ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations for infusion
2.
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
1
monoclonal antibody produced by recombinant DNA technology in a Chinese hamster
ovary (CHO) cell line and conjugated to the chelating agent MX-DTPA.
The final formulation after radiolabelling contains 2.08 mg ibritumomab tiuxetan [
90
Y] in a total
volume of 10 ml.
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.
3.
Kit for radiopharmaceutical preparations for infusion.
Ibritumomab tiuxetan vial: Clear colourless solution.
Sodium acetate vial: Clear colourless solution.
Formulation buffer vial: Clear colourless solution.
4.
[
90
Y]-radiolabelled Zevalin is indicated as consolidation therapy after remission induction in
previously untreated patients with follicular lymphoma. The benefit of Zevalin following rituximab in
combination with chemotherapy has not been established.
[
90
Y]-radiolabelled Zevalin is indicated for the treatment of adult patients with rituximab relapsed or
refractory CD20+ follicular B-cell non-Hodgkin's lymphoma (NHL).
2
[
90
Y]-radiolabelled Zevalin must only be received, handled and administered by qualified personnel
and must be prepared in accordance with both radiation safety and pharmaceutical quality
requirements (for more details see also sections 4.4, 6.6 and 12).
Posology
Zevalin must be used following pretreatment with rituximab. Please refer to the Summary of Product
Characteristics of rituximab for detailed guidance on its use.
The treatment regimen consists of two intravenous administrations of rituximab and one
administration of [
90
Y]-radiolabelled Zevalin solution in the following order:
Day 1: intravenous infusion of 250 mg/m
2
rituximab.
Day 7 or 8 or 9:
-
intravenous infusion of 250 mg/m
2
rituximab shortly (within 4 hours) before
administration of [
90
Y]-radiolabelled Zevalin solution.
-
10-minute intravenous infusion of [
90
Y]-radiolabelled Zevalin solution.
Repeated use:
Data on the re-treatment of patients with Zevalin are not available.
The recommended radioactivity dose of [
90
Y]-radiolabelled Zevalin solution is:
Treatment of rituximab relapsed or refractory CD20+ follicular B-cell non-Hodgkin's lymphoma
(NHL):
-
patients with ≥ 150,000 platelets/mm
3
: 15 MBq/kg body weight.
-
patients with 100,000-150,000 platelets/mm
3
: 11 MBq/kg
The maximum dose must not exceed 1200 MBq.
Repeated use: Data on the re-treatment of patients with [90Y]-radiolabeled Zevalin are not available.
Consolidation therapy after remission induction in previously untreated patients with follicular
lymphoma
-
patients with ≥ 150,000 platelets/mm³: 15 MBq/kg up to a maximum of 1200 MBq.
- For patients with less than 150,000 platelets per mm³ see section ‘4.4’
Repeated use: Data on the re-treatment of patients with [90Y]-radiolabelled Zevalin are not available.
Special populations
Paediatric use
Zevalin is not recommended for use in children and adolescents below 18 years due to a lack of
data on safety and efficacy.
Geriatric patients
Limited data in elderly patients (aged ≥ 65 years) are available. No overall differences in safety or
efficacy were observed between these patients and younger patients.
Patients with hepatic impairment
The safety and efficacy have not been studied in patients with hepatic impairment.
Patients with renal impairment
The safety and efficacy have not been studied in patients with renal impairment.
3
Method of administration
The [
90
Y]-radiolabelled Zevalin solution must be prepared according to section 12.
Before administration to the patient, the percent radioincorporation of the prepared [
90
Y]-radiolabelled
Zevalin must be checked according to the procedure outlined in section 12.
If the average radiochemical purity is less than 95%, the preparation must not be administered.
The prepared solution must be given as a slow intravenous infusion over 10 minutes.
The infusion must not be administered as an intravenous bolus.
Zevalin may be infused directly by stopping the flow from an infusion bag and administering it
directly into the line. A 0.2 or 0.22 micron low protein-binding filter must be on line between the
patient and the infusion port. The line must be flushed with at least 10 ml of sodium chloride 9 mg/ml
(0.9%) solution for injection after the infusion of Zevalin.
-
Hypersensitivity to ibritumomab tiuxetan, to yttrium chloride, or to any of the excipients.
-
Hypersensitivity to rituximab or to other murine-derived proteins
Since the Zevalin regimen includes rituximab, see also the Summary of Product Characteristics of
rituximab.
[
90
Y]-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’).
