Zevalin

Generic Name: Ibritumomab Tiuxetan
Class: Antineoplastic Agents
VA Class: AN600
Chemical Name: N - [2 - [bis(carboxymethyl)amino] - 3 - (4 - isothiocyanatophenyl)propyl] - N - [2 - [bis(carboxymethyl)amino]propyl] glycine conjugate dimer disulfide with mouse monoclonal IDEC-Y2B8k-chain anti-(human CD20 (antigen)) (mouse monoclonal IDEC-Y2B8 γ1-chain) immuglobulin G1
CAS Number: 206181-63-7

Warning(s)

  • Rituximab-related Infusion Reactions
  • Fatalities have occurred within 24 hours following rituximab infusion, an essential component of the ibritumomab tiuxetan therapeutic regimen.1 2

  • Fatalities were associated with hypoxia, pulmonary infiltrates, ARDS, MI, ventricular fibrillation, or cardiogenic shock.1

  • Approximately 80% of fatal infusion reactions occurred with initial infusion of rituximab.1 4

  • If severe infusion-related effects develop, immediately discontinue rituximab and yttrium Y 90 ibritumomab tiuxetan.1 (See Infusion-related Effects under Cautions.)

  • Cytopenias
  • Most patients receiving the ibritumomab tiuxetan therapeutic regimen develop prolonged and severe cytopenias.1

  • Do not use in patients with ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve.1 (See Hematologic Effects under Cautions.)

  • Severe Cutaneous and Mucocutaneous Reactions
  • Severe, sometimes fatal, cutaneous and mucocutaneous reactions reported.1 11 (See Severe Cutaneous and Mucocutaneous Reactions under Cautions.)

  • If severe cutaneous or mucocutaneous reactions occur, discontinue ibritumomab tiuxetan therapeutic regimen.1 11

  • Yttrium Y 90 Ibritumomab Tiuxetan
  • Dosage of yttrium Y 90 ibritumomab tiuxetan should not exceed 32 mCi.1

Introduction

Radioimmunotherapeutic agent; a murine anti-human antigen CD20 monoclonal antibody (conjugated with the chelating agent tiuxetan) that readily chelates the radioisotopes indium 111 and yttrium 90.1 2 3 5 7

Uses for Zevalin

Non-Hodgkin’s Lymphoma

Part of a specific therapeutic regimen (ibritumomab tiuxetan therapeutic regimen) for treatment of relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL) (designated an orphan drug by FDA for this use).1 2 12 18 Safety and efficacy not evaluated in patients with ≥25% involvement of bone marrow by lymphoma and/or impaired bone marrow reserve (e.g., prior myeloablative therapies, prior external beam radiation to >25% of active marrow, neutrophil count <1500/mm3).1 5

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Ibritumomab tiuxetan therapeutic regimen also used for consolidation treatment of newly diagnosed follicular NHL in patients who have achieved partial or complete response to first-line induction chemotherapy.1 17 Safety and efficacy not evaluated in patients with ≥25% involvement of bone marrow by lymphoma and/or impaired bone marrow reserve (e.g., prior myeloablative therapies, prior external beam radiation to >25% of active marrow, platelet count <150,000/mm3).1

Zevalin Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

  • Use only by qualified clinicians experienced in the safe use and handling of radionuclides.7 15

  • The ibritumomab tiuxetan therapeutic regimen is intended for use as a single course of treatment.1 Regimen (administered in 2 steps) consists of 2 low doses of rituximab and a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.1 2 3 5 7 Biodistribution evaluation (administration of an imaging dose of indium In 111 ibritumomab tiuxetan followed by 2 or 3 whole body scans), previously required after first dose of rituximab, no longer is required as part of regimen.16 19

  • To minimize risk of infusion-related reactions, administer oral premedication with acetaminophen (650 mg) and an antihistamine (e.g., diphenhydramine [50 mg]) prior to each infusion of rituximab.1 4

  • When used as consolidation therapy, initiate ibritumomab tiuxetan therapeutic regimen when platelet counts are ≥150,000/mm3, between 6–12 weeks following last dose of first-line induction chemotherapy.1

  • Distribution is restricted.2 (See Preparations.)

