Ibritumomab tiuxetan

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# Black Box Warning

# Overview
Ibritumomab tiuxetan is an monoclonal antibody that is FDA approved for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) and also indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Ibritumomab  is indicated for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).
- Ibritumomab  is indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.
- Administer the Ibritumomab  therapeutic regimen as outlined .
- Initiate the Ibritumomab  therapeutic regimen following recovery of platelet counts to 150,000/mm3 at least 6 weeks, but no more than 12 weeks, following the last dose of first-line chemotherapy.
- Only administer Rituxan/Ibritumomab  in facilities where immediate access to resuscitative measures is available.
- Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.
- Administer rituximab 250 mg/m2 intravenously at an initial rate of 50 mg/hr. In the absence of infusion reactions, escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Do not mix or dilute rituximab with other drugs.
- Immediately stop the rituximab infusion for serious infusion reactions and discontinue the Ibritumomab  therapeutic regimen .
- Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. If symptoms improve, continue the infusion at one-half the previous rate.
- Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally prior to rituximab infusion.
- Administer rituximab 250 mg/m2 intravenously at an initial rate of 100 mg/hr. Increase rate by 100 mg/hr increments at 30 minute intervals, to a maximum of 400 mg/hr, as tolerated. If infusion reactions occurred during rituximab infusion on Day 1 of treatment, administer rituximab at an initial rate of 50 mg/hr and escalate the infusion rate in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
- Administer Y-90 Ibritumomab  injection through a free flowing intravenous line within 4 hours following completion of rituximab infusion. Use a 0.22 micron low-protein-binding in-line filter between the syringe and the infusion port. After injection, flush the line with at least 10 mL of normal saline.
- If platelet count  150,000/mm3, administer Y-90 Ibritumomab  over 10 minutes as an intravenous injection at a dose of Y-90 0.4 mCi per kg (14.8 MBq per kg) actual body weight.
- If platelet count  100,000 but  149,000/mm3, in relapsed or refractory patients, administer Y-90 Ibritumomab  over 10 minutes as an intravenous injection at a dose of Y-90 0.3 mCi per kg (11.1 MBq per kg) actual body weight.
- Do not administer more than 32 mCi (1184 MBq) Y-90 Ibritumomab  dose regardless of the patients body weight.
- Monitor patients closely for evidence of extravasation during the injection of Y-90 Ibritumomab . Immediately stop infusion and restart in another limb if any signs or symptoms of extravasation occur .
- A clearly-labeled kit is required for preparation of Yttrium-90 (Y-90) Ibritumomab . Follow the detailed instructions for the preparation of radiolabeled Ibritumomab  .
- Required materials not supplied in the kit:
- Yttrium-90 Chloride Sterile Solution
- Three sterile 1 mL plastic syringes
- One sterile 3 mL plastic syringe
- Two sterile 10 mL plastic syringes with 18-20 G needles
- ITLC silica gel strips
- 0.9% Sodium Chloride aqueous solution for the chromatography solvent
- Developing chamber for chromatography
- Suitable radioactivity counting apparatus
- Filter, 0.22 micrometer, low-protein-binding
- Appropriate acrylic shielding for reaction vial and syringe for Y-90
- Method:
- Allow contents of the refrigerated Y-90 Ibritumomab  kit (Ibritumomab  vial, 50 mM sodium acetate vial, and formulation buffer vial) to reach room temperature.
- Place the empty reaction vial in an appropriate acrylic shield.
- Determine the amount of each component needed:
- Calculate volume of Y-90 Chloride equivalent to 40 mCi based on the activity concentration of the Y-90 Chloride stock.