[
90
Y]-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:
- > 25% of the bone marrow infiltrated by lymphoma cells
- prior external beam radiation affecting more than 25% of active bone marrow
- platelet counts <100,000/mm
3
(monotherapy) and <150,000/mm
3
(consolidation treatment)
- neutrophil counts < 1,500/mm
3
-
prior bone marrow transplant or stem cell support
Haematological toxicity
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
4
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).
Treatment with growth factors
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).
Human anti-murine antibodies
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
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
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
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.
Contraception
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 [
90
Y]-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).
Immunization
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
5
(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.
NHL with CNS involvement
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.
Extravasation
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.
Excipients
The final [
90
Y]-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’).
Pregnancy
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.
Lactation
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
6
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).
Fertility
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 [
90
Y]-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.
The radiation dose resulting from therapeutic exposure may result in secondary malignancies and in
development of hereditary defects. 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:
Infections
Haemorrhage while thrombocytopenic
Myelodysplastic syndrome / acute myeloid leukaemia
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.
Infection
Sepsis
Pneumonia
Myelodysplastic syndrome / Acute myeloid leukaemia
Anaemia
Pancytopenia
Haemorrhage while thrombocytopenic
Intracranial haemorrhage while thrombocytopenic
Mucocutaneous reactions, including Stevens-Johnson Syndrome
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
7
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
System Organ Class
(MedDRA)
Very common
Common
Uncommon
Rare
Not known
Infections and
infestations
Infection*
*,
Sepsis*,
Pneumonia*,
Urinary tract
infection,
Oral candidiasis
Neoplasms benign,
malignant and
unspecified (incl cysts
and polyps)
Tumour pain,
Myelodysplastic
syndrome/Acute
myeloid
leukaemia*
Meningioma
Blood and lymphatic
system disorders
Thrombocytopenia,
Leukocytopenia,
Neutropenia,
Anaemia*
Febrile neutropenia,
Pancytopenia*,
Lymphocytopenia
Immune system
disorders
Hypersensitivity
reaction
Metabolism and
nutrition disorders
Anorexia
Psychiatric disorders
Anxiety,
Insomnia
Nervous system
disorders
Dizziness,
Headache
Cardiac disorders
Tachycardia
Vascular disorders
Petechiae**
Haemorrhage while
thrombocytopenic
*
Hypertension**
Hypotension**
Intracranial
haemorrhage while
thrombocyto-
penic*
Respiratory, thoracic,
and mediastinal
disorders
Cough,
Rhinitis
Gastrointestinal
disorders
Nausea
Vomiting,
Abdominal pain,
8
System Organ Class
(MedDRA)
Very common
Common
Uncommon
Rare
Not known
Diarrhoea,
Dyspepsia,
Throat irritation,
Constipation
Reproductive system
and breast disorders
Amenorrhea
**
Skin and
subcutaneous tissue
disorders
Rash,
Pruritus
Mucocutaneous
reaction
(including Stevens
Johnson
Syndrome) *
Musculoskeletal and
connective tissue
disorders
Arthralgia,
Myalgia,
Back pain,
Neck pain
General disorders and
administration site
conditions
Asthenia,
Pyrexia,
Rigors
Fatigue**
Pain,
Flu-like symptoms,
Malaise,
Peripheral oedema,
Sweating increased
Extravasation
with subsequent
infusion site
reactions,
Damage to
lymphoma-
surrounding 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.
Blood and lymphatic system disorders
Haematological toxicity has been very commonly observed in clinical trials, and is dose-limiting
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 and infestations
-
Data from 349 patients with relapsed or refractory low-grade, follicular lymphoma, or
transformed non-Hodgkin’s lymphoma studied in five trials:
During the first 13 weeks after treatment with Zevalin
,
patients very commonly developed
infections. Grade 3 and grade 4 infections were reported commonly. During follow-up,
infections occurred commonly. Of these, grade 3 was common, grade 4 uncommon.
-
Data from 204 patients receiving Zevalin as consolidation therapy after first line remission
induction:
Infections were very commonly observed.
9
Infections may be bacterial, fungal, viral including reactivation of latent viruses.
General disorders and administration site conditions
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
Immune system disorders
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 3/4) hypersensitivity reactions including anaphylaxis occur in less than 1% of patients (see
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
-
Secondary malignancies
Myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML) has been reported in five
out of 211 patients assigned to treatment with Zevalin.
