VA Class:AN600
Ibritumomab, a murine anti-human antigen CD20 monoclonal antibody conjugated with the chelating agent tiuxetan, readily chelates the radioisotopes indium 111 and yttrium 90 and is used as a radioimmunotherapeutic agent.1, 2, 3, 5, 7
Relapsed or Refractory Low-grade or Follicular Non-Hodgkin's Lymphoma
Ibritumomab tiuxetan, as part of a specific therapeutic regimen (ibritumomab tiuxetan therapeutic regimen), is used for the treatment of relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL);1, 12 ibritumomab tiuxetan is designated an orphan drug by the US Food and Drug Administration (FDA) for this use.2, 18
Safety and efficacy of the ibritumomab tiuxetan therapeutic regimen in the treatment of relapsed or refractory low-grade or follicular B-cell NHL have been established in 3 studies in 214 patients with relapsed or refractory low-grade or follicular B-cell NHL, including follicular NHL that was refractory to rituximab therapy.1, 2, 8, 9, 10 Patients in these studies received an ibritumomab tiuxetan therapeutic regimen that consisted of 2 low doses (250 mg/m2) of rituximab, an imaging dose (5 mCi) of ibritumomab tiuxetan labeled with indium 111 (indium In 111 ibritumomab tiuxetan) coupled with 2 or 3 whole body scans, and a standard (0.4 mCi/kg) or modified therapeutic dose (0.3 mCi/kg) of ibritumomab tiuxetan labeled with yttrium 90 (yttrium Y 90 ibritumomab tiuxetan).1, 3, 5, 8, 9, 10
The first study8 was a single-arm study in 54 patients with relapsed follicular NHL that was refractory to rituximab therapy.1 Patients had a World Health Organization (WHO) performance status of 0-2, less than 25% involvement of the bone marrow by lymphoma, no prior bone marrow transplantation, and acceptable hematologic, renal, and hepatic function.1 In this study, patients received the standard ibritumomab tiuxetan regimen and had an overall response rate (primary efficacy end point) of 74% (15% complete responses, 59% partial responses).1, 2 The median duration of response was 6.4 months (range: 0.5 to longer than 49.9 months), and the median time to disease progression was 6.8 months (range: 1.1 to longer than 50.9 months).1 Long-term responses (duration of response at least 12 months) were observed in 19% of the patients in this study.13
The second study was a randomized, open-label, comparative study in 130 patients with relapsed or refractory low-grade or follicular B-cell NHL.1 Patients received no prior rituximab therapy and had a WHO performance status of 0-2, less than 25% involvement of the bone marrow by lymphoma, no prior bone marrow transplantation, and acceptable hematologic function.1 In this study, patients were randomized to receive either the standard ibritumomab tiuxetan therapeutic regimen or IV rituximab (375 mg/m2 once weekly for 4 weeks).1, 5, 6, 9 The overall response rate (primary efficacy end point) was higher in patients receiving the ibritumomab tiuxetan therapeutic regimen (83% [38% confirmed complete responses]) than in those receiving rituximab (55% [18% confirmed complete responses]).1, 5, 6, 9 Similarly, among patients with bulky or chemotherapy-resistant disease, the overall response rate was higher in patients who received the ibritumomab tiuxetan therapeutic regimen (70 or 73%, respectively) than in those who received rituximab (55 or 42%, respectively).2 However, the median duration of response and time to disease progression were similar between patients receiving the ibritumomab tiuxetan therapeutic regimen (14.3 and 12.1 months, respectively) and those receiving rituximab (11.5 and 10.1 months, respectively).1, 9, 16 Long-term responses (duration of response at least 12 months) were observed in 42% of the patients in this study.13
The third study was a single-arm study in 30 patients with relapsed or refractory low-grade, follicular B-cell NHL who had a platelet count of 100,000-149,000/ mm3.1, 10 Patients with 25% or greater involvement of the bone marrow by lymphoma, prior myeloablative therapy with stem cell support, prior external beam radiation to greater than 25% of active marrow, or neutrophil count less than 1,500/mm3 were excluded from the study.1 In this study, administration of yttrium Y 90 ibritumomab tiuxetan at a lower dosage (0.3 mCi/kg) resulted in an overall response rate of 89% and a median duration of response of 11.6 months; however, the incidence of adverse hematologic events was higher in this study than in previous studies.1 (See Hematologic Effects under Warnings/Precautions: Warnings, in Cautions.) Long-term responses (duration of response at least 12 months) were observed in 47% of the patients in this study.13
Newly Diagnosed Follicular Non-Hodgkin's Lymphoma
