Professional Information
Ibritumomab Tiuxetan (Systemic)
VA CLASSIFICATION
Primary: AN900
Commonly used brand name(s): Zevalin.
Other commonly used names are:
IDEC-2B8 (ibritumomab tiuxetan)IDEC-Y2B8 (yttrium-90-ibritumomab tiuxetan)IDEC-In2B8 (indium-111-ibritumomab tiuxetan)IDEC-129 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Monoclonal antibody—
Antineoplastic (radioactive)—
Indications
Accepted
Lymphomas, non-Hodgkin's (treatment)—Yttrium-90 Ibritumomab tiuxetan (co-administered with rituximab) is indicated for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including rituximab refractory follicular non-Hodgkin's lymphoma. {01}
Physical Properties
Nuclear Data {01}
| Radionuclide (half-life) |
Mode of decay (product of decay) |
Principal photon emissions (keV) |
Mean number of photons/disintegration |
| In 111 (67.3 hours) |
Electron capture (Cadmium-111) |
Gamma-2 (171.3) |
0.902 |
| Gamma-3 (245.4) |
0.94 |
||
| Y 90 (64.1 hours) |
Emission of beta particles (Zirconium-90) |
Beta minus (750–935) |
1 |
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Ibritumomab tiuxetan therapeutic regimen kit for the preparation of Indium-111 (In-111) ibritumomab tiuxetan and Yttrium-90 (Y-90) ibritumomab tiuxetan. {01}
Ibritumomab tiuxetan is an immunoconjugate resulting from a stable thiourea covalent bond between the monoclonal antibody ibritumomab and the linker-chelator tiuxetan. {01}
The antibody moiety of ibritumomab, a murine IgG 1 kappa monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. Ibritumomab is produced in Chinese hamster ovary cells and is composed of two kappa light chains of 213 amino acids each and two murine gamma 1 heavy chains of 445 amino acids each. Ibritumomab has an approximate apparent affinity (KD) for the CD20 antigen between 14 to 18 nM. More than 90% of B-cell non-Hodgkin's lymphomas (NHL) have CD20 antigen expressed on pre-B and mature B lymphocytes. The CD20 antigen is not internalized upon antibody binding and is not shed from the cell surface. {01}
The linker-chelator, tiuxetan, provides a high affinity, conformationally restricted chelation site for Indium-111 or Yttrium-90. {01}
Molecular weight—
148 kD {01}
Binding affinity
Ibritumomab has an approximate apparent affinity (K D) for the CD20 antigen between 14 to 18 nM.{01}
Mechanism of action/Effect:
Regions of ibritumomab bind to the CD20 antigen on B lymphocytes and induce apoptosis (programmed cell death) in CD20+ B-cell lines in vitro. Tiuxetan (chelator) tightly binds In-111 or Y-90. The chelator complex covalently links to the amino acids of exposed lysines and arginines contained within the antibody (ibritumomab). Beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells. {01}
Ibritumomab tiuxetan does not bind selectively to neoplastic cells; cross-reactivity was observed in vitro 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 such as large and small intestines. Nonlymphoid tissues or gonadal tissues were not observed to bind ibritumomab tiuxetan. {01}
Other actions/effects:
IgG and IgA median serum levels remained within the normal range throughout the period of B-cell depletion. {01}
IgM median serum levels decreased (median 49 mg per dL, range 13 to 3990 mg per dL) after treatment and recovered to normal values by 6 months after treatment. {01}
Distribution:
Only 18% of known sites of disease were imaged when In-111 ibritumomab tiuxetan was administered without unlabeled ibritumomab. {01}
Detection of sites of disease improved to 56% and 92% when In-111 ibritumomab tiuxetan was preceded by unlabeled ibritumomab 1 mg per kg of body weight or 2.5 mg per kg of body weight, respectively. {01}
Half-life:
The mean effective half-life of Y-90 activity in blood was 30 hours. {01}
The mean area under the fraction of injected activity (FIA) versus time curve of Y-90 in blood was 39 hours. {01}
Onset of action:
The median number of B cells was zero (range, 0 to 1084 cells per cubic millimeter) at four weeks following administration of ibritumomab tiuxetan therapeutic regimen. {01}
Time to peak concentration: In-111 ibritumomab tiuxetan—
Visual evaluation of whole body planar view anterior and posterior gamma images for biodistribution studies are acquired at 2 to 24 hours and 48 to 72 hours following administration of In-111 ibritumomab tiuxetan. A third image at 90 to 120 hours following administration of In-111 ibritumomab tiuxetan may be necessary to resolve ambiguities.{01}
Images should be obtained using a large field of view gamma camera equipped with a medium energy collimator. Calibrate the gamma camera using the 171 and 245 keV photopeaks for In-111 with a 15 to 20% symmetric window. The scan speed should be 10 centimeters per minute for the first scan, 7 centimeters per minute for the second scan, and 5 centimeters per minute for the optional third scan using a 256 x 1024 computer acquisition matrix.{01}
