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IBRITUMOMAB TIUXETAN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ibritumomab is a murine monoclonal antibody to CD20 antigen, which is conjugated with tiuxetan to provide a chelation site for radioactive isotopes. This linker-chelator is able to provide a high affinity, restricted chelation site for Indium-111 or Yttrium-90. This radiolabelled drug is used in the treatment of relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.

Specific Substances

    1) Ibritumomabum Tiuxetanum
    2) CAS 206181-63-7

Available Forms Sources

    A) FORMS
    1) Ibritumomab tiuxetan is prepared in two different kits: the In-111 Zevalin(TM) kit is used for radiolabeling of Ibritumomab tiuxetan with In-111 which is administered first, and approximately 7 to 9 days later the Y-90 Zevalin(TM) kit is used for radiolabeling of Ibritumomab tiuxetan with Y-90 (Prod Info ZEVALIN(R) intravenous injection, 2013).
    a) For preparation of a single dose the In-111 Zevalin(TM) or the Y-90 Zevalin(TM) kit contains four vials: one vial containing 3.2 mg of ibritumomab tiuxetan in 2 mL of 0.9% sodium chloride solution; one vial containing 50 mM sodium acetate; one vial containing formulation buffer, and one empty reaction vial (Prod Info ZEVALIN(R) intravenous injection, 2013).
    B) USES
    1) Ibritumomab tiuxetan is part of a therapeutic regimen administered in conjunction with rituximab for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, this can include patients with rituximab refractory follicular non-Hodgkin's lymphoma (Prod Info ZEVALIN(R) intravenous injection, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ibritumomab tiuxetan is used to treat patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Ibritumomab tiuxetan is normally administered within several hours of rituximab; therefore, some adverse events may be related to either agent. Refer to RITUXIMAB management as needed.
    B) PHARMACOLOGY: Regions of ibritumomab bind to the CD20 antigen on B lymphocytes and induce apoptosis (programmed cell death) in CD20+ B-cell lines in vitro. Tiuxetan (chelator) tightly binds Y-90. The chelator complex covalently links to the amino acids of exposed lysines and arginines contained within the antibody (ibritumomab). Beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells. Ibritumomab tiuxetan does not bind selectively to neoplastic cells.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (10% OR GREATER): Cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and fever. Myelosuppression may be prolonged and can result in grade 3/4 thrombocytopenia, neutropenia, anemia, and possibly hemorrhage. OTHER EFFECTS: Severe cutaneous and mucocutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis and exfoliative dermatitis), vomiting, dyspnea, dizziness, arthralgia, anorexia, anxiety, ecchymosis, headache, throat irritation, back pain, flushing, peripheral edema, angioedema, extravasation injury, rash, and pruritus. Fatal infusion reactions (hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock) have also been reported, but are likely related to rituximab infusion administered in conjunction with ibritumomab.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In clinical trials, the administration of doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ibritumomab tiuxetan caused severe, prolonged hematological toxicities. When single doses up to 50 mCi (1850 MBq) and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) were studied in a limited number of patients, autologous stem cell support was required in some patients to manage hematological toxicity.
    0.2.20) REPRODUCTIVE
    A) Ibritumomab tiuxetan is classified as FDA pregnancy category D. Although there are no adequate and well-controlled studies in pregnant women, ibritumomab tiuxetan may cause fetal harm.
    0.2.21) CARCINOGENICITY
    A) No long-term studies to assess the potential carcinogenicity of ibritumomab tiuxetan have been performed; however, radiation is a potential carcinogen