The ibritumomab tiuxetan therapeutic regimen is 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 of the ibritumomab tiuxetan therapeutic regimen as consolidation therapy for newly diagnosed follicular NHL have been established in a randomized, phase 3, open-label study in 414 patients who achieved partial or complete response to first-line induction chemotherapy.1, 17 Patients had histologically confirmed grade 1 or 2 follicular NHL, stage III or IV disease, less than 25% involvement of the bone marrow by lymphoma, no prior external beam radiation or myeloablative therapy, and a platelet count of 150,000/ mm3 or greater.1, 17 Approximately 9.5% of patients previously received single-agent chlorambucil, 5% received fludarabine or a fludarabine-containing regimen, 71% received cyclophosphamide-containing combination chemotherapy (i.e., CHOP, CHOP-like, CVP/COP), and 14% received rituximab-containing combination chemotherapy as first-line induction therapy.1 In this study, patients were randomized to receive either the ibritumomab tiuxetan therapeutic regimen (consisting of 2 low doses [250 mg/m2] of rituximab administered one week apart, with the second dose immediately followed by yttrium Y 90 ibritumomab tiuxetan [0.4 mCi/kg]) or no further therapy; yttrium Y 90 ibritumomab tiuxetan was administered between 6-12 weeks following the last dose of chemotherapy.1, 17 The primary efficacy end point was prolongation of progression-free survival.1 After a median observation of 3.5 years, patients receiving the ibritumomab tiuxetan therapeutic regimen had longer median progression-free survival (38 months) compared with those receiving no further treatment (18 months).1, 17 The number of deaths was too small to permit a reliable comparison of survival between the two treatment groups.1 Among patients with newly diagnosed follicular NHL who had partial response to first-line induction chemotherapy, complete response was achieved in 77% of patients receiving consolidation therapy, compared with 17.5% of those receiving no further treatment; the final complete response rate was 87.4% following consolidation with the ibritumomab tiuxetan therapeutic regimen compared with 53.3% following no further treatment.17 Among patients who were bcl-2 polymerase chain reaction (PCR) positive after first-line induction chemotherapy, conversion to bcl-2 PCR-negative status was observed in 90% of patients receiving consolidation therapy, compared with 36% of those receiving no further treatment.17
Yttrium Y 90 ibritumomab tiuxetan is a radiopharmaceutical and should be prepared and used only by qualified clinicians experienced in the safe use and handling of radionuclides.7, 15
Because the ibritumomab tiuxetan therapeutic regimen may be associated with severe, potentially fatal infusion-related reactions, premedication with acetaminophen (650 mg orally) and an antihistamine (e.g., diphenhydramine [50 mg orally]) should be administered prior to each infusion of rituximab.1, 4
When used as consolidation therapy in patients with newly diagnosed follicular non-Hodgkin's lymphoma (NHL), the ibritumomab tiuxetan therapeutic regimen should be initiated when platelet counts are 150,000/mm3 or greater, between 6-12 weeks following the last dose of first-line induction chemotherapy.1
Reconstitution and Administration
Rituximab is administered by IV infusion.1 The drug must be diluted prior to IV infusion and should not be mixed or diluted with other drugs.1, 4 The manufacturer's labeling should be consulted for additional information on the reconstitution and administration of rituximab.1
The manufacturer's labeling should be consulted for detailed information on the preparation of yttrium Y 90 ibritumomab tiuxetan.1
Yttrium Y 90 ibritumomab tiuxetan is administered by slow IV injection (over 10 minutes).1, 5, 7 Prior to the injection of yttrium Y 90 ibritumomab tiuxetan, a 0.22-µm low-protein-binding filter should be placed in-line between the syringe and the infusion port.1 Following injection of the drug, the line should be flushed with at least 10 mL of 0.9% sodium chloride solution.1 Standard precautions should be taken to avoid extravasation of yttrium Y 90 ibritumomab tiuxetan (e.g., establishing a free-flowing IV line, ensuring adequate blood return upon needle aspiration) prior to administration of the radioimmunotherapeutic agent.1, 16 The infusion site should be closely monitored for signs of extravasation (e.g., swelling, pain, discomfort); should manifestations of extravasation appear, the infusion should immediately be stopped and restarted in another limb, and a radiation safety officer should be consulted.1, 2, 16 Specific treatment for yttrium Y 90 ibritumomab tiuxetan-induced extravasation reactions has not been fully determined; however, the 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 Because no penetrating γ waves are produced during therapy with yttrium Y 90 ibritumomab tiuxetan, the risk of exposure to radiation is presumed to be low in health-care professionals, family members, and the patient's other close personal contacts.2, 7 Although standard precautions for reducing the risk of radiation exposure (i.e., minimizing duration of exposure, maximizing distance from original source, using shielding) in such individuals are not necessary,2 some clinicians recommend that universal precautions for minimizing exposure to blood and other body fluids (e.g., saliva, urine, stool) should be followed.7