The radiopharmaceutical, In-111 ibritumomab tiuxetan, is expected to be easily detectable in the blood pool areas at the first time point, with less activity in the blood pool on later images. Low uptake is seen in lungs, kidneys, and urinary bladder. Moderately high to high uptake is seen in normal liver and spleen. Uptake localized to lymphoid aggregates in the bowel wall has been reported. Uptake by tumor in soft tissue may be visualized as areas of increased intensity and tumor-bearing areas in normal organs may be seen as areas of increased or decreased intensity.{01}
Time to peak effect:
The median number of B cells was zero (range, 0 to 1084 cells per cubic millimeter) at four weeks following administration of ibritumomab tiuxetan therapeutic regimen. By approximately 12 weeks following treatment, B cell recovery began in clinical studies. {01}
Duration of action:
The median level of B cells was within normal range (32 to 341 cells per cubic millimeter) by 9 months following treatment in clinical studies. {01}
Radiation dosimetry:
{01}
| Estimated absorbed radiation doses* |
||||
|---|---|---|---|---|
| Organ |
Y-90 ibritumomab tiuxetan (mGy/MBq) |
In-111 ibritumomab tiuxetan (mGy/MBq) |
||
| Median |
Range |
Median |
Range |
|
| Spleen 1 |
9.4 |
1.8-14.4 |
0.9 |
0.2-1.2 |
| Testes1 |
9.1 |
5.4-11.4 |
0.6 |
0.4-0.8 |
| Liver1 |
4.8 |
2.3-8.1 |
0.7 |
0.3-1.1 |
| Lower large intestinal wall1 |
4.8 |
3.1-8.2 |
0.4 |
0.2-0.6 |
| Upper large intestinal wall 1 |
3.6 |
2.0-6.7 |
0.3 |
0.2-0.6 |
| Heart wall1 |
2.8 |
1.5-3.2 |
0.4 |
0.2-0.5 |
| Lungs1 |
2.0 |
1.2-3.4 |
0.2 |
0.1-0.4 |
| Small intestine1 |
1.4 |
0.8-2.1 |
0.2 |
0.1-0.3 |
| Red marrow2 |
1.3 |
0.7-1.8 |
0.2 |
0.1-0.2 |
| Urinary bladder wall3 |
0.9 |
0.7-2.1 |
0.2 |
0.1-0.2 |
| Bone surfaces2 |
0.9 |
0.5-1.2 |
0.2 |
0.1-0.2 |
| Ovaries3 |
0.4 |
0.3-0.5 |
0.2 |
0.2-0.2 |
| Uterus3 |
0.4 |
0.3-0.5 |
0.2 |
0.1-0.2 |
| Adrenals3 |
0.3 |
0.0-0.5 |
0.2 |
0.1-0.3 |
| Brain3 |
0.3 |
0.0-0.5 |
0.1 |
0.0-0.1 |
| Breasts3 |
0.3 |
0.0-0.5 |
0.1 |
0.0-0.1 |
| Gallbladder wall3 |
0.3 |
0.0-0.5 |
0.3 |
0.1-0.4 |
| Muscle3 |
0.3 |
0.0-0.5 |
0.1 |
0.0-0.1 |
| Pancreas3 |
0.3 |
0.0-0.5 |
0.2 |
0.1-0.3 |
| Skin3 |
0.3 |
0.0-0.5 |
0.1 |
0.0-0.1 |
| Stomach3 |
0.3 |
0.0-0.5 |
0.1 |
0.1-0.2 |
| Thymus3 |
0.3 |
0.0-0.5 |
0.1 |
0.1-0.2 |
| Thyroid 3 |
0.3 |
0.0-0.5 |
0.1 |
0.0-0.1 |
| Kidneys1 |
0.1 |
0.0-0.2 |
0.2 |
0.1-0.2 |
| Total body3 |
0.5 |
0.2-0.7 |
0.1 |
0.1-0.2 |
1 Organ region of interest {01}
2 Sacrum region of interest {01}
3 Whole body region of interest {01}
Renal
A median of 7.2% of the injected Y-90 activity was excreted in urine over 7 days. {01}
Precautions to Consider
For information pertaining to the Precautions to Consider for rituximab, a component of the ibritumomab tiuxetan therapeutic regimen, see Rituximab (Systemic).
Cross-sensitivity and/or related problems
Patients with Type I hypersensitivity or anaphylactic reactions to murine proteins or to ibritumomab tiuxetan, rituximab, yttrium chloride or indium chloride {01}
Carcinogenicity/Mutagenicity
Long-term animal studies have not been performed to establish the carcinogenic or mutagenic potential for ibritumomab tiuxetan therapeutic regimen. Radiation is a potential carcinogen and mutagen. Ibritumomab tiuxetan results in a significant radiation dose to the testes. {01}
Tumorigenicity
Of 349 patients treated, one developed a Grade 1 meningioma, three developed acute myelogenous leukemia, and two developed myelodysplastic syndrome following ibritumomab tiuxetan therapeutic regimen. The onset of the secondary malignancy was 8 to 34 months following ibritumomab tiuxetan therapeutic regimen and 4 to 14 years following the patients' diagnosis of non-Hodgkin's lymphoma. {01}
Pregnancy/Reproduction
Fertility—
Long-term animal studies have not been performed to determine the effects of ibritumomab tiuxetan therapeutic regimen on fertility in females or males. Ibritumomab tiuxetan results in a significant radiation dose to the testes; the radiation dose to the ovaries has not been established. There is potential risk that the ibritumomab tiuxetan therapeutic regimen could cause toxic effects on the female and male gonads. Effective contraception methods are recommended during treatment and for up to 12 months following ibritumomab tiuxetan therapeutic regimen. {01}
Pregnancy—
Ibritumomab tiuxetan crosses the placenta and has been shown to cause fetal harm. Risk benefit must be carefully considered when this medication is required in life-threatening situations or in serious diseases for which other medications cannot be used or are ineffective.
