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drug-monograph
A - Drug Name
tositumomab
SYNONYM(S): 131I–tositumomab; Anti-B1 Monoclonal Antibody; Tositumomab and iodine I-131 tositumomab
B - Mechanism of Action and Pharmacokinetics
The Bexxar® treatment regimen is comprised of two products: tositumomab, a murine IgG2a lambda monoclonal antibody, and 131I–tositumomab, a radio-iodinated derivative of tositumomab that has been covalently linked to iodine-131 (I-131).
Tositumomab reacts specifically with the CD20 antigen, a hydrophobic transmembrane phosphoprotein found on the surface of normal and malignant B-lymphocytes and is expressed on >90% of B-cell non-Hodgkin’s lymphomas. Unlabelled antibody is administered prior to the radiolabelled dose (I-131 tositumomab) to saturate non-tumour B cells in the circulation and organs, resulting in increased uptake of radiolabelled tositumomab.
The high-energy beta particles emitted by I-131 are cytotoxic over distances of 1-2mm (average path length 0.8mm, maximum 2.4mm). Antigen-negative tumour cells are eradicated by crossfire from neighbouring antibody-coated cells. In addition to cell death associated with ionizing radiation from the radioisotope, other possible mechanisms of action include induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity mediated by the antibody.
For complete information regarding the administration and use of Bexxar ®, please consult the Product Monograph.
Absorption
Oral: no
Distribution
| Cross blood brain barrier? | no information found |
| PPB | no information found |
Metabolism
Tositumomab is expected to be degraded to small peptides and amino acids by ubiquitous proteolytic enzymes.
| Active metabolites | no |
| Inactive metabolites | no |
Elimination
The clearance of tositumomab is 68.2mL/h and is increased in patients with a high tumour burden, splenomegaly, or marrow involvement. Elimination of iodine-131 occurs by decay and excretion in the urine (98%), with 67% eliminated in the urine after 5 days.
| Half-life | t1/2 (effective) : 65 hours t1/2 (131Iodine) : 8 days |
C - Indications and Status
Health Canada Approvals:
Tositumomab and 131I-tositumomab, comprising the Bexxar® therapeutic regimen, is indicated for the treatment of patients with CD20 positive relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin’s lymphoma, including patients with rituximab-refractory non-Hodgkin’s lymphoma.
Tositumomab and 131I-tositumomab, comprising the Bexxar® therapeutic regimen, is indicated for the treatment of patients with CD20 positive relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin’s lymphoma, including patients with rituximab-refractory non-Hodgkin’s lymphoma.
D - Adverse Effects
Emetogenic Potential:
Minimal
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Venous thromboembolism (2%) | E | ||||
| Dermatological | Rash (17%) (may be severe) | I E | |||
| Gastrointestinal | Abdominal pain (15%) | E | |||
| Anorexia, weight loss (14%) | E | ||||
| Constipation (6%) | E | ||||
| Diarrhea (12%) | E | ||||
| Dyspepsia (6%) | E | ||||
| Mucositis (2%) | E | ||||
| Nausea, vomiting (36%) | I E | ||||
| General | Edema (9%) | E | |||
| Fatigue (46%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (53%) (grade 3 or 4; may be severe) | E | |||
| Hepatobiliary | ↑ LFTs (<1%) (may be severe) | E | |||
| Hypersensitivity | Infusion related reaction (29%) (severe- 6%) | I | |||
| Immune | Antibody response (10%) (HAMA) | D | |||
| Infection | Infection (57%) (severe- 9%) | E | |||
| Injection site | Injection site reaction (3%) | I | |||
| Metabolic / Endocrine | Hypothyroidism (18%) | E D L | |||
| Musculoskeletal | Musculoskeletal pain (13%) | E | |||
| Neoplastic | Leukemia (secondary) (3%) (or MDS) | L | |||
| Other (other malignancies have been reported) | L | ||||
| Nervous System | Anxiety (3%) | I E | |||
| Depression (1%) | E | ||||
| Dizziness (5%) | I E | ||||
| Headache (16%) | E | ||||
| Insomnia (4%) | E | ||||
| Neuropathy (rare, severe) | E | ||||
| Somnolence (5%) | E | ||||
| Ophthalmic | Conjunctivitis (2%) | E | |||
| Respiratory | Cough, dyspnea (21%) | E | |||
| Urinary | Urinary symptoms (4%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common severe adverse reactions are myelosuppression and hypersensitivity.
