Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations forinfusion

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

Zevalin is used to treat patients suffering from specific subgroups of B-cell non-Hodgkin?s lymphoma (CD20+ indolent or transformed B-cell NHL) if an earlier rituximab, another monoclonal antibody, treatment has not worked, or has stopped working (refractory or relapsed disease).

Zevalin is also used in previously untreated patients with follicular lymphoma. It is used as a consolidation therapy to improve the reduction in the number of lymphoma cells (remission) achieved with the initial chemotherapy regimen.

You must not be given Zevalin:

• if you are allergic (hypersensitive) to any of the following: - ibritumomab tiuxetan, yttrium chloride or to any of the other ingredients of Zevalin (listed in section 6 ?What Zevalin contains?) - rituximab or other murine-derived proteins
• if you are pregnant or breast-feeding (see also section ?pregnancy and breast feeding?).

Take special care with Zevalin In the following cases, Zevalin use is not recommended since its safety and efficacy have not been established more than a quarter of your bone marrow contains malignant abnormal cells. If you have had external beam radiation a type of radiotherapy to more than a quarter of your bone marrow. If you receive Zevalin alone and the number of your blood platelets is fewer than 100,000mm3If the number of your blood platelets is fewer than 150,000mm3 after chemotherapy

If the number of your white blood cells is fewer than 1,500mm3If you have had a bone marrow transplant or have received blood stem cells in the past.

If you have been treated with other proteins (especially mouse-derived) before Zevalin treatment, you may be more likely to have an allergic reaction. You may, therefore, need to be tested for special antibodies.

In addition, Zevalin is not recommended for the use in patients with non-Hodgkin?s lymphoma involving the brain and/or spinal cord as those patients were not included in clinical studies.

Children:

Zevalin is not recommended for use in children below age 18 since safety and efficacy have not been established.

Elderly patients:

Limited data in elderly patients (aged 65 years or over) are available. No overall differences in safety or efficacy were observed between these patients and younger patients.

Using other medicines

Please tell your doctor or pharmacist if you are using or have recently used any other medicines, including medicines obtained without a prescription.
In particular, your doctor will need to interrupt treatment with growth factors such as filgrastim for a period of three weeks before giving you Zevalin to two weeks after Zevalin treatment. If you are given Zevalin less than 4 months after chemotherapy containing the active substance fludarabine, you may have a higher risk of having a reduced number of blood cells. Please tell your doctor that you were given Zevalin if you are due for vaccination after using it.

Pregnancy and breast-feeding

Zevalin must not be used during pregnancy. Your doctor will perform tests to exclude pregnancy before you start the treatment. Women of child-bearing potential and male patients must use reliable contraception during treatment with Zevalin and for up to one year after stopping treatment. There is a potential risk that ionizing radiation by Zevalin could harm your ovaries and testicles. Please ask your doctor how this may affect you, especially if you are planning on having children in the future.

Women must not breast-feed during treatment and for 12 months following the treatment. .

Driving and using machines

Zevalin can affect your abilityto drive and use machines, as dizziness is a common side effect. Please be cautious until you are sure you are not affected.

Important information about some of the ingredients of Zevalin

This medicine contains up to 28 mg sodium per dose, depending on the radioactivity concentration. To be taken into consideration by patients on a controlled sodium diet.

Zevalin must be handled and administered by experienced professionals in a medical facility authorized to use radioactive medicines.

The dose of Zevalin depends on your body weight, blood platelet counts and what Zevalin is being used for (indication). The maximum dose must not exceed 1200 MBq (?megabecquerel?, a unit to measure radioactivity).

Zevalin is used with another medicine containing the active substance rituximab.

You will be given a total of 3 infusions in the course of two visits to a medical facility, 7 to 9 days apart.

• On day 1 you will be given one rituximab infusion
• On day 7, 8, or 9 you will be given one rituximab infusion, followed by one Zevalin infusion shortly afterwards (within 4 hours).

