Bexxar

Generic Name: Tositumomab
Class: Antineoplastic Agents
VA Class: AN600
CAS Number: 192391-48-3

Warning(s)

  • Use only by qualified clinicians who are experienced in the safe use and handling of therapeutic radionuclides and who have been or are in the process of being certified by GlaxoSmithKline in dose calculation and administration.1 7

  • Serious, including fatal, hypersensitivity reactions reported.1 Drugs for treatment of severe hypersensitivity reactions should be available for immediate use.1 If severe tositumomab-induced reactions occur, discontinue therapy immediately and initiate appropriate medical treatment.7 (See Anaphylaxis under Cautions.)

  • Risk of severe thrombocytopenia and neutropenia.1 Do not use in patients with >25% lymphoma marrow involvement and/or impaired bone marrow reserve.1 (See Hematologic Effects under Cautions.)

  • Risk of fetal harm.1 Pregnancy category X.1 (See Contraindications and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Introduction

Radioimmunotherapeutic agent; a murine anti-human antigen CD20 monoclonal antibody that covalently binds the radioisotope iodine I 131.1 3 7

Uses for Bexxar

Non-Hodgkin’s Lymphoma

Used as part of a specific therapeutic regimen (tositumomab therapeutic regimen) for treatment of antigen CD20-expressing relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin’s lymphoma, including rituximab-refractory disease (designated an orphan drug by FDA for this use).1 2 7

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Efficacy determined based on durable responses; actual clinical benefits (e.g., effects on survival) not clearly elucidated.1

Has been used in rituximab-naive patients with follicular non-Hodgkin’s lymphoma, with or without transformation, whose disease was refractory to or had progressed following therapy with other antineoplastic agents.1 4 5 6 7

Safety and efficacy not evaluated in patients with >25% lymphoma marrow involvement and/or impaired bone marrow reserve (e.g., platelet count <100,000/mm3, neutrophil count <1500/mm3).1 7

Under investigation for use in the initial treatment of antigen CD20-positive advanced follicular lymphoma.8 11

Bexxar Dosage and Administration

General

  • Use only by qualified clinicians who have completed or are participating in the certification program created by GlaxoSmithKline, which is designed to ensure proper preparation, dosage calculation, and administration of the tositumomab therapeutic regimen.1 7

  • Consult manufacturer’s labeling and associated literature (e.g., Workbook for Dosimetry Methodology and Administration Set-Up, provided with the Bexxar Dosimetric Package7 ) prior to use.1

  • The tositumomab therapeutic regimen consists of daily administration of thyroid protective agents, 2 doses of unlabeled tositumomab (to decrease splenic targeting and increase the terminal half-life of the radiolabeled antibody),7 a dosimetric dose of iodine I 131 tositumomab followed by whole body dosimetry and biodistribution evaluation, and a therapeutic dose of iodine I 131 tositumomab.1 Regimen administered in 2 steps: dosimetric step and therapeutic step.1 7

  • Intended for use as a single course of treatment.1 7 Safety of multiple courses or of other forms of therapeutic irradiation in combination with the tositumomab therapeutic regimen not established.1 7

Premedication

  • To minimize risk of severe infusion-related reactions, administer oral acetaminophen (650 mg) and diphenhydramine hydrochloride (50 mg) 30 minutes prior to infusion of tositumomab in both the dosimetric and therapeutic steps.1 7 (See Infusion-related Effects under Cautions.)

  • Initiate thyroid protective therapy at least 24 hours prior to administration of the first dose of iodine I 131 tositumomab (in the dosimetric step); continue for 14 days after administration of the iodine I 131 tositumomab therapeutic dose.1 7 Recommended regimens of thyroid protective agents include: 4 drops of a potassium iodide solution containing 1 g/mL (i.e., SSKI) orally 3 times daily, 20 drops of strong iodine solution (Lugol’s solution) orally 3 times daily, or 130 mg of potassium iodide (as tablets) orally once daily.1 Do not administer dosimetric dose of iodine I 131 tositumomab if patients have not yet received at least 3 doses of potassium iodide solution, 3 doses of strong iodine solution, or 1 dose (130 mg) of potassium iodide (as tablets).1

Whole Body Dosimetry and Biodistribution Evaluation

  • To determine biodistribution of iodine I 131 tositumomab7 and therapeutic dose, perform whole body scans at 3 time points following administration of the dosimetric dose: within 1 hour of infusion (prior to urination), 2–4 days after infusion (immediately following urination), and 6–7 days after infusion (immediately following urination).1 7