The ibritumomab tiuxetan therapeutic regimen is intended for use as a single course of treatment.1 The regimen consists of 2 low doses of rituximab (to deplete peripheral B lymphocytes and to improve distribution of ibritumomab tiuxetan) 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 was required after the first dose of rituximab; however, such evaluation is no longer required as part of the ibritumomab tiuxetan therapeutic regimen.16, 19
For the treatment of relapsed or refractory low-grade or follicular B-cell NHL, or for consolidation treatment of newly diagnosed follicular NHL in patients who have achieved partial or complete response to first-line induction chemotherapy, the ibritumomab tiuxetan therapeutic regimen is administered in 2 steps.1 Step 1 (administered on day 1) involves IV infusion of rituximab.1 Step 2 (administered on day 7, 8, or 9) consists of a second IV infusion of rituximab, followed within 4 hours by IV injection of yttrium Y 90 ibritumomab tiuxetan.1
Step 1 (administered on day 1) begins with IV infusion of a single dose (250 mg/m2) of rituximab, infused at an initial rate of 50 mg/hour.1 If infusion-related events do not occur, the infusion rate may be increased in increments of 50 mg/hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1 If severe infusion-related events develop, rituximab infusion should be immediately stopped and the ibritumomab tiuxetan therapeutic regimen discontinued.1 If less severe infusion-related events develop, rituximab infusion should be temporarily slowed or interrupted; the infusion may be resumed at one-half the previous rate when symptoms improve.1
Step 2 (administered on day 7, 8, or 9) begins with a second IV infusion of rituximab (250 mg/m2), infused at an initial rate of 100 mg/hour; the infusion rate may be increased, as tolerated, in increments of 100 mg/hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1 If infusion-related events developed during administration of the first dose of rituximab (on day 1), the second dose of rituximab should be infused at an initial rate of 50 mg/hour, and the infusion rate should be increased in increments of 50 mg/hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1 The second rituximab dose should be followed within 4 hours by slow IV injection (over 10 minutes) of yttrium Y 90 ibritumomab tiuxetan at a therapeutic dose of 0.4 mCi/kg (for patients with relapsed or refractory NHL or newly diagnosed NHL who have platelet counts of 150,000/mm3 or greater) or 0.3 mCi/kg (for patients with relapsed or refractory NHL who have platelet counts of 100,000-149,000/mm3).1, 2, 5 The prescribed, measured, and administered dose of yttrium Y 90 ibritumomab tiuxetan must not exceed the absolute maximum allowable dose of 32 mCi, regardless of the patient's weight.1, 5
The manufacturer recommends that patients with relapsed or refractory NHL who have platelet counts of 100,000-149,000/mm3 receive a lower therapeutic dose of yttrium Y 90 ibritumomab tiuxetan (0.3 mCi/kg).1, 5 (See Dosage and Administration: Dosage.)
The manufacturer makes no other special population (e.g., hepatic or renal impairment) dosage recommendations at this time.1
The manufacturer states that there are no contraindications to the use of ibritumomab tiuxetan.1
Yttrium Y 90 ibritumomab tiuxetan is a radiopharmaceutical and should be used only by qualified clinicians experienced in the safe use and handling of radionuclides.15
Because the ibritumomab tiuxetan therapeutic regimen includes the use of rituximab, the prescribing information for rituximab also should be consulted for detailed information on the usual cautions, precautions, and contraindications of this drug.1
Severe infusion-related effects, sometimes fatal, have been reported in patients receiving rituximab infusion, an essential component of the ibritumomab tiuxetan therapeutic regimen.1, 2 In some patients, death has occurred within 24 hours of rituximab infusion.1 These fatal reactions were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome (ARDS), myocardial infarction (MI), ventricular fibrillation, or cardiogenic shock.1 Approximately 80% of fatal infusion reactions occurred in association with the initial infusion of rituximab, with a usual time of onset of severe reactions between 30-120 minutes after starting the infusion.1, 4 If severe infusion-related effects (e.g., urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, ARDS, MI, ventricular fibrillation, cardiogenic shock) develop, rituximab and yttrium Y 90 ibritumomab tiuxetan should be immediately discontinued.1 If less severe infusion-related events develop, rituximab infusion should be temporarily slowed or interrupted.1 (See Dosage and Administration: Dosage.)For detailed information on infusion-related effects, including their management, see Cautions: Infusion-related Effects, in Rituximab 10:00.