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor serial CBC with differential and platelet count.
    E) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) in patients who develop severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Severe nausea and vomiting may respond to a combination of agents from different drug classes. Severe, potentially fatal infusion reactions (hypotension, angioedema, bronchospasm, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock) have occurred, but are likely related to the rituximab infusion administered prior to ibritumomab therapy.
    C) INTRATHECAL OVERDOSE
    1) No clinical reports ibritumomab tiuxetan are available, information is derived from experience with other agents. Keep the patient upright if possible. Immediately drain at least 20 ml CSF; drainage of up to 70 ml has been tolerated in adults. Follow with CSF exchange (remove serial 20 ml aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). For large overdoses, consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    F) ANTIDOTE
    1) None
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors to patients who develop severe neutropenia following a significant overdose. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) EXTRAVASATION INJURY
    1) Monitor infusion site for erythema or signs of injury. Moist desquamation has been observed up to 2 weeks following exposure. Frequent dressing changes and silver sulfadiazine cream have been used. Consult plastic surgeon as indicated.
    L) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of ibritumomab tiuxetan. Some toxic effects of overdose may be delayed (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking ibritumomab tiuxetan may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    O) PHARMACOKINETICS
    1) Renal excretion: 7.2% of injected Y-90 activity. Elimination half-life: 27 to 30 hours.
    P) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: In clinical trials, the administration of doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ibritumomab tiuxetan caused severe hematological toxicities. When single doses up to 50 mCi (1850 MBq) and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) were studied in a limited number of patients, autologous stem cell support was required in some patients to manage hematological toxicity.
    B) THERAPEUTIC: ADULT: MAXIMUM DOSE: 32 mCi (1184 MBq) infused over 10 minutes. CHILD: Safety and effectiveness in children have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Ibritumomab tiuxetan is used to treat patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Ibritumomab tiuxetan is normally administered within several hours of rituximab; therefore, some adverse events may be related to either agent. Refer to RITUXIMAB management as needed.
    B) PHARMACOLOGY: Regions of ibritumomab bind to the CD20 antigen on B lymphocytes and induce apoptosis (programmed cell death) in CD20+ B-cell lines in vitro. Tiuxetan (chelator) tightly binds Y-90. The chelator complex covalently links to the amino acids of exposed lysines and arginines contained within the antibody (ibritumomab). Beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells. Ibritumomab tiuxetan does not bind selectively to neoplastic cells.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (10% OR GREATER): Cytopenias, fatigue, nasopharyngitis, nausea, abdominal pain, asthenia, cough, diarrhea, and fever. Myelosuppression may be prolonged and can result in grade 3/4 thrombocytopenia, neutropenia, anemia, and possibly hemorrhage. OTHER EFFECTS: Severe cutaneous and mucocutaneous reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis and exfoliative dermatitis), vomiting, dyspnea, dizziness, arthralgia, anorexia, anxiety, ecchymosis, headache, throat irritation, back pain, flushing, peripheral edema, angioedema, extravasation injury, rash, and pruritus. Fatal infusion reactions (hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock) have also been reported, but are likely related to rituximab infusion administered in conjunction with ibritumomab.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In clinical trials, the administration of doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ibritumomab tiuxetan caused severe, prolonged hematological toxicities. When single doses up to 50 mCi (1850 MBq) and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) were studied in a limited number of patients, autologous stem cell support was required in some patients to manage hematological toxicity.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever was reported in 17% of patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma treated with ibritumomab tiuxetan (n=349) (Prod Info ZEVALIN(R) IV kit, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=349), the following respiratory adverse events were reported (% all grades, % grade 3/4): dyspnea (14%, 2%), increased cough (10%, 0%), rhinitis (6%, 0%), and bronchospasm (5%, 0%) (Prod Info ZEVALIN(R) IV kit, 2007).