  • If biodistribution is acceptable, the therapeutic step may be administered; do not initiate therapeutic step in patients with altered biodistribution.1 7

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer tositumomab and iodine I 131 tositumomab by IV infusion.1

Administer via an IV tubing set with an inline 0.22-mcm filter.1 Must use same IV tubing set and filter throughout entire dosimetric or therapeutic step; may lose up to 7% of iodine I 131 tositumomab dose if filter changed.1

Administer tositumomab therapeutic regimen in 2 steps (dosimetric step and the therapeutic step);1 7 each step consists of sequential IV infusion of an unlabeled dose of tositumomab followed by iodine I 131 tositumomab.1 Administer therapeutic step 7–14 days after the dosimetric step.1

Generally can be administered on an outpatient basis.7 Follow institutional radiation safety practices and applicable federal guidelines during preparation and administration of iodine I 131 tositumomab to minimize exposure of patients and medical personnel to radiation.1

Dilution

To prepare dosimetric dose (tositumomab), withdraw 32 mL from a 50 mL bag of sterile 0.9% sodium chloride for injection.1 Add 450 mg tositumomab (entire contents of two 225-mg vials) to infusion bag containing 18 mL of 0.9% sodium chloride to yield a final volume of 50 mL.1

Invert or rotate bag to mix solution; do not shake.1

Tositumomab must be diluted prior to IV infusion and should not be mixed or diluted with other drugs.1 7

Consult manufacturer’s labeling and associated literature (e.g., Workbook for Dosimetry Methodology and Administration Set-Up, provided with the Bexxar Dosimetric Package7 ) for detailed information on the preparation of iodine I 131 tositumomab.1

Rate of Administration

Tositumomab: Administer over 60 minutes.1

Iodine I 131 tositumomab: Administer over 20 minutes.1

If mild to moderate infusion-related reactions occur, reduce infusion rate by 50%.1 If severe infusion-related reactions occur, temporarily interrupt infusion; once manifestations of infusion reactions have resolved completely, resume infusion but reduce infusion rate by 50%.1

Dosage

Adults

Non-Hodgkin’s Lymphoma
IV

Dosimetric step (day 0): 450 mg tositumomab (over 60 minutes), followed by 5 mCi iodine I 131 tositumomab (containing 35 mg of tositumomab).1 7 Determine biodistribution of iodine I 131 tositumomab7 and therapeutic dose.1 7 Do not proceed with therapy in patients with altered distribution.1 7 (See Whole Body Dosimetry and Biodistribution Evaluation under Dosage and Administration.)

Therapeutic step (given on 1 day between days 7–14): 450 mg tositumomab (over 60 minutes), followed by iodine I 131 tositumomab at a therapeutic dose (i.e., activity of iodine 131) calculated to deliver 75 centigrays (cGy) total body irradiation (with 35 mg of tositumomab) for patients with platelet counts of ≥150,000/mm3 or 65 cGy (with 35 mg of tositumomab) for those with platelet counts ≥100,000 but <150,000/mm3.7 Calculate activity of iodine I 131 required to deliver desired total body irradiation (i.e., 75 or 65 cGy) using the following equation:

Iodine I 131 activity (mCi) = (activity hours [mCi hr] / residence time [hr]) × (desired total body dose [cGy] / 75 cGy)

(To determine activity hours and residence time, see Workbook for Dosimetry Methodology and Administration Set-Up, provided with the Bexxar Dosimetric Package.) For assistance with calculations, call the Bexxar Service Center at 1-877-423-9927.1

Prescribing Limits

Adults

Non-Hodgkin’s Lymphoma
IV

Maximum 88 cGy iodine I 131 tositumomab used in clinical studies.1

Cautions for Bexxar

Contraindications

  • Iodine I 131 tositumomab contraindicated in pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Known hypersensitivity to tositumomab, murine proteins, iodine I 131, or any ingredient in the formulation.1 7

    Platelet counts <100,000/mm3.1

Warnings/Precautions

Warnings

Consult prescribing information for thyroid protective agents for detailed information on usual cautions, precautions, and contraindications of these agents.7

Hematologic Effects

Risk of severe, potentially life-threatening cytopenias (e.g., neutropenia, thrombocytopenia, anemia);1 7 granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), epoetin alfa, platelet transfusions, or red blood cell transfusions required in some patients.1 Time to nadir was 4–7 weeks following therapeutic dose;1 4 5 6 median duration of cytopenia was approximately 30 days.1 7 Possible prolonged cytopenia (>90 days following treatment).1 7 (See Laboratory Monitoring under Cautions.)