Severe myelosuppression is common, with a nadir of 4 to 7 weeks and may be prolonged up to 90 days after infusion (5-7%). 15-16% of patients required red cell and platelet transfusions. Safety has not been established in patients with platelets < 100 x 109/L or neutrophils < 1.5 x 109/L.
Severe and sometimes fatal hypersensitivity reactions have been reported. Symptoms include fever, chills, bronchospasm, hypotension, dyspnea, etc., and have been reported during or within 48 hours after the infusion. Patients must be premedicated prior to infusions; appropriate medications for the treatment of hypersensitivity reactions, as well as resuscitation equipment, must be available. Patients who have prior exposure to murine proteins should be screened for human anti-mouse antibodies (HAMA) as they may be at higher risk of allergic or serious hypersensitivity reactions during administration of tositumomab and 131I–tositumomab.
Infusion reactions are common during or within 48 hours of the intravenous infusion of the Bexxar® regimen; if they occur, the infusion rate should be decreased by 50%, temporarily interrupted, or in rare cases, discontinued.
Cases of acute leukemia and myelodysplastic syndrome have been described, as have other malignancies.
Axonal neuropathy with quadriparesis has been described
As I131 is used, SSKI, Lugol’s solution, or potassium iodide must be administered prior to and after exposure, in order to reduce the risk of hypothyroidism.
E - Dosing
Note: Bexxar® is a complex radioisotope-containing regimen and should only be administered in specialized units by authorized personnel. Full details of the prescribing and dosing recommendations are beyond the scope of this monograph and only a brief summary is provided; please consult the Product Monograph.
Patients with >25% marrow involvement by NHL or with significant myelosuppression (ANC < 1.5 x 109/L or platelets < 100 x 109/L) should not be treated with Bexxar®.
A single course of treatment should be planned; no data is available for multiple courses nor combination therapy.
The therapeutic regimen of tositumomab and 131I–tositumomab consists of four components administered in two discrete steps: the dosimetric step is followed by the therapeutic step 7-14 days later. Patients must receive premedication as listed below: (Continued on next page)
- Saturated solution of potassium iodide (SSKI) 4 drops orally three times daily, or Lugol’s solution 20 drops orally three times daily, or potassium iodide tablets 130mg orally daily should be administered at least 24 hours prior to administration of the iodine I-131 dosimetric dose and continued until 2 weeks after administration of the I-131 tositumomab therapeutic dose. Patients should not receive the dosimetric dose of iodine I-131 tositumomab unless they have received at least three doses of SSKI, or three doses of Lugol’s solution, or one dose of 130 mg potassium iodide tablets at least 24 hours prior to the dosimetric dose.
- Administer acetaminophen 650 mg and diphenhydramine 50 mg orally 30 minutes prior to administration of tositumomab in the dosimetric and therapeutic steps.
Adults:
Day -1 |
Begin Thyroprotective Regimen ↓ |
|
Day 0 |
Premedication ↓ |
|
|
Dosimetric Step ↓ |
|
|
Administer Tositumomab followed by 131I –tositumomab ↓ |
|
|
Whole Body Dosimetry and Biodistribution |
|
|
Day 2,3 or 4 |
Whole Body Dosimetry and Biodistribution |
|
Day 6 or 7 |
Whole Body Dosimetry and Biodistribution |
|
|
Is biodistribution acceptable? → ↓ |
If NO, do not administer Therapeutic Step |
|
If YES, |
|
|
Calculate doses |
|
|
Day 7 (or up to 14) |
Therapeutic Step* |
|
Premedication |
|
|
Administer Tositumomab followed by 131I –tositumomab |
|
* Doses should be modified in the presence of thrombocytopenia (100 to <150 x 109/L).
Dosage with Toxicity:
Hematologic Toxicities:
- 131I-tositumomab should not be given to patients with platelet count less than 100 x 109/L. Also do not administer if patient has ANC < 1.5 x 109/L, impaired bone marrow reserve, prior myeloablative therapy with stem cell support, or bone marrow involvement greater than 25%.
Dose modification for other toxicity:
- Tositumomab and 131I–tositumomab should be permanently discontinued in patients who develop severe hypersensitivity reactions.
Dosage with Hepatic Impairment:
No data available
Dosage with Renal Impairment:
No data available; however the kidneys are the main route of excretion of 131I–tositumomab, and reduced clearance may result in increased radioactivity exposure.
Dosage in the elderly:
Although not specifically studied, the duration of myelosuppression appears longer in older patients.