Cytopenias with delayed onset and prolonged duration, some complicated by hemorrhage and severe infection, are the most common severe adverse effects associated with the ibritumomab tiuxetan therapeutic regimen.1 When used according to recommended dosages, the incidences of severe thrombocytopenia and neutropenia are higher in patients with mild thrombocytopenia at baseline (platelet counts of 100,000-149,000/mm3) compared with those with normal baseline platelet counts (150,000/mm3 or greater).1 Among patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) receiving yttrium Y 90 ibritumomab tiuxetan, severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3) or thrombocytopenia (platelet count less than 50,000/mm3) occurred in 57 or 61%, respectively, of patients with normal baseline platelet counts compared with 74 or 78%, respectively, of those with mild thrombocytopenia at baseline.1, 2 Among patients with newly diagnosed NHL who had normal baseline platelet counts, severe neutropenia or thrombocytopenia occurred in 65 or 61% of patients, respectively.1 Grade 3 or 4 anemia occurred in 17% of patients with relapsed or refractory NHL and in 5% of patients with newly diagnosed NHL receiving the ibritumomab tiuxetan therapeutic regimen.1, 2 In all patients, the median time to nadir ANC, platelet count, or hemoglobin concentration was 61-62, 49-53, or 68-69 days, respectively, following administration of yttrium Y 90 ibritumomab tiuxetan; severe neutropenia or thrombocytopenia persisted for a median of 22-29 or 24-35 days, respectively, and the median time to ANC or platelet count recovery was 12-15 days, respectively.1 Neutropenia and thrombocytopenia were more severe and more prolonged in patients who received the ibritumomab tiuxetan therapeutic regimen after first-line therapy with fludarabine or a fludarabine-containing regimen; in these patients, severe neutropenia or thrombocytopenia persisted for a median of 37 or 56 days, respectively, and the median time to ANC or platelet count recovery was 20 or 35 days, respectively.1 Filgrastim or erythropoietin was administered in 13 or 8%, respectively, of patients with relapsed or refractory NHL; granulocyte colony-stimulating factors or erythropoiesis-stimulating agents were administered in 14 or 5%, respectively, of patients with newly diagnosed NHL.1 Platelet transfusions were required in approximately 22% of all patients receiving the ibritumomab tiuxetan therapeutic regimen.1 Red blood cell transfusions were required in 20% of patients with relapsed or refractory NHL and in 2% of patients with newly diagnosed NHL.1, 2, 6 Severe cytopenias persisting more than 12 weeks following administration of the ibritumomab tiuxetan therapeutic regimen can occur.1 Severe hematologic effects occur more frequently in patients receiving the ibritumomab tiuxetan therapeutic regimen than in those receiving rituximab.2, 6
Patients should be monitored for manifestations of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months following completion of the ibritumomab tiuxetan therapeutic regimen.1 (See Hematologic Monitoring under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)Use of drugs that interfere with platelet function or coagulation following the ibritumomab tiuxetan therapeutic regimen should be avoided.1 (See Drug Interactions: Anticoagulants and Drugs Affecting Platelet Function.)
