The following adverse reactions are discussed in greater detail in other sections of the label:

• Serious Infusion Reactions [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]
• Prolonged and Severe Cytopenias [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]
• Severe Cutaneous and Mucocutaneous Reactions [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]
• Secondary Leukemia and Myelodysplastic Syndrome [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]

The most common adverse reactions of 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 of the Zevalin therapeutic regimen are prolonged and severe cytopenias, infections (predominantly bacterial in origin), hemorrhage while thrombocytopenic, severe cutaneous and mucocutaneous reactions, infusion reactions (bronchospasm and angioedema), myeloid malignancies and myelodysplasias. Because the Zevalin therapeutic regimen includes the use of rituximab, see prescribing information for rituximab.

Clinical 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 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 with a single course at the recommended dose and schedule. The safety population included patients enrolled on the following clinical trials: a dose escalation Phase 1 trial, a Phase 2 open label trial, a randomized Phase 3 trial, and an open label expanded access trial. Patients on these trials were required to have acceptable hematologic, renal and hepatic function, less than 25% bone marrow involvement by NHL, prior external beam radiation therapy not to exceed 25% of the bone marrow, and no prior history of myeloablative therapy/autologous bone marrow transplantation. Patients were not permitted to receive hematopoietic growth factors beginning 2 weeks prior to administration of the Zevalin therapeutic regimen.

Table 2 lists adverse reactions that occurred in ≥5% of patients. A more detailed description of hematologic toxicities, is provided in Table 3.

Table 2. Incidence of Adverse Reactions in ≥5 % of Patients Receiving the Zevalin therapeutic regimen^† (N = 349)

The following adverse reactions (except for those noted in Table 7) occurred in between 1 and 4% of patients: urticaria (4%), anxiety (4%), dyspepsia (4%), sweats (4%), petechiae (3%), epistaxis (3%), allergic reaction (2%), and melena (2%).

Severe or life-threatening adverse reactions occurring in 1-5% of patients included pancytopenia (2%), infusion reaction (1%), gastrointestinal hemorrhage (1%), melena (1%), tumor pain (1%), and apnea (1%). The following severe or life-threatening reactions occurred in <1% of patients: angioedema, tachycardia, urticaria, arthritis, lung edema, pulmonary embolus, encephalopathy, hematemesis, subdural hematoma, and vaginal hemorrhage.

Hematologic Reactions

Hematologic toxicity was the most frequently observed adverse reaction in clinical trials. Patients in clinical studies were not permitted to receive hematopoietic growth factors beginning 2 weeks prior to administration of the Zevalin therapeutic regimen. Table 3 presents the incidence and duration of severe hematologic toxicity for patients with normal baseline platelet count (≥150,000/mm³) treated with the Zevalin therapeutic regimen and patients with mild thrombocytopenia (platelet count 100,000 to 149,000/mm³) at baseline who were treated with a modified Zevalin therapeutic regimen that included a lower Y-90 Zevalin dose at 0.3 mCi per kg (11.1 MBq per kg).

Table 3. Severe Hematologic Toxicity

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%.

Infections

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

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of HAMA/HACA to the Zevalin therapeutic regimen with the incidence of antibodies to other products may be misleading.

HAMA and HACA response data on 446 patients from 8 clinical studies conducted over a 10-year time period are available. Overall, 11/446 (2.5%) had evidence of either HAMA formation (N=8) or HACA formation (N=4). Six of these patients developed HAMA/HACA after treatment with Zevalin and 5 were HAMA/HACA positive at baseline. Of the 6 who were HAMA/HACA positive, only one was positive for both. Furthermore, in 6 of the 11 patients, the HAMA/HACA reverted to negative within 2 weeks to 3 months. No patients had increasing levels of HAMA/HACA at the end of the studies.

Only 6/446 patients (1.3%) had developed evidence of antibody formation after treatment with Zevalin, and of these, many either reverted to negative or decreased over time. This data demonstrates that HAMA/HACA develop infrequently, are typically transient, and do not increase with time.

Post-Marketing Experience

The 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.

• Cutaneous and mucocutaneous reactions: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]
• Infusion site erythema and ulceration following extravasation [see BOXED WARNINGS, WARNINGS and PRECAUTIONS]
• Radiation injury in tissues near areas of lymphomatous involvement within a month of Zevalin administration.

No formal drug interaction studies have been performed with Zevalin. Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia.

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