Y-90 ibritumomab tiuxetan can cause fetal harm when administered to a pregnant woman. Adequate and well-controlled studies in pregnant women are not available. {01}
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ibritumomab tiuxetan therapeutic regimen. Effective contraception methods are recommended during treatment and for up to 12 months following ibritumomab tiuxetan therapeutic regimen. The patient should be apprised of the potential hazard to the fetus if ibritumomab tiuxetan is used during pregnancy or if the patient becomes pregnant while receiving ibritumomab tiuxetan. {01}
FDA Pregnancy Category D
Breast-feeding
It is not known if ibritumomab tiuxetan is distributed into breast milk. Breast-feeding is not recommended during ibritumomab tiuxetan therapeutic regimen because human IgG is distributed into human milk and the potential for ibritumomab tiuxetan exposure in the infant is unknown (adverse effects, mutagenicity, carcinogenicity). Formula feeding should be substituted for breast feeding. {01}
Pediatrics
No information is available on the relationship of age to the effects of ibritumomab tiuxetan in the pediatric population. Safety and efficacy have not been established. {01}
Geriatrics
Although appropriate studies on the relationship of age to the effects of ibritumomab tiuxetan have not be performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of ibritumomab tiuxetan in the elderly. However, some elderly patients may have greater sensitivity to the effects of ibritumomab tiuxetan therapeutic regimen. {01}
No overall differences in safety or effectiveness were observed between older subjects (132 of 349 age 65 years and over; 41 of 349 age 75 years and over) and younger subjects in clinical studies of 349 patients treated with the ibritumomab tiuxetan therapeutic regimen. {01}
For information pertaining to the Medication Advisory Screening of rituximab, a component of the ibritumomab tiuxetan therapeutic regimen, see Rituximab (Systemic).
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Formal drug interaction studies have not been performed with ibritumomab tiuxetan. {01}
» Anticoagulants {01} (Ibritumomab tiuxetan results in severe and prolonged cytopenias in most patients. {01} The potential benefits of medications which interfere with coagulation should be weighed against the potential increased risks of bleeding and hemorrhage in these patients. {01})
» Bone marrow depressants{01} (see Appendix II) (Ibritumomab tiuxetan results in severe and prolonged cytopenias in most patients. {01} Ibritumomab tiuxetan should not be administered to patients with impaired bone marrow reserves. {01})
» Platelet function, interferes with {01} (see Appendix II) (Ibritumomab tiuxetan results in severe and prolonged cytopenias in most patients. {01} The potential benefits of medications which interfere with platelet function should be weighed against the potential increased risks of bleeding and hemorrhage in these patients. {01})
Vaccines (The safety of immunization with live viral vaccines following the ibritumomab therapeutic regimen have not been studied. {01}.)
(The ability of patients who received the ibritumomab tiuxetan therapeutic regimen to generate a primary or anamnestic humoral response to any vaccine has not be studied. {01})
(The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. )
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
» B-cell counts, or
» Neutrophil counts, or
» Platelet counts (severe and prolonged decreases can be expected {01})
Blood pressure (may be decreased, especially in patients with severe infusion reaction {01})
Hemoglobin concentrations, or
Hematocrit (may be decreased {01})
Immunoglobulin concentrations ( IgM may be decreased {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Biodistribution of In-111 ibritumomab tiuxetan, altered {01} (Characterized by: • The blood pool is not visualized on the first image indicating rapid clearance of the radiopharmaceutical by the reticuloendothelial system to the liver, spleen, and/or marrow
• 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
• Intense areas of uptake throughout the normal bowel comparable to uptake by the liver on the second or third day images
)
» Bone marrow reserve, impaired{01} (Impaired bone marrow reserve is defined as any one of the following: • Prior myeloablative therapy with stem cell support
• Prior external beam radiation to less than 25% of active marrow
• Platelet count less than 100,000 cells per cubic millimeter
• Neutrophil count less than 1,500 cells per cubic millimeter
• Hypocellular bone marrow (£15% cellularity or marked reduction in bone marrow precursors)
• Patients with a history of failed stem cell collection
)
» Hypersensitivity (type I) or previous anaphylactic reaction to ibritumomab tiuxetan {01}
» Hypersensitivity (type I) or previous anaphylactic reaction to rituximab {01} (Ibritumomab tiuxetan is not know to cross-react with rituximab, however a separate infusion of rituximab is administered as a component of the ibritumomab tiuxetan therapeutic regimen)
For information pertaining to the severe infusion reactions associated with rituximab, a component of the ibritumomab tiuxetan therapeutic regimen, see Rituximab (Systemic)
» Hypersensitivity (type I) or previous anaphylactic reaction to yttrium chloride {01}
» Hypersensitivity (type I) or previous anaphylactic reaction to indium chloride {01}
