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Tositumomab and Iodine I 131 Tositumomab

Pronunciation

(toe si TYOO mo mab & EYE oh dyne eye one THUR tee one toe si TYOO mo mab)

Index Terms

  • 131 I Anti-B1 Antibody
  • 131 I-Anti-B1 Monoclonal Antibody
  • Anti-CD20-Murine Monoclonal Antibody I-131
  • Iodine I 131 Tositumomab and Tositumomab
  • Tositumomab I-131

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Note: Not all components are shipped from the same facility. When ordering, ensure that all will arrive on the same day.

Kit [dosimetric package]: Tositumomab 225 mg/16.1 mL [2 vials], tositumomab 35 mg/2.5 mL [1 vial], and iodine I 131 tositumomab 0.1 mg/mL and 0.61mCi/mL (20 mL) [1 vial] [DSC]

Kit [therapeutic package]: Tositumomab 225 mg/16.1 mL [2 vials], tositumomab 35 mg/2.5 mL [1 vial], and iodine I 131 tositumomab 1.1 mg/mL and 5.6 mCi/mL (20 mL) [1 or 2 vials] [DSC]

Brand Names: U.S.

  • Bexxar [DSC]

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody
  • Radiopharmaceutical

Pharmacology

Tositumomab is a murine IgG2a lambda monoclonal antibody which binds to the CD20 antigen, expressed on B-lymphocytes and on >90% of B-cell non-Hodgkin's lymphomas. Iodine I 131 tositumomab is a radio-iodinated derivative of tositumomab covalently linked to iodine 131. The possible actions of the regimen include apoptosis, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and radiation-induced cell death. Administration results in depletion of CD20 positive cells.

Distribution

Tositumomab: Vd increased with high tumor burden, splenomegaly, or bone marrow involvement

Excretion

Iodine-131 elimination occurs by decay and urinary excretion; after 5 days total body clearance is 67% of a dose (98% in urine)

Onset of Action

CD20-positive cell depletion: ≤7 weeks

Duration of Action

CD20-positive cell recovery begins at ~12 weeks

Half-Life Elimination

Tositumomab: 67 hours (range: 28-115 hours); decreased with high tumor burden, splenomegaly, or bone marrow involvement

Use: Labeled Indications

Treatment of relapsed or refractory CD20 positive, low-grade, follicular, or transformed non-Hodgkin's lymphoma (NHL), with progression during or after rituximab treatment

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Non-Hodgkin’s lymphoma (NHL), relapsed or refractory: IV: Dosing consists of four components administered in 2 steps. Refer to manufacturer’s labeling for additional details. Indicated for a single treatment course. Thyroid protective agents (SSKI, Lugol's solution or potassium iodide) should be administered beginning at least 24 hours prior to step 1 (Refer to Additional Information or Pharmacotherapy Pearls). Premedicate with acetaminophen 650 mg and diphenhydramine 50 mg orally 30 minutes prior to step 1 and step 2.

Step 1: Dosimetric step (Day 0):

Tositumomab 450 mg administered over 60 minutes

Iodine I 131 tositumomab (containing I-131 5 mCi and tositumomab 35 mg) administered over 20 minutes

Note: Whole body dosimetry and biodistribution should be determined on Day 0; days 2, 3, or 4; and day 6 or 7 prior to administration of Step 2. If biodistribution is not acceptable, do not administer the therapeutic step. On day 6 or 7, calculate the patient specific activity of iodine I 131 tositumomab to deliver 75 cGy total body dose (TBD) or 65 cGy TBD (in mCi).

Step 2: Therapeutic step (one dose administered 7-14 days after step 1):

Tositumomab 450 mg administered over 60 minutes

Iodine I 131 tositumomab:

Platelets ≥150,000/mm3: Iodine I 131 calculated to deliver 75 cGy total body irradiation and tositumomab 35 mg over 20 minutes

Platelets ≥100,000/mm3 and <150,000/mm3: Iodine I 131 calculated to deliver 65 cGy total body irradiation and tositumomab 35 mg over 20 minutes

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No specific dosage adjustment provided in manufacturer’s labeling (has not been studied). However, greater exposure to I-131 Tositumomab may occur in patients with renal impairment.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Infusion-related toxicity (with tositumomab or iodine I-131 tositumomab):

Mild-to-moderate: Reduce infusion rate by 50%

Severe: Interrupt infusion; after complete resolution, resume with previous infusion rate reduced by 50%

Serious allergic reaction: Discontinue infusion.

Reconstitution

Radiopharmaceutical; use appropriate precautions for handling and disposal.

Tositumomab: Withdraw and discard 32 mL of saline from a 50 mL bag of NS. Add contents of both 225 mg vials of tositumomab (total 32 mL) to remaining NS to make a final volume of 50 mL. Gently mix by inverting bag; do not shake.

