Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Ceft Biopharma s.r.o., Trtinova 260/1, Cakovice, 196 00 Praha 9, Czech Republic
Since the Zevalin regimen includes rituximab, see also the Summary of Product Characteristics of rituximab.
[90Y]-radiolabelled Zevalin solution must only be received, handled and administered by qualified personnel with the appropriate government authorization for the use and manipulation of radionuclides within a designated clinical setting. Its receipt, preparation, use, transfer, storage, and disposal are subject to the regulations and/or appropriate authorisation/licences of the local competent official organisations.
Radiopharmaceuticals must be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions must be taken, complying with the requirements of Good Manufacturing Practice of pharmaceuticals. Infusions must be administered under the close supervision of an experienced physician with full resuscitation facilities immediately available (for radiopharmaceutical precautions see also sections ‘4.2 and 12’).
[90Y]-radiolabelled Zevalin solution must not be administered to patients who are likely to develop life-threatening haematological toxicity signs.
Zevalin must not be administered in patients mentioned below, as safety and efficacy have not been established:
Special caution is required with respect to bone marrow depletion. In most patients, administration of Zevalin (after pretreatment with rituximab) results in severe and prolonged cytopenia which is generally reversible (see section 4.8). Therefore, complete blood cell and platelet counts must be monitored following Zevalin treatment weekly until levels recover or as clinically indicated. The risk of haematological toxicity may be increased after prior therapy with fludarabine containing regimens (for details see section 4.5).
Patients must not receive growth factor treatment such as G-CSF for 3 weeks prior to Zevalin administration as well as for 2 weeks following completion of the treatment in order to assess the adequate bone marrow reserve correctly and because of the potential sensitivity of rapidly dividing myeloid cells to radiation (see also section 4.5).
Patients who had received murine-derived proteins before Zevalin treatment must be tested for human anti-murine antibodies (HAMA). Patients who have developed HAMAs may have allergic or hypersensitivity reactions when treated with Zevalin or other murine-derived proteins.
After use of Zevalin, patients must generally be tested for HAMA before any further treatment with murine-derived proteins.
Infusion reactions may occur during or following Zevalin administration after pretreatment with Rituximab. Signs and symptoms of infusion reactions may include dizziness, cough, nausea, vomiting, rash, pruritus, tachycardia, asthenia, pyrexia and rigors (see section 4.8). In case of a potential severe infusion reaction treatment must be stopped immediately.
Hypersensitivity reactions following Zevalin administration are commonly observed. Severe hypersensitivity reactions including anaphylaxis occur in <1% of patients (see also section 4.8). In case of hypersensitivity reactions, Zevalin infusion must be stopped immediately. Medicinal products for the treatment of hypersensitivity reactions, e.g. adrenaline, antihistamines and corticosteroids, must be available for immediate use in the event of an allergic reaction during administration of rituximab or Zevalin.
Severe mucocutaneous reactions, including Stevens-Johnson Syndrome, some with fatal outcome, have been reported in association with Zevalin after pretreatment with rituximab. The onset of the reactions varied from days to months. In patients experiencing a severe mucocutaneous reaction treatment must be discontinued.
Long-term animal studies on the effect on fertility and reproductive function have not been performed. There is a potential risk that ionizing radiation by [90Y]-radiolabelled Zevalin could cause toxic effects on female and male gonads. Due to the nature of the compound, women of child-bearing potential, as well as males, must use effective contraceptive methods during and up to 12 months after treatment with Zevalin (see also section 4.6 and 5.2).
The safety and efficacy of immunization with any vaccine, particularly live viral vaccines, following therapy with Zevalin have not been studied. Due to the potential risk of developing viral infections it is not recommended to administer live viral vaccines to patients who have recently received Zevalin (see section 4.5). A potentially limited ability to generate a primary or anamnestic humoral response to any vaccine following Zevalin treatment has to be taken into consideration.
No data are available on patients with CNS-lymphoma as those patients were not included in clinical studies. The use of Zevalin is therefore not recommended in NHL patients with CNS involvement.