» Hypersensitivity (type I) or previous anaphylactic reaction to murine proteins {01}
» Lymphoma marrow involvement ³ 25%{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Complete blood counts and
» Platelet counts (should be performed weekly following ibritumomab tiuxetan therapeutic regimen and continued until cell counts recover; in patients who develop severe cytopenia, monitor more frequently or as clinically indicated {01})
(careful monitoring for and management of cytopenias and their complications for up to 3 months after ibritumomab tiuxetan therapeutic regimen is recommended. Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests{01})
Side/Adverse Effects
Note: The ibritumomab tiuxetan therapeutic regimen includes IV infusion of rituximab. Adverse events were followed for 12 weeks following the first rituximab infusion of the ibritumomab tiuxetan therapeutic regimen. All adverse events are included, regardless of relationship of the adverse event to the therapeutic intervention performed (rituximab, In-111 ibritumomab tiuxetan (radiolabeled), or Y-90 ibritumomab tiuxetan (radiolabeled). For information pertaining to the Side/Adverse Effects of rituximab, a component of the ibritumomab tiuxetan therapeutic regimen, see Rituximab (Systemic).{01}
Note: Creutzfeldt-Jakob disease (CJD)—This product contains a derivative of human blood, albumin. It carries an extremely remote, theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD). {01}
Hypersensitivity reactions—Intravenous administration of proteins to patients may cause anaphylactic and other hypersensitivity reactions. {01}.
Human anti-mouse antibodies (HAMA) should be screened for in patients with prior exposure to murine proteins. Patients with evidence of HAMA may be at increased risk of allergic or serious hypersensitivity reactions during ibritumomab tiuxetan therapeutic regimen administration. {01}
Infectious events—During the first 3 months after initiating ibritumomab tiuxetan therapeutic regimen, 29% of patients developed infections; 3% of patients developed serious infections (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infections) and 2% of patients developed life-threatening infections (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis). {01}
During follow-up from 3 months to 4 years after initiating ibritumomab tiuxetan therapeutic regimen, 6% of patients developed infections; 2% of patients developed serious infections (urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, intravenous drug-associated viral hepatitis) and 1% of patients developed life-threatening infections (bacterial pneumonia, respiratory disease, sepsis). {01}
Infusion reactions—Severe infusion reactions, including some fatalities, have been reported following rituximab infusion, an essential component of the ibritumomab tiuxetan therapeutic regimen. Fatalities occurred within 24 hours of rituximab infusion and 80% occurred in association with the first rituximab infusion with the time to onset of 30 to 120 minutes. The signs and symptoms associated with these fatal infusion reactions may include angioedema, bronchospasm, hypotension, or hypoxia. The most severe manifestations and sequelae may include acute respiratory distress syndrome, cardiogenic shock, myocardial infarction, pulmonary infiltrates, or ventricular fibrillation. Patients who develop severe infusion reactions should have rituximab, In-111 ibritumomab tiuxetan, and Y-90 ibritumomab tiuxetan infusions discontinued. {01}
Immunogenicity—There were 8 of 211 (3.8%) patients who received the ibritumomab tiuxetan therapeutic regimen in clinical trials (followed for 90 days) with evidence of human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA) at any time during the course of the study. Test results were considered positive for antibodies to ibritumomab or rituximab using kinetic enzyme immunoassays to ibritumomab or rituximab. The incidence of antibody positivity in an assay is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including sample handling and concomitant medications. Comparisons of the incidence of HAMA/HACA to the ibritumomab tiuxetan therapeutic regimen with the incidence of antibodies to other products may be misleading. {01}
Patients who are leukopenic may not demonstrate evidence of immunogenicity. {01}
Radionuclide exposure—The exposure rate constant for 37 MBq (1 mCi) of In-111 is 8.3 × 10 4 C per kg body weight per hour (3.2 R per hr) at 1 cm. {01}
Viral disease transmission—This product contains a derivative of human blood, albumin. It carries an extremely remote risk for transmission of viral diseases. {01}
Note: Many side effects of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Anemia {01} (pale skin; troubled breathing with exertion; unusual bleeding or bruising; unusual tiredness or weakness)
angioedema {01} (large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, sex organs )
bronchospasm {01} (cough; difficulty breathing; noisy breathing; shortness of breath; tightness in chest; wheezing)
hemorrhage while thrombocytopenic {01} (bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath)—resulting in deaths
infection {01} ( fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
neutropenia {01} (chills; cough; fever; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands)
thrombocytopenia {01} (black, tarry stools; bleeding gums; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising ){01}