- The volume of 50 mM Sodium Acetate solution needed is 1.2 times the volume of Y-90 Chloride solution determined in step 3.a, above.
- Calculate the volume of formulation buffer needed to bring the reaction vial contents to a final volume of 10 mL.
- Transfer the calculated volume of 50 mM Sodium Acetate to the empty reaction vial. Coat the entire inner surface of the reaction vial by gentle inversion or rolling.
- Transfer 40 mCi of Y-90 Chloride to the reaction vial using an acrylic shielded syringe. Mix the two solutions by gentle inversion or rolling.
- Transfer 1.3 mL of Ibritumomab  (ibritumomab tiuxetan) to the reaction vial. Do not shake or agitate the vial contents.
- Allow the labeling reaction to proceed at room temperature for 5 minutes. A shorter or longer reaction time may adversely alter the final labeled product.
- Immediately after the 5-minute incubation period, transfer the calculated volume of formulation buffer from step 3.c. to the reaction vial. Gently add the formulation buffer down the side of the reaction vial. If necessary, withdraw an equal volume of air to normalize pressure.
- Measure the final product for total activity using a radioactivity calibration system suitable for the measurement of Y-90.
- Using the supplied labels, record the date and time of preparation, the total activity and volume, and the date and time of expiration, and affix these labels to the shielded reaction vial container.
- Patient Dose: Calculate the volume required for a Y-90 Ibritumomab  dose.  Withdraw the required volume from the reaction vial. Assay the syringe in the dose calibrator suitable for the measurement of Y-90. The measured dose must be within 10% of the prescribed dose of Y-90 Ibritumomab  and must not exceed 32 mCi (1184 MBq). Using the supplied labels, record the patient identifier, total activity and volume and the date and time of expiration, and affix these labels to the syringe and shielded unit dose container.
- Determine Radiochemical Purity .
- Store Yttrium-90 Ibritumomab  at 2-8C (36-46F) until use and administer within 8 hours of radiolabeling. Immediately prior to administration, assay the syringe and contents using a radioactivity calibration system suitable for the measurement of Y-90.
- Use the following procedures for radiolabeling Y-90 Ibritumomab :
- Place a small drop of Y-90 Ibritumomab  at the origin of an ITLC silica gel strip.
- Place the ITLC silica gel strip into a chromatography chamber with the origin at the bottom and the solvent front at the top. Allow the solvent (0.9% NaCl) to migrate at least 5 cm from the bottom of the strip. Remove the strip from the chamber and cut the strip in half. Count each half of the ITLC silica gel strip for one minute (CPM) with a suitable counting apparatus.
- Calculate the percent RCP as follows:
- Repeat the ITLC procedure if the radiochemical purity is <95%. If repeat testing confirms that radiochemical purity is <95%, do not administer the Y-90 Ibritumomab  dose.
- During clinical trials with Ibritumomab , estimations of radiation-absorbed doses for Y-90 Ibritumomab  were performed using sequential whole body images and the MIRDOSE 3 software program. The estimated radiation absorbed doses to organs and marrow from a course of the Ibritumomab  therapeutic regimen are summarized in Table 1. Absorbed dose estimates for the lower large intestine, upper large intestine, and small intestine have been modified from the standard MIRDOSE 3 output to account for the assumption that activity is within the intestine wall rather than the intestine contents.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibritumomab in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ibritumomab in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ibritumomab in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ibritumomab in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ibritumomab in pediatric patients.

