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Black Box Warning
WARNING
See full prescribing information for complete Boxed Warning.
SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, AND SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS
Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the Zevalin therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Discontinue rituximab and Y-90 Zevalin infusions in patients who develop severe infusion reactions.
Prolonged and Severe Cytopenias: Y-90 Zevalin administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 Zevalin to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve [see Warnings and Precautions (5.2) andAdverse Reactions (6.1)].
Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the Zevalin therapeutic regimen. Discontinue rituximab and Y-90 Zevalin infusions in patients experiencing severe cutaneous or mucocutaneous reactions [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].
Dosing: The dose of Y-90 Zevalin should not exceed 32.0 mCi (1184 MBq)
Overview
Ibritumomab tiuxetan is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Relapsed or Refractory, Low-grade or Follicular NHL
Zevalin is indicated for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).
Previously Untreated Follicular NHL
Zevalin is indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.
Recommended Dosing Schedule
Administer the Zevalin therapeutic regimen as outlined in Section 2.1.
Initiate the Zevalin therapeutic regimen following recovery of platelet counts to ≥150,000/mm3 at least 6 weeks, but no more than 12 weeks, following the last dose of first-line chemotherapy.
Only administer Rituxan/Zevalin in facilities where immediate access to resuscitative measures is available.
Overview of Dosing Schedule
TABLE02
Zevalin Therapeutic Regimen Dosage and Administration
Day 1:
Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.
Administer rituximab 250 mg/m2 intravenously at an initial rate of 50 mg/hr. In the absence of infusion reactions, escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Do not mix or dilute rituximab with other drugs.
Immediately stop the rituximab infusion for serious infusion reactions and discontinue the Zevalin therapeutic regimen .
Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. If symptoms improve, continue the infusion at one-half the previous rate.
Day 7, 8 or 9:
Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.
Administer rituximab 250 mg/m2 intravenously at an initial rate of 100 mg/hr. Increase rate by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr, as tolerated. If infusion reactions occurred during rituximab infusion on Day 1 of treatment, administer rituximab at an initial rate of 50 mg/hr and escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
Administer Y-90 Zevalin injection through a free flowing intravenous line within 4 hours following completion of rituximab infusion. Use a 0.22 micron low-protein-binding in-line filter between the syringe and the infusion port. After injection, flush the line with at least 10 mL of normal saline.
If platelet count ≥ 150,000/mm3, administer Y-90 Zevalin over 10 minutes as an intravenous injection at a dose of Y-90 0.4 mCi per kg (14.8 MBq per kg) actual body weight.
If platelet count ≥ 100,000 but ≤ 149,000/mm3, in relapsed or refractory patients, administer Y-90 Zevalin over 10 minutes as an intravenous injection at a dose of Y-90 0.3 mCi per kg (11.1 MBq per kg) actual body weight.
Do not administer more than 32 mCi (1184 MBq) Y-90 Zevalin dose regardless of the patient’s body weight.
Monitor patients closely for evidence of extravasation during the injection of Y-90 Zevalin. Immediately stop infusion and restart in another limb if any signs or symptoms of extravasation occur [see Warnings and Precautions (5.6)].
Directions for Preparation of Radiolabeled Y-90 Zevalin Doses
A clearly-labeled kit is required for preparation of Yttrium-90 (Y-90) Zevalin. Follow the detailed instructions for the preparation of radiolabeled Zevalin .
Required materials not supplied in the kit:
Yttrium-90 Chloride Sterile Solution
Three sterile 1 mL plastic syringes
One sterile 3 mL plastic syringe
Two sterile 10 mL plastic syringes with 18-20 G needles
ITLC silica gel strips
0.9% Sodium Chloride aqueous solution for the chromatography solvent
Developing chamber for chromatography
Suitable radioactivity counting apparatus
Filter, 0.22 micrometer, low-protein-binding
Appropriate acrylic shielding for reaction vial and syringe for Y-90
Method:
Allow contents of the refrigerated Y-90 Zevalin kit (Zevalin vial, 50 mM sodium acetate vial, and formulation buffer vial) to reach room temperature.
Place the empty reaction vial in an appropriate acrylic shield.
Determine the amount of each component needed:
Calculate volume of Y-90 Chloride equivalent to 40 mCi based on the activity concentration of the Y-90 Chloride stock.
The volume of 50 mM Sodium Acetate solution needed is 1.2 times the volume of Y-90 Chloride solution determined in step 3.a, above.
Calculate the volume of formulation buffer needed to bring the reaction vial contents to a final volume of 10 mL.
Transfer the calculated volume of 50 mM Sodium Acetate to the empty reaction vial. Coat the entire inner surface of the reaction vial by gentle inversion or rolling.
Transfer 40 mCi of Y-90 Chloride to the reaction vial using an acrylic shielded syringe. Mix the two solutions by gentle inversion or rolling.