Note: The most frequently observed adverse event in clinical trials was hematologic events. {01}
Hemoglobin—
The median time to hemoglobin nadir was 68 days. {01}
Neutropenia—
In patients with normal baseline platelet counts (³ 150,000 cells per cubic millimeter) treated with ibritumomab tiuxetan therapeutic regimen using 0.4 mCi per kilogram of body weight of Y-90 ibritumomab tiuxetan developed a median absolute neutrophil count nadir of 800 cells per cubic millimeter with a median duration of absolute neutrophil count less than 1,000 cells per cubic millimeter of 22 days. {01}
In patients with mild thrombocytopenia at baseline (platelet count 100,000 to 149,000 cells per cubic millimeter) treated with modified ibritumomab tiuxetan therapeutic regimen using 0.3 mCi per kilogram of body weight of Y-90 ibritumomab tiuxetan developed a median absolute neutrophil count nadir of 600 cells per cubic millimeter with a median duration of absolute neutrophil count less than 1,000 cells per cubic millimeter of 29 days. {01}
The median time to absolute neutrophil count nadir was 62 days. {01}
Thrombocytopenia—
In patients with normal baseline platelet counts (³ 150,000 cells per cubic millimeter) treated with ibritumomab tiuxetan therapeutic regimen using 0.4 mCi per kilogram of body weight of Y-90 ibritumomab tiuxetan developed a median nadir of 41,000 cells per cubic millimeter with a median duration of platelets less than 50,000 cells per cubic millimeter of 24 days. {01}
In patients with mild thrombocytopenia at baseline (platelet count 100,000 to 149,000 cells per cubic millimeter) treated with modified ibritumomab tiuxetan therapeutic regimen using 0.3 mCi per kilogram of body weight of Y-90 ibritumomab tiuxetan developed a median nadir of 24,000 cells per cubic millimeter with a median duration of platelets less than 50,000 cells per cubic millimeter of 35 days. {01}
The median time to platelet count nadir was 62 days. {01}
Treatment of hematologic toxicity—
Erythropoietin was given to 8% of 211 patients of whom data were collected about growth factor use. {01}
Filgrastim was given to 13% of 211 patients of whom data were collected about growth factor use. {01}
Platelet transfusions were given to 22% of 211 patients of whom data were collected about transfusion use. {01}
Incidence less frequent
Allergic reaction {01} (cough; difficulty swallowing; dizziness; fast heartbeat; hives; itching; puffiness or swelling of the eyelids or around the eyes, face, lips or tongue; shortness of breath; skin rash; tightness in chest; unusual tiredness or weakness; wheezing)
apnea {01} (bluish lips or skin; not breathing)
epistaxis {01} ( bloody nose that does not stop after pinching the nasal alae together and holding them continuously for 5 to 10 minutes)
hemorrhage, gastrointestinal {01} (black, tarry stools; bloody stools; vomiting of blood or material that looks like coffee grounds)
infection, severe {01} (chills; confusion; dizziness; lightheadedness; fainting; fast heartbeat; fever; rapid, shallow breathing)
melena {01} (bloody, black, or tarry stools)
pain at site of tumor {01}
pancytopenia {01} (chest pain or discomfort; shortness of breath; unusual bleeding or bruising; bloody nose; unusual vaginal bleeding; pinpoint red spots on skin; bloody, black, or tarry stools; blood in urine; unusual tiredness or weakness; fever; skin rash; chills; cough; diarrhea; headache; pale skin; painful or difficult urination; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands)
petechia {01} (small red or purple spots on skin)
Incidence rare
Encephalopathy {01} (agitation; back pain; blurred vision; coma; confusion; dizziness; drowsiness; fever; hallucinations; headache; irritability; mood or mental changes; seizures; stiff neck; unusual tiredness or weakness; vomiting)
hematemesis {01} (vomiting of blood or material that looks like coffee grounds)
hematoma, subdural {01} (blurred vision; irregular heartbeat; nausea and vomiting; severe headache)
hemorrhage, cerebral {01} (blurred vision; headache, sudden and severe; inability to speak; seizures; slurred speech; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe)
hemorrhage, vaginal {01} (heavy nonmenstrual vaginal bleeding)
pulmonary edema {01} (chest pain; difficult, fast, noisy breathing, sometimes with wheezing; blue lips and fingernails; pale skin; increased sweating; coughing that sometimes produces a pink frothy sputum; shortness of breath; swelling in legs and ankles)
pulmonary embolus {01} (anxiety; chest pain; cough; fainting; fast heartbeat; sudden shortness of breath or troubled breathing; dizziness or lightheadedness )
tachycardia {01} (fast, pounding, or irregular heartbeat or pulse)
urticaria, severe {01} (hives or welts; itching; redness of skin; skin rash)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abdominal enlargement {01} (swelling of abdominal or stomach area; full or bloated feeling or pressure in the stomach)
anorexia {01} (loss of appetite, weight loss)
anxiety {01} (fear; nervousness)
arthralgia {01} (pain in joints; muscle pain or stiffness; difficulty in moving)
asthenia {01} (lack or loss of strength)
chills {01} —seek medical attention if associated with signs or symptoms of infection
constipation {01} (difficulty having a bowel movement (stool))
cough {01}
dizziness {01}
dyspnea {01} ( difficult or labored breathing; shortness of breath; tightness in chest; wheezing )