# Contraindications
- None.

# Warnings
- Rituximab, alone or as a component of the Ibritumomab  therapeutic regimen, can cause severe, including fatal, infusion reactions. These reactions typically occur during the first rituximab infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reactions may include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. Temporarily slow or interrupt the rituximab infusion for less severe infusion reactions. Immediately discontinue rituximab and Y-90 Ibritumomab  administration for severe infusion reactions. Only administer Rituxan/Ibritumomab  in facilities where immediate access to resuscitative measures is available .
- Cytopenias with delayed onset and prolonged duration, some complicated by hemorrhage and severe infection, are the most common severe adverse reactions of the Ibritumomab  therapeutic regimen. When used according to recommended doses, the incidences of severe thrombocytopenia and neutropenia are greater in patients with mild baseline thrombocytopenia ( 100,000 but  149,000 /mm3) compared to those with normal pretreatment platelet counts. Severe cytopenias persisting more than 12 weeks following administration can occur. Monitor complete blood counts (CBC) and platelet counts following the Ibritumomab  therapeutic regimen weekly until levels recover or as clinically indicated .
- Do not administer the Ibritumomab  therapeutic regimen to patients with  25% lymphoma marrow involvement and/or impaired bone marrow reserve. Monitor patients for cytopenias and their complications (e.g., febrile neutropenia, hemorrhage) for up to 3 months after use of the Ibritumomab  therapeutic regimen. Avoid using drugs which interfere with platelet function or coagulation following the Ibritumomab  therapeutic regimen.
- Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis, some fatal, were reported in post-marketing experience. The time to onset of these reactions was variable, ranging from a few days to 4 months after administration of the Ibritumomab  therapeutic regimen. Discontinue the Ibritumomab  therapeutic regimen in patients experiencing a severe cutaneous or mucocutaneous reaction .
- In a post-marketing registry designed to collect biodistribution images and other information in reported cases of altered biodistribution, there were 12 (1.3%) patients reported to have altered biodistribution among 953 patients registered.
- The radiation dose resulting from therapeutic exposure to Y-90 radiolabeled Ibritumomab  may result in secondary malignancies.
- Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients with relapsed or refractory NHL enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to the diagnosis of MDS or AML was 1.9 years following treatment with the Ibritumomab  therapeutic regimen; however, the cumulative incidence continues to increase .
- Among 204 patients receiving Y-90 Ibritumomab  following first-line chemotherapy, 26 (12.7%) patients in the Ibritumomab  arm developed a second primary malignancy compared to 14 (6.8%) of patients in the control arm. Seven patients (3.4%, 7/204) were diagnosed with MDS/AML after receiving Ibritumomab , compared to one patient (0.5%, 1/205) in the control arm, with a median follow-up of 7.3 years. Deaths due to second primary malignancy included 8 (3.9%) patients in the Ibritumomab  arm compared to 3 (1.5%) patients in the control arm. Deaths due to MDS/AML included five (2.5%) patients in the Ibritumomab  arm compared to no patients in the control arm.
- Monitor patients closely for evidence of extravasation during Ibritumomab  infusion. Immediately terminate the infusion if signs or symptoms of extravasation occur and restart in another limb .
- The safety of immunization with live viral vaccines following the Ibritumomab  therapeutic regimen has not been studied. Do not administer live viral vaccines to patients who have recently received Ibritumomab. The ability to generate an immune response to any vaccine following the Ibritumomab  therapeutic regimen has not been studied.
- During and after radiolabeling Ibritumomab  with Y-90, minimize radiation exposure to patients and to medical personnel, consistent with institutional good radiation safety practices and patient management procedures.
- Based on its radioactivity, Y-90 Ibritumomab  may cause fetal harm when administered to a pregnant woman. If the Ibritumomab  therapeutic regimen is administered during pregnancy, the patient should be apprised of the potential hazard to a fetus.   Advise women of childbearing potential to use adequate contraception for a minimum of twelve months

