Boxed warningThe FDA label of this medicine carries a boxed warning, the strongest warning the FDA gives. Read it under warnings and precautions.
Indications
Zevalin is a CD20-directed radiotherapeutic antibody administered as part of the Zevalin therapeutic regimen indicated for the treatment of adult patients with: relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) ( 1.1 ). previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy ( 1.2 ).
1.1Relapsed or Refractory, Low-grade or Follicular NHL
Zevalin is indicated for the treatment of adult patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).
1.2Previously Untreated Follicular NHL
Zevalin is indicated for the treatment of previously untreated follicular NHL in adult patients who achieve a partial or complete response to first-line chemotherapy.
Contraindications
None. None.
Warnings and precautions
Serious Infusion Reactions: Immediately discontinue rituximab and Y-90 Zevalin. ( 5.1 , 6.1 ) Prolonged and Severe Cytopenias: Do not administer Zevalin to patients with ≥ 25% lymphoma marrow involvement or impaired bone marrow reserve. ( 5.2 , 6.1 ) Severe Cutaneous and Mucocutaneous Reactions: Discontinue rituximab and Zevalin infusions if patients develop severe cutaneous or mucocutaneous reactions. ( 5.3 , 6.2 ) Development of Leukemia and Myelodysplastic Syndrome: Monitor patients for hematological toxicity including secondary malignancies.
( 5.4 , 6.1 ) Extravasation: Monitor for extravasation and terminate infusion if it occurs. Resume infusion in another limb. ( 5.5 , 6.2 ) Immunization: Do not administer live viral vaccines to patients who recently received Zevalin. ( 5.6 ) Embryo-fetal Toxicity: May cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.8 , 8.1 , 8.3 )
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 rituximab/Zevalin in facilities where immediate access to resuscitative measures is available [ see Boxed Warning and Dosage and Administration ( 2.2 ) ]. See also prescribing information for rituximab.
5.2Prolonged 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/mm 3 ) 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 [ see Boxed Warning and Adverse Reactions ( 6.1 ) ]. 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.
5.3Severe 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 [ see Boxed Warning and Adverse Reactions ( 6.2 ) ].
5.4Risk 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 [ see Adverse Reactions ( 6.1 ) ]. 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.
Monitor patients for hematological toxicity including development of MDS or AML.
5.5Extravasation
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 [ see Dosage and Administration ( 2.2 ) ] .
5.6Risks 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.
5.7 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.
5.8Embryo-Fetal Toxicity Based
on its radioactivity, Y-90 Zevalin may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for a minimum of twelve months after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .
Interactions
Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia. No formal drug interaction studies have been performed with Zevalin. Monitor patients receiving medications that interfere with platelet function or coagulation more frequently for thrombocytopenia. ( 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on its radioactivity, Y-90 Zevalin may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . Immunoglobulins are known to cross the placenta. There are no available data on Zevalin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months. Inform women who become pregnant while receiving Zevalin of the potential fetal risks.
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Adverse reactions
The following serious adverse reactions are discussed in greater detail in other sections of the label: Serious Infusion Reactions [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] . Prolonged and Severe Cytopenias [ see Boxed Warning and Warnings and Precautions ( 5.2 ) ]. Severe Cutaneous and Mucocutaneous Reactions [ see Boxed Warning and Warnings and Precautions ( 5.3 ) ]. Leukemia and Myelodysplastic Syndrome [ see Warnings and Precautions ( 5.4 ) ].
Common adverse reactions ( > 10%) in clinical trials were: cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Acrotech Biopharma Inc. at 1-866-298-8433 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The reported safety data reflects exposure to Zevalin in 349 patients with relapsed or refractory, low-grade, follicular or transformed NHL across 5 trials (4 single arm and 1 randomized) and in 206 patients with previously untreated follicular NHL in a randomized trial (FIT study) who received any portion of the Zevalin therapeutic regimen.
The safety data reflect exposure to Zevalin in 270 patients with relapsed or refractory NHL with platelet counts ≥150,000/ mm 3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Zevalin (Group 1 in Table 4 ), 65 patients with relapsed or refractory NHL with platelet counts of ≥ 100,000 but ≤ 149,000 /mm 3 who received 0.3 mCi/kg (11.1 MBq/kg) of Y-90 Zevalin (Group 2 in Table 4 ), and 204 patients with previously untreated NHL with platelet counts ≥150,000/ mm 3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Zevalin; all patients received a single course of Zevalin.