Iodine I 131 tositumomab: Calculate volume required for an iodine I 131 tositumomab activity of 5 mCi (specification sheet provided with product). If the amount of tositumomab contained in the iodine I 131 tositumomab solution contains <35 mg of tositumomab, use the 35 mg vial of tositumomab to prepare a final concentration of tositumomab 35 mg. Using NS, the final volume should equal 30 mL. Gently mix by inverting or rotating; do not shake.

Administration

IV: Refer to manufacturer’s labeling for additional details.

Tositumomab: Infuse over 60 minutes

Iodine I 131 tositumomab: Infuse over 20 minutes

Administer via an IV tubing set with an in-line 0.22 micron filter; do not change primary infusion set or filter at any time during the dosimetric or therapeutic step; changing the filter may result in up to a 7% loss of the iodine I 131 tositumomab dose (use the same infusion set and filter for tositumomab and iodine I 131 tositumomab). Flush with NS after Iodine I 131 tositumomab infusion.

Prior to infusion, patients should be premedicated (with acetaminophen and an antihistamine) and a thyroid-protective agent should be started. Reduce the rate of tositumomab or iodine 131 tositumomab infusion by 50% for mild-to-moderate infusion-related toxicities; interrupt for severe infusion reaction (once severe infusion reaction has resolved, infusion may be restarted at half the previous rate). Discontinue for serious allergic reaction.

Radiopharmaceutical; use appropriate precautions for handling and disposal.

Storage

Tositumomab: Store under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from strong light. Following dilution, tositumomab is stable for 24 hour when refrigerated or 8 hours at room temperature.

Iodine I 131 tositumomab: Store frozen at less than or equal to -20°C in the original lead pots. Allow ~60 minutes for thawing at ambient temperature. Thawed doses are stable for up to 8 hours at 2°C to 8°C (36°F to 46°F) or room temperature. Solutions diluted for infusion should be refrigerated prior to administration; do not freeze.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Anticoagulants: May enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fever (37%), pain (19%), chills (18%), headache (16%)

Dermatologic: Rash (17%; grades 3/4: <1%)

Endocrine & metabolic: Hypothyroidism (7% to 19%)

Gastrointestinal: Nausea (36%), abdominal pain (15%), vomiting (15%), anorexia (14%), diarrhea (12%)

Hematologic: Myelosuppression (grades 3/4: 71%; nadir: 4-7 weeks; duration: ~30 days), neutropenia (grades 3/4: 63%; median duration: 31 days; grade 4: 25%), thrombocytopenia (grades 3/4: 53%; median duration: 32 days; grade 4: 21%), lymphocytopenia (recovery: ~12 weeks after treatment), anemia (grades 3/4: 29%; median duration: 23 days; grade 4: 5%), secondary leukemia/myelodysplastic syndrome (overall: 3% to 10%; 2-year follow-up: 2% to 5%; 5-year follow-up: 6% to 15%), hemorrhage (12%)

Neuromuscular & skeletal: Weakness (46%), myalgia (13%)

Respiratory: Cough (21%), pharyngitis (12%), dyspnea (11%)

Miscellaneous: Infusion-related reactions (29%, occurred within 14 days of infusion, included bronchospasm, chills, dyspnea, fever, hypotension, nausea, rigors, diaphoresis); infection (21% to 45%, serious: 9%);g HAMA-positive seroconversion (10% to 11%)

1% to 10%:

Cardiovascular: Hypotension (7%), peripheral edema (9%), chest pain (7%), vasodilation (5%)

Central nervous system: Dizziness (5%), somnolence (5%)

Dermatologic: Pruritus (10%)

Gastrointestinal: Constipation (6%), dyspepsia (6%), weight loss (6%)

Local: Injection site hypersensitivity

Neuromuscular & skeletal: Arthralgia (10%), back pain (8%), neck pain (6%)

Respiratory: Rhinitis (10%), pneumonia (6%)

Miscellaneous: Diaphoresis (8%), hypersensitivity/allergic reaction (6%), secondary malignancies (nonhematologic: 5%)

<1% (Limited to important or life-threatening): Anaphylactic reaction, angioedema, bacteremia, bronchitis, dehydration, flu-like syndrome, herpes virus infection, laryngismus, pleural effusion, septicemia, serum sickness, skin infections

ALERT: U.S. Boxed Warning

Bone marrow suppression:

The tositumomab and iodine I 131 tositumomab therapeutic regimen resulted in severe and prolonged thrombocytopenia and neutropenia in more than 70% of the patients in clinical studies. The tositumomab and iodine I 131 tositumomab therapeutic regimen should not be administered to patients with greater than 25% lymphoma marrow involvement, platelet count less than 100,000 cells/mm3 or neutrophil count less than 1,500 cells/mm3.

Serious allergic reactions (including anaphylaxis):

Serious, including fatal, allergic reactions have occurred during or following administration of the tositumomab and iodine I 131 tositumomab therapeutic regimen. Have medications for the treatment of allergic reactions available for immediate use. Permanently discontinue the tositumomab and iodine I 131 tositumomab therapeutic regimen for serious allergic reactions and administer appropriate medical treatment.