# Adverse Reactions

## Clinical Trials Experience
- The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Serious Infusion reaction
- Prolonged and Severe Cytopenias
- Severe Cutaneous and Mucocutaneous Reactions
- Leukemia and Myelodysplastic Syndrome
- The most common adverse reactions of Ibritumomab  are cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and pyrexia.
- The most serious adverse reactions of Ibritumomab  are prolonged and severe cytopenias (thrombocytopenia, anemia, lymphopenia, neutropenia) and secondary malignancies.
- Because the Ibritumomab  therapeutic regimen includes the use of rituximab.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The reported safety data reflects exposure to Ibritumomab  in 349 patients with relapsed or refractory, low-grade, follicular or transformed NHL across 5 trials (4 single arm and 1 randomized) and in 206 patients with previously untreated follicular NHL in a randomized trial (Study 4) who received any portion of the Ibritumomab  therapeutic regimen. The safety data reflect exposure to Ibritumomab  in 270 patients with relapsed or refractory NHL with platelet counts 150,000/ mm3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Ibritumomab  (Group 1 in Table 4), 65 patients with relapsed or refractory NHL with platelet counts of  100,000 but  149,000 /mm3 who received 0.3 mCi/kg (11.1 MBq/kg) of Y-90 Ibritumomab  (Group 2 in Table 4), and 204 patients with previously untreated NHL with platelet counts 150,000/ mm3 who received 0.4 mCi/kg (14.8 MBq/kg) of Y-90 Ibritumomab ; all patients received a single course of Ibritumomab .
- Table 2 displays selected adverse reaction incidence rates in patients who received any portion of the Ibritumomab  therapeutic regimen (n=206) or no further therapy (n=203) following first-line chemotherapy (Study 4).
- Patients in clinical studies were not permitted to receive hematopoietic growth factors beginning 2 weeks prior to administration of the Ibritumomab  therapeutic regimen.
- The incidence and duration of severe hematologic toxicity in previously treated NHL patients (N=335) and in previously untreated patients (Study 4) receiving Y-90 Ibritumomab  are shown in Table 4.
- Cytopenias were more severe and more prolonged among eleven (5%) patients who received Ibritumomab  after first-line fludarabine or a fludarabine-containing chemotherapy regimen as compared to patients receiving non-fludarabine-containing regimens. Among these eleven patients, the median platelet nadir was 13,000/mm3 with a median duration of platelets below 50,000/mm3 of 56 days and the median time for platelet recovery from nadir to Grade 1 toxicity or baseline was 35 days. The median ANC was 355/mm3, with a median duration of ANC below 1,000/mm3 of 37 days and the median time for ANC recovery from nadir to Grade 1 toxicity or baseline was 20 days.
- The median time to cytopenia was similar across patients with relapsed/refractory NHL and those completing first-line chemotherapy, with median ANC nadir at 61-62 days, platelet nadir at 49-53 days, and hemoglobin nadir at 68-69 days after Y-90-Ibritumomab  administration.
- Information on hematopoietic growth factor use and platelet transfusions is based on 211 patients with relapsed/refractory NHL and 206 patients following first-line chemotherapy. Filgrastim was given to 13% of patients and erythropoietin to 8% with relapsed or refractory disease; 14% of patients receiving Ibritumomab  following first-line chemotherapy received Granulocyte-colony stimulating factors and 5% received erythopoiesis stimulating agents. Platelet transfusions were given to approximately 22% of all Ibritumomab -treated patients. Red blood cell transfusions were given to 20% of patients with relapsed or refractory NHL and 2% of patients receiving Ibritumomab  following first-line chemotherapy.
- In relapsed or refractory NHL patients, infections occurred in 29% of 349 patients during the first 3 months after initiating the Ibritumomab  therapeutic regimen and 3% developed serious infections (urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection). Life-threatening infections were reported in 2% (sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis). From 3 months to 4 years after Ibritumomab  treatment, 6% of patients developed infections; 2% were serious (urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated viral hepatitis) and 1% were life-threatening infections (bacterial pneumonia, respiratory disease, and sepsis).
- When administered following first-line chemotherapy (Table 2), Grade 3-4 infections occurred in 8% of Ibritumomab  treated patients and in 2% of controls and included neutropenic sepsis (1%), bronchitis, catheter sepsis, diverticulitis, herpes zoster, influenza, lower respiratory tract infection, sinusitis, and upper respiratory tract infection.
- Among 746 patients with relapsed/refractory NHL, 19 (2.6%) patients developed MDS/AML with a median follow-up of 4.4 years. The overall incidence of MDS/AML among the 211 patients included in the clinical studies was 5.2% (11/211), with a median follow-up of 6.5 years and median time to development of MDS/AML of 2.9 years. The cumulative Kaplan-Meier estimated incidence of MDS/secondary leukemia in this patient population was 2.2% at 2 years and 5.9% at 5 years. The incidence of MDS/AML among the 535 patients in the expanded access programs was 1.5% (8/535) with a median follow-up of 4.4 years and median time to development of MDS/AML of 1.5 years. Multiple cytogenetic abnormalities were described, most commonly involving chromosomes 5 and/or 7. The risk of MDS/AML was not associated with the number of prior treatments (0-1 versus 2-10).
- Among 204 patients receiving Y-90-Ibritumomab  following first-line treatment, 7 (3%) patients developed MDS/AML between approximately 2 and 7 years after Ibritumomab  administration

## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of the Ibritumomab  therapeutic regimen in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the Ibritumomab  therapeutic regimen.
- Cutaneous and mucocutaneous reactions: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis.
- Infusion site erythema and ulceration following extravasation .
- Radiation injury in tissues near areas of lymphomatous involvement within a month of Ibritumomab  administration.
- As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of HAMA/HACA to the Ibritumomab  therapeutic regimen with the incidence of antibodies to other products may be misleading.
- HAMA and HACA response data on 446 patients from 8 clinical studies conducted over a 10-year time period are available. Overall, 11/446 (2.5%) had evidence of either HAMA formation (N=8) or HACA formation (N=4). Six of these patients developed HAMA/HACA after treatment with Ibritumomab  and 5 were HAMA/HACA positive at baseline. Of the 6 who were HAMA/HACA positive, only one was positive for both. Furthermore, in 6 of the 11 patients, the HAMA/HACA reverted to negative within 2 weeks to 3 months. No patients had increasing levels of HAMA/HACA at the end of the studies.
- Only 6/446 patients (1.3%) had developed evidence of antibody formation after treatment with Ibritumomab , and of these, many either reverted to negative or decreased over time. This data demonstrates that HAMA/HACA develop infrequently, are typically transient, and do not increase with time.

