Ibritumomab Tiuxetan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Intravenous [preservative free]:

Zevalin Y-90: 3.2 mg/2 mL [pyrogen free; contains albumin human]

Pharmacology

Mechanism of Action

Ibritumomab is a monoclonal antibody directed against the CD20 antigen found on pre-B and mature B lymphocytes (normal and malignant). Ibritumomab binding induces apoptosis in B lymphocytes in vitro. It is combined with the chelator tiuxetan, which acts as a specific chelation site for Yttrium-90 (Y-90). The monoclonal antibody acts as a delivery system to direct the radioactive isotope to the targeted cells, however, binding has been observed in lymphoid cells throughout the body and in lymphoid nodules in organs such as the large and small intestines. Beta-emission induces cellular damage through the formation of free radicals (in both target cells and surrounding cells).

Pharmacokinetics/Pharmacodynamics

Distribution

To lymphoid cells throughout the body and in lymphoid nodules in organs such as the large and small intestines, spleen, testes, and liver

Metabolism

Has not been characterized; the product of yttrium-90 radioactive decay is zirconium-90 (nonradioactive)

Excretion

A median of 7.2% of the radiolabeled activity was excreted in urine over 7 days

Duration of Action

B cell recovery begins in ~12 weeks; generally in normal range within 9 months

Half-Life Elimination

Y-90 ibritumomab: 30 hours; Yttrium-90 decays with a physical half-life of 64 hours

Use: Labeled Indications

Non-Hodgkin lymphoma: Treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma (NHL); treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

Contraindications

There are no contraindications listed within the manufacturer's labeling.

Canadian labeling: Known type I hypersensitivity or anaphylactic reaction to ibritumomab tiuxetan, murine proteins, or any component of the formulation, including yttrium chloride and rituximab; pregnancy; breastfeeding

Dosage and Administration

Dosing: Adult

Note: Premedicate with oral acetaminophen 650 mg and oral diphenhydramine 50 mg prior to each rituximab infusion. Allow at least 6 weeks, but no more than 12 weeks following first-line chemotherapy before treatment initiation; platelets should recover to ≥150,000/mm³ prior to initiation of treatment regimen.

Non-Hodgkin lymphoma: Ibritumomab is administered only as part of the Zevalin therapeutic regimen (a combined treatment regimen with rituximab). The regimen consists of two steps:

Day 1:

Rituximab: IV: 250 mg/m² at an initial rate of 50 mg/hour. If hypersensitivity or infusion-related events do not occur, increase infusion in increments of 50 mg/hour every 30 minutes, to a maximum of 400 mg/hour. Stop rituximab and discontinue regimen for severe infusion reaction. For less severe infusion reactions, temporarily slow or interrupt; the infusion may be resumed at one-half the previous rate upon improvement of symptoms.

Day 7, 8, or 9 of treatment:

Rituximab: IV: 250 mg/m² at an initial rate of 100 mg/hour (50 mg/hour if infusion-related events occurred with the day 1 infusion). If hypersensitivity or infusion-related events do not occur, increase infusion in increments of 100 mg/hour every 30 minutes, to a maximum of 400 mg/hour, as tolerated (increase in 50 mg/hour increments every 30 minutes if initial infusion rate was 50 mg/hour).

Y-90 ibritumomab (within 4 hours after completion of the rituximab infusion): IV:

Platelet count ≥150,000 cells/mm³: 0.4 mCi/kg (14.8 MBq/kg) actual body weight over 10 minutes; maximum dose: 32 mCi (1184 MBq)

Platelet count between 100,000 to 149,000 cells/mm³ (in relapsed or refractory patients): 0.3 mCi/kg (11.1 MBq/kg) actual body weight over 10 minutes; maximum dose: 32 mCi (1184 MBq)

Platelet count <100,000 cells/mm³: Do not administer

Maximum dose: The prescribed, measured, and administered dose of Y-90 ibritumomab must not exceed 32 mCi (1184 MBq), regardless of the patient's body weight

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Radiopharmaceutical; use appropriate precautions for handling and disposal. To prepare radiolabeled injection and determine radiochemical purity, follow detailed preparation guidelines provided by manufacturer. Use appropriate shielding during and after radiolabeling.

Administration

Rituximab: Administer the first infusion of rituximab at an initial rate of 50 mg/hour. If hypersensitivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. Immediately stop infusion for severe infusion reaction (discontinue ibritumomab regimen); less severe reactions may be managed by slowing or interrupting infusion. For less severe reactions, infusion may continue at one-half the previous rate upon improvement of patient symptoms. If infusion reaction did not occur in initial rituximab infusion, subsequent rituximab infusion can be administered at an initial rate of 100 mg/hour and increased in 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour as tolerated. If infusion reaction occurred with initial rituximab infusion, initiate at 50 mg/hour with increases of 50 mg/hour increments every 30 minutes.