The risk of developing secondary myelodysplasia or leukaemia following therapy with
alkylating agents is well known. Since all of these patients had previously received treatment
regimens including alkylating agents, available results provide insufficient data on whether
Zevalin contributes to an increased risk of MDS/AML, or on the extent of risk.
Doses up to 19.2 MBq/kg of Zevalin have been administered in clinical trials. Expected
haematological toxicity was observed, including grade 3 or 4. Patients recovered from these toxicity
signs, and overdoses were not associated with serious or fatal outcome.
There is no known specific antidote for [
90
Y]-radiolabelled Zevalin overdosage. Treatment consists of
discontinuation of Zevalin and supportive therapy, which may include growth factors. If available,
autologous stem cell support must be administered to manage haematological toxicity.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Various therapeutic radiopharmaceuticals, ATC code: V10XX02
Mechanism of action
Ibritumomab tiuxetan is a recombinant murine IgG
1
kappa monoclonal antibody specific for the B-cell
antigen CD20. Ibritumomab tiuxetan targets the antigen CD20 which is located on the surface of
malignant and normal B-lymphocytes. During B-cell maturation, CD20 is first expressed in the
midstage of B-lymphoblast (pre-B-cell), and is lost during the final stage of B-cell maturation to
plasma cells. It is not shed from the cell surface and does not internalise on antibody binding.
[
90
Y]-radiolabelled ibritumomab tiuxetan binds specifically to CD20-expressing B-cells, including
malignant cells. The isotope yttrium-90 is a pure β-emitter and has a mean path length of about 5 mm.
This results in the ability to kill both targeted and neighbouring cells.
10
The conjugated antibody has an apparent affinity constant for the CD20 antigen of approximately
17 nM. The binding pattern is very restricted, with no cross-reactivity to other leukocytes or to other
types of human tissue.
Rituximab pretreatment is necessary to clear circulating B-cells, enabling ibritumomab tiuxetan [
90
Y]
to deliver radiation more specifically to the lymphoma B-cells. Rituximab is administered in a reduced
dose when compared with the approved monotherapy.
Pharmacodynamic effects
Treatment with [
90
Y]-radiolabelled Zevalin also leads to depletion of normal CD20+ B-cells.
Pharmacodynamic analysis demonstrated that this was a temporary effect; recovery of normal B-cells
began within 6 months and median counts of B-cells were within normal range within 9 months after
treatment.
Clinical safety and efficacy
The safety and efficacy of the Zevalin therapeutic regimen were evaluated in two multi-center trials
enrolling a total of 197 subjects. The Zevalin therapeutic regimen was administered in two steps (see
4.2). The efficacy and safety of a variation of the Zevalin therapeutic regimen employing a reduced
dose of ibritumomab tiuxetan [
90
Y] was further defined in a third study enrolling a total of 30 patients
who had mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm
3
).
Study 1
was a single-arm study of 54 patients with relapsed follicular lymphoma refractory to
rituximab treatment. Patients were considered refractory if their last prior treatment with rituximab did
not result in a complete or partial response, or if time to disease progression (TTP) was 6 months.
The primary efficacy endpoint of the study was the overall response rate (ORR) using the International
Workshop Response Criteria (IWRC). Secondary efficacy endpoints included time to disease
progression (TTP) and duration of response (DR). In a secondary analysis comparing objective
response to the Zevalin therapeutic regimen with that observed with the most recent treatment with
rituximab, the median duration of response following the Zevalin therapeutic regimen was 6 vs.
4 months. Table 1 summarizes efficacy data from this study.
Study 2
was a randomized, controlled, multicenter study comparing the Zevalin therapeutic regimen
versus treatment with rituximab. The trial was conducted in 143 rituximab-naïve patients with relapsed
or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL), or transformed B-cell NHL. A
total of 73 patients received the Zevalin therapeutic regimen, and 70 patients received rituximab given
as an intravenous infusion at 375 mg/m
2
weekly times 4 doses. The primary efficacy endpoint of the
study was to determine the ORR using the IWRC (see Table 2). The ORR was significantly higher
(80% vs. 56%, p = 0.002) for patients treated with the Zevalin therapeutic regimen. The secondary
endpoints, duration of response and time to progression, were not significantly different between the
two treatment arms.
11
Table 2.