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Rituximab Administration

Administer rituximab by IV infusion; rituximab must be diluted prior to IV infusion.1 4 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Consult manufacturer’s labeling for additional information on the reconstitution and administration of rituximab.1

Ibritumomab Tiuxetan Administration

Administer yttrium Y 90 ibritumomab tiuxetan by slow IV injection (over 10 minutes).1 5 7

A 0.22-mcm low-protein-binding filter should be inline between syringe and infusion port prior to injection of yttrium Y 90 ibritumomab tiuxetan.1 Following injection, flush line with at least 10 mL of 0.9% sodium chloride solution.1

Observe standard precautions to avoid extravasation of yttrium Y 90 ibritumomab tiuxetan (e.g., establish free-flowing IV line prior to administration, ensure adequate blood return upon needle aspiration).1 16 Closely monitor infusion site for signs of extravasation (e.g., swelling, pain, discomfort); if manifestations of extravasation appear, immediately stop infusion, restart infusion in another limb, and consult radiation safety officer.1 2 16 Specific treatment for yttrium Y 90 ibritumomab tiuxetan-induced extravasation reactions not fully determined; however, manufacturer states that recommendations for treatment of extravasation of vesicant chemotherapeutic agents (e.g., heating affected area to increase blood flow and accelerate drug clearance, moving affected area repeatedly to increase blood flow, using saline to increase volume in which radionucleotide is distributed to reduce absorbed radiation dose, using dimethylsulfoxide [DMSO] or other free-radical scavengers, liposuction, surgical excision and grafting [particularly after evidence of necrosis]) also may apply to radiopharmaceuticals.16

Yttrium Y 90 ibritumomab tiuxetan can be routinely administered on an outpatient basis.1 2 7 Presumably low risk of exposure to radiation in health-care professionals, family members, and other close personal contacts.2 7 Standard precautions for reducing risk of radiation exposure not necessary;2 however, some clinicians recommend following universal precautions for minimizing exposure to blood and other body fluids (e.g., saliva, urine, stool).7

Preparation of Radiolabeled Ibritumomab Tiuxetan

Consult manufacturer’s labeling for detailed information on preparation of yttrium Y 90 ibritumomab tiuxetan.1

Rate of Administration

Rituximab step 1: Administer at initial rate of 50 mg/hour.1 If no infusion reactions occur, increase infusion rate in 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.1 If severe infusion-related events develop, immediately stop rituximab infusion and discontinue ibritumomab tiuxetan therapeutic regimen.1 If less severe infusion-related events develop, reduce infusion rate or temporarily interrupt infusion; when symptoms improve, resume infusion at one-half previous rate.1

Rituximab step 2: If no infusion-related event occurred during step 1, administer at an initial rate of 100 mg/hour.1 Increase infusion rate in 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour as tolerated.1 If infusion-related events occurred during step 1, administer at an initial rate of 50 mg/hour.1 Increase infusion rate in 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.1

Yttrium Y 90 ibritumomab tiuxetan: Administer over 10 minutes.1

Dosage

Available as ibritumomab tiuxetan; dosage expressed in terms of ibritumomab tiuxetan.1

Adults

Non-Hodgkin’s Lymphoma
Relapsed or Refractory Low-grade or Follicular B-cell NHL
IV

Step 1 (day 1): 250 mg/m2 rituximab.1 (See Rate of Administration under Dosage and Administration.)