Dosage based on gender:
Female patients were observed to have lower median clearance and volume of distribution, and higher median Cmax than males.
Children:
The safety and effectiveness of the tositumomab and 131I -tositumomab therapeutic regimen in children have not been established.
F - Administration Guidelines
Bexxar® is a complex radioisotope-containing regimen and should only be administered in specialized units by authorized personnel.
The tositumomab and 131I -tositumomab therapeutic regimen should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe infusion-related reactions.
Precautions should be taken to avoid extravasation. A free-flowing intravenous line should be established prior to administration of tositumomab and 131I–tositumomab infusions. Close monitoring for evidence of extravasation is required.
Consult the Product Monograph for detailed administration guidelines.
G - Special Precautions
Other:
Tositumomab and 131I–tositumomab are contraindicated in patients with known hypersensitivity or anaphylactic reactions to murine proteins, iodine preparations, or to any component of the therapeutic regimen, and in patients with significant marrow infiltration ( >25%) or impairment (platelets < 100 x109/L or ANC < 1.5 x109/L). Do not use live vaccines.
131I -tositumomab is radioactive, emitting both β and γ radiation. Treatment can be administered as an outpatient with the appropriate license conditions as granted by the Canadian Nuclear Safety Commission. It may be received, prepared, assayed, and administered only by authorized personnel. Appropriate cautions and shielding should be used during preparation and administration of 131I–tositumomab. Patients should be advised to follow close contact precautions to limit low-level radiation exposure for approximately two weeks after the therapeutic dose of 131I–tositumomab. (Refer to the product monograph for details on precautions.)
Hypothyroidism may occur; thyroid blockers (SSKI, Lugol’s solution, or potassium iodide tablets) are mandatory.
Tositumomab and 131I–tositumomab are carcinogenic, mutagenic and fetotoxic and is contraindicated in pregnancy. Transplacental passage of radioiodide may cause severe and possibly irreversible hypothyroidism in neonates. Individuals of childbearing age should be advised to use effective contraceptive methods during treatment and up to 12 months after. Limited data suggest a risk of miscarriage up to one year after 131I treatment. Both iodine-131 and possibly tositumomab are excreted in human milk. Breastfeeding is contraindicated. Permanent effects on fertility are possible.
H - Interactions
No formal drug interaction studies have been performed with tositumomab and 131I–tositumomab. Due to the frequent occurrence of prolonged and severe thrombocytopenia, the potential benefits of medications that interfere with platelet function and/or anticoagulation should be weighed against the potential increased risks of bleeding and hemorrhage. Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia. In addition, the transfusion practices for such patients may need to be modified given the increased risk of bleeding.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Anticoagulants | May ↑ bleeding | Additive effect with thrombocytopenia | monitor |
| Antiplatelet agents (e.g. aspirin, NSAIDs, glycoprotein IIb/IIIa antagonists, clopidrogrel, ticlopidine, cat’s claw, dong quai, evening primrose, feverfew, garlic, ginger, gingko, red clover, horse chestnut, green tea, ginseng etc.) | May ↑ bleeding | Additive effect with thrombocytopenia | Monitor |
I - Recommended Clinical Monitoring
Recommended Clinical Monitoring
| Monitor Type | Monitor Frequency |
|---|---|
| Liver function tests | Baseline |
| Patients who have had prior exposure to murine proteins should be screened for HAMA as they may be at increased risk for hypersensitivity | Prior to treatment |
| Renal function tests | Baseline and prior to treatment |
| Monitor all patients closely, especially those with pre-existing cardiac and pulmonary conditions or prior significant cardiac adverse events. | |
| Complete blood count (CBC) with differential; prior to and weekly following administration of tositumomab and 131I-tositumomab until levels recover; monitoring should be more frequent in patients who develop moderate or severe cytopenia, or as clinically indicated. | |
| TSH and/or signs or symptoms of hypothyroidism at baseline, every 6 months for the first 2 years, and annually thereafter | |
| Vital signs and signs and symptoms of infusion-related or allergic reactions to be monitored during each of the infusions. Watch for signs and symptoms for up to 48 hours after the infusion. | |
| Clinical assessment of bleeding, infection and GI effects |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
K - References
Product Monograph: Bexxar® (tositumomab and 131I–tositumomab. GlaxoSmithKline Inc. (Canada), April 19, 2013.
October 2017 Full revision; note adverse effects, dosing, pregnancy and lactation, monitoring sections
L - Disclaimer
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Last Updated: July 21, 2026