Summary of Efficacy Data
in patients with relapsed/refractory low-grade or
follicular non-Hodgkin's lymphoma (NHL), or transformed B-cell NHL
Study 1
Study 2
Zevalin
therapeutic
regimen
N = 54
Zevalin
therapeutic
regimen
N = 73
Rituximab
N = 70
Overall Response Rate (%)
74
80
56
Complete Response Rate (%)
15
30
16
CRu Rate
2
(%)
0
4
4
Median DR
3,4
(Months)
[Range
5
]
6.4
[0.5-24.9+]
13.9
[1.0-30.1+]
11.8
[1.2-24.5]
Median TTP
3,6
(Months)
[Range
5
]
6.8
[1.1-25.9+]
11.2
[0.8-31.5+]
10.1
[0.7-26.1]
1
IWRC: International Workshop response criteria
2
CRu: Unconfirmed complete response
3
Estimated with observed range.
4
Duration of response: interval from the onset of response to disease progression.
5
“+” indicates an ongoing response.
6
Time to Disease Progression: interval from the first infusion to disease progression.
Study 3
was a single arm study of 30 patients with relapsed or refractory low-grade, follicular, or
transformed B-cell NHL who had mild thrombocytopenia (platelet count 100,000 to 149,000
cells/mm
3
). Excluded from the study were patients with 25% lymphoma marrow involvement and/or
impaired bone marrow reserve. Patients were considered to have impaired bone marrow reserve if they
had any of the following: prior myeloablative therapy with stem cell support; prior external beam
radiation to >25% of active marrow; a platelet count <100,000 cells/mm
3
; or neutrophil count <1,500
cells/mm
3
. In this study, a modification of the Zevalin therapeutic regimen with a lower [
90
Y]-Zevalin
activity per body weight (11 MBq/kg) was used. Objective, durable clinical responses were observed
[67% ORR (95% CI: 48-85%), 11.8 months median DR (range: 4-17 months)] and resulted in a
greater incidence of haematologic toxicity (see 4.8) than in Studies 1 and 2.
Study 4
investigated the efficacy and safety of Zevalin consolidation in patients with advanced-stage
follicular lymphoma responding to first-line chemotherapy. Major inclusion criteria were:
CD20+ grade 1 or 2 follicular lymphoma; stage III or IV at diagnosis; normal peripheral
blood cell counts; < 25% bone marrow involvement; age ≥ 18 yrs; and complete response
(CR/Cru) or partial response (PR) after first-line chemotherapy determined by physical
examination, CT scans and bone marrow biopsy. After completing induction therapy, patients
were randomized to receive either Zevalin (250 mg/m
2
rituximab on day -7 and on day 0
followed on day 0 by Zevalin 15 MBq/kg body weight; maximal dose 1200 MBq; [n=208]) or no
further treatment (control; n=206). Induction therapies included CVP n=106, CHOP (-like) n=188,
fludarabine combinations n=22, chlorambucil n=39 and rituximab-chemotherapy combinations
n=59. With a median follow-up of 2.9 years, the median progression free survival (PFS)
increased from 13.5 months (control) to 37 months (Zevalin; p<0.0001; HR 0.465). For patient
subgroups in PR or CR after induction, median PFS was 6.3 vs 29.7 months (p<0.0001; HR
0.304) and 29.9 vs 54.6 months (p=0.015; HR 0.613), respectively. After Zevalin consolidation,
77% of patients in PR after induction therapy converted to CR. Patients whose response status
changed after Zevalin from PR to CR showed a significantly longer median progression free survival
12
time (986 days) compared to those patients who remained in PR (median progression free survival
time of 460 days, p=0.0004). In total, 87% of patients were in CR(u); 76% in CR and 11% in CRu.
5.2 Pharmacokinetic properties
In patients given intravenous infusions of 250 mg/m
2
rituximab followed by intravenous injections of
15 MBq/kg of [
90
Y]-radiolabelled Zevalin, the median serum effective half-life of ibritumomab
tiuxetan [
90
Y] was 28 h.
As
90
Y forms a stable complex with ibritumomab tiuxetan, the biodistribution of the radiolabel follows
the biodistribution of the antibody. Irradiation by the emitted beta particles from
90
Y occurs in a radius
of 5 mm around the isotope.
In clinical studies, the [
90
Y]-radiolabelled Zevalin after pretreatment with rituximab results in a
significant radiation dose to the testes. The radiation dose to the ovaries has not been established.
There is a potential risk that [
90
Y]-radiolabelled Zevalin after pretreatment with rituximab could cause
toxic effects on the male and female gonads (see sections 4.4 and 4.6).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on studies of single and repeated dose
toxicity.