Step 2 (day 7, 8, or 9): A second 250-mg/m2 dose of rituximab, then (within 4 hours) 0.4 mCi/kg yttrium Y 90 ibritumomab tiuxetan (for patients with platelet counts ≥150,000/mm3) or 0.3 mCi/kg yttrium Y 90 ibritumomab tiuxetan (for patients with platelet counts of 100,000–149,000/mm3).1 2 5

Consolidation Therapy for Newly Diagnosed NHL
IV

Step 1 (day 1): 250 mg/m2 rituximab.1 (See Rate of Administration under Dosage and Administration.)

Step 2 (days 7, 8, or 9): A second 250-mg/m2 dose of rituximab, then (within 4 hours) 0.4 mCi/kg yttrium Y 90 ibritumomab tiuxetan (for patients with platelet counts ≥150,000/mm3).1

Prescribing Limits

Adults

Non-Hodgkin’s Lymphoma
IV

Yttrium Y 90 ibritumomab tiuxetan: maximum 32 mCi regardless of patient’s weight.1 5

Special Populations

No special population dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Zevalin

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Infusion-related Effects

Risk of severe, potentially fatal infusion-related effects associated with rituximab infusion.1 Onset of most severe reactions between 30–120 minutes after starting first rituximab infusion;1 4 fatalities reported within 24 hours of infusion.1 (See Boxed Warning.)

If severe infusion-related effects (e.g., urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, ARDS, MI, ventricular fibrillation, cardiogenic shock) develop, immediately discontinue rituximab and yttrium Y 90 ibritumomab tiuxetan.1 4

For less severe infusion reactions, temporarily slow or interrupt rituximab infusion; if symptoms improve, continue at half the previous rate.1 (See Rate of Administration under Dosage and Administration.)

Monitor closely for extravasation during infusion of yttrium Y 90 ibritumomab tiuxetan.1 16 If signs or manifestations of extravasation (e.g., swelling, pain, discomfort) occur, immediately terminate the infusion and restart in another limb.1 (See Ibritumomab Tiuxetan Administration under Dosage and Administration.)

Hematologic Effects

Cytopenias (e.g., thrombocytopenia, neutropenia, anemia) with delayed onset and prolonged duration, some complicated by hemorrhage and severe infection, considered most common severe adverse effects associated with regimen.1 Severe thrombocytopenia and neutropenia occur more frequently in patients with mild thrombocytopenia at baseline (platelet counts of 100,000–149,000/mm3) than in those with normal baseline platelet counts (≥150,000/mm3).1

Median time to nadir ANC, platelet count, or hemoglobin concentration was 61–62, 49–53, or 68–69 days, respectively.1 Median duration of cytopenia was 22–35 days, and median time to ANC or platelet count recovery was 12–15 days.1

Possible prolonged severe cytopenia (>12 weeks following treatment).1

Filgrastim, erythropoietin, platelet transfusions, or red blood cell transfusions required in some patients.1 2 6

Monitor for manifestations of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months following completion of therapy.1 (See Hematologic Monitoring under Cautions.) Avoid use of drugs that interfere with platelet function or coagulation.1 (See Specific Drugs under Interactions.)

Do not use in patients with ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve.1 (See Non-Hodgkin’s Lymphoma under Uses.)

Severe Cutaneous and Mucocutaneous Reactions

Severe, sometimes fatal, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis reported.1 11 Time to onset was variable, ranging from a few days to 4 months following completion therapy.1

Discontinue therapy in patients experiencing a severe cutaneous or mucocutaneous reaction.1

Other Warnings and Precautions

Concomitant Use with Rituximab

When used in therapeutic regimen with rituximab, consider the cautions, precautions, and contraindications associated with rituximab.1

Altered Biodistribution

In a postmarketing registry designed to collect biodistribution images and other information in reported cases of altered biodistribution, 12 of 953 patients (1.3%) reportedly had altered biodistribution.1

Myelodysplastic Syndrome and Secondary Leukemia

Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) reported.1 2 6

Among patients with relapsed or refractory NHL, median time to diagnosis of MDS or AML following treatment was 1.9 years; cumulative incidence increases with longer follow-up.1 Multiple cytogenetic abnormalities reported, most commonly involving chromosomes 5 and/or 7.1 Risk of developing MDS/AML not associated with the number of prior treatments.1 14