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.
Table 2 displays selected adverse reaction incidence rates in patients who received any portion of the Zevalin therapeutic regimen (n=206) or no further therapy (n=203) following first-line chemotherapy (FIT study). Table 2. Per-Patient Incidence (%) of Selected Between-group difference of ≥5% Adverse Reactions Occurring in ≥ 5% of Patients with Previously Untreated Follicular NHL Treated with the Zevalin Therapeutic Regimen Zevalin (n=206) Observation (n=203) All Grades NCI CTCAE version
Grade 2-4 hematologic toxicity occurred in 86% of Zevalin-treated patients. Table 3. Per-Patient Incidence (%) of Hematologic Adverse Reactions in Patients with Relapsed or Refractory Low-grade, Follicular or Transformed B-cell NHL Occurring within the 12 weeks following the first rituximab infusion of the Zevalin therapeutic regimen (N = 349) All Grades % Grade 3-4 % Thrombocytopenia 95 63 Neutropenia 77 60 Anemia 61 17 Ecchymosis 7 <1 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 (FIT study) receiving Y-90 Zevalin are shown in Table 4 . Table 4. Severe Hematologic Toxicity in Patients Receiving Zevalin Baseline Platelet Count Group 1 (n=270) ≥ 150,000/mm 3 Group 2 (n=65 ) ≥ 100,000 but ≤ 149,000/mm 3 FIT study (n=204) ≥ 150,000/mm 3 Y-90 Zevalin Dose 0.4 mCi/kg (14.8 MBq/kg) 0.3 mCi/kg (11.1 MBq/kg) 0.4 mCi/kg (14.8 MBq/kg) ANC Median nadir (per mm 3 ) 800 600 721 Per patient Incidence ANC <1000/mm 3 57% 74% 65% Per Patient Incidence ANC <500/mm 3 30% 35% 26% Median Duration (Days) Day from last ANC ≥1000/mm 3 to first ANC ≥1000/mm 3 following nadir, censored at next treatment or death ANC <1000/mm 3 22 29 29 Median Time to Recovery Day from nadir to first count at level of Grade 1 toxicity or baseline 12 13 15 Platelets Median nadir (per mm 3 ) 41,000 24,000 42,000 Per Patient Incidence Platelets <50,000/mm 3 61% 78% 61% Per Patient Incidence Platelets <10,000/mm 3 10% 14% 4% Median Duration (Days) Day from last platelet count ≥50,000/mm 3 to day of first platelet count ≥50,000/mm 3 following nadir, censored at next treatment or death Platelets <50,000/mm 3 24 35 26 Median Time to Recovery 13 14 14 Cytopenias were more severe and more prolonged among eleven (5%) patients who received Zevalin after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non-fludarabine-containing regimens.
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
IBRITUMOMAB TIUXETAN 3.2MG/2ML
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA125019.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Among these eleven patients, the median platelet nadir was 13,000/mm 3 with a median duration of platelets below 50,000/mm 3 of 56 days and the median time for platelet recovery from nadir to Grade 1 toxicity or baseline was 35 days. The median ANC was 355/mm 3 , with a median duration of ANC below 1,000/mm 3 of 37 days and the median time for ANC recovery from nadir to Grade 1 toxicity or baseline was 20 days. The median time to cytopenia was similar across patients with relapsed/refractory NHL and those completing first-line chemotherapy, with median ANC nadir at 61-62 days, platelet nadir at 49-53 days, and hemoglobin nadir at 68-69 days after Y-90-Zevalin administration.
Information on hematopoietic growth factor use and platelet transfusions is based on 211 patients with relapsed/refractory NHL and 206 patients following first-line chemotherapy. Filgrastim was given to 13% of patients and erythropoietin to 8% with relapsed or refractory disease; 14% of patients receiving Zevalin following first-line chemotherapy received granulocyte-colony stimulating factors and 5% received erythopoiesis-stimulating agents.
Platelet transfusions were given to approximately 22% of all Zevalin-treated patients. Red blood cell transfusions were given to 20% of patients with relapsed or refractory NHL and 2% of patients receiving Zevalin following first-line chemotherapy. Infections In relapsed or refractory NHL patients, infections occurred in 29% of 349 patients during the first 3 months after initiating the Zevalin therapeutic regimen and 3% developed serious infections (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection).
Life-threatening infections were reported in 2% (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis). From 3 months to 4 years after Zevalin treatment, 6% of patients d
