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adverse reactions
6 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 6.1 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 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 2.0 Grade 3-4 All Grades Grade 3-4 % % % % Gastrointestinal Disorders Abdominal pain 17 2 13 <1 Diarrhea 11 0 3 0 Nausea 18 0 2 0 Body as a Whole Asthenia 15 1 8 <1 Fatigue 33 1 9 0 Influenza-like illness 8 0 3 0 Pyrexia 10 3 4 0 Musculoskeletal Myalgia 9 0 3 0 Metabolism Anorexia 8 0 2 0 Respiratory, Thoracic & Media Cough 11 <1 5 0 Pharyngolaryngeal pain 7 0 2 0 Epistaxis 5 2 <1 0 Nervous System Dizziness 7 0 2 0 Vascular Hypertension 7 3 2 <1 Skin & Subcutaneous Night sweats 8 0 2 0 Petechiae 8 2 0 0 Pruritus 7 0 1 0 Rash 7 0 <1 0 Infections & Infestations Bronchitis 8 0 3 0 Nasopharyngitis 19 0 10 0 Rhinitis 8 0 2 0 Sinusitis 7 <1 <1 0 Urinary tract infection 7 <1 3 0 Blood and Lymphatic System Thrombocytopenia 62 51 1 0 Neutropenia 45 41 3 2 Anemia 22 5 4 0 Leukopenia 43 36 4 1 Lymphopenia 26 18 9 5 Table 3 shows hematologic toxicities in 349 Zevalin-treated patients with relapsed or refractory, low-grade, follicular or transformed B-cell NHL. 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. 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 developed infections; 2% were serious (urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated viral hepatitis) and 1% were life-threatening infections (bacterial pneumonia, respiratory disease, and sepsis). When administered following first-line chemotherapy (Table 2), Grade 3-4 infections occurred in 8% of Zevalin treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection. Leukemia and Myelodysplastic Syndrome Among 746 patients with relapsed/refractory NHL, 19 (2.6%) patients developed MDS/AML 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). Among 204 patients receiving Y-90-Zevalin following first-line treatment, 7 (3%) patients developed MDS/AML between approximately 2 to 7 years after Zevalin administration [ see Warnings and Precautions ( 5.4 ) ]. 6.2 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 Warning and Warnings and Precautions ( 5.3 ) ]. Infusion site erythema and ulceration following extravasation [ see Warnings and Precautions ( 5.5 ) ]. Radiation injury in tissues near areas of lymphomatous involvement within a month of Zevalin administration. 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection 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 antibodies to the Zevalin therapeutic regimen in the studies described below with the incidence of antibodies in other studies or 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.