Among patients with newly diagnosed NHL receiving the regimen as consolidation therapy, AML was diagnosed within 3 years following treatment.1

Fetal/Neonatal Morbidity and Mortality

Yttrium Y 90 ibritumomab tiuxetan may cause fetal harm.1 Avoid pregnancy during therapy and for at least 12 months following completion of therapy.1 2 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Extravasation

Closely monitor patients for manifestations of extravasation (e.g., swelling, pain, discomfort) during infusion of yttrium Y 90 ibritumomab tiuxetan.1 If manifestations of extravasation appear, immediately stop infusion, restart infusion in another limb, and consult radiation safety officer.1 2 16 (See Ibritumomab Tiuxetan Administration under Dosage and Administration.)

Hematologic Monitoring

Following completion of therapy, monitor CBCs and platelet counts weekly until levels return to normal or as clinically indicated.1 2 Monitor for manifestations of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months following completion of therapy.1 More frequent laboratory monitoring for thrombocytopenia recommended in patients receiving anticoagulants or drugs affecting platelet function.1 (See Specific Drugs under Interactions.)

Radionuclide Precautions

Contents of ibritumomab tiuxetan kit are not radioactive.1 However, employ institutional good radiation safety practices and patient management procedures during and after radiolabeling of ibritumomab tiuxetan with yttrium 90 to minimize exposure of patients and medical personnel to radiation.1

Creutzfeldt-Jakob Disease and Viral Diseases

Because the ibritumomab tiuxetan therapeutic regimen contains albumin human, the preparations carry an extremely remote risk for transmitting viral diseases or Creutzfeldt-Jakob disease.1 No cases of transmission of viral diseases or Creutzfeldt-Jakob disease reported with albumin human.1

Infectious Complications

Severe (e.g., urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, upper respiratory tract infection) or life-threatening infections (e.g., sepsis, empyema, pneumonia, febrile neutropenia, fever, biliary stent-associated cholangitis) reported in patients with relapsed or refractory NHL; may occur up to 4 years following completion of therapy.1 2

Grade 3–4 infection (e.g., neutropenic sepsis, bronchitis, catheter sepsis, diverticulitis, herpes zoster infection, influenza, lower respiratory tract infection, sinusitis, upper respiratory tract infection) reported in patients with newly diagnosed NHL receiving the regimen as consolidation therapy.1

Immunologic Effects

Positive human antimurine antibody (HAMA) or human antichimeric antibody (HACA) responses detected following ibritumomab tiuxetan therapeutic regimen.1 2 3 6 HAMA/HACA responses develop infrequently, are typically transient, and do not increase with time.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Because human IgG is distributed into human milk, manufacturer states ibritumomab would be expected to be present in human milk.1 Discontinue nursing or do not administer regimen.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 2

Geriatric Use

No overall differences relative to younger adults, but increased sensitivity cannot be ruled out.1

Hematologic Impairment

Do not administer ibritumomab tiuxetan therapeutic regimen to patients with hematologic impairment.1 2 (See Hematologic Effects under Cautions.)

Common Adverse Effects

Cytopenias (e.g., thrombocytopenia,1 2 9 neutropenia,1 2 9 anemia1 2 9 ), fatigue,1 nasopharyngitis,1 nausea,1 2 7 9 abdominal pain,1 2 7 9 asthenia,1 2 7 9 cough,1 2 9 diarrhea,1 pyrexia.1

Interactions for Zevalin

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Anticoagulants

Possible increased risk of thrombocytopenia, bleeding, and hemorrhage15

Avoid use following administration of ibritumomab tiuxetan therapeutic regimen; if use cannot be avoided, more frequent laboratory monitoring for thrombocytopenia recommended1