Close monitoring for evidence of extravasation during the injection of Zevalin is required in order to avoid radiation-associated tissue damage. If any signs or symptoms of extravasation have occurred, the infusion must be immediately terminated and restarted in another vein.
The use of Zevalin is associated with an increased risk of secondary malignancies, including acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), (see also section 4.8).
The final [90Y]-radiolabelled Zevalin solution contains up to 28 mg sodium per dose, depending on the radioactivity concentration. Patients on a controlled sodium diet must take this into consideration.
There are no known interactions with other medicinal products. No interaction studies have been performed.
Growth factor treatment such as G-CSF must not be given to patients for 3 weeks prior to Zevalin administration as well as for 2 weeks following completion of the treatment (see also section 4.4).
In a clinical trial in which Zevalin was administered as consolidation after prior first line chemotherapy, a higher frequency of severe and prolonged neutropenia and thrombocytopenia was observed in patients who had received Zevalin within 4 months after a combination chemotherapy of fludarabine with mitoxantrone and/or cyclophosphamide compared to those patients who had received any other chemotherapy. Hence the risk of haematological toxicity may be increased when Zevalin is administered shortly (<4 months) after fludarabine-containing regimens (see also section 4.4).
The safety and efficacy of immunization with any vaccine, particularly live viral vaccines, following therapy with Zevalin have not been studied (see also section ‘Special warnings and precautions for use’).
Animal reproduction studies were not conducted with ibritumomab tiuxetan. Since IgGs are known to cross the placenta, and because of the significant risk associated with radiation, Zevalin is contraindicated during pregnancy (see section 4.3).
Pregnancy must be excluded before the start of treatment in women.
Any woman who has missed a period must be assumed to be pregnant until proven otherwise and alternative therapies which do not involve ionising radiation must be then considered.
Women of childbearing potential as well as males must use effective contraceptive methods during and up to 12 months after treatment with Zevalin.
Although it is not known whether ibritumomab tiuxetan is excreted in human milk, maternal IgGs are known to be excreted in human milk. Therefore, women must discontinue breast-feeding, as the potential for absorption and immunosuppression in the infant is unknown. Zevalin must be used following pretreatment with rituximab for which breast-feeding is not recommended during treatment and up to 12 months following treatment (please refer to the Summary of Product Characteristics of rituximab for detailed guidance on its use).
No animal studies have been performed to determine the effects of Zevalin on fertility in males or females. There is a potential risk that ionizing radiation by [90Y]-radiolabelled Zevalin could cause toxic effects on female and male gonads (see sections 4.4 and 5.2). Patients should be advised that fertility may be affected and that male patients may wish to consider semen cryopreservation.
Zevalin could affect the ability to drive and to use machines, as dizziness has been reported as a common side effect.
Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself.
Since Zevalin is used after pretreatment with rituximab (for details see section 4.2), see also the prescribing information of rituximab.
The overall safety profile of Zevalin after pretreatment with rituximab is based on data from 349 patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma studied in five clinical trials, on data from a study with 204 patients receiving Zevalin as consolidation therapy after first-line remission induction, and from post-marketing surveillance.
The most frequently observed adverse drug reactions in patients receiving Zevalin after pretreatment with rituximab are thrombocytopenia, leukocytopenia, neutropenia, anaemia, infections, pyrexia, nausea, asthenia, rigors, petechiae, and fatigue.
The most serious adverse drug reactions in patients receiving Zevalin after pretreatment with rituximab are:
Fatal outcomes have been reported for each of the following serious adverse drug reactions. These reports originated either from clinical trials or from postmarking experience.
The frequencies of the adverse drug reactions which were considered to be at least possibly related to Zevalin after pretreatment with rituximab are represented in the table below. These adverse drug reactions are based upon 349 patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma studied in 5 clinical trials. In addition, the adverse drug reactions marked with ** were observed in the study with 204 patients receiving Zevalin as consolidation therapy after first-line remission induction where indicated. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.
Adverse reactions listed below are classified according to frequency and System Organ Class (MedDRA).