ecchymoses {01} ( bruising; large, flat, blue or purplish patches in the skin)
edema, peripheral {01} (swelling of hands, ankles, feet, or lower legs)
fever {01} —seek medical attention if associated with signs or symptoms of infection
flushing {01} (feeling of warmth; redness of the face, neck, arms and occasionally, upper chest)
gastrointestinal symptoms {01} (abdominal pain or stomach pain; diarrhea or increased bowel movements; loose or liquid stools; nausea or feeling of upset stomach or feeling like you may vomit; vomiting)
headache, mild {01} (pain in one or more areas of the head.)— seek medical attention if severe
hypotension {01} (blurred vision; confusion; dizziness; faintness or lightheadedness when getting up from a lying or sitting position; sudden sweating; unusual tiredness or weakness)
insomnia {01} (sleeplessness; trouble sleeping; unable to sleep )
myalgia {01} ( joint pain; swollen joints; muscle aching or cramping; muscle pains or stiffness; difficulty in moving)
pain {01}
pain, back {01}
pruritus {01} (itching skin )
rash {01}
rhinitis {01} (stuffy nose; runny nose; sneezing)
throat irritation {01}
Incidence less frequent
Arthritis {01} (pain, swelling, or redness in joints; muscle pain or stiffness; difficulty in moving)
dyspepsia {01} (acid or sour stomach; belching; heartburn; indigestion; stomach discomfort, upset or pain)
urticaria, mild {01} (hives or welts; itching; redness of skin; skin rash)
Those indicating need for medical attention only if they occur after medication is discontinued
Incidence less frequent
Hemorrhage {01} (bleeding gums; coughing up blood; difficulty in breathing or swallowing; dizziness; headache; increased menstrual flow or vaginal bleeding; nosebleeds; paralysis; prolonged bleeding from cuts; red or dark brown urine; red or black, tarry stools; shortness of breath)
hemorrhage, cerebral {01} (blurred vision; headache, sudden and severe; inability to speak; seizures; slurred speech; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe)
infection, severe {01} (chills; confusion; dizziness; lightheadedness; fainting; fast heartbeat; fever; rapid, shallow breathing)
leukemia, acute myelogenous {01} (bone pain)— secondary malignancy occurred in 3 of 349 patients treated with ibritumomab tiuxetan
myelodysplastic syndrome {01} — secondary malignancy occurred in 2 of 349 patients treated with ibritumomab tiuxetan
neutropenia, febrile {01} (black, tarry stools; chills; cough; fever; lower back or side pain; painful or difficult urination; pale skin; shortness of breath; sore throat; ulcers, sores, or white spots in mouth; unusual bleeding or bruising; unusual tiredness or weakness)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Clinical effects of overdose
Severe hematological toxicities (without fatalities or second organ injury) were observed in clinical trials following doses as high as 0.52 mCi per kilogram of body weight (19.2 MBq per kilogram of body weight) of Y-90 ibritumomab tiuxetan.{01}
In a limited number of patients, single doses of up to 50 mCi (1850 MBq) of Y-90 ibritumomab tiuxetan and multiple doses of 20 mCi (749 MBq) followed by 40 mCi (1480 MBq) of Y-90 ibritumomab tiuxetan were studied. Autologous stem cell support to manage hematological toxicity was required in some patients.{01}
Treatment of overdose
Specific treatment:
There is no known specific antidote to ibritumomab tiuxetan. Treatment is generally symptomatic and supportive. {01}
Monitoring:
Careful monitoring for and management of cytopenias and their complications for up to 3 months after administration of Y-90 ibritumomab tiuxetan is recommended. {01}
Supportive care:
Management of cytopenias may include platelet transfusions, red blood cell transfusions, administration of growth factors such as erythropoietin, and/or autologous stem cell support. {01}
Infections that develop due to neutropenia should be managed with appropriate antimicrobial therapy.
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ibritumomab Tiuxetan (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Description of use
Action in the body: Localization at sites of tumor spread or growth, the Y-90 beta emission induces cellular damage by free radical formation in the target and neighboring cells.
Before using this medication
» Conditions affecting use, especially:
Not recommended for use in patients with Type I hypersensitivity or previous anaphylactic reactions to ibritumomab, indium, murine proteins, rituximab, or yttrium.
Carcinogenicity/Mutagenicity
Radiation is a potential carcinogen and mutagen. Ibritumomab tiuxetan results in a significant radiation dose to the testes.
Tumorigenicity—
Of 349 patients treated, one developed a Grade 1 meningioma, three developed acute myelogenous leukemia, and two developed myelodysplastic syndrome following ibritumomab tiuxetan therapeutic regimen. The onset of the secondary malignancy was 8 to 34 months following ibritumomab tiuxetan therapeutic regimen and 4 to 14 years following the patients' diagnosis of non-Hodgkin's lymphoma.
Fertility—
Fertility—Y-90 ibritumomab tiuxetan results in significant radiation dose to the testes; the radiation dose to the ovaries has not been established. There is potential risk that the ibritumomab tiuxetan therapeutic regimen could cause toxic effects on the female and male gonads. Effective contraception methods are recommended during treatment and for up to 12 months following ibritumomab tiuxetan therapeutic regimen.
