ASH News Daily 2017 - Issue 2 - A-25

ZEVALIN® (ibritumomab tiuxetan) for Intravenous Injection BRIEF SUMMARY. Please see full Prescribing Information,
including Boxed WARNINGS for ZEVALIN and rituximab.
INDICATIONS AND USAGE:
ZEVALIN is a CD20-directed radiotherapeutic antibody administered as part of the ZEVALIN therapeutic regimen indicated for the treatment of patients with:
* Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).
* Previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy.
WARNING: SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, and SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS
Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These
fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic
shock. Most (80%) fatalities occurred with the first rituximab infusion. Discontinue rituximab and Y-90 ZEVALIN infusions in patients who develop severe
infusion reactions.
Prolonged and Severe Cytopenias: Y-90 ZEVALIN administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 ZEVALIN
to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve.
Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic
regimen. Discontinue rituximab and Y-90 ZEVALIN infusions in patients experiencing severe cutaneous or mucocutaneous reactions.
Dosing: The dose of Y-90 ZEVALIN should not exceed 32.0 mCi (1184 MBq).
DOSAGE AND ADMINISTRATION: Day 1: Administer rituximab 250 mg/m2
IV. Day 7, 8, or 9: Administer rituximab 250 mg/m2 IV infusion. If platelets
≥ 150,000/mm3: Within 4 hours after rituximab infusion, administer 0.4
mCi/kg (14.8 MBq per kg) Y-90 ZEVALIN IV. If platelets ≥ 100,000 but
≤ 149,000/mm3 in relapsed or refractory patients: Within 4 hours after
rituximab infusion, administer 0.3 mCi/kg (11.1 MBq per kg) Y-90 ZEVALIN
IV. Only administer Rituxan/ZEVALIN in facilities where immediate access to
resuscitative measures is available.
DOSAGE FORMS AND STRENGTHS: 3.2 mg per 2 mL in a single-use vial.
CONTRAINDICATIONS: None.
WARNINGS AND PRECAUTIONS: (Please also see BOXED Warning)
Serious Infusion Reactions: See also prescribing information for rituximab.
Rituximab, alone or as a component of the ZEVALIN therapeutic regimen,
can cause severe, including fatal, infusion reactions. These reactions typically
occur during the first rituximab infusion with time to onset of 30 to 120
minutes. Signs and symptoms of severe infusion reactions may include
urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary
infiltrates, acute respiratory distress syndrome, myocardial infarction,
ventricular fibrillation, and cardiogenic shock. Temporarily slow or interrupt
the rituximab infusion for less severe infusion reactions. Immediately
discontinue rituximab and Y-90 ZEVALIN administration for severe infusion
reactions. Only administer Rituxan/ZEVALIN in facilities where immediate
access to resuscitative measures is available.
Prolonged and Severe Cytopenias: Cytopenias with delayed onset and
prolonged duration, some complicated by hemorrhage and severe infection,
are the most common severe adverse reactions of the ZEVALIN therapeutic
regimen. When used according to recommended doses, the incidences of
severe thrombocytopenia and neutropenia are greater in patients with mild
baseline thrombocytopenia (≥ 100,000 but ≤ 149,000 /mm3) compared
to those with normal pretreatment platelet counts. Severe cytopenias
persisting more than 12 weeks following administration can occur. Monitor
complete blood counts (CBC) and platelet counts following the ZEVALIN
therapeutic regimen weekly until levels recover or as clinically indicated. Do
not administer the ZEVALIN therapeutic regimen to patients with ≥ 25%
lymphoma marrow involvement and/or impaired bone marrow reserve. Monitor
patients for cytopenias and their complications (e.g., febrile neutropenia,
hemorrhage) for up to 3 months after use of the ZEVALIN therapeutic
regimen. Avoid using drugs which interfere with platelet function or
coagulation following the ZEVALIN therapeutic regimen.
Severe Cutaneous and Mucocutaneous Reactions: Erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis,
and exfoliative dermatitis, some fatal, were reported in post-marketing
experience. The time to onset of these reactions was variable, ranging from
a few days to 4 months after administration of the ZEVALIN therapeutic
regimen. Discontinue the ZEVALIN therapeutic regimen in patients experiencing a severe cutaneous or mucocutaneous reaction.
Altered Biodistribution: In a post-marketing registry designed to collect biodistribution images and other information in reported cases of altered biodistribution, there were 12 (1.3%) patients reported to have altered biodistribution
among 953 patients registered.

Risk of Developing Myelodysplastic Syndrome, Leukemia, and Other
Malignancies: The radiation dose resulting from therapeutic exposure to Y-90
radiolabeled ZEVALIN may result in secondary malignancies. Myelodysplastic
syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in
5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical
studies and 1.5% (8/535) of patients included in the expanded-access trial,
with median follow-up of 6.5 and 4.4 years, respectively. Among the 19
reported cases, the median time to the diagnosis of MDS or AML was 1.9
years following treatment with the ZEVALIN therapeutic regimen; however, the
cumulative incidence continues to increase. Among 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.
Extravasation: Monitor patients closely for evidence of extravasation during
ZEVALIN infusion. Immediately terminate the infusion if signs or symptoms of
extravasation occur and restart in another limb.
Risks of Immunization: The safety of immunization with live viral vaccines
following the ZEVALIN therapeutic regimen has not been studied. Do not
administer live viral vaccines to patients who have recently received ZEVALIN.
The ability to generate an immune response to any vaccine following the
ZEVALIN therapeutic regimen has not been studied.
Radionuclide Precautions: During and after radiolabeling ZEVALIN with Y-90,
minimize radiation exposure to patients and to medical personnel, consistent
with institutional good radiation safety practices and patient management
procedures.
Embryo-fetal Toxicity: Based on its radioactivity, Y-90 ZEVALIN may cause
fetal harm when administered to a pregnant woman. If the ZEVALIN
therapeutic regimen is administered during pregnancy, the patient should
be apprised of the potential hazard to a fetus. Advise women of childbearing
potential to use adequate contraception for a minimum of twelve months.
ADVERSE REACTIONS: Common adverse reactions (≥ 10%) in clinical
trials were: cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain,
asthenia, cough, diarrhea, and pyrexia. The most common adverse reactions
of ZEVALIN are cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain,
asthenia, cough, diarrhea and pyrexia. The most serious adverse reactions of
ZEVALIN are prolonged and severe cytopenias (thrombocytopenia, anemia,
lymphopenia, neutropenia) and secondary malignancies. Because the
ZEVALIN therapeutic regimen includes the use of rituximab, see prescribing
information for rituximab.
Prolonged and Severe Cytopenias: Patients in clinical studies were not
permitted to receive hematopoietic growth factors beginning 2 weeks prior
to administration of the ZEVALIN therapeutic regimen. The incidence and
duration of severe hematologic toxicity in previously treated NHL patients
(N=335) and in previously untreated patients (Study 4) receiving Y-90
ZEVALIN are shown in the table below.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 2