Drugs affecting platelet function

Possible increased risk of thrombocytopenia, bleeding, and hemorrhage15

Avoid use following administration of ibritumomab tiuxetan therapeutic regimen; if use cannot be avoided, more frequent laboratory monitoring for thrombocytopenia recommended1

Hematopoietic growth factors

Altered biodistribution of ibritumomab (increased uptake in bone marrow) may occur due to increased marrow activity from recent administration of hematopoietic growth factors1

In clinical studies, use of growth factors was prohibited 2 weeks before initiation of regimen1

Vaccines

Safety of immunization with live virus vaccines following therapy not studied1

Ability of patients receiving ibritumomab tiuxetan therapeutic regimen to generate an immune response to any vaccine not studied1

Do not administer live viral vaccines for 12 months following the ibritumomab tiuxetan therapeutic regimen1

Zevalin Pharmacokinetics

Absorption

Onset

Median number of circulating B cells drops to 0 (range: 0–1084 cells/mm3) at 4 weeks following treatment.1

Distribution

Extent

Binding observed on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, lymphoid follicles of the tonsil, and lymphoid nodules of other organs (e.g., large and small intestines).1 2

Human IgG distributed into milk.1 Ibritumomab tiuxetan expected to distribute into milk.1

Elimination

Elimination Route

Approximately 7.2% of injected dose of yttrium Y 90 ibritumomab tiuxetan is excreted in urine within 7 days.1 2 7

Half-life

Yttrium 90: Physical half-life is 64.1 hours (2.67 days).1 Mean effective half-life in blood is 30 hours; mean area under the fraction of injected activity-time curve in blood is 39 hours.1

Stability

Storage

Parenteral

Injection

Ibritumomab tiuxetan kit: 2–8°C; do not freeze.1

Yttrium Y 90 ibritumomab tiuxetan: 2–8°C until use.1 Administer within 8 hours of radiolabeling.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium acetate

Sodium chloride 0.9%

Actions

  • Ibritumomab tiuxetan radiolabeled with yttrium 90 (yttrium Y 90 ibritumomab tiuxetan) is used for radioimmunotherapy.1 2 3 5 7

  • Ibritumomab binds specifically to antigen CD20 (expressed on normal pre-B and mature B lymphocytes and on essentially all B-cell non-Hodgkin’s lymphomas),1 2 triggering apoptosis of normal and malignant B cells through complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.1 2

  • Yttrium 90 responsible for the primary cytotoxic effect of yttrium Y 90 ibritumomab tiuxetan; induces cellular damage by forming free radicals in target and neighboring cells.1 2

  • Median number of circulating B cells drops to 0 (range: 0–1084 cells/mm3) at 4 weeks following completion of therapy.1 Recovery of B cells begins at approximately 3 months; median levels of B cells return to normal by 9 months.1 2 Median serum concentrations of IgG and IgA remain within normal range throughout the period of B-cell depletion; median serum IgM concentrations decline to below normal values but return to normal by 6 months following treatment.1

Advice to Patients

  • Risk of rituximab-related infusion reactions.1 Importance of taking premedications as prescribed and informing a clinician if severe infusion reactions occur.1

  • Risk of cytopenias (e.g., thrombocytopenia, neutropenia, anemia).1 Importance of reporting to a clinician any signs or symptoms of cytopenias (e.g., bleeding, easy bruising, petechiae or purpura, pallor, weakness, fatigue, infection, pyrexia).1

  • Importance of avoiding drugs that interfere with platelet function, unless directed by a clinician.1

  • Risk of severe cutaneous or mucocutaneous reaction.1 Importance of promptly seeking medical attention if diffuse rash, bullae, or desquamation of the skin or oral mucosa develops.1 11

  • Importance of not receiving live viral vaccines for 12 months after completion of therapy.1

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 Necessity of advising women to use an effective method of contraception while receiving therapy and for at least 12 months following completion of therapy.1 Necessity of advising pregnant women of risk to the fetus.1 Importance of discontinuing nursing during and after therapy.1

  • Importance of advising family members and other close contacts to follow standard precautions for minimizing exposure to blood and other body fluids (e.g., saliva, urine, stool).2 7

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs (e.g., live viral vaccines, medications that interfere with platelet function or coagulation) and dietary or herbal supplements, as well as any concomitant illnesses.1 (See Interactions.)