# Drug Interactions
- No formal drug interaction studies have been performed with Ibritumomab . Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
- Based on its radioactivity, Y-90 Ibritumomab  may cause fetal harm when administered to a pregnant woman. Immunoglobulins are known to cross the placenta. There are no adequate and well-controlled studies in pregnant women. Animal reproductive toxicology studies of Ibritumomab  have not been conducted.
- Advise women of childbearing potential to use adequate contraception for a minimum of twelve months. Inform women who become pregnant while receiving Ibritumomab  of the potential fetal risks
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ibritumomab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Ibritumomab during labor and delivery.

### Nursing Mothers
- Because human IgG is excreted in human milk, it is expected that Ibritumomab  would be present in human milk. Because of the potential for adverse reactions in nursing infants from Y-90 Ibritumomab , a decision should be made to discontinue nursing or not administer the Ibritumomab  therapeutic regimen, taking into account the importance of the drug to the mother.

### Pediatric Use
- The safety and effectiveness of Ibritumomab  have not been established in pediatric patients.

### Geriatic Use
- Of 349 patients with relapsed/refractory NHL treated with the Ibritumomab  therapeutic regimen in clinical studies, 38% (132 patients) were age 65 years and over, while 12% (41 patients) were age 75 years and over.
- Of 414 patients enrolled in Study 4 (Ibritumomab  following first-line chemotherapy) 206 patients received Ibritumomab . Of these patients 14% (29 patients) were 65 years and over, while 2% (4 patients) were 75 years and older. In the control arm, 10% (21 patients) were 65 years or over and 0% (0 patients) were 75 years or older.
- No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

### Gender
There is no FDA guidance on the use of Ibritumomab with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ibritumomab with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ibritumomab in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ibritumomab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ibritumomab in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ibritumomab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Monitoring of Ibritumomab in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Ibritumomab in the drug label.

# Overdosage
- Severe cytopenias which may require stem cell support have occurred at doses higher than the recommended maximum total dose of 32 mCi (1184 MBq).
There is limited information regarding Chronic Overdose of Ibritumomab  in the drug label.

# Pharmacology

## Mechanism of Action
- Ibritumomab tiuxetan binds specifically to the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35). The apparent affinity (KD) of ibritumomab tiuxetan for the CD20 antigen ranges between approximately 14 to 18 nM. The CD20 antigen is expressed on pre-B and mature B lymphocytes and on > 90% of B-cell non-Hodgkins lymphomas (NHL). The CD20 antigen is not shed from the cell surface and does not internalize upon antibody binding.
- The chelate tiuxetan, which tightly binds Y-90, is covalently linked to ibritumomab. The beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells.
- Ibritumomab tiuxetan binding was observed in vitro on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, and lymphoid follicles of the tonsil, as well as lymphoid nodules of other organs such as the large and small intestines.

## Structure
- Ibritumomab (ibritumomab tiuxetan)  is  the immunoconjugate resulting from a stable thiourea covalent bond between the monoclonal antibody ibritumomab and the linker-chelator tiuxetan -3-(p-isothiocyanatophenyl)-propyl]--2-(methyl)-ethyl]glycine. This linker-chelator provides a high affinity, conformationally restricted chelation site for Indium-111 or Yttrium-90. The approximate molecular weight of ibritumomab tiuxetan is 148 kD. The antibody moiety of Ibritumomab  is ibritumomab, a murine IgG1 kappa monoclonal antibody directed against the CD20 antigen.
Ibritumomab tiuxetan is a clear, colorless, sterile, pyrogen-free, preservative-free solution that may contain translucent particles. Each single-use vial includes 3.2 mg of ibritumomab tiuxetan in 2 mL of 0.9% Sodium Chloride.
Physical/Radiochemical Characteristics of Y-90
Yttrium-90 decays by emission of beta particles, with a physical half-life of 64.1 hours (2.67 days). The product of radioactive decay is non-radioactive Zirconium-90. The range of beta particles in soft tissue (90) is 5 mm. Radiation emission data for Y-90 are summarized in Table 5.
- The exposure rate for 1 mCi (37 MBq) of Y-90 is 8.3 x 10-3 C/kg/hr (32 R/hr) at the mouth of an open Y-90 vial.
- To allow correction for physical decay of Y-90, the fractions that remain at selected intervals before and after the time of calibration are shown in Table 6.