How much Zevalin is given

For consolidation therapy in patients with follicular lymphoma

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

For therapy of patients with relapsed or refractory Non-Hodgkin?s lymphoma not responding to rituximab

- The usual dose is 11 or 15 MBq per kg body weight, depending on your blood platelet count.

Preparation of Zevalin

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

How Zevalin is given

Zevalin is given by intravenous infusion (drip into a vein) usually lasting about 10 minutes.

After you are given Zevalin

The amount of radiation that your body will be exposed to due to Zevalin is smaller than with radiotherapy. Most radioactivity will decay within the body, but a small part will be eliminated through your urine. Therefore, for one week after the Zevalin infusion you must wash your hands thoroughly each time after urinating.

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

If your doctor plans to treat you with some other antibody after treatment with Zevalin, you will need to be tested for special antibodies. Your doctor will tell you if this applies to you.

If you have received more Zevalin than you should

Your doctor will treat you, as appropriate, if you have any particular ill effects. This may include discontinuation of Zevalin therapy and treatment with growth factors or your own stem cells.

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

Tell your doctor immediately if you notice symptoms of any of the following:
- infection: fever, chills
- blood poisoning (sepsis): fever and chills, changes in mental status, rapid breathing, increased heart rate, decreased urine output, low blood pressure, shock, problems with bleeding or clotting
- infections of the lung (pneumonia): breathing difficulties

Low counts of blood cells unusual bruising, more bleeding then usual after injury, fever, or if you feel unusually tired or breathless severe mucous membrane reactions, which may occur days or months after Zevalin andor rituximab administration. Your doctor will immediately stop the treatment. extravasation leakage of the infusion to the surrounding tissue pain, burning sensation, stinging or another reaction at the infusion site during administration. Your doctor will immediately stop the infusion and restart it using another vein. allergic hypersensitivity reactionsinfusion reactions symptoms for allergic reactions infusion reactions may be skin reactions, breathing difficulties, swelling, itching, flushing, chills, dizziness as potential sign for low blood pressure. Depending on the kindseverity of reaction your doctor will decide if treatment must be stopped immediately.

Side effects may occur with certain frequencies, which are defined as follows:
- very common: occur in at least 1 in 10 patients
- common: occur in at least 1 in 100 patients but less than 1 in 10 patients
- uncommon: occur in at least 1 in 1,000 patients but less than 1 in 100 patients - rare: occur in at least 1 in 10,000 patients but less than 1 in 1,000 patients
- very rare: occur in less than 1 in 10,000 patients
- not known: frequency cannot be estimated from the available data.

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

The side effects marked with two asterisks (**) were observed additionally under consolidation therapy.

Very common side effects

• decreased number of blood platelets, white and red blood cells ( thrombocytopenia, leukocytopenia, neutropenia, anaemia )*
• feeling sick (nausea)
• weakness, fever, chills (rigor)
• infection*
• tiredness**
• red pinpoint spots under the skin ( petechia)**

Common side effects

• blood poisoning ( sepsis)*; infection of the lungs (pneumonia)*; urinary tract infection, fungal infections in the mouth such as oral thrush ( oral candidiasis)
• other blood related cancers ( myelodysplastic syndrome (MDS) / acute myeloid leukaemia (AML)) *; tumour pain
• fever with decrease in the number of specific white blood cells (febrile neutropenia); decreased counts of all blood cells (pancytopenia)*; decreased number of lymphocytes (lymphocytopenia)
• allergic ( hypersensitivity) reactions
• severe loss of appetite (anorexia)
• feeling anxious ( anxiety); trouble sleeping ( insomnia)
• dizziness; headache,
• bleeding due to decreased blood platelet counts*,
• cough; runny nose
• vomiting, stomach ( abdominal) pain; diarrhoea; indigestion; throat irritation; constipation
• rash; itching ( pruritus)
• joint pain ( arthralgia) aching muscles ( myalgia); back pain; neck pain
• pain; flu-like symptoms; generally feeling unwell ( malaise), swelling caused by build-up of fluid in the arms and legs and other tissues ( peripheral oedema); increased sweating
• high blood pressure ( hypertension)**
• low blood pressure ( hypotension)**
• absence of menstruation (amenorrhea)**