Y-90 ibritumomab: Begin within 4 hours of completion of rituximab infusion. Inject slowly, over 10 minutes through a 0.22 micron low protein binding in-line filter (filter placed between syringe and infusion port) into a free-flowing IV line. After injection, flush line with at least 10 mL normal saline. Avoid extravasation; closely monitor infusion site; if signs or symptoms of extravasation occur, stop infusion and restart in another limb.

Radiopharmaceutical; use appropriate precautions for handling and disposal.

Storage

Store kits at 2°C to 8°C (36°F to 46°F). Do not freeze. Administer Y-90 ibritumomab tiuxetan within 8 hours of radiolabeling.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Anticoagulants: May enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (33%)

Gastrointestinal: Nausea (18%), abdominal pain (17%), diarrhea (11%)

Hematologic & oncologic: Thrombocytopenia (62% to 95%; grades 3/4: 51% to 63%; nadir: 49-53 days; median duration: 24 days; median time to recovery: 13 days), neutropenia (45% to 77%; grades 3/4: 41% to 60%; nadir: 61-62 days; median duration: 22 days; median time to recovery: 12 days), anemia (22% to 61%; grades 3/4: 5% to 17%; nadir: 68-69 days), leukopenia (43%; grades 3/4: 36%), lymphocytopenia (26%; grades 3/4: 18%), metastases (1% to 13%; includes acute myelogenous leukemia and myelodysplastic syndrome)

Infection: Infection (within first 3 months: 29%; serious: 1% to 3%; 3 months to 4 years after treatment: 6%)

Neuromuscular & skeletal: Weakness (15%)

Respiratory: Nasopharyngitis (19%), cough (11%)

1% to 10%:

Cardiovascular: Hypertension (7%)

Central nervous system: Dizziness (7%)

Dermatologic: Night sweats (8%), pruritus (7%), skin rash (7%)

Gastrointestinal: Anorexia (8%)

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Petechia (8%), bruise (7%), severe cytopenia (prolonged: 5%)

Immunologic: Antibody development (HAMA/HACA: 1% to 3%)

Neuromuscular & skeletal: Myalgia (9%)

Respiratory: Bronchitis (8%), flu-like symptoms (8%), rhinitis (8%), pharyngolaryngeal pain (7%), sinusitis (7%), epistaxis (5%)

Miscellaneous: Fever (10%), biodistribution altered (1%)

<1%, postmarketing, and/or case reports: Adult respiratory distress syndrome, angioedema, bullous dermatitis, cardiogenic shock, chills, dyspnea, erythema multiforme, exfoliative dermatitis, febrile neutropenia, headache, hypoxia, infusion-related reaction, injection site reaction (erythema/ulceration following extravasation), myocardial infarction, pain, pulmonary infiltrates, radiation injury (delayed [~1 month]; in tissues in or near areas of lymphomatous involvement), sepsis, Stevens-Johnson syndrome, tissue necrosis (following Yttrium-90-ibritumomab extravasation), toxic epidermal necrolysis, ventricular fibrillation, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Delayed, prolonged, and severe cytopenias (thrombocytopenia and neutropenia) are common. Do not administer to patients with ≥25% lymphoma marrow involvement, patients with impaired bone marrow reserve (eg, prior myeloablative treatment, platelet count <100,000/mm³, neutrophil count <1,500/mm³, hypocellular marrow), or to patients with prior stem cell collection failure. In studies, the median platelet, ANC, and hemoglobin nadir was 49 to 53 days, 61 to 62 days, and 68 to 69 days, respectively. Cytopenias may persist beyond 12 weeks. The median duration of thrombocytopenia and neutropenia was 24 to 35 days and 22 to 29 days respectively, and the median time to platelet and ANC recovery was 13 to 14 days and 12 to 15 days, respectively. Patients with mild baseline thrombocytopenia (100,000 to 149,000/mm³) may experience higher incidences of severe neutropenia and thrombocytopenia. Hemorrhage may occur due to thrombocytopenia; avoid concomitant use of medications interfering with coagulation or platelet function. Monitor CBC and platelets weekly until recovery or as clinically indicated. Closely monitor patients for complications of cytopenias (eg, febrile neutropenia, hemorrhage) for up to 3 months after administration.
• Cutaneous/mucocutaneous reactions: [US Boxed Warning]: Severe cutaneous and mucocutaneous skin reactions have been reported (with fatalities). Discontinue all components of the therapeutic regimen in patients experiencing severe cutaneous or mucocutaneous skin reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis. Onset may occur within days to 4 months following infusion.
• Extravasation/radiation necrosis: Infusion site erythema and ulceration have been reported following extravasation; monitor infusion site; promptly terminate infusion with symptoms/signs of extravasation (restart in another limb). There is a case report of (delayed) erythema and ulceration, which is described as radiation necrosis following yttrium-90-ibritumomab extravasation (Williams 2006).
• Infusion reactions: [US Boxed Warning]: Serious fatal infusion reactions may occur with the rituximab component of the therapeutic regimen. Immediately stop infusion and discontinue all components of the therapeutic regimen in patients who develop severe infusion reactions. Fatalities due to rituximab infusion were associated with acute respiratory distress syndrome, hypoxia, pulmonary infiltrates, cardiogenic shock, MI, or ventricular fibrillation; 80% of fatalities occurred with the first rituximab infusion. Administer in a facility with immediate access to resuscitative measures. Infusion reactions typically occur with the first rituximab infusion (onset within 30 to 120 minutes). Other reactions may include hypotension, angioedema, bronchospasm, and urticaria. Less severe reactions may be managed by slowing or temporarily interrupting infusion.
• Radiation injury: Delayed (up to 1 month) radiation injury has occurred in or near areas of lymphomatous involvement.
• Secondary malignancies: Malignancies due to the radiation dose from therapeutic exposure may occur. Secondary malignancies (acute myelogenous leukemia and/or myelodysplastic syndrome) have been reported; the median time to secondary malignancy diagnosis following ibritumomab treatment was 1.9 years with a range of 0.4 to 6.3 years (Czuczman 2007).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Albumin: Product contains albumin, which confers a theoretical risk of transmission of viral disease or Creutzfeldt-Jakob disease.

