"The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency&rsq"...
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].
- Prolonged and Severe Cytopenias [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
- Severe Cutaneous and Mucocutaneous Reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
- Leukemia and Myelodysplastic Syndrome [see WARNINGS AND PRECAUTIONS].
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 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 (Study 4) 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/mm3 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 to 149,000/mm3 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/mm3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Zevalin; all patients received a single course of Zevalin.
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 (Study 4).
Table 2. Per-Patient Incidence (%) of Selecteda
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 Gradesb||Gradeb 3-4||All Gradesb||Gradeb 3-4|
|Abdominal pain||17||2||13||< 1|
|Body as a Whole|
|Respiratory, Thoracic & Media|
|Skin & Subcutaneous|
|Infections & Infestations|
|Sinusitis||7||< 1||< 1||0|
|Urinary tract infection||7||< 1||3||0|
|Blood and Lymphatic System|
| a) Between-group difference of ≥ 5%
b) NCI CTCAE version 2.0
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 NHLa (N = 349)
| All Grades
| Grade 3-4
|a) Occurring within the 12 weeks following the first rituximab infusion of the Zevalin therapeutic regimen|
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 Table 4.
Table 4. Severe Hematologic Toxicity in Patients Receiving
|Baseline Platelet Count|| Group 1
| Group 2
100,000 to 149,000/mm3
| Study 4
|Y-90 Zevalin Dose|| 0.4 mCi/kg
| 0.3 mCi/kg
| 0.4 mCi/kg
|Median nadir (per mm3)||800||600||721|
|Per Patient Incidence ANC < 1000/mm3||57%||74%||65%|
|Per Patient Incidence ANC < 500/mm3||30%||35%||26%|
|Median Duration (Days) ANC < 1000/mm3||22||29||29|
|Median Time to Recoveryb||12||13||15|
|Median nadir (per mm3)||41,000||24,000||42,000|
|Per Patient Incidence Platelets < 50,000/mm3||61%||78%||61%|
|Per Patient Incidence Platelets < 10,000/mm3||10%||14%||4%|
|QMedian Duration (Days)c Platelets < 50,000/mm3||24||35||26|
|Median Time to Recoveryb||13||14||14|
|a) Day from last ANC ≥ 1000/mm3 to first ANC
≥ 1000/mm3 following nadir, censored at next treatment or death
b) Day from nadir to first count at level of Grade 1 toxicity or baseline
c) Day from last platelet count ≥ 50,000/mm3 to day of first platelet count ≥ 50,000/mm3 following nadir, censored at next treatment or death
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/mm3 with a median duration of platelets below 50,000/mm3 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/mm3, with a median duration of ANC below 1,000/mm3 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.
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, 2(1%) developed AML at approximately 2 and 3.3 years after Zevalin administration, respectively.
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.
KAMA 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 KAMA 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.
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].
- Infusion site erythema and ulceration following extravasation [see WARNINGS AND PRECAUTIONS].
- Radiation injury in tissues near areas of lymphomatous involvement within a month of Zevalin administration.
Read the Zevalin (ibritumomab tiuxetan) Side Effects Center for a complete guide to possible side effects
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/21/2011
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