Uncommon side effects:

• rapid heart beat ( tachycardia),

Rare side effects:

• benign brain tumour ( meningioma),
• bleeding in the head due to decreased blood platelet counts*,

Side effects for which frequency is not known:

• reaction of the skin and mucous membranes (including Stevens-Johnson Syndrome) *
• leakage of the infusion to the surrounding tissue ( extravasation), causing skin inflammation (infusion site dermatitis) and shedding ( infusion site desquamation) or injection site ulcers
• tissue damage around tumours of the lymph system and complications due to swelling of such tumours

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use Zevalin after the expiry date which is stated on the pack.

This medicine will be stored by a healthcare professional.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Store the vials in the original package in order to protect from light.
Storage must be in accordance with national regulations for radioactive materials.

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

What Zevalin contains

The active substance is ibritumomab tiuxetan. Each vial contains 3.2 mg ibritumomab tiuxetan in 2 ml solution 1.6 mg per ml. The other ingredients are ibritumomab tiuxetan vial sodium chloride, water for injections sodium acetate vial sodium acetate, water for injections formulation buffer vial 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

Y ibritumomab tiuxetan in a total The final formulation after radiolabelling contains 2.08 mg 90volume of 10 ml.

What Zevalin looks like and contents of the pack

Zevalin is a kit for radiopharmaceutical preparation for infusion, containing:

• One ibritumomab tiuxetan glass vial, with 2 ml clear, colourless solution.
• One sodium acetate glass vial, with 2 ml clear, colourless solution.
• One formulation buffer glass vial, with 10 ml clear, colourless solution.
• One reaction glass vial (empty)

Marketing Authorisation Holder and Manufacturer

Bayer Schering Pharma AG, 13342 Berlin, Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. The list of local representatives is located at the end of this leaflet/booklet.

Luxembourg Luxemburg Bayer SA-NV TélTel 32-02-535 6311 Magyarország Bayer Hungária KFT Tel 36-1-487 4100 Malta Alfred Gera and Sons Ltd. Tel 356-21 44 62 05 Nederland Bayer B.V., Bayer Schering Pharma Tel 31-0297-28 06 66 Norge Bayer AS Tlf 47-24 11 18 00 Österreich Bayer Austria Ges. m. b. H. Tel 43-01-711 460 Polska Bayer Sp. z o.o. Tel 48-22-572 35 00 Portugal Bayer Portugal S.A Tel 351-21-416 42 00 România SC Bayer SRL Tel 40-021-528 59 00 Slovenija Bayer d. o. o. Tel 386-01-58 14 400 Slovenská republika Bayer, spol. s r.o. Tel 421-02-59 21 31 11 SuomiFinland Bayer Oy, Bayer Schering Pharma PuhTel 358-020-78521 Sverige Bayer AB Tel 46-08-580 223 00 United Kingdom Bayer plc Tel 44-01635-56 30 00 België Belgique Belgien Bayer SA-NV TélTel 32-02-535 6311 35902-81 401 01 eská republika Bayer s.r.o. Tel 420-266 101 111 Danmark Bayer AS Tlf 45-45 235 000 Deutschland Bayer Vital GmbH Tel 49-0214-30 513 48 Eesti Bayer OÜ Tel 372-655 85 65 Bayer 30-210-618 75 00 España Química Farmacéutica Bayer S.L. Tel 34-93-495 65 00 France Bayer Santé Tél 33-03-28 16 34 00 Ireland Bayer Limited Tel 353-01-2999 313 Ísland Icepharma hf. Tel 354-540 8000 Italia Bayer S.p.A. Tel 39-02-3978 1 NOVAGEM Limited 357-22-747 747 Latvija SIABayer Tel 371-67 84 55 63 Lietuva UAB Bayer Tel 370-5-233 68 68

This leaflet was last approved in