Zevalin (Page 3 of 6)

3 DOSAGE FORMS AND STRENGTHS

Injection: 3.2 mg ibritumomab tiuxetan per 2 mL as a clear, colorless solution, that may contain translucent particles, in a single-dose vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Serious Infusion Reactions

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.

5.2 Prolonged 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/mm3) 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.

5.3 Severe 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) ].

5.4 Risk 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.

5.5 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 [see Dosage and Administration (2.2) ].

5.6 Risks 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.

5.8 Embryo-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)].

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) ].

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/ 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 but ≤ 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.

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 * Adverse Reactions Occurring in ≥ 5% of Patients with Previously Untreated Follicular NHL Treated with the Zevalin Therapeutic Regimen
*
Between-group difference of ≥5%
NCI CTCAE version 2.0
Zevalin (n=206) Observation (n=203)
All Grades 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 * (N = 349
*
Occurring within the 12 weeks following the first rituximab infusion of the Zevalin therapeutic regimen
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
*
Day from last ANC ≥1000/mm3 to first ANC ≥1000/mm3 following nadir, censored at next treatment or death
Day from nadir to first count at level of Grade 1 toxicity or baseline
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
Baseline Platelet Count Group 1 (n=270) ≥ 150,000/mm3 Group 2 (n=65 ) ≥ 100,000 but ≤ 149,000/mm3 FIT study (n=204) ≥ 150,000/mm3
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 mm3) 800 600 721
Per Patient Incidence ANC <1000/mm3 57% 74% 65%
Per Patient IncidenceANC <500/mm3 30% 35% 26%
Median Duration (Days)* ANC <1000/mm3 22 29 29
Median Time to Recovery 12 13 15
Platelets
Median nadir (per mm3) 41,000 24,000 42,000
Per Patient IncidencePlatelets <50,000/mm3 61% 78% 61%
Per Patient Incidence Platelets <10,000/mm3 10% 14% 4%
Median Duration (Days)Platelets <50,000/mm3 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/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.

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) ].

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