Safety not established in patients with >25% lymphoma marrow involvement and/or impaired bone marrow reserve (e.g., platelet count <100,000/mm3, neutrophil count <1500/mm3); do not administer tositumomab therapeutic regimen in such patients.1 7

Secondary Malignancies

Risk of secondary malignancies (e.g., myelodysplastic syndrome,1 4 5 7 acute myelogenous leukemia,1 7 nonmelanomatous skin cancers).1 Median time to development of myelodysplastic syndrome was 31–34 months.1

Fetal/Neonatal Morbidity and Mortality

Iodine I 131 may cause fetal harm (e.g., severe and potentially irreversible hypothyroidism).1 (See Contraindications under Cautions.) Rule out pregnancy prior to initiation of therapy; avoid pregnancy during and for up to 12 months following completion of therapy.1 If patient becomes pregnant, apprise of potential fetal hazard.1

Hypothyroidism

Risk of hypothyroidism.1 5 7

To minimize uptake of radioactive iodine by thyroid gland and to reduce occurrence of hypothyroidism, initiate thyroid protective therapy in all patients at least 24 hours prior to administration of the iodine I 131 tositumomab dosimetric dose and continue for 14 days after administration of the iodine I 131 tositumomab therapeutic dose.1 7 (See Premedication under Dosage and Administration.)

Do not administer tositumomab therapeutic regimen to patients unable to tolerate thyroid protective agents or in those who have not yet received adequate prophylaxis with these agents.1

Evaluate patients for manifestations of hypothyroidism before beginning therapy and annually thereafter.1 (See Laboratory Monitoring under Cautions.)

Altered Biodistribution

Do not initiate therapeutic step in patients with altered biodistribution of iodine I 131 tositumomab (as determined by imaging studies and dosimetry evaluation with the dosimetric dose of iodine I 131 tositumomab).1 7 (See Whole Body Dosimetry and Biodistribution Evaluation under Dosage and Administration.)

Sensitivity Reactions

Anaphylaxis

Severe and occasionally fatal hypersensitivity reactions, including anaphylaxis, reported.1

Risk of anaphylaxis (e.g., angioedema, bronchospasm) or other hypersensitivity reactions (e.g., injection site hypersensitivity, laryngismus, serum sickness).1 Risk increased in patients with human antimurine antibodies (HAMA).1 (See Human Antimurine Antibodies [HAMA] under Cautions.)

Drugs for the treatment of hypersensitivity reactions (e.g., epinephrine, antihistamines, corticosteroids) should be available for immediate use in case a reaction occurs during administration.1 If severe tositumomab-induced reactions occur, discontinue therapy immediately and initiate appropriate medical treatment.7

Major Toxicities

Infectious Complications

Viral infections (e.g., rhinitis, pharyngitis, flu symptoms, herpes)1 5 6 7 and serious infections requiring hospitalization (e.g., pneumonia, bacteremia, septicemia, bronchitis, skin infections) reported.1

General Precautions

Radionuclide Precautions

Due to presence of radioactive component (iodine I 131 tositumomab), follow institutional radiation safety practices and applicable federal guidelines to minimize exposure of patients and medical personnel to radiation.1 Provide patients with oral and written instructions for minimizing radiation exposure to family members, other close contacts, or the general public for approximately 1–2 weeks after completion of therapy.1 7

Laboratory Monitoring

Monitor CBCs with differential and platelet counts prior to initiation of therapy and weekly for at least 10–12 weeks after completion of therapy or until severe cytopenias have completely resolved; more frequent monitoring recommended in patients with evidence of moderate or severe cytopenias.1

Monitor serum thyrotropin (thyroid-stimulating hormone, TSH) concentrations prior to initiation of therapy and annually thereafter.1

Measure Scr immediately prior to initiation of therapy.1

Human Antimurine Antibodies (HAMA)

