ibritumomab tiuxetan

SYNONYM(S):   IDEC-129; IDEC-2B8; yttrium-90-ibritumomab tiuxetan

COMMON TRADE NAME(S):   Zevalin ® (Servier)

Health Canada Approvals:

Ibritumomab tiuxetan, as part of the ZEVALIN® therapeutic regimen, is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular non-Hodgkin’s lymphoma.

Emetogenic Potential:  

(Also consult the rituximab drug monograph for adverse effects)

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Hypertension (2%)	I  E
	Venous thromboembolism (rare)	E
Dermatological	Alopecia (1%)	I  E
	Rash (8%) (may be severe)	I  E
Gastrointestinal	Abdominal pain (16%)	E
	Anorexia (8%)	E
	Constipation (5%)	E
	Diarrhea (9%)	E
	Dyspepsia (4%)	E
	Mucositis (2%) (may be severe)	I  E  D
	Nausea, vomiting (31%)	I  E
General	Edema (8%)	E
	Fatigue (43%)	E
	Pain (13%)	E
Hematological	Myelosuppression ± infection, bleeding (severe 78% - observed with 0.3 mCi/kg 90Y dosing)	E
Hepatobiliary	↑ LFTs (2%)	E
Hypersensitivity	Hypersensitivity (5%) (severe 1%)	I
Immune	Antibody response (4%) (HAMA / HACA)	E
Injection site	Injection site reaction	I
Metabolic / Endocrine	Abnormal electrolyte(s) (2%) (↓ Ca, K)	E
	Hyperglycemia (3%)	E
Musculoskeletal	Musculoskeletal pain (8%)	E
Neoplastic	Leukemia (secondary) (2%) (AML or MDS)	L
Nervous System	Anxiety (4%)	E
	Depression (2%)	E
	Dizziness (10%)	I  E
	Headache (12%)	E
	Insomnia (5%)	E
Ophthalmic	Conjunctivitis (3%)	E
Renal	Creatinine increased (1%) (may be severe)	E
Respiratory	Cough (10%)	E
	Cough, dyspnea (14%)	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)

Manufacturer’s guidelines for rituximab use should be consulted in addition to this monograph, as it is an integral part of the regimen.

The most severe adverse reactions caused by the ibritumomab tiuxetan therapeutic regimen include infections (predominantly bacterial in origin; may also be atypical including reactivation), allergic reactions (bronchospasm and angioedema), and hemorrhage while thrombocytopenic.  Some patients have developed myeloid malignancies and dysplasias. 

Cytopenias associated with the ibritumomab tiuxetan therapeutic regimen were severe and very common, especially in patients with baseline thrombocytopenia. The median time to nadir was 7-9 weeks and the median recovery times were 1 to 3 weeks.

Rare cases of severe mucocutaneous reactions (erythema multiforme, including Stevens-Johnson syndrome and toxic epidermal necrolysis), have been reported.  Onset varied from within days to months. 

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous administration of proteins to patients. Medications for the treatment of hypersensitivity reactions (e.g., epinephrine, antihistamines and corticosteroids) should be available for immediate use in the event of an allergic reaction during administration of ibritumomab tiuxetan. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA). Patients with evidence of HAMA have not been studied and may be at increased risk of allergic or serious hypersensitivity reactions during ibritumomab tiuxetan therapeutic regimen administration.  Patients who have had ibritumomab should be tested for HAMA before any further treatment with mouse-derived proteins.

Infusion reactions associated with rituximab are common, including fever and chills/rigors, urticaria, pruritus, bronchospasm, angioedema, hypotension and flushing. These reactions generally occur within 30 minutes to 2 hours after the first infusion, resolve with slowing or interruption of the rituximab infusion and with supportive care (IV saline, diphenhydramine and acetaminophen). Rarely, severe infusion reaction to rituximab can be fatal. Refer to the Rituximab drug monograph.

Other:

Ibritumomab tiuxetan is contraindicated in patients with known type I hypersensitivity or anaphylactic reactions to murine proteins or to any component of the ibritumomab tiuxetan therapeutic regimen, including yttrium chloride and rituximab. The formulation contains albumin. It should not be administered to patients with ≥25% lymphoma marrow involvement, failed stem cell transplants and/or impaired bone marrow reserve.  Growth factors such as G-CSF should not be used 3 weeks before or 2 weeks after ibritumomab tiuxetan.  Live vaccines should not be used. The use of ⁹⁰Y-ibritumomab is not recommended in NHL patients with CNS involvement.

Caution should be exercised in patients taking anticoagulants or drugs known to impair platelet function (including NSAIDs and COX-2 inhibitors). Risk of hematological toxicity may be increased when ibritumomab tiuxetan is administered shortly (< 4 months) after fludarabine-containing regimens.

⁹⁰Y- ibritumomab tiuxetan is fetotoxic, carcinogenic and mutagenic. Second malignancies have been reported.  IgGs can cross the placenta; due to the risk of radiation, use in pregnancy is contraindicated. Before starting treatment, a pregnancy test should be conducted to rule out pregnancy. Individuals of childbearing potential (both sexes) should use effective contraceptive methods during treatment and for up to 12 months following the ibritumomab tiuxetan therapeutic regimen.  Since human IgG is excreted in human milk, breastfeeding is contraindicated during and for one year after treatment.

No formal drug interaction studies have been performed with ibritumomab tiuxetan.

 

AGENT	EFFECT	MECHANISM	MANAGEMENT
Anticoagulants	↑ bleeding (may increase)	Additive effect with thrombocytopenia	Caution; monitor patient closely
Antiplatelet agents (i.e. aspirin, NSAIDs, glycoprotein II b/III a antagonists, clopidogrel, ticlopidine, cat’s claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng)	↑ bleeding (may increase)	Additive effect with thrombocytopenia	Caution; monitor patients closely
Vaccines	May impair response to vaccination	immunosuppression	Avoid
Growth factors (i.e. filgrastim)	Potential sensitivity of dividing myeloid cells to radiation		Avoid for 3 weeks before and 2 weeks after 90Y- Ibritumomab
Fludarabine-containing regimens	↑ risk of hematologic toxicity	Additive	Do not use within 4 months before ibritumomab treatment

Monitor Type	Monitor Frequency
Patients who have had prior exposure to murine proteins (murine or chimeric antibodies) should be screened for HAMA/HACA prior to treatment and may be at increased risk for hypersensitivity reactions
Renal function tests	baseline and regular
Liver function tests	baseline and regular
CBC and platelet counts; weekly until recovery and more frequently in patients who develop severe cytopenias, who are on antiplatelet drugs or are at risk of bleeding, or as clinically indicated
Careful monitoring and management of cytopenias and their complications for up to three months after use of the ibritumomab tiuxetan therapeutic regimen
Monitor for infusion-related or allergic reactions, infection, GI, hepatic, skin, bleeding, cardiac and pulmonary toxicity

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Product Monograph: Zevalin® (ibritumomab). Bayer Inc., December 23, 2009.

Wagner HN, Wiseman GA, Marcus CS, et al. Administration guidelines for radioimmunotherapy of non-Hodgkin’s lymphoma with 90Y-labeled anti-CD20 monoclonal antibody. J Nucl Med 2002; 43:267–72.

_{^{August 2012:  Entire document revision}}