Zevalin (Ibritumomab Tiuxetan) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

ZEVALIN drug label information in our database does not contain a dedicated section on drug interactions. Please check subsections of WARNINGS AND PRECAUTIONS as well as other sources.

OVERDOSAGE

Doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ZEVALIN were administered in ZEVALIN therapeutic regimen clinical trials and severe hematological toxicities were observed. No fatalities or second organ injury resulting from overdosage administrations were documented. However, single doses up to 50 mCi (1850 MBq) of Y-90 ZEVALIN, and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) of Y-90 ZEVALIN were studied in a limited number of subjects. In these trials, some patients required autologous stem cell support to manage hematological toxicity.

CONTRAINDICATIONS

The ZEVALIN therapeutic regimen is contraindicated in patients with known Type I hypersensitivity or anaphylactic reactions to murine proteins or to any component of this product, including Rituximab, yttrium chloride, and indium chloride.

WARNINGS (SEE BOX WARNING)

Altered Biodistribution: Y-90 ZEVALIN should not be administered to patients with altered biodistribution of In-111 ZEVALIN. The expected biodistribution of In-111 ZEVALIN includes easily detectable uptake in the blood pool areas on the first day image, with less activity in the blood pool areas on the second or third day image; moderately high to high uptake in normal liver and spleen during the first day and the second or third day image; and moderately low or very low uptake in normal kidneys, urinary bladder, and normal bowel on the first day image and the second or third day image. Altered biodistribution of In-111 ZEVALIN can be characterized by diffuse uptake in normal lung more intense than the cardiac blood pool on the first day image or more intense than the liver on the second or third day image; kidneys with greater intensity than the liver on the posterior view of the second or third day image; or intense areas of uptake throughout the normal bowel comparable to uptake by the liver on the second or third day images.

Severe Infusion Reactions (See PRECAUTIONS, Hypersensitivity): The ZEVALIN therapeutic regimen may cause severe, and potentially fatal, infusion reactions. These severe reactions typically occur during the first Rituximab infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reaction may include hypotension, angioedema, hypoxia, or bronchospasm, and may require interruption of Rituximab, In-111 ZEVALIN, or Y-90 ZEVALIN administration. The most severe manifestations and sequelae may include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Because the ZEVALIN therapeutic regimen includes the use of Rituximab, see also prescribing information for RITUXAN (Rituximab).

CYTOPENIAS (SEE ADVERSE REACTIONS, HEMATOLOGIC EVENTS):

The most common severe adverse events reported with the ZEVALIN therapeutic regimen were thrombocytopenia (61% of patients with platelet counts <50,000 cells/mm³) and neutropenia (57% of patients with absolute neutro-phil count (ANC) <1,000 cells/mm³) in patients with >/=150,000 platelets/mm³ prior to treatment. Both incidences of severe thrombocytopenia and neutropenia increased to 78% and 74% for patients with mild thrombocytopenia at baseline (platelet count of 100,000 to 149,000 cells/mm³). For all patients, the median time to nadir was 7-9 weeks and the median duration of cytopenias was 22-35 days. In <5% of cases, patients experienced severe cytopenia that extended beyond the prospectively defined protocol treatment period of 12 weeks following administration of the ZEVALIN therapeutic regimen. Some of these patients eventually recovered from cytopenia, while others experienced progressive disease, received further anti-cancer therapy, or died of their lymphoma without having recovered from cytopenia. The cytopenias may have influenced subsequent treatment decisions.

Hemorrhage, including fatal cerebral hemorrhage, and severe infections have occurred in a minority of patients in clinical studies. Careful monitoring for and management of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months after use of the ZEVALIN therapeutic regimen are necessary. Caution should be exercised in treating patients with drugs that interfere with platelet function or coagulation following the ZEVALIN therapeutic regimen and patients receiving such agents should be closely monitored.

The ZEVALIN therapeutic regimen should not be administered to patients with >/= 25% lymphoma marrow involvement and/or impaired bone marrow reserve, e.g., prior myeloablative therapies; platelet count <100,000 cells/mm³; neutrophil count <1,500 cells/mm³; hypocellular bone marrow ( Secondary Malignancies: Out of 349 patients treated with the ZEVALIN therapeutic regimen, three cases of acute myelogenous leukemia and two cases of myelodysplastic syndrome have been reported following the ZEVALIN therapeutic regimen (see ADVERSE REACTIONS).

Pregnancy Category D: Y-90 ZEVALIN can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Creutzfeldt-Jakob disease (CJD): This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

REFERENCES

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8. Wiseman GA, White CA, Stabin M, Dunn WL, Erwin W, Dahlbom M, et al. Phase I/II 90Y ZevalinTM (90yttrium ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma. Eur J Nucl Med 2000;27(7):766-77.
9. Wiseman GA, White CA, Sparks RB, Erwin WD, Podoloff DA, Lamonica DA, et al. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol 2001;39(1-2):181-94.
10. Siegel J, Lee R, Pawlyk D, Horowitz J, Sharkey R, Goldenberg D. Sacral scintigraphy for bone marrow dosimetry in radioimmunotherapy. Int J Appl Radiat Instr 1989;16(Part B):553-9.
11. Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's Lymphoma. J. Clin Oncol 2002 in press.
12. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 1999;17(4):1244-53.
13. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-hodgkins lymphoma. J Clin Oncol. 2002;20(10):2453-63.
14. Wiseman GA, Gordon LI, Multani PS, Witzig TE, Spies S, Bartlett NL, et al. Ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-hodgkins lymphoma patients with mild thrombocytopenia: a phase II multicenter trial. Blood 2002; 99(12):4336-4342.

Rx Only

In-111 ZEVALIN kit, NDC 64406-104-04

Y-90 ZEVALIN kit, NDC 64406-103-03

© 2002 IDEC Pharmaceuticals Corporation

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San Diego, CA 92121

U.S. License Number 1235

Protected by one or more U.S. Patents.

Issue date: January 2003