Development of HAMA1 4 5 6 reported.1 7 Presence of HAMA may affect accuracy of diagnostic tests and may affect toxicity profile and efficacy of therapeutic agents that rely on murine antibody technology.1 HAMA-positive patients may be at increased risk of severe hypersensitivity reactions (e.g., anaphylaxis) or other adverse effects if they undergo in vivo diagnostic testing or treatment with murine monoclonal antibodies.1 7

Screen patients previously treated with murine proteins for presence of HAMA prior to initiation of therapy.1

GI Effects

Nausea,1 4 5 6 7 vomiting,1 5 6 abdominal pain,1 7 anorexia,1 5 diarrhea,1 constipation,1 or dyspepsia1 reported; effects temporally related to infusion of tositumomab.1 Nausea, vomiting, and abdominal pain typically reported within days of administration; diarrhea generally reported days to weeks after infusion.1

Infusion-related Effects

Infusion-related effects (e.g., fever,1 4 5 6 7 rigors or chills,1 4 5 7 sweating,1 hypotension,1 5 dyspnea,1 bronchospasm,1 nausea1 ) reported during or within 48 hours of first dose.1 Adjustment of infusion rate, temporary interruption of infusion, or permanent discontinuance of therapy required in some patients.1 Symptomatic management required in more severe cases.1

Value of premedication (e.g., acetaminophen, diphenhydramine) in preventing infusion-related toxicity not evaluated.1

Specific Populations

Pregnancy

Category X.1 (See Contraindications and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Iodine I 131 is distributed into milk and may reach concentrations that equal or exceed maternal plasma concentrations.1 Immunoglobulins are known to distribute into milk; potential for absorption and adverse effects of tositumomab in infants not known.1 Discontinue nursing and substitute infant formula for breast milk prior to initiation of therapy.1

Pediatric Use

Safety and efficacy not established in children ≤18 years of age.1 7

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Lower overall response rate, shorter duration of response, and lower incidence (but longer duration) of severe adverse hematologic effects observed in these patients.1 Possibility of increased sensitivity cannot be ruled out.1

Renal Impairment

Safety of tositumomab therapeutic regimen not established.1 Iodine I 131 tositumomab and iodine I 131 excreted principally by the kidneys; possible decreased clearance and increased exposure to iodine I 131.1

Common Adverse Effects

Neutropenia, thrombocytopenia, anemia, asthenia,1 4 7 infection,1 fever,1 nausea.1 4

Interactions for Bexxar

No formal drug interaction studies to date.1

Specific Drugs

Drug

Interaction

Comments

Anticoagulants and drugs affecting platelet function

Possible increased risk of bleeding and hemorrhage1

Vaccines

Safety of immunization with live virus vaccines following therapy not studied1

Ability to generate primary or anamnestic humoral response to any vaccine following therapy not studied1

Bexxar Pharmacokinetics

Absorption

Onset

Median number of circulating B cells drops to 0 (range: 0–490 cells/mm3) at 7 weeks following treatment.1

Duration

Recovery of B cells begins at approximately 12 weeks; median levels of B cells return to normal by 6 months.1 7

Distribution

Special Populations

Larger volume of distribution in patients with high tumor burden, splenomegaly, or bone marrow involvement.1

Elimination

Elimination Route

Approximately 67% of IV dose of iodine I 131 tositumomab is cleared from the body within 5 days; 98% of excreted drug recovered in urine.1 7

Half-life

Iodine I 131: Physical half-life is 8 days.1 7

Iodine I 131 tositumomab: Median total-body effective half-life is 67 hours (range 28–115 hours).1

Special Populations

Faster clearance and shorter terminal half-life in patients with high tumor burden, splenomegaly, or bone marrow involvement.1

Renal impairment may reduce clearance.1

Stability

Storage

Parenteral

Tositumomab Injection

2–8°C; do not freeze.1 Protect from strong light.1 Do not shake.1 Discard unused portion.1

Following dilution, 2–8°C up to 24 hours or at room temperature up to 8 hours; do not freeze.1 Refrigeration (at 2–8°C) preferred since product contains no preservatives.1 Discard unused portion.1

Iodine I 131 Tositumomab Injection

Freeze at -20°C or below in original lead pots.1

Following thawing, 2–8°C or at room temperature up to 8 hours.1

Following dilution, 2–8°C; do not freeze.1 Discard unused portion according to federal and state laws.1