## Pharmacodynamics
- In clinical studies, administration of the Ibritumomab  therapeutic regimen resulted in sustained depletion of circulating B cells. At four weeks, the median number of circulating B cells was zero (range, 0-1084/mm3). B-cell recovery began at approximately 12 weeks following treatment, and the median level of B cells was within the normal range (32 to 341/mm3) by 9 months after treatment. Median serum levels of IgG and IgA remained within the normal range throughout the period of B-cell depletion. Median IgM serum levels dropped below normal (median 49 mg/dL, range 13-3990 mg/dL) after treatment and recovered to normal values by 6-months post therapy.

## Pharmacokinetics
- Pharmacokinetic and biodistribution studies were performed using In-111 Ibritumomab  (5 mCi  In-111, 1.6 mg ibritumomab tiuxetan). In an early study designed to assess the need for pre-administration of unlabeled antibody, only 18% of known sites of disease were imaged when In-111 Ibritumomab  was administered without unlabeled ibritumomab. When preceded by unlabeled ibritumomab (1.0 mg/kg or 2.5 mg/kg), In-111 Ibritumomab  detected 56% and 92% of known disease sites, respectively. These studies were conducted with a Ibritumomab  therapeutic regimen that included unlabeled ibritumomab.
- In pharmacokinetic studies of patients receiving the Ibritumomab  therapeutic regimen, the mean effective half-life for Y-90 activity in blood was 30 hours, and the mean area under the fraction of injected activity (FIA) vs. time curve in blood was 39 hours. Over 7 days, a median of 7.2% of the injected activity was excreted in urine.

## Nonclinical Toxicology
- Carcinogenicity and mutogenicity studies have not been conducted. However, radiation is a potential carcinogen and mutagen.
- No animal studies have been performed to determine the effects of Ibritumomab  on fertility in males or females. In clinical studies, the Ibritumomab  therapeutic regimen results in a significant radiation dose to the testes: the radiation dose to the ovaries has not been established . There is a potential risk that the Ibritumomab  therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the Ibritumomab  therapeutic regimen.
- Animal reproductive toxicology studies of the Ibritumomab  therapeutic regimen have not been conducted. Because the Ibritumomab  therapeutic regimen includes the use of rituximab, also see prescribing information for rituximab.