The human radiation dose estimates derived from biodistribution studies in mice with [
90
Y]- or
[
111
In]-radiolabelled ibritumomab tiuxetan predicted acceptable radiation to normal human tissue with
limited levels of skeleton and bone marrow radiation. The linker chelate tiuxetan forms a stable
complex with the radioisotopes yttrium-90 and indium-111 and only negligible degradation due to
radiolysis is expected.
The single and repeated dose toxicity studies of the non-radioactive compound in cynomolgus
monkeys did not indicate any other risk than the expected B-cell depletion arising from the use of
ibritumomab tiuxetan alone or in combination with rituximab. Studies on reproductive and
developmental toxicity have not been performed.
Studies on the mutagenic and carcinogenic potential of Zevalin have not been performed. Due to the
exposure to ionising radiation derived from the radiolabel, a risk of mutagenic and carcinogenic effects
has to be taken into account.
6.
6.1
List of excipients
Ibritumomab tiuxetan vial
:
Sodium chloride
Water for injections
Sodium acetate vial
:
Sodium acetate
Water for injections
Formulation buffer vial
:
Disodium phosphate dodecahydrate
Human albumin solution
Hydrochloric acid, diluted (for pH adjustment)
13
Pentetic acid
Potassium chloride
Potassium dihydrogen phosphate
Sodium chloride
Sodium hydroxide
Water for injections
6.2 Incompatibilities
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.
6.3 Shelf life
4 years.
After radiolabelling, an immediate use is recommended. Chemical and physical in-use stability has
been demonstrated for 8 hours at 2°C - 8°C and protected from light.
6.4
Special precautions for storage
Store in a refrigerator (2C – 8C). Do not freeze.
Store the vials in the original package in order to protect from light.
Storage must be in accordance with local requirements for radioactive materials.
For storage conditions of the radiolabelled product, see section 6.3.
6.5 Nature and contents of container
Zevalin is supplied as a kit for the preparation of yttrium-90 (
90
Y) radiolabelled ibritumomab tiuxetan.
Zevalin contains 1 of each of the following:
Ibritumomab tiuxetan vial
: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing
2 ml solution.
Sodium acetate vial
: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing 2 ml
solution.
Formulation buffer vial
: type I glass vial with a rubber stopper (teflon-lined bromobutyl) containing
10 ml solution.
Reaction vial:
type I glass vial with a rubber stopper (teflon-lined bromobutyl)
Pack size of 1 kit.
6.6 Special precautions for disposal
Any unused product or waste material must be disposed of in accordance with local requirements.
Contaminated materials must be disposed of as radioactive waste by the authorised route.
14
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/03/264/001
9.
Date of first authorisation: 16 January 2004
11. DOSIMETRY
Yttrium-90 decays by the emission of high-energy beta particles, with a physical half-life of
64.1 hours (2.67 days). The product of radioactive decay is stable zirconium-90. The path length of
beta emission (
90
) by yttrium-90 in tissue is 5 mm.
Analyses of estimated radiation absorbed dose were carried out using quantitative imaging with the
gamma-emitter [
111
In]-radiolabelled
Zevalin
,
blood sampling, and the MIRDOSE3 software program.
The imaging dose of [
111
In]-radiolabelled Zevalin
was always given immediately following an infusion
with rituximab at 250 mg/m² to deplete peripheral CD20+ cells and to optimise bio-distribution.
Following administration of [
111
In]-radiolabelled
Zevalin
,
whole body scans were performed at up to
eight time-points, acquiring both anterior and posterior images.
Blood samples, used to calculate
residence times for red marrow, were drawn up to eight time-points.
Based upon dosimetry studies with [
111
In]-radiolabelled
Zevalin, the estimated radiation dosimetry for
individual organs following administration of [
90
Y]-radiolabelled Zevalin at activities of 15 MBq/kg
and 11 MBq/kg was calculated according to Medical Internal Radiation Dosimetry (MIRD) (Table 3).
The estimated radiation-absorbed doses to normal organs were substantially below recognised upper
safety limits. Individual patient dosimetry results were not predictive for [
90
Y]-radiolabelled Zevalin
toxicity.
15
Table 3.