The ibritumomab tiuxetan therapeutic regimen should not be used in patients with 25% or greater involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve.1
Severe Cutaneous and Mucocutaneous Reactions
Severe cutaneous and mucocutaneous reactions, sometimes fatal, have been reported during postmarketing surveillance.1, 11 These reactions have included erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis.1, 11 The time to onset of these reactions was variable, ranging from a few days to 4 months following completion of the ibritumomab tiuxetan therapeutic regimen.1 The ibritumomab tiuxetan therapeutic regimen should be discontinued in patients experiencing a severe cutaneous or mucocutaneous reaction.1
Other Warnings and Precautions
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) have been reported in about 19 of 746 (2.6%) patients with relapsed or refractory NHL receiving ibritumomab tiuxetan therapy in clinical studies or in the expanded-access trial; the median time to diagnosis of MDS or AML was 1.9 years following completion of therapy.1 Among the 211 patients included in clinical studies, MDS/AML was reported in about 5.2% of those receiving ibritumomab tiuxetan after a median follow-up of 6.5 years; the median time to diagnosis of MDS or AML was 2.9 years following ibritumomab tiuxetan therapy.1 Among the 535 patients included in the expanded-access trial, MDS/AML was reported in about 1.5% of those receiving ibritumomab tiuxetan after a median follow-up of 4.4 years; the median time to diagnosis of MDS or AML was 1.5 years following ibritumomab tiuxetan therapy.1 The cumulative incidence of MDS/AML among patients receiving ibritumomab tiuxetan has been increasing with longer follow-up; among the 211 patients included in clinical studies, the cumulative estimated incidence of MDS/secondary leukemia was 2.2% at 2 years and 5.9% at 5 years.1 Multiple cytogenetic abnormalities have been reported, particularly involving chromosome 5 and/or 7.1 The risk of developing MDS/AML does not appear to be associated with the number of prior treatments (0-1 versus 2-10).1, 14
Among 204 patients with newly diagnosed NHL, 1% were diagnosed with AML within 3 years after receiving the ibritumomab tiuxetan therapeutic regimen as consolidation therapy.1
Fetal/Neonatal Morbidity and Mortality
Yttrium Y 90 ibritumomab tiuxetan may cause fetal harm when administered to pregnant women.1 There are no adequate and well-controlled studies to date in humans.1 Pregnancy should be avoided during therapy and for at least 12 months following completion of therapy.1, 2 (See Advice to Patients.) If yttrium Y 90 ibritumomab tiuxetan is used during pregnancy or if the patient becomes pregnant while receiving therapy, the patient should be apprised of the potential hazard to the fetus.1
Patients should be monitored closely for manifestations of extravasation (e.g., swelling, pain, discomfort) during infusion of yttrium Y 90 ibritumomab tiuxetan.1 If manifestations of extravasation appear, the infusion should immediately be stopped and restarted in another limb, and a radiation safety officer should be consulted.1, 2, 16 (See Dosage and Administration: Reconstitution and Administration.)
Following the ibritumomab tiuxetan therapeutic regimen, complete blood cell counts (CBCs) and platelet counts should be monitored weekly until levels return to normal or as clinically indicated.1 Patients should be monitored for manifestations of cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months following completion of the ibritumomab tiuxetan therapeutic regimen.1 More frequent laboratory monitoring for thrombocytopenia is recommended in patients receiving anticoagulants or drugs affecting platelet function.1 (See Drug Interactions: Anticoagulants and Drugs Affecting Platelet Function.)
The contents of the ibritumomab tiuxetan kit are not radioactive.1 However, institutional good radiation safety practices and patient management procedures should be employed 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 have been reported with albumin human.1 (See Risk of Transmissible Agents in Plasma-derived Preparations: Risk of Creutzfeldt-Jakob Disease under Cautions: Precautions and Contraindications, in Albumin Human 16:00.)
Among patients with relapsed or refractory NHL, infection was reported in 29% of patients within the first 3 months following initiation of the ibritumomab tiuxetan therapeutic regimen; 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) occurred in 3 or 2% of patients, respectively.1, 2 Infection was reported in 6% of patients during a follow-up period of 3 months to 4 years; severe or life-threatening infections occurred in 2 or 1% of these patients, respectively.1
Among patients with newly diagnosed NHL, 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) was reported in 8% of those receiving the ibritumomab tiuxetan therapeutic regimen as consolidation therapy.1
Transiently positive human antimurine antibody (HAMA) or human antichimeric antibody (HACA) responses were detected in about 1.3% of patients (6/446) receiving the ibritumomab tiuxetan therapeutic regimen in clinical studies.1, 2, 3, 6 HAMA or HACA concentrations reverted to negative within 2 weeks to 3 months after completion of therapy; no patients had increasing concentrations of HAMA or HACA at the end of the studies.1
Category D.1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Category D.1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Because human immunoglobulin G (IgG) is distributed into milk, it is expected that ibritumomab tiuxetan would be present in milk.1 Because of the potential for adverse reactions to yttrium Y 90 ibritumomab tiuxetan in nursing infants, a decision should be made whether to discontinue nursing or not administer the ibritumomab tiuxetan therapeutic regimen, taking into account the importance of the regimen to the woman.1