Pregnancy—Not recommended for use during pregnancy. Ibritumomab tiuxetan crosses the placenta and has been shown to cause fetal harm.
Breast-feeding—Not recommended during ibritumomab tiuxetan therapeutic regimen.
Use in children—Safety and efficacy have not ben established.
Use in the elderly—No overall differences in safety or effectiveness were observed between older subjects (132 of 349 age 65 years and over; 41 of 349 age 75 years and over) and younger subjects in clinical studies of 349 patients treated with the ibritumomab tiuxetan therapeutic regimen.
Other medications, especially anticoagulants , bone marrow depressants, vaccines, platelet function altering medications, or previous cytotoxic drug therapy or radiation therapy.
Other medical problems, especially altered biodistribution of In-111 ibritumomab tiuxetan or impaired bone marrow reserve.
Proper use of this medication
» Proper dosing
Proper storage
Precautions while using this medication
» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral polio virus vaccine or wearing a protective mask that covers nose and mouth
» Caution if bone marrow depression occurs:Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occur
Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur
Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done
Not touching eyes or inside of nose unless hands washed immediately before
Using caution ot avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters
Avoid contact sports or other situations where bruising or injury could occur
In-111 ibritumomab tiuxetan and Y-90 ibritumomab tiuxetan are radiopharmaceuticals. Care should be taken to minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.
Side/adverse effects
Signs of potential side effects, especially anemia, angioedema, bronchospasm, hemorrhage, infection, neutropenia, thrombocytopenia, allergic reaction, apnea, epistaxis, gastrointestinal hemorrhage, severe infection, melena, pain at site of tumor, pancytopenia, petechia, encephalopathy, hematemesis, subdural hematoma, cerebral hemorrhage, pulmonary edema, pulmonary embolus, tachycardia, severe urticaria
General Dosing Information
For information pertaining to the General Dosing of rituximab, a component of the ibritumomab tiuxetan therapeutic regimen, see Rituximab (Systemic).
Ibritumomab tiuxetan should be used only by physicians and other professionals qualified by training and experienced in the safe use and handling of radionuclides and who are authorized by the Nuclear Regulatory Commission (NRC) or the appropriate Agreement State agency, if required, or, outside the U.S., the appropriate authority.{01}
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of ibritumomab tiuxetan therapeutic regimen. These may include: extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool and secretions for occult blood; care in use of toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests
In-111 ibritumomab tiuxetan and Y-90 ibritumomab tiuxetan are radiopharmaceuticals. Care should be taken to minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures, during and after radiolabeling of ibritumomab tiuxetan with In-111 or Y-90. {01}
Guidelines for the receipt, storage, handling, dispensing, and disposal of radioactive materials are available from scientific, professional, state, federal, and international bodies. Handling of this radiopharmaceutical should be limited to those individuals who are appropriately qualified and authorized
For treatment of adverse effects
Medications for the treatment of hypersensitivity reactions, including epinephrine, antihistamines, and corticosteroids, should be available for immediate use in the event of an allergic reaction during administration of ibritumomab tiuxetan therapeutic regimen. {01}
Patients who develop severe infusion reactions should have rituximab, In-111 ibritumomab tiuxetan, and Y-90 ibritumomab tiuxetan infusions discontinued and appropriate medical treatment should be initiated. {01}
Due to the possibility of hypersensitivity reactions with the administration of rituximab as part of the ibritumomab tiuxetan regimen, premedication with acetaminophen and diphenhydramine should be administered with each dose of rituximab.{01}
Parenteral Dosage Forms
Note: The dose of rituximab is lower when used as part of the ibritumomab tiuxetan therapeutic regimen, as compared to the dose of rituximab when used as a single agent. {01}
IBRITUMOMAB TIUXETAN INJECTION
Usual Adult Dose
Lymphomas, non-Hodgkin's (treatment)
Ibritumomab tiuxetan therapeutic regimen is administered in two steps:
• Step 1—Intravenous infusion, rituximab (not included in ibritumomab tiuxetan kit) 250 milligrams per square meter of body surface area preceding (within 4 hours) an intravenous push (over 10 minutes) dose of 5 mCi (1.6 milligrams total antibody dose) of In-111 ibritumomab tiuxetan. {01}
• Wait seven to nine days following step 1. {01} Assess biodistribution. If biodistribution is not acceptable, do not proceed.{01}
• Step 2—Infusion, rituximab (not included in ibritumomab tiuxetan kit) 250 milligrams per square meter of body surface area preceding (within 4 hours) an intravenous push (over 10 minutes) dose of 0.4 mCi per kilogram of body weight of Y-90 ibritumomab tiuxetan. {01}
Note: Patients with mild thrombocytopenia—The dose of Y-90 ibritumomab tiuxetan (in Step 2) should be reduced to 0.3 mCi per kilogram of body weight (11.1 MBq per kilogram of body weight) for patients with a baseline platelet count between 100,000 and 149,000 cells per cubic millimeter. {01}
Do not treat patients with baseline platelet count less than 100,000 cells per cubic millimeter. {01}
Rituximab dose—The dose of rituximab is lower when used as part of the ibritumomab tiuxetan therapeutic regimen, as compared to the dose of rituximab when used as a single agent. {01}
Usual adult prescribing limits
Maximum allowable dose—The prescribed, measured, and administered dose of Y-90 ibritumomab tiuxetan should not exceed 32 mCi (1,184 MBq). {01}
Usual Pediatric Dose
Lymphomas, non-Hodgkin's B-cell (treatment)
The safety and efficacy have not been established. {01}
Usual Geriatric Dose
See Usual adult dose.