Estimated Radiation Absorbed Doses From [
90
Y]-Zevalin
[
90
Y]-Zevalin
mGy/MBq
Organ
Median
Range
Spleen
1
9.4
1.8 - 20.0
Liver
1
4.8
2.9 - 8.1
Lower Large Intestinal Wall
1
4.7
3.1 – 8.2
Upper Large Intestinal Wall
1
3.6
2.0 – 6.7
Heart Wall
1
2.9
1.5 - 3.2
Lungs
1
2.0
1.2 - 3.4
Testes
1
1.5
1.0 – 4.3
Small Intestine
1
1.4
0.8 – 2.1
Red Marrow
2
1.3
0.6 - 1.8
Urinary Bladder Wall
3
0.9
0.7 - 1.3
Bone Surfaces
2
0.9
0.5 - 1.2
Ovaries
3
0.4
0.3 - 0.5
Uterus
3
0.4
0.3 - 0.5
Adrenals
3
0.3
0.2 - 0.5
Brain
3
0.3
0.2 - 0.5
Breasts
3
0.3
0.2 - 0.5
Gallbladder Wall
3
0.3
0.2 - 0.5
Muscle
3
0.3
0.2 - 0.5
Pancreas
3
0.3
0.2 - 0.5
Skin
3
0.3
0.2 - 0.5
Stomach
3
0.3
0.2 - 0.5
Thymus
3
0.3
0.2 - 0.5
Thyroid
3
0.3
0.2 - 0.5
Kidneys
1
0.1
0.0 - 0.3
Total Body
3
0.5
0.4- 0.7
1
Organ region of interest
2
Sacrum region of interest
3
Whole body region of interest
16
12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
Read complete directions thoroughly before starting the preparation procedure.
Proper aseptic technique and precautions for handling radioactive materials must be employed.
Waterproof gloves must be utilised in the preparation and during the determination of radiochemical
purity of [
90
Y]-radiolabelled Zevalin.
Radiation protection precaution in accordance with local regulations must be taken, since
administration of radiopharmaceuticals creates risks for other persons from external radiation or
contamination from spills of urine, vomiting, etc..
Characteristics of yttrium-90
The following minimum yttrium-90 characteristics are recommended:
Radioactivity concentration at time of use 1.67 to 3.34 GBq/ml
Total extractable activity to deliver at time of use 1.48 GBq corresponding to 0.44 ml to
0.89 ml of yttrium-90 solution
HCl concentration
0.035-0.045 M
Chloride identification
Positive
Yttrium identification
Positive
Radiochemical purity of the yttrium-90 chloride
solution
95% of free ionic yttrium-90
Bacterial endotoxins 150 EU/ml
Sterility No growth
Radionuclidic purity strontium-90 content 0.74 MBq strontium-90 /
37 GBq yttrium-90
Metal impurities
Total metals* 50 ppm
Individual metals* 10 ppm each
* Metals to be included need to be based on the specific manufacturing process. Control of these
metals can be achieved either through process validation or release test.
Additional testing that might be required for suitability assessment:
Process-specific impurities:
Total organic carbon (e.g. organic chelators)
Below limit of quantitation*
Process residuals (e.g. ammonia, nitrate)
Below limit of quantitation*
Total Alpha impurities
Below limit of quantitation*
17
Total other Beta impurities (non-strontium-90) Below limit of quantitation*
Total Gamma impurities Below limit of quantitation*
* Needs to be included as release test or controlled through process validation if above limit of
quantitation
Directions for radio-labelling of Zevalin with yttrium-90
:
Sterile, pyrogen-free yttrium-90 chloride of the above specified quality must be used for the
preparation of [
90
Y]-radiolabelled Zevalin.
Before radiolabelling, bring refrigerated Zevalin cold kit to room temperature 25°C.
Clean the rubber stopper of all cold kit vials and the yttrium-90 chloride vial with a suitable alcohol
swab and allow to air dry.
Place cold kit reaction vial in a suitable dispensing shield (plastic enclosed in lead).
Step 1: Transfer sodium acetate solution to the reaction vial
Using a 1-ml sterile syringe, transfer sodium acetate solution to reaction vial. The volume of sodium
acetate solution added is equivalent to 1.2 times the volume of yttrium-90 chloride to be transferred in
step 2.
Step 2: Transfer yttrium-90 chloride to the reaction vial
Aseptically transfer 1500 MBq of yttrium-90 chloride with a 1 ml sterile syringe to the reaction vial
containing the sodium acetate solution transferred in step 1. Mix completely by coating the entire inner
surface of the reaction vial. Mix by inversion, rolling the container, avoid foaming or agitating the
solution.
