What is it and how is it used?
Zevalin is a kit for the preparation of the active substance ibritumomab tiuxetan [ Y], a monoclonal antibody labelled with the radioactive substance yttrium-90 ( Y). 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.
What do you have to consider before using it?
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”).
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.
How is it used?
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 Y (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.
What are possible side effects?
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
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.
How should it be stored?
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 is it?
Zevalin is a kit for the preparation of a ‘radiolabelled’ infusion (drip into a vein) of the active substance ibritumomab tiuxetan.
What is it used for?
Zevalin is not used directly, but it must be radiolabelled before use. Radiolabelling is a technique where a substance is tagged (labelled) with a radioactive compound. Zevalin is radiolabelled by mixing it with a solution of radioactive yttrium ( Y) chloride.
The radiolabelled medicine is used to treat adult patients with follicular B-cell non-Hodgkin’s lymphoma. This is a cancer of the lymph tissue (part of the immune system) that affects a type of white blood cell called B-lymphocytes, or B-cells. Zevalin is used in the following groups of patients:
- patients who have gone into remission (reduction in the number of cancerous cells) after their first ‘induction treatment’ (initial chemotherapy treatment) for lymphoma. Zevalin is given as ‘consolidation therapy’ to improve the remission;
- patients in whom rituximab (another treatment for non-Hodgkin’s lymphoma) is no longer effective or whose disease has come back after rituximab treatment. The medicine can only be obtained with a prescription.
How is it used?
Radiolabelled Zevalin treatment should only be handled and given by someone who is authorised to use radioactive medicines.
Before treatment with radiolabelled Zevalin, the patients must first receive an infusion of rituximab (at a dose lower than would be used for treatment) to clear B-cells from their circulation, leaving the cancerous B-cells in the lymph tissue. This enables Zevalin to deliver radiation more specifically to the cancerous B–cells. This is followed, seven to nine days later, by a second infusion of rituximab and an injection of radiolabelled Zevalin. Zevalin must be given as a slow infusion lasting 10 minutes. The dose of Zevalin is calculated to give the appropriate amount of radioactivity for the patient’s condition, based on the blood cell count.
How does it work?
The active substance in Zevalin, ibritumomab, is a monoclonal antibody. A monoclonal antibody is an antibody (a type of protein) that has been designed to recognise and bind to a specific structure (called
How has it been studied?
For consolidation therapy, Zevalin has been studied in one main study involving 414 patients who had achieved a partial or complete remission during induction treatment for non-Hodgkin’s lymphoma. The study compared patients who received Zevalin and patients who received no additional treatment. The main measure of effectiveness was the length of time the patients survived without their disease getting worse.
Zevalin has also been studied in a total of 306 patients with non-Hodgkin’s lymphoma who were not responding to other treatments or whose disease had come back after previous treatment. The main study compared the effectiveness of Zevalin with that of rituximab in 143 patients. In an additional study, 57 patients with follicular lymphoma who had been previously treated and were not responding to rituximab received Zevalin. In both studies, the main measure of effectiveness was the number of patients whose disease responded partially or completely to treatment.
What benefits has it shown during the studies?
When Zevalin was used as consolidation therapy, patients survived for longer without their disease getting worse than when they received no further treatment. Patients receiving radiolabelled Zevalin survived for an average of 37 months until their disease got worse, compared with 14 months in those who did not receive any further treatment. However, there were too few patients who had received rituximab as part of their induction treatment to determine whether there would be a benefit of using Zevalin as consolidation treatment in these patients.
In patients who were not responding to other treatments or whose disease had come back after previous treatment, Zevalin was more effective than rituximab: 80% of the patients receiving radiolabelled Zevalin responded, compared with 56% of the patients receiving rituximab. However, the time taken for the disease to get worse after treatment was the same in both groups (about 10 months). In the additional study, radiolabelled Zevalin brought about a response in about half of the patients.
What is the risk associated?
Radiolabelled Zevalin is radioactive and its use may carry a risk of cancer and hereditary defects. The doctor who prescribes it must ensure that the risks linked to the exposure to the radioactivity are lower than the risks from the disease itself. The most common side effects with Zevalin (seen in more than 1 patient in 10) are anaemia (low red blood cell counts), leucocytopenia and neutropenia (low white blood cell counts), thrombocytopenia (low blood platelet counts), asthenia (weakness), pyrexia (fever), rigors (stiffness) and nausea (feeling sick). For the full list of all side effects reported with Zevalin, see the Package Leaflet.
Zevalin should not be used in people who may be hypersensitive (allergic) to ibritumomab, yttrium chloride, mouse proteins or any of the other ingredients. Zevalin must not be used in patients who are pregnant or breast feeding.
Why has it been approved?
The Committee for Medicinal Products for Human Use (CHMP) decided that Zevalin’s benefits are greater than its risks as consolidation therapy after remission induction in previously untreated patients with follicular lymphoma and for the treatment of adult patients with rituximab relapsed or refractory CD20-positive follicular B-cell non-Hodgkin's lymphoma. The Committee recommended that Zevalin be given marketing authorisation.
Zevalin was originally authorised under ‘Exceptional Circumstances’ because it had not been possible to obtain complete information about Zevalin. As the company had supplied the additional information requested, the ‘Exceptional Circumstances’ ended on 22 May 2008.
Further information
The European Commission granted a marketing authorisation valid throughout the European Union for Zevalin to Bayer Schering Pharma AG on 16 January 2004. The marketing authorisation was renewed on 16 January 2009.
Name
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations for
infusion
Composition
Zevalin is supplied as a kit for the preparation of yttrium-90 radiolabelled ibritumomab tiuxetan. The kit contains one ibritumomab tiuxetan vial, one sodium acetate vial, one formulation buffer vial, and one empty reaction vial.
One ibritumomab tiuxetan vial contains 3.2 mg ibritumomab tiuxetan* in 2 ml solution (1.6 mg per ml).
*murine IgG monoclonal antibody produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell line and conjugated to the chelating agent MX-DTPA.
Excipients
This medicinal product can contain up to 28 mg sodium per dose, depending on the radioactivity concentration. To be taken into consideration by patients on a controlled sodium diet.
For a full list of excipients, see section 6.1.
Pharmaceutical Form
Kit for radiopharmaceutical preparations for infusion.
Ibritumomab tiuxetan vial: Clear colourless solution.
Sodium acetate vial: Clear colourless solution.
Formulation buffer vial: Clear colourless solution.
