One glass vial of sodium acetate, with 2 ml of colourless, clear solution.

• One glass vial of buffer solution, with 10 ml of yellow to amber clear solution.

• One glass reaction vial (under vacuum).

Marketing Authorisation 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 the most recent revision of this leaflet:

Further information

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

This package leaflet is available on the European Medicines Agency website in all languages of the European Union/European Economic Area.