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Prolonged and Severe Cytopenias:
Y-90 Zevalin administration results in severe and prolonged cytopenias in most patients. Do not administer the Zevalin therapeutic regimen to patients with = 25% lymphoma marrow involvement and/or impaired bone marrow reserve [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the Zevalin therapeutic regimen. Discontinue rituximab, In-111 Zevalin, and Y-90 Zevalin infusions in patients experiencing severe cutaneous or mucocutaneous reactions [see Warnings and Precautions (5.3) and Adverse Reactions (6.3)]. Dosing
In-111 Zevalin and Y-90 Zevalin are radiopharmaceuticals and should be used only by physicians and other professionals qualified by training and experienced in the safe use and handling of radionuclides. CONTRAINDICATIONS The Zevalin therapeutic regimen is contraindicated in patients with known Type I hypersensitivity or anaphylactic reactions to murine proteins or to any component of this product, including Rituximab, yttrium chloride, and indium chloride. WARNINGS Altered Biodistribution: Y-90 Zevalin should not be administered to patients with altered biodistribution of In-111 Zevalin. In a postmarketing 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. For descriptions of expected and altered biodistribution image characteristics, see DOSAGE AND ADMINISTRATION, IMAGE ACQUISITION and INTERPRETATION. Severe Infusion Reactions: The ZEVALIN therapeutic regimen may cause severe, and potentially fatal, infusion reactions. These severe reactions typically occur during the first Rituximab infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reaction may include hypotension, angioedema, hypoxia, or bronchospasm, and may require interruption of Rituximab, In-111 Zevalin, or Y-90 Zevalin administration. The most severe manifestations and sequelae may include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Because the Zevalin therapeutic regimen includes the use of Rituximab, see also prescribing information for RITUXAN (Rituximab). Cytopenias: The most common severe adverse events reported with the Zevalin therapeutic regimen were thrombocytopenia (61% of patients with platelet counts <50,000 cells/mm3) and neutropenia (57% of patients with absolute neutrophil count (ANC) <1,000 cells/mm3) in patients with ≥150,000 platelets/mm3 prior to treatment. Both incidences of severe thrombocytopenia and neutropenia increased to 78% and 74% for patients with mild thrombocytopenia at baseline (platelet count of 100,000 to 149,000 cells/mm3). For all patients, the median time to nadir was 7-9 weeks and the median duration of cytopenias was 22-35 days. In <5% of cases, patients experienced severe cytopenia that extended beyond the prospectively defined protocol treatment period of 12 weeks following administration of the ZEVALIN therapeutic regimen. Some of these patients eventually recovered from cytopenia, while others experienced progressive disease, received further anti-cancer therapy, or died of their lymphoma without having recovered from cytopenia. The cytopenias may have influenced subsequent treatment decisions. Hemorrhage, including fatal cerebral hemorrhage, and severe infections have occurred in a minority of patients in clinical studies. Careful monitoring for and management of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months after use of the ZEVALIN therapeutic regimen are necessary[1]. Caution should be exercised in treating patients with drugs that interfere with platelet function or coagulation following the Zevalin therapeutic regimen and patients receiving such agents should be closely monitored. The Zevalin therapeutic regimen should not be administered to patients with Severe Cutaneous and Mucocutaneous Reactions (See BOXED WARNING and ADVERSE REACTIONS) There have been postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis in patients who received the ZEVALIN therapeutic regimen. Some of these events were fatal. The onset of the reactions was variable; in some cases, acute (days) and in others, delayed (3-4 months). Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further components of the Zevalin therapeutic regimen and should seek prompt medical evaluation[1]. Secondary Leukemia and Myelodysplastic Syndrome: Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients 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 (see ADVERSE REACTIONS); however, the cumulative incidence continues to increase. Pregnancy Category D: Y-90 Zevalin can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Creutzfeldt-Jakob Disease (CJD): This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS The Zevalin therapeutic regimen is intended as a single course treatment. The safety and toxicity profile from multiple courses of the Zevalin therapeutic regimen or of other forms of therapeutic irradiation preceding, following, or in combination with the Zevalin therapeutic regimen have not been established. Radionuclide Precautions: The contents of the Zevalin kit are not radioactive. However, during and after radiolabeling Zevalin with In-111 or Y-90, care should be taken to minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.Hypersensitivity: Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and corticosteroids, should be available for immediate use in the event of an allergic reaction during administration of Zevalin. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA). Patients with evidence of HAMA have not been studied and may be at increased risk of allergic or serious hypersensitivity reactions during Zevalin therapeutic regimen administrations. Immunization: The safety of immunization with live viral vaccines following the Zevalin therapeutic regimen has not been studied. Also, the ability of patients who received the Zevalin therapeutic regimen to generate a primary or anamnestic humoral response to any vaccine has not been studied. 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. Laboratory Monitoring: Complete blood counts (CBC) and platelet counts should be obtained weekly following the Zevalin therapeutic regimen and should continue until levels recover. CBC and platelet counts should be monitored more frequently in patients who develop severe cytopenia, or as clinically indicated. Drug Interactions: No formal drug interaction studies have been performed with Zevalin. Due to the frequent occurrence of severe and prolonged thrombocytopenia, the potential benefits of medications which interfere with platelet function and/or anticoagulation should be weighed against the potential increased risks of bleeding and hemorrhage. Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia. In addition, the transfusion practices for such patients may need to be modified given the increased risk of bleeding. Patients in clinical studies were prohibited from receiving growth factor treatment for 2 weeks prior to the Zevalin therapeutic regimen as well as for 2 weeks following completion of the regimen. Carcinogenesis, Mutagenesis, Impairment of Fertility: No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of the Zevalin therapeutic regimen, or to determine its effects on fertility in males or females. However, radiation is a potential carcinogen and mutagen. The Zevalin therapeutic regimen results in a significant radiation dose to the testes. The radiation dose to the ovaries has not been established. There have been no studies to evaluate whether the Zevalin therapeutic regimen causes hypogonadism, premature menopause, azoospermia and/or mutagenic alterations to germ cells. There is a potential risk that the Zevalin therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the Zevalin therapeutic regimen. Pregnancy Category D (SEE WARNINGS). Nursing Mothers: It is not known whether Zevalin is excreted in human milk. Because human IgG is excreted in human milk and the potential for Zevalin exposure in the infant is unknown, women should be advised to discontinue nursing and formula feeding should be substituted for breast feedings. Geriatric Use: Of 349 patients treated with the Zevalin therapeutic regimen in clinical studies, 38% (132 patients) were age 65 years and over, while 12% (41 patients) were age 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pediatric Use: The safety and effectiveness of the Zevalin therapeutic regimen in children have not been established. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label:
The most common adverse reactions with the Zevalin therapeutic regimen are neutropenia, thrombocytopenia, anemia, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea), increased cough, dyspnea, dizziness, arthralgia, anorexia, anxiety, and ecchymosis. The most serious adverse reactions with the Zevalin therapeutic regimen are prolonged and severe cytopenias, infections (predominantly bacterial in origin), hemorrhage while thrombocytopenic (resulting in deaths), and allergic reactions (bronchospasm and angioedema). In addition, patients who have received the Zevalin therapeutic regimen have developed myeloid malignancies and dysplasias. Fatal infusion reactions have occurred following the infusion of Rituximab as a component of regimens other than the Zevalin therapeutic regimen. Because the Zevalin therapeutic regimen includes the use of Rituximab, also see prescribing information for RITUXAN (Rituximab). Clinical Trials ExperienceBecause 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 data below reflect exposure to the Zevalin therapeutic regimen in 349 patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma treated at the recommended dose and schedule. Table 7 lists adverse events that occurred in 5% of patients. A more detailed description of the incidence and duration of hematologic toxicities, according to baseline platelet count (as an indicator of bone marrow reserve) is provided in Table 8, Hematologic Toxicity. Table 7. Incidence of Adverse Events in ≥5% of Patients Receiving the Zevalin Therapeutic Regimen† (N = 349)
†Adverse events were followed for a period of 12 weeks following the first Rituximab infusion of the Zevalin therapeutic regimen.