Step 3: Transfer ibritumomab tiuxetan solution to the reaction vial
Using a 2-3 ml sterile syringe, transfer 1.3 ml ibritumomab tiuxetan solution to the reaction vial. Mix
completely by coating the entire inner surface of the reaction vial. Mix by inversion, rolling the
container, avoid foaming or agitating the solution.
Incubate the yttrium-90 chloride/acetate/ibritumomab tiuxetan solution at room temperature for five
minutes. Labelling time longer than six minutes or shorter than four minutes will result in inadequate
radioincorporation.
Step 4: Add the formulation buffer to the reaction vial
Using a 10-ml syringe with a large bore needle (18-20 G), draw formulation buffer that will result in a
combined total volume of 10 ml.
After the 5-minute incubation period, withdraw from the reaction vial the same volume of air as the
formulation buffer to be added in order to normalise pressure and immediately thereafter gently add
the formulation buffer down the side of the reaction vial to terminate incubation. Do not foam, shake,
or agitate the mixture.
Step 5: Assay the [
90
Y]-radiolabelled Zevalin solution for its specific radioactivity
18
Radiochemical purity of the radiolabelled preparation applies as long as more than 95% of yttrium-90
is incorporated into the monoclonal antibody.
Before administration to the patient, the percent radioincorporation of the prepared [
90
Y]-radiolabelled
Zevalin must be checked according to the procedure outlined below.
Caution
: Patient dose not to exceed 1200 MBq.
Instructions for determining the percent radioincorporation
The radioincorporation assay for radiochemical purity, is performed by Instant Thin Layer
Chromatography (ITLC) and must be carried out according to the following procedure.
Required materials not supplied in the Zevalin kit
:
- Developing chamber for chromatography
- Mobile phase: sodium chloride 9 mg/ml (0.9%) solution, bacteriostatic-free
- ITLC strips (e.g. ITLC TEC-Control Chromatography Strips, Biodex, Shirley, New York, USA, Art.
Nr. 150-772 or equivalent, dimensions: approximately 0.5-1 cm x 6 cm)
- Scintillation vials
- Liquid scintillation cocktail (e.g. Ultima Gold, catalog No. 6013329, Packard Instruments, USA or
equivalent)
Assay procedure:
1.) Add approximately 0.8 ml sodium chloride 9 mg/ml (0.9%) solution to developing chamber
assuring the liquid will not touch the 1.4 cm origin mark on the ITCL strip.
2.) Using a 1 ml insulin syringe with a 25- to 26-G needle, place a hanging drop (7-10 µl) of [
90
Y]-
radiolabelled Zevalin
onto the ITLC strip at its origin. Spot one strip at a time and run three ITLC
strips. It may be necessary to perform a dilution (1:100) before application of the [
90
Y]-radiolabelled
Zevalin to the ITLC strips.
3.) Place ITLC strip in the developing chamber and allow the solvent front to migrate past the 5.4 cm
mark.
4.) Remove ITLC strip and cut in half at the 3.5 cm cut line. Place each half into separate scintillation
vials to which 5 ml LSC cocktail must be added (e.g. Ultima Gold, catalog No. 6013329, Packard
Instruments, USA or equivalent). Count each vial in a beta counter or in an appropriate counter for one
minute (CPM), record net counts, corrected for background.
5.) Calculate the average Radiochemical Purity (RCP) as follows:
6.) Average % RCP =
net CPM bottom half
x 100
net CPM top half + net CPM bottom half
7.) If the average radiochemical purity is less than 95%, the preparation must not be administered.
19
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
20
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Biogen IDEC, Inc.14 Cambridge Center
Cambridge, MA 02142
USA
Name and address of the manufacturer responsible for batch release
Bayer Schering Pharma AG
Müllerstrasse 178
13342 Berlin
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.1 of the Risk Management Plan (RMP) presented
in Module 1.8.2 of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP must be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP must be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the EMEA
21
ANNEX III
LABELLING AND PACKAGE LEAFLET
22
A. LABELLING
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations for infusion
Ibritumomab tiuxetan [
90
Y]
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 3.2 mg ibritumomab tiuxetan* to be diluted in 2 ml solution (1.6 mg per ml).
*recombinant murine IgG
1
monoclonal antibody produced by DNA technology in a Chinese hamster
ovary (CHO) cell line and conjugated to the chelating agent MX-DTPA.
3. LIST OF EXCIPIENTS
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
Water for injections
Please see the package leaflet for further information.
4.