# Clinical Studies
- Study 1 was a single arm study of 54 patients with relapsed follicular lymphoma, who were refractory to rituximab treatment. Patients had a World Health Organization (WHO) Performance Status (PS) 0-2, <25% bone marrow involvement by NHL, no prior bone marrow transplantation, and acceptable hematologic, renal, and hepatic function. Refractoriness to rituximab was defined as failure to achieve a complete or partial response or time-to-disease-progression (TTP) of < 6 months. The main efficacy outcome measure of the study was the overall response rate (ORR) using the International Workshop Response Criteria (IWRC). Other efficacy outcome measures included time-to-disease-progression (TTP) and duration of response (DR). Table 7 summarizes efficacy data from Study 1.
- Study 2 was a randomized (1:1), open-label, multicenter study comparing the Ibritumomab  therapeutic regimen with rituximab. The trial was conducted in 130 patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL); no patient had received prior rituximab. Patients had histologically confirmed NHL requiring therapy, a WHO PS 0-2, <25% bone marrow involvement by NHL, no prior bone marrow transplantation, and acceptable hematologic function. Sixty-four patients received the Ibritumomab  therapeutic regimen, and 66 patients received rituximab given as an IV infusion at 375 mg per m2 weekly times 4 doses. The main efficacy outcome measure of the study was ORR using the IWRC. The ORR was significantly higher for patients receiving the Ibritumomab  therapeutic regimen (83% vs. 55%, p<0.001). Time-to-disease-progression was not significantly different between study arms. Table 7 summarizes efficacy data from Study 2.
- Study 3 was a single arm study of 30 patients of whom 27 had relapsed or refractory low-grade, follicular NHL and a platelet count 100,000 to 149,000/mm3. Patients with  25% lymphomatous marrow involvement, prior myeloablative therapy with stem cell support, prior external beam radiation to > 25% of active marrow or neutrophil count <1,500/mm3 were ineligible for Study 3. All patients received Y-90 Ibritumomab  . Objective, durable clinical responses were observed .
- Study 4 was a multi-center, randomized, open-label study conducted in patients with follicular NHL with a partial (PR) or complete response (CR/CRu) upon completion of first-line chemotherapy. Randomization was stratified by center and response to first-line therapy (CR or PR). Key eligibility criteria were <25% bone marrow involvement, no prior external beam radiation or myeloablative therapy, and recovery of platelets to normal levels. Patients were randomized to receive Ibritumomab  (n=208) or no further therapy (n=206). Y-90 Ibritumomab  was administered at least 6 weeks but no more than 12 weeks following the last dose of chemotherapy. The main efficacy outcome measure was progression-free survival (PFS) assessed by study investigators using the International Workshop to Standardize Response Criteria for non-Hodgkins Lymphoma (1999).
- Among the 414 patients, 49% were male, 99% were Caucasian, 12% were 65 years old, 83% had a WHO performance status of 0, and 65% had Stage IV disease. Thirty-nine (9.5%) patients received single agent chlorambucil, 22 (5%) patients received fludarabine or a fludarabine-containing regimen, 294 (71%) patients received cyclophosphamide-containing combination chemotherapy  and 59 (14%) patients received rituximab-containing combination chemotherapy as first-line treatment.
- Progression-free survival was significantly prolonged among Ibritumomab -treated patients compared to those receiving no further treatment . The number of patients who died was too small to permit a reliable comparison on survival.
- The results for PFS are presented in Figure 1.
- Figure 1. Study 4: Kaplan-Meier Estimator for Investigator-Assessed Progression Free Survival Time

# How Supplied
- A kit is used for preparing Y-90 radiolabeled Ibritumomab  (NDC 68152-103-03). The contents of all vials are sterile, pyrogen-free, contain no preservatives, and are not radioactive. The kit contains four identification labels and the following four vials:
- One (1) Ibritumomab  vial containing 3.2 mg ibritumomab tiuxetan in 2 mL 0.9% Sodium Chloride as a clear, colorless solution.
- One (1) 50 mM Sodium Acetate Vial containing 13.6 mg Sodium Acetate trihydrate in 2 mL Water for Injection, USP as a clear, colorless solution.
- One (1) Formulation Buffer Vial containing 750 mg Albumin (Human), 76 mg Sodium Chloride, 28 mg Sodium Phosphate Dibasic Dodecahydrate, 4 mg Pentetic Acid, 2 mg Potassium Phosphate Monobasic and 2 mg Potassium Chloride in 10 mL Water for Injection, pH 7.1 as a clear yellow to amber colored solution.
- One (1) empty Reaction Vial.
- Yttrium-90 Chloride Sterile Solution is shipped directly from the supplier upon placement of an order for the Y-90 Ibritumomab  kit.
- Rituximab (Rituxan, Biogen Idec and Genentech USA) must be ordered separately.

## Storage
- Store the kit at 2-8C (36-46F). Do not freeze.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise patients:
- To contact a healthcare professional for severe signs and symptoms of Infusion reaction.
- To take premedications as prescribed .
- To report any signs or symptoms of cytopenias (bleeding, easy bruising, petechiae or purpura, pallor, weakness or fatigue) .
- To avoid medications that interfere with platelet function, except as directed by a healthcare professional .
- To seek prompt medical evaluation for diffuse rash, bullae, or desquamation of the skin or oral mucosa .
- To immediately report symptoms of infection (e.g. pyrexia) .
- That immunization with live viral vaccines is not recommended for 12 months following the Ibritumomab  therapeutic regimen .
- To use effective contraceptive methods during treatment and for a minimum of 12 months following Ibritumomab  therapy .
- To discontinue nursing during and after Ibritumomab  treatment

# Precautions with Alcohol
- Alcohol-Ibritumomab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Zevalin

# Look-Alike Drug Names
There is limited information regarding Ibritumomab tiuxetan Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price