    B) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Bronchospasm was reported in 5% of patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma treated with ibritumomab tiuxetan (n=349). Because serious allergic reactions have been reported, medications for the treatment of anaphylactic and other hypersensitivity reactions (eg, epinephrine, antihistamines, corticosteroids) should be available. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA) as patients with evidence of HAMA may be at increased risk of serious reactions (Prod Info ZEVALIN(R) IV kit, 2007).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, (n=349), the following nervous system adverse events were reported (% all grades, % grade 3/4): asthenia (43%, 3%), headache (12%, 1%), dizziness (10%, less than 1%), and insomnia (5%, 0%) (Prod Info ZEVALIN(R) IV kit, 2007).
    B) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Cerebral hemorrhage has been reported infrequently in patients receiving ibritumomab tiuxetan therapy. Of three patients that developed cerebral hemorrhage, 2 patients developed the event during grade 4 thrombocytopenia approximately 5 to 8 weeks after therapy. The other patient died of cerebral hemorrhage due to progression of his lymphoma (Morschhauser et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=349), the following gastrointestinal adverse events were reported (% all grades, % grade 3/4): nausea (31%, 1%), abdominal pain (16%, 3%), vomiting (12%, 0%), throat irritation (10%, 0%), diarrhea (9%, less than 1%), anorexia (8%, 0%), abdominal enlargement (5%, 0%), and constipation (5%, 0%)(Prod Info ZEVALIN(R) IV kit, 2007).
    b) INCIDENCE: In a prospective, multicenter, nonrandomized phase 2 trial in elderly patients previously treated with chemotherapy and receiving a single dose of yttrium-90 ibritumomab tiuxetan, gastrointestinal toxicity was the most common grade 3/4 nonhematologic event reported, with 10% of patients experiencing symptoms (Morschhauser et al, 2007).
    c) Nausea, abdominal pain, and anorexia have been described by some non-Hodgkin's lymphoma patients (less than 10%) during or following the radioimmunotherapy protocol (Witzig et al, 1999a). Some of these effects have been reported with rituximab monoimmunotherapy, and the contributing role of rituximab pretreatment is unclear.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) GENERAL: The most common severe adverse events in clinical trials were thrombocytopenia and neutropenia. Hemorrhage, including fatal cerebral hemorrhage, and severe infections have been reported. Patients should be monitored for up to 3 months after ibritumomab tiuxetan therapy for cytopenias and complications of febrile neutropenia and hemorrhage. In clinical trials (n=349), 5 cases of secondary malignancies were reported (Prod Info ZEVALIN(R) IV kit, 2007; Cersosimo, 2003).
    b) INCIDENCE: Based on safety data collected on 349 patients in multiple clinical trials receiving ibritumomab tiuxetan therapy, grade 3/4 thrombocytopenia occurred in 61% to 63% of patients and grade 3/4 neutropenia occurred in 57% to 60%. Of these patients, approximately 20% required blood transfusions or platelets (Witzig, 2003; Borghaei et al, 2004).
    1) Patients previously treated with fludarabine (ie, lower platelet count at the start of therapy) were also more likely to develop grade 3/4 hematologic toxicities following ibritumomab tiuxetan, which may be associated with a higher number of previous treatments (Borghaei et al, 2004).
    B) ACUTE MYELOID LEUKEMIA, DISEASE
    1) WITH THERAPEUTIC USE
    a) Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 2.6% (n=19/746) of patients included in clinical studies and expanded access programs. For all 19 cases, the median follow up was 4.4 years and the median time to diagnosis was 1.9 years. The expanded access trial (n=535, median follow-up of 4.4 years) reported 8 (1.5%) cases of the MDS/AML, with a median time to development of 1.5 years. Among the patients included in clinical studies (n=211, median follow up of 6.5 years), 11 (5.2%) patients developed MDS/AML, with a median time to development of 2.9 years. The cumulative Kaplan-Meier estimated incidences of MDS/secondary leukemia in this patient population at 2 years and 5 years were 2.2% and 5.9%, respectively. Although multiple cytogenic abnormalities were described, chromosomes 5 and/or 7 were most commonly involved. The number of prior treatments (0-1 vs 2-10) was not associated with the risk of developing MDS/AML (Prod Info ZEVALIN(R) IV injection kit, 2007).
    C) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=349), 61% of patients with a platelet count of at least 150,000 cells/cubic millimeter (mm(3)) prior to therapy developed thrombocytopenia with a platelet count less than 50,000 cells/cubic millimeter (mm(3); median 41,000 cells/mm(3)); 57% of patients developed neutropenia with an absolute neutrophil count (ANC) of less than 1000 cells/mm(3) (median 800 cells/mm(3)). In patients with mild thrombocytopenia at baseline (platelet count of 100,000 to 149,000 cells/mm(3)), 78% developed severe thrombocytopenia (median platelet count 24,000 cells/mm(3)) and 74% developed severe neutropenia (median ANC 600 cells/mm(3)). Median time to platelet nadir was 53 days with a median duration of 35 days; median ANC nadir was at 62 days with a median duration of 22 days. Twenty-two percent of patients received platelet transfusions; 20% received red blood cell transfusions; 13% received filgrastim; and 8% received erythropoietin. Severe cytopenia extended beyond 12 weeks after administration of ibritumomab tiuxetan in less than 5% of patients (Prod Info ZEVALIN(R) IV kit, 2007).
    b) PREDICTORS: The likely predictors of myelosuppression is the degree of bone marrow reserve (eg, platelet count), along with the degree of radiation