Transfer 1.3 mL of Zevalin (ibritumomab tiuxetan) to the reaction vial. Do not shake or agitate the vial contents.
Allow the labeling reaction to proceed at room temperature for 5 minutes. A shorter or longer reaction time may adversely alter the final labeled product.
Immediately after the 5-minute incubation period, transfer the calculated volume of formulation buffer from step 3.c. to the reaction vial. Gently add the formulation buffer down the side of the reaction vial. If necessary, withdraw an equal volume of air to normalize pressure.
Measure the final product for total activity using a radioactivity calibration system suitable for the measurement of Y-90.
Using the supplied labels, record the date and time of preparation, the total activity and volume, and the date and time of expiration, and affix these labels to the shielded reaction vial container.
Patient Dose: Calculate the volume required for a Y-90 Zevalin dose [see Dosage and Administration (2.2)]. Withdraw the required volume from the reaction vial. Assay the syringe in the dose calibrator suitable for the measurement of Y-90. The measured dose must be within 10% of the prescribed dose of Y-90 Zevalin and must not exceed 32 mCi (1184 MBq). Using the supplied labels, record the patient identifier, total activity and volume and the date and time of expiration, and affix these labels to the syringe and shielded unit dose container.
Determine Radiochemical Purity .
Store Yttrium-90 Zevalin at 2-8°C (36-46°F) until use and administer within 8 hours of radiolabeling. Immediately prior to administration, assay the syringe and contents using a radioactivity calibration system suitable for the measurement of Y-90.
Procedure for Determining Radiochemical Purity
Use the following procedures for radiolabeling Y-90 Zevalin:
Place a small drop of Y-90 Zevalin at the origin of an ITLC silica gel strip.
Place the ITLC silica gel strip into a chromatography chamber with the origin at the bottom and the solvent front at the top. Allow the solvent (0.9% NaCl) to migrate at least 5 cm from the bottom of the strip. Remove the strip from the chamber and cut the strip in half. Count each half of the ITLC silica gel strip for one minute (CPM) with a suitable counting apparatus.
Calculate the percent RCP as follows:
TABLE03
Repeat the ITLC procedure if the radiochemical purity is <95%. If repeat testing confirms that radiochemical purity is <95%, do not administer the Y-90 Zevalin dose.
Radiation Dosimetry
During clinical trials with Zevalin, estimations of radiation-absorbed doses for Y-90 Zevalin were performed using sequential whole body images and the MIRDOSE 3 software program. The estimated radiation absorbed doses to organs and marrow from a course of the Zevalin therapeutic regimen are summarized in Table 1. Absorbed dose estimates for the lower large intestine, upper large intestine, and small intestine have been modified from the standard MIRDOSE 3 output to account for the assumption that activity is within the intestine wall rather than the intestine contents.
TABLE04
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibritumomab tiuxetan in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibritumomab tiuxetan in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ibritumomab tiuxetan in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibritumomab tiuxetan in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ibritumomab tiuxetan in pediatric patients.
Contraindications
None.
Warnings
WARNING
See full prescribing information for complete Boxed Warning.
SERIOUS INFUSION REACTIONS, PROLONGED AND SEVERE CYTOPENIAS, AND SEVERE CUTANEOUS AND MUCOCUTANEOUS REACTIONS
Serious Infusion Reactions: Deaths have occurred within 24 hours of rituximab infusion, an essential component of the Zevalin therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Discontinue rituximab and Y-90 Zevalin infusions in patients who develop severe infusion reactions.
Prolonged and Severe Cytopenias: Y-90 Zevalin administration results in severe and prolonged cytopenias in most patients. Do not administer Y-90 Zevalin to patients with ≥ 25% lymphoma marrow involvement and/or impaired bone marrow reserve [see Warnings and Precautions (5.2) andAdverse Reactions (6.1)].
Severe Cutaneous and Mucocutaneous Reactions: Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the Zevalin therapeutic regimen. Discontinue rituximab and Y-90 Zevalin infusions in patients experiencing severe cutaneous or mucocutaneous reactions [see Warnings and Precautions (5.3) and Adverse Reactions (6.2)].
Dosing: The dose of Y-90 Zevalin should not exceed 32.0 mCi (1184 MBq)
Serious Infusion Reactions
See also prescribing information for rituximab.
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 Rituxan/Zevalin in facilities where immediate access to resuscitative measures is available [see Boxed Warning andDosage and Administration (2.2)].
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 Altered Biodistribution
In a post-marketing 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.
5.5 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.
5.6 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)].
5.7 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.
5.8 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.
5.9 Embryo-Fetal Toxicity
Based on its radioactivity, Y-90 Zevalin may cause fetal harm when administered to a pregnant woman. If the Zevalin therapeutic regimen is administered during pregnancy, the patient should be apprised of the potential hazard to a fetus. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ibritumomab tiuxetan in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ibritumomab tiuxetan in the drug label.