Usual geriatric prescribing limits
Example: See Usual adult prescribing limits.
Strength(s) usually available
U.S.—
3.2 mg of ibritumomab tiuxetan in 2 mL of 0.9% sodium chloride solution per vial (sterile, pyrogen-free; no preservatives) (Rx) [Zevalin (Kit contains 4 vials—1 vial of ibritumomab tiuxetan, 1 vial 50 mM sodium acetate (13.6 mg of sodium acetate trihydrate in 2 mL of Water for injection), 1 vial formulation buffer (750 mg of human albumin, 76 mg of sodium chloride, 21 mg of sodium phosphate dibasic heptahydrate, 4 mg of pentetic acid, 2 mg of potassium phosphate monobasic, and 2 mg of potassium chloride in 10 mL of water for injection adjusted to pH 7.1 with either sodium hydroxide or hydrochloric acid), and 1 empty reaction vial)]
Canada—
Not commercially available.
Packaging and storage:
Before radiolabeling, store between 2 and 8°C (36 and 46°F), unless otherwise specified by manufacturer. {01} Do not freeze.
Note: Product should be brought to room temperature before radiolabeling.
Indium-111(Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 12 hours of radiolabeling. {01}
Yttrium-90 (Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 8 hours of radiolabeling. {01}
Preparation of dosage form:
Read all directions thoroughly and assemble all materials before starting the radiolabeling procedure. {01}
Significant differences exist in the preparation of the In-111 ibritumomab tiuxetan and the Y-90 ibritumomab tiuxetan dose. {01}
See the manufacturer's package insert for instructions. {01}
Preparation of the Indium-111 (Zevalin) dose
• The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. The dose calibrator must be operated in accordance with the manufacturer's specifications and quality control for the measurement of In-111. {01}
• Proper aseptic technique and precautions for handling radioactive materials should be employed. Waterproof gloves should be utilized in the preparation and during the determination of radiochemical purity of In-111 (Zevalin). Appropriate shielding should be used during radiolabeling, and use of a syringe shield is recommended during administration to the patient. {01}
• To prepare injection, a sterile, pyrogen-free indium In 111 chloride solution is used. The use of high purity In-111 chloride manufactured by Amersham Health, Inc. or Mallinckrodt, Inc. is required. Isotope solution must be buffered with sodium acetate before adding to the ibritumomab tiuxetan solution. See manufacturer's package insert for instructions. {01}
• Determine radiochemical purity. See manufacturer's package insert for instructions.{01}
• Indium-111 (Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 12 hours of radiolabeling. {01}
• See Usual adult dosestep 1 for dosage and administration of Indium-111(Zevalin). {01}
• Discard needles, syringes, and vials in accordance with local, state, and federal regulations governing radioactive and biohazardous waste. {01}
Preparation of the Yttrium-90 (Zevalin) dose
• The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. The dose calibrator must be operated in accordance with the manufacturer's specifications and quality control for the measurement of Y-90.{01}
• Proper aseptic technique and precautions for handling radioactive materials should be employed. Waterproof gloves should be utilized in the preparation and during the determination of radiochemical purity of Y-90 (Zevalin). Appropriate shielding should be used during radiolabeling, and use of a syringe shield is recommended during administration to the patient.{01}
• To prepare injection, a sterile, pyrogen-free yttrium Y 90 chloride solution is used. The use of high purity Y-90 chloride manufactured by MDS Nordion is required. Isotope solution must be buffered with sodium acetate before adding to the (Zevalin) solution. See manufacturer's package insert for instructions.
• Determine radiochemical purity. See manufacturer's package insert for instructions.{01}
• Yttrium-90 (Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 8 hours of radiolabeling. {01}
• See Usual adult dosestep 2 for dosage and administration of Yttrium-90 (Zevalin).{01}
• Yttrium-90 (Zevalin) is suitable for administration on an outpatient basis. No special shielding is necessary, other than the use of vial and syringe shields for preparation and injection. {01}
• Discard needles, syringes, and vials in accordance with local, state, and federal regulations governing radioactive and biohazardous waste. {01}
Stability:
Indium-111 (Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 12 hours of radiolabeling. {01}
Yttrium-90(Zevalin) should be stored between 2 and 8°C (36 and 46°F) until use and administered within 8 hours of radiolabeling. {01}
Caution:
Note: Caution—Radioactive material.
Additional information:
The ibritumomab tiuxetan vial contains a protein solution that may develop translucent particulates. These particulates will be removed by filtration prior to administration. {01}
Developed: 11/18/2002
References
- Product Information: ZevalinTM, Ibritumomab Tiuxetan. IDEC Pharmaceuticals Corporation, San Diego, CA, (PI revised 01/2002) reviewed 08/2002.
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