Special handling:

• Radiopharmaceutical: Use appropriate precautions for handling, disposal, and minimizing exposure to patients and health care personnel. Use only under supervision of individuals with experience/training in the handling of radioactive materials approved by the applicable regulatory authority. The contents of the kit are not radioactive until radiolabeling occurs. During and after radiolabeling, adequate shielding should be used with this product, minimize radiation exposure (to patient and health care professionals) in accordance with institutional radiation safety practices.

Other warnings/precautions:

• Biodistribution: In a postmarketing registry of biodistribution images, biodistribution was altered in a limited number of patients.
• Experienced professionals: Use should be reserved to physicians and other professionals qualified and experienced in the safe handling of radiopharmaceuticals, and in monitoring and emergency treatment of infusion reactions.
• Hepatitis B screening: American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation. Screen for HBV infection with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, IV drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg positive/anti-HBc positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.
• Immunizations: Do not administer live viral vaccines to patients who have recently received ibritumomab treatment. The safety of immunization with live vaccines following ibritumomab therapy has not been studied; the ability to generate a response to any vaccine after receiving treatment has not been studied.
• Maximum dose: [US Boxed Warning]: Do not exceed the Y-90 ibritumomab maximum allowable dose of 32 mCi (1184 MBq). To be used as part of the Zevalin therapeutic regimen (in combination with rituximab).

Monitoring Parameters

CBC with differential and platelet counts weekly until recovery, or as clinically indicated. Platelet count must be obtained prior to day 7, 8, or 9; monitor for cytopenias (and related complications) for up to 3 months after use.

Hepatitis B virus screening recommendations (ASCO provisional clinical opinion update [Hwang 2015]): Screen for hepatitis B virus (HBV) infection with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Monitor for signs of active hepatitis B infection (during and for up to 12 months after therapy completion). Monitor for infusion-related allergic reactions (typically within 30 to 120 minutes of administration), for extravasation during ibritumomab infusion; and for severe cutaneous and mucocutaneous reactions.

Pregnancy

Pregnancy Considerations

Based on the radioactivity, Y-90 ibritumomab may cause fetal harm if administered during pregnancy. In addition, ibritumomab tiuxetan is a humanized monoclonal antibody (IgG₁). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Evaluate pregnancy status prior to therapy. Women of reproductive potential should avoid becoming pregnant during treatment with ibritumomab tiuxetan. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment and for at least 12 months following the last dose.

Patient Education

What is this drug used for?

• It is used to treat a type of lymphoma.

Frequently reported side effects of this drug

• Loss of strength and energy
• Fatigue
• Diarrhea
• Nausea
• Nose irritation
• Throat irritation
• Abdominal pain
• Flu-like symptoms
• Muscle pain
• Lack of appetite
• Night sweats

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Infection
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; menstruation; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe dizziness
• Passing out
• Severe headache
• Vision changes
• Chest pain
• Shortness of breath
• Abnormal heartbeat
• Pale skin
• Pinpoint red spots on skin
• Severe injection site redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.