Compatibility

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

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%

Actions

  • Tositumomab binds specifically to antigen CD20 (expressed on pre-B cells and at higher density on mature B cells and on essentially all B-cell non-Hodgkin’s lymphomas),1 4 7 triggering apoptosis, complement-dependent cytotoxicity, and antibody-dependent cell-mediated cytotoxicity of normal and malignant B cells.1 4 7

  • Iodine I 131 (radioactive component of iodine I 131 tositumomab) triggers cell death.1

  • Depletes B cells.7 Median serum IgM concentrations decline at week 7 and week 13 but return to normal by 6 months following treatment; median serum concentrations of IgG and IgA remain within normal range.7

Advice to Patients

  • Importance of advising patients that a radioactive material may be present in their body for several days after treatment.1 Importance of providing patient-specific oral and written instructions for minimizing radiation exposure to family members, other close contacts, or the general public for approximately 1–2 weeks following therapy.1 7

  • Necessity of advising male and female patients to use an effective method of contraception while receiving the tositumomab therapeutic regimen and for up to 12 months following completion of therapy.1

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1 Importance of women avoiding pregnancy during therapy; advise pregnant women of risk to the fetus.1 Importance of advising women to discontinue nursing and to substitute infant formula for breast milk prior to initiation of therapy.1

  • Risk of cytopenia, secondary malignancies, and hypothyroidism.1 Importance of adhering to thyroid protective therapy and periodic hematologic monitoring.1

  • Possibility of developing a HAMA immune response that could affect results of in vitro or in vivo diagnostic tests or of therapies that rely on murine antibody technology.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

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

Preparations

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

Distribution restricted to qualified clinicians and facilities equipped to handle radionuclides (e.g., nuclear pharmacies);7 not available through community pharmacies.7 Qualified clinicians may order by calling 877-4BEXXAR (877-423-9927).7

Commercially available as 2 separate package configurations, the Bexxar Dosimetric Package and the Bexxar Therapeutic Package.1 The radioactive (iodine I 131 tositumomab) and nonradioactive ingredients (tositumomab) of each package arrive separately (but to the same nuclear pharmacy) from MDS Nordion and McKesson BioServices, respectively.7

Tositumomab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Kit

2 Vials (225 mg/16.1 mL) and 1 Vial (35 mg/2.5 mL) Tositumomab

1 Vial Iodine I 131 Tositumomab (0.61 mCi/mL at calibration)

Bexxar Dosimetric Packaging

GlaxoSmithKline

2 Vials (225 mg/16.1 mL) and 1 Vial (35 mg/2.5 mL) Tositumomab

1 or 2 Vials Iodine I 131 Tositumomab (5.6 mCi/mL at calibration)

Bexxar Therapeutic Packaging

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Bexxar (tositumomab and iodine I 131 tositumomab) prescribing information. Research Triangle Park, NC; 2005 Oct.

2. Food and Drug Administration. List of all orphan products designated and approved. From FDA web site. 2003 May.

3. Horning SJ, Younes A, Jain V et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol. 2005;23:712-9

4. Kaminski, Estes J, Zasadny et al. Radioimmunotherapy with3I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood. 2000; 96:1259-66. [IDIS 451112] [PubMed 10942366]

5. Kaminski MS, Zelenetz AD, Press OW et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s Lymphomas. J Clin Oncol. 2001; 19:3918-28. [IDIS 470962] [PubMed 11579112]

6. Vose JM, Wahl RL, Saleh M et al. Multicenter phase II study of iodine I 131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin’s Lymphomas. J Clin Oncol. 2000; 18:1316-23. [IDIS 444942] [PubMed 10715303]

7. GlaxoSmithKline, Philadelphia, PA: Personal communication.

8. Kaminski MS, Tuck M, Estes J et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005; 352:441-9. [PubMed 15689582]

9. Davies AJ, Rohatiner AZ, Howell S et al. Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2004; 22:1469-79. [PubMed 15084620]

10. Fisher RI, Kaminski MS, Wahl RL et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin’s lymphomas. J Clin Oncol. 2005; 23:7565-73. [PubMed 16186600]

11. Press OW, Unger JM, Braziel RM et al. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol. 2006; 24:4143-9. [PubMed 16896003]

a. AHFS drug information 2003. McEvoy GK, ed. Asparaginase. Bethesda, MD: American Society of Health-System Pharmacists; 2003:892-5.

e. Trissel LA. Handbook on injectable drugs. 12 ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:521-31.

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