Radiation exposure:

The tositumomab and iodine I 131 tositumomab therapeutic regimen may be administered only under the supervision of physicians who are certified under or participating in the tositumomab and iodine I 131 tositumomab therapeutic regimen certification program and who are authorized under the Radioactive Materials License at their clinical site. Follow institutional radiation safety practices and applicable federal guidelines to minimize radiation exposure during handling and after administration of the tositumomab and iodine I 131 tositumomab therapeutic regimen.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [U.S. Boxed Warning]: Severe and prolonged cytopenias, including neutropenia and thrombocytopenia are common; do not administer in patients with >25% lymphoma marrow involvement, platelet count <100,000/mm3 or neutrophil count <1500/mm3. Hematologic toxicity is reported to be the most common adverse effect with 27% patients requiring supportive care; cytopenias may be prolonged and severe.

• Hypersensitivity/anaphylactoid reactions: [U.S. Boxed Warning]: Serious hypersensitivity reactions (including anaphylaxis) have been reported; permanently discontinue for severe reaction; medications for the treatment of reactions should be readily available in the event of severe reactions. Signs and symptoms of severe allergic reactions include fever, rigors/chills, sweating, hypotension, dyspnea, bronchospasm, or nausea; may occur during or within 48 hours of infusion. Premedicate with acetaminophen and diphenhydramine prior to both the dosimetric and therapeutic doses.

• Hypothyroidism: Treatment may lead to hypothyroidism; patients should receive thyroid-blocking medications beginning at least 24 hours prior to the dosimetric dose and continued for 2 weeks after the therapeutic dose. The median time to development of hypothyroidism was 16 months (range: up to 90 months). Evaluate TSH and for signs and symptoms of hypothyroidism at baseline and annually thereafter.

• Infusion reactions: Patients should be premedicated to prevent infusion-related reactions; interrupt infusion and/or decrease infusion rate for infusion-related reactions.

• Secondary malignancies: Myelodysplastic syndrome (MDS) and acute leukemia have been reported; median time to development was 31 months. Nonhematologic malignancies, including skin cancer and solid tumors, have also been reported following use.

Disease-related concerns:

• Renal impairment: Safety has not been established in patients with renal impairment. Excretion is primarily renal; impaired renal function may increase exposure; clearance of radiolabeled iodine is decreased in patients with renal impairment or genitourinary obstruction.

Special populations:

• Elderly: The duration of severe hematologic toxicity may be prolonged in the elderly.

• Women of childbearing potential: Women of childbearing potential should be advised of potential fetal risk; effective contraceptive measures should be used during and for 12 months following treatment (males and females).

Special handling:

• Radioactive isotopes: [U.S. Boxed Warning]: Treatment involves radioactive isotopes and should only be administered by or under supervision of physicians enrolled in the Bexxar® therapeutic regimen certification program; appropriate precautions for handling and administration must be followed. Patients must be instructed in measures to minimize exposure of others.

• Radiopharmaceutical: Use appropriate precautions for handling, disposal, and minimizing exposure to patients and healthcare personnel. Use only under supervision of individuals who have received training in the handling of radioactive materials and who are authorized by the applicable regulatory authority.

Other warnings/precautions:

• Immunizations: The safety and efficacy of live vaccines in patients who have received therapy with tositumomab have not been established. Avoid administration of live vaccines in patients recently treated with tositumomab.

Monitoring Parameters

CBC with differential (baseline and weekly for up to 12 weeks, or longer for persistent severe cytopenia); signs and symptoms of hypothyroidism and TSH (prior to therapy and every 6 months for life; Hamnvik, 2011); renal function; signs/symptoms of infusion or allergic reaction

Following infusion of the iodine I 131 tositumomab dosimetric dose, the total body gamma camera counts and whole body images should be taken within 1 hour of the infusion and prior to urination, and 2-4 days after the infusion and following urination, and 6-7 days after the infusion and following urination.

Pregnancy Risk Factor

D

Pregnancy Considerations

Iodine-131 crosses the placenta and may cause severe and irreversible hypothyroidism in neonates; women of childbearing potential should be advised of potential fetal risk. The risk of miscarriage may also be increased for up to 1 year after treatment. Pregnancy should be ruled out prior to therapy. Males and females of childbearing potential should be instructed to use effective contraception during and for 12 months following treatment. Fertility may be affected for up to 12 months following therapy. Infants born to treated mothers should be monitored for hypothyroidism.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, headache, cough, muscle pain, joint pain, back pain, constipation, abdominal pain, diarrhea, lack of appetite, fatigue, or neck pain. Have patient report immediately to prescriber signs of infection; severe dizziness; passing out; severe nausea; vomiting; bruising; bleeeding; loss of strength and energy; black, tarry, or bloody stools; angina; flushing; pale skin; injection site irritation; shortness of breath; swelling of arms or legs; excessive weight loss; skin growths; sweating a lot; vomiting blood; or wound healing impairment (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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