Note: All adverse events are included, regardless of relationship
The following adverse events (except for those noted in Table 7) occurred in between 1 and 4% of patients during the treatment period: urticaria (4%), anxiety (4%), dyspepsia (4%), sweats (4%), petechia (3%), epistaxis (3%), allergic reaction (2%), and melena (2%). Severe or life-threatening adverse events occurring in 1-5% of patients (except for those noted in Table 7) consisted of pancytopenia (2%), allergic reaction (1%), gastrointestinal hemorrhage (1%), melena (1%), tumor pain (1%), and apnea (1%). The following severe or life threatening events occurred in <1% of patients: angioedema, tachycardia, urticaria, arthritis, lung edema, pulmonary embolus, encephalopathy, hematemesis, subdural hematoma, and vaginal hemorrhage. Hematologic Events:
Hematologic toxicity was the most frequently observed adverse event in clinical trials. Table 8 presents the incidence and duration of severe hematologic toxicity for patients with normal baseline platelet count
* Median duration of neutropenia for patients with ANC <1000 cells/mm3 (Date from last laboratory value showing ANC ≥1000 cells/mm3 to date of first laboratory value following nadir showing ANC ≥1000 cells/mm3, censored at initiation of next treatment or death) # Median duration of thrombocytopenia for patients with platelets <50,000 cells/mm3 (Date from last laboratory value showing platelet count ≥50,000 cells/mm3 to date of first laboratory value following nadir showing platelet count ≥50,000 cells/mm3, censored at initiation of next treatment or death) Median time to ANC nadir was 62 days, to platelet nadir was 53 days, and to hemoglobin nadir was 68 days. Information on growth factor use and platelet transfusions is based on 211 patients for whom data were collected. Filgrastim was given to 13% of patients and erythropoietin to 8%. Platelet transfusions were given to 22% of patients and red blood cell transfusions to 20%. Infectious Events: During the first 3 months after initiating the Zevalin therapeutic regimen, 29% of patients developed infections. Three percent of patients developed serious infections comprising urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection. Life threatening infections were reported for 2% of patients that included sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent associated cholangitis. During follow up from 3 months to 4 years after the start of treatment with ZEVALIN, 6% of patients developed infections. Two percent of patients had serious infections comprising urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated viral hepatitis. One percent of patients had life threatening infections that included bacterial pneumonia, respiratory disease, and sepsis. Secondary Leukemia and Myelodysplastic Syndrome: There were 19 cases of MDS/AML reported among 746 (2.6%) patients included in clinical studies and the expanded access programs, with a median follow-up of 4.4 years. The overall incidence of MDS/AML among the 211 patients included in the clinical studies was 5.2% (11/211), with a median follow-up of 6.5 years and median time to development of MDS/AML of 2.9 years. The cumulative Kaplan-Meier estimated incidence of MDS/secondary leukemia in this patient population was 2.2% at 2 years and 5.9% at 5 years. The incidence of MDS/AML among the 535 patients in the expanded access programs was 1.5% (8/535) with a median follow-up of 4.4 years and median time to development of MDS/AML of 1.5 years. Multiple cytogenetic abnormalities were described, most commonly involving chromosomes 5 and/or 7. The risk of MDS/AML was not associated with the number of prior treatments (0-1 versus 2-10). Immunogenicity: Of 211 patients who received the Zevalin therapeutic regimen in clinical trials and who were followed for 90 days, there were eight (3.8%) patients with evidence of human anti mouse antibody (HAMA) (n=5) or human anti-chimeric antibody (HACA) (n=4) at any time during the course of the study[1]. Two patients had low titers of HAMA prior to initiation of the Zevalin therapeutic regimen; one remained positive without an increase in titer while the other had a negative titer post-treatment. Three patients had evidence of HACA responses prior to initiation of the Zevalin therapeutic regimen; [7] one had a marked increase in HACA titer while the other two had negative titers post-treatment. Of the three patients who had negative HAMA or HACA titers prior to the Zevalin therapeutic regimen, two developed HAMA in absence of HACA titers, and one had both HAMA and HACA positive titers post-treatment. Evidence of immunogenicity may be masked in patients who are lymphopenic. There has not been adequate evaluation of HAMA and HACA at delayed timepoints, concurrent with the recovery from lymphopenia at 6-12 months, to establish whether masking of the immunogenicity at early timepoints occurs. The data reflect the percentage of patients whose test results were considered positive for antibodies to ibritumomab or Rituximab using kinetic enzyme immunoassays to ibritumomab and Rituximab. The observed incidence of antibody positivity in an assay is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including sample handling and concomitant medications. Comparisons of the incidence of HAMA/HACA to the Zevalin therapeutic regimen with the incidence of antibodies to other products may be misleading. Post-marketing ExperienceThe following adverse reactions have been identified during post-approval use of the Zevalin therapeutic regimen in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the Zevalin therapeutic regimen.
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Please consult full prescribing information for Zevalin and Rituximab, including their respective Boxed WARNINGS.
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