Safety and efficacy of the ibritumomab tiuxetan therapeutic regimen have not been established in children younger than 18 years of age.1, 2
Of the 349 patients with relapsed or refractory NHL receiving the ibritumomab tiuxetan therapeutic regimen in clinical studies, 38% were 65 years of age or older and 12% were 75 years of age or older.1 Of the 206 patients with newly diagnosed NHL receiving the ibritumomab tiuxetan therapeutic regimen as consolidation therapy in the controlled clinical study, 14% were 65 years of age or older and 2% were 75 years of age or older.1
No overall differences were observed between geriatric and younger patients in clinical studies; however, the possibility that some older patients may exhibit increased sensitivity to the ibritumomab tiuxetan therapeutic regimen cannot be ruled out.1
Adverse effects occurring in 10% or more of patients receiving the ibritumomab tiuxetan therapeutic regimen include 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 and pyrexia.1
Because the ibritumomab tiuxetan therapeutic regimen includes the use of rituximab, the prescribing information for rituximab also should be consulted for detailed information on the safety profile of this drug.1
No formal drug interaction studies of ibritumomab tiuxetan have been performed.1
In clinical studies, the use of hematopoietic growth factor was prohibited for the 2 weeks preceding ibritumomab tiuxetan therapy;1 altered biodistribution of ibritumomab tiuxetan characterized by increased uptake in the bone marrow may occur in patients with increased marrow activity caused by recent administration of hematopoietic growth factors.15
Anticoagulants and Drugs Affecting Platelet Function
Potential pharmacologic interaction (increased risk of thrombocytopenia, bleeding, and hemorrhage).15 Use of anticoagulants or drugs affecting platelet function following administration of the ibritumomab tiuxetan therapeutic regimen should be avoided.1 If such use cannot be avoided, more frequent laboratory monitoring for thrombocytopenia is recommended.1
The safety of immunization with live virus vaccines following the ibritumomab tiuxetan therapeutic regimen has not been studied.1 Live virus vaccines should not be administered within 12 months after completion of the regimen.1 The ability of patients to generate an immune response to any vaccine following therapy with the ibritumomab tiuxetan therapeutic regimen also has not been studied.1
Ibritumomab, a murine anti-human antigen CD20 monoclonal antibody conjugated with the chelating agent tiuxetan, readily chelates the radioisotopes indium 111 and yttrium 90.1, 2, 7 Ibritumomab tiuxetan radiolabeled with yttrium 90 (yttrium Y 90 ibritumomab tiuxetan) is used for radioimmunotherapy.1, 2, 3, 5, 7
The immunologic component of yttrium Y 90 ibritumomab tiuxetan (ibritumomab) is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain sequences;1, 2, 5 ibritumomab is the parent murine monoclonal antibody from which the chimeric human-murine anti-human antigen CD20 monoclonal antibody rituximab was developed.3, 7 Like rituximab, ibritumomab binds specifically to antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein located on normal pre-B and mature B lymphocytes; antigen CD20 also is expressed on greater than 90% of B-cell non-Hodgkin's lymphomas (NHL) but is not found on hematopoietic stem cells, early pre-B cells, normal plasma cells, or other normal tissues.1, 2 Results of in vitro studies indicate that, following binding of the Fab domain of ibritumomab to antigen CD20, the Fc domain triggers apoptosis of normal and malignant B cells through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).2, 15 The radioactive component of yttrium Y 90 ibritumomab tiuxetan (yttrium 90) induces cellular damage by forming free radicals in the target and neighboring cells and is responsible for the primary cytotoxic effect of the radioimmunotherapeutic agent.1, 2
Following IV injection, binding of ibritumomab tiuxetan has been 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
In patients receiving the ibritumomab tiuxetan therapeutic regimen, the mean effective half-life of yttrium 90 activity in blood is 30 hours, and the mean area under the fraction of injected activity-time curve in blood is 39 hours.1 Approximately 7.2% of the injected dose of yttrium Y 90 ibritumomab tiuxetan is excreted in urine within 7 days.1, 2, 7
Rapid and sustained depletion of circulating B cells occurs as a result of the cellular damage of B cells induced by the ibritumomab tiuxetan therapeutic regimen.1, 2 Following completion of therapy, recovery of B cells begins at approximately 3 months, and median levels of B cells return to normal by 9 months.1, 2 Median serum concentrations of IgG and IgA remain within the 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
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 evaluation 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 the ibritumomab tiuxetan therapeutic regimen 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 concomitant 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 diseases.1
Importance of informing patients of other important precautionary information. (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
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
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) |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 2, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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. 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 with 90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med . 2002; 43:267-72. [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. [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. [Web]
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. [Web]
19. Food and Drug Administration. Supplemental BLA approval. Rockville, MD. 2011 Nov 18. From FDA website. [Web]