Kit for radiopharmaceutical preparations for infusion.
One ibritumomab tiuxetan vial.
2 ml of sodium acetate solution
10 ml of formulation buffer
Empty reaction vial (10 ml)
24
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Must be administered by authorised personnel only.
8.
EXPIRY DATE
EXP
After radiolabelling, immediate use is recommended. Chemical and physical in-use stability has been
demonstrated for 8 hours at 2°C - 8°C and protected from light.
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
Do not freeze.
Store the vials in the original container in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material must be disposed of in accordance with local requirements.
Contaminated materials must be disposed of as radioactive waste by the authorised route.
Bayer Schering Pharma AG, 13342 Berlin, Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/03/264/001
25
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
26
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
IBRITUMOMAB TIUXETAN SOLUTION VIAL
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations
Ibritumomab tiuxetan solution
Intravenous infusion, after preparation.
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3.2 mg/2 ml
6.
OTHER
27
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SODIUM ACETATE VIAL
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations
Sodium acetate solution
Intravenous infusion, after preparation.
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
2 ml
6.
OTHER
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
FORMULATION BUFFER SOLUTION VIAL
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations
Formulation buffer solution
Intravenous infusion, after preparation.
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
REACTION VIAL
1.
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations
Reaction vial
Intravenous infusion, after preparation.
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Empty
6.
OTHER
30
B. PACKAGE LEAFLET
31
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zevalin 1.6 mg/ml kit for radiopharmaceutical preparations for infusion
Ibritumomab tiuxetan [
90
Y]
Read all of this leaflet carefully before you are given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
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.
In this leaflet:
1.
What Zevalin is and what it is used for
2.
Before you are given Zevalin
3.
How to use Zevalin
4.
Possible side effects
5.
How to store Zevalin
6.
Further information
1.
WHAT ZEVALIN IS AND WHAT IT IS USED FOR
Zevalin is a kit for the preparation of the active substance ibritumomab tiuxetan [
90
Y], a monoclonal
antibody labelled with the radioactive substance yttrium-90 (
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.
2.
BEFORE YOU ARE GIVEN ZEVALIN
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
100,000/mm
3
If the number of your blood platelets is fewer than 150,000/mm
3
after chemotherapy
32
If the number of your white blood cells is fewer than 1,500/mm
3
If 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 ability
to 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.
3.
HOW TO USE ZEVALIN
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).
33
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
90
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.
4.
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
34
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 and/or
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
)
reactions/infusion 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 kind/severity 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
)**
35
-
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.
5.
HOW TO STORE ZEVALIN
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.
6.
FURTHER INFORMATION
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
The final formulation after radiolabelling contains 2.08 mg [
90
Y] ibritumomab tiuxetan in a total
volume of 10 ml.
What Zevalin looks like and contents of the pack
Zevalin is a kit for radiopharmaceutical preparation for infusion, containing:
36
-
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
37
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.
België / Belgique / Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 6311
Luxembourg / Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 6311
България
Байер България ЕООД
Тел: +359–(0)2-81 401 01
Magyarország
Bayer Hungária KFT
Tel: +36-1-487 4100
Česká republika
Bayer s.r.o.
Tel: +420-266 101 111
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Danmark
Bayer A/S
Tlf: +45-45 235 000
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31-(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf: +47-24 11 18 00
Eesti
Bayer OÜ
Tel: +372-655 85 65
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 460
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30-210-618 75 00
Polska
Bayer Sp. z o.o.
Tel: +48-22-572 35 00
España
Química Farmacéutica Bayer S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A
Tel: +351-21-416 42 00
France
Bayer Santé
Tél: +33-(0)3-28 16 34 00
România
SC Bayer SRL
Tel: +40-(0)21-528 59 00
Ireland
Bayer Limited
Tel: +353-(0)1-2999 313
Slovenija
Bayer d. o. o.
Tel: +386-(0)1-58 14 400
Ísland
Icepharma hf.
Tel: +354-540 8000
Slovenská republika
Bayer, spol. s r.o.
Tel: +421-(0)2-59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-3978 1
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358-(0)20-78521
Κύπρος
NOVAGEM Limited
Τηλ: +
357-22-747 747
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIABayer
Tel: +371-67 84 55 63
United Kingdom
Bayer plc
Tel: +44-(0)1635-56 30 00
Lietuva
UAB Bayer
Tel: +370-5-233 68 68
This leaflet was last approved in
38
Source: European Medicines Agency
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