Frequency groupings are defined according to the following convention: (very common ≥1/10, common ≥1/100 to <1/10, uncommon ≥1/1,000 to 1/100, rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Zevalin after pretreatment with rituximab:
Very common: Infection*
Common: Sepsis*, Pneumonia*, Urinary tract infection, Oral candidiasis
Common: Tumour pain, Myelodysplastic syndrome/Acute myeloid leukaemia*,**
Rare: Meningioma
Very common: Thrombocytopenia, Leukocytopenia, Neutropenia, Anaemia*
Common: Febrile neutropenia, Pancytopenia*, Lymphocytopenia
Common: Hypersensitivity reaction
Common: Anorexia
Common: Anxiety, Insomnia
Common: Dizziness, Headache
Uncommon: Tachycardia
Very common: Petechiae**
Common: Haemorrhage while thrombocytopenic* Hypertension** Hypotension**
Rare: Intracranial haemorrhage while thrombocytopenic*
Common: Cough, Rhinitis
Very common: Nausea
Common: Vomiting, Abdominal pain, Diarrhoea, Dyspepsia, Throat irritation, Constipation
Common: Amenorrhea**
Common: Rash, Pruritus
Not known: Mucocutaneous reaction (including Stevens Johnson Syndrome)*
Common: Arthralgia, Myalgia, Back pain, Neck pain
Very common: Asthenia, Pyrexia, Rigors Fatigue**
Common: Pain, Flu-like symptoms, Malaise, Peripheral oedema, Sweating increased
Not known: Extravasation with subsequent infusion site reactions, Damage to lymphomasurrounding tissue and complications due to lymphoma swelling
* fatal outcome has been observed
** has been observed in a study with 204 patients receiving Zevalin as consolidation after first-line remission induction
The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Haematological toxicity has been very commonly observed in clinical trials, and is dose-limiting (see also section ‘Special warnings and precautions for use’). Median time to blood platelet and granulocyte nadirs were around 60 days after start of treatment. In clinical trials with the indication of relapsed and refractory NHL, grade 3 or 4 thrombocytopenia was reported with median times to recovery of 13 and 21 days and grade 3 or 4 neutropenia with median times to recovery of 8 and 14 days. Following Zevalin as consolidation after first line remission induction the median times to recovery was 20 days and 35 days for grade 3 or 4 thrombocytopenia and 20 days and 28 days for grade 3 or 4 neutropenia.
Infections may be bacterial, fungal, viral including reactivation of latent viruses.
Reports of extravasation with subsequent infusion site reactions including e.g. infusion site dermatitis, infusion site desquamation, and infusion site ulcer have been received.
Zevalin-associated radiation might cause damage to lymphoma-surrounding tissue and complications due to lymphoma swelling.
Data from 349 patients with relapsed or refractory low-grade, follicular lymphoma, or transformed non-Hodgkin’s lymphoma studied in five trials:
Hypersensitivity reactions following Zevalin administration are commonly observed. Severe (Grade ¾) hypersensitivity reactions including anaphylaxis occur in less than 1% of patients (see also section ‘Special warnings and precautions for use’).
Myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) has been reported in eleven out of 211 patients with relapsed or refractory NHL assigned to treatment with Zevalin in four studies.
From the final analysis at around 7.5 years of a study investigating the efficacy and safety of Zevalin consolidation in patients with advanced-stage follicular lymphoma responding to first-line chemotherapy (Study 4, Section 5.1) of the 204 patients receiving Y-90 Zevalin following first line chemotherapy, 26 (12.7%) patients in the Zevalin arm developed a second primary malignancy compared to 14 (6.8%) of patients in the control arm. Seven patients (3.4%, 7/204) were diagnosed with MDS/AML after receiving Zevalin, compared to one patient (0.5%, 1/205) in the control arm, with a median follow-up of 7.3 years. Deaths due to second primary malignancy included 8 (3.9%) patients in the Zevalin arm compared to 3 (1.5%) patients in the control arm. Deaths due to MDS/AML included five (2.5%) patients in the Zevalin arm compared to no patients in the control arm.
The risk of developing secondary myelodysplasia or leukaemia following therapy with alkylating agents is well known.
Reporting suspected adverse reactions afterauthorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 12.
No incompatibilities have been observed between Zevalin and infusion sets.
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