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution is restricted to qualified and appropriately licensed clinicians and facilities equipped to handle radionuclides (e.g., nuclear pharmacies); the regimen is not available through community pharmacies.2

Ibritumomab tiuxetan is commercially available as a kit that contains all of the nonradioactive ingredients necessary to prepare a single dose of yttrium Y 90 ibritumomab tiuxetan.1 Yttrium 90 chloride sterile solution is shipped directly from the supplier when the yttrium Y 90 ibritumomab tiuxetan (Y-90 Zevalin) kit is ordered.1 Rituximab must be ordered separately.1

Ibritumomab Tiuxetan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Kit

1 Vial, 3.2 mg/2 mL, Injection, for preparation of radioactive pharmaceutical, Ibritumomab Tiuxetan (Zevalin, preservative-free)

1 Vial, 50 mM/2 mL (Sodium Acetate Injection)

1 Vial (Formulation Buffer Injection; with albumin)

1 Vial (Reaction Vial, sterile, and empty)

Y-90 Zevalin (available with 4 identification labels)

Spectrum

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 2, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Spectrum Pharmaceuticals, Inc. Zevalin (ibritumomab tiuxetan) injection prescribing information. Irvine, CA; 2011 Nov.

2. IDEC Pharmaceuticals, San Diego, CA: Personal communication.

3. Witzig TE. Radioimmunotherapy for patients with relapsed B-cell non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2001; 48(Suppl 1):S91-5. [PubMed 11587375]

4. Biogen Idec/Genentech, Inc. Rituxan (rituximab) prescribing information. San Diego/South San Francisco, CA; 2007 Feb 21.

5. Wiseman GA, White CA, Sparks RB 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; 39:181-94. [PubMed 11418315]

6. Maung K, D’Orazio AI. 6th European Hematology Association Meeting. Frankfurt, Germany. June 21-24, 2001. Clin Lymphoma. 2001; 2:74-9. [PubMed 11712544]

7. Wagner HN Jr, Wiseman GA, Marcus CS et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med. 2002; 43:267-72. [IDIS 476756] [PubMed 11850494]

8. Witzig TE, Flinn IW, Gordon LI et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002; 20:3262-9. [PubMed 12149300]

9. Witzig TE, Gordon LI, Cabanillas F 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-Hodgkin’s lymphoma. J Clin Oncol. 2002; 20:2453-63. [IDIS 486286] [PubMed 12011122]

10. Wiseman GA, Gordon LI, Multani PS et al. Ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin’s lymphoma patients with mild thrombocytopenia: a phase II multicenter trial. Blood. 2002; 99:4336-42. [PubMed 12036859]

11. Kooijmans-Coutinho M. Dear healthcare professional letter regarding severe cutaneous or mucocutaneous reactions associated with Zevalin. Cambridge, MA: Biogen Idec; 2005 Oct. From FDA website.

12. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

13. Witzig TE, Molina A, Gordon LI et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer. 2007; 109:1804-10. [PubMed 17380530]

14. Cell Therapeutics, Seattle, WA: Personal communication.

15. Biogen Idec. Zevalin (ibritumomab tiuxetan) injection prescribing information. Cambridge, MA; 2007 Jan.

16. Spectrum Pharmaceuticals, Inc, Irvine, CA: Personal communication.

17. Morschhauser F, Radford J, Van Hoof A et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008; 26:5156-64. [PubMed 18854568]

18. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA website.

19. Food and Drug Administration. Supplemental BLA approval. Rockville, MD. 2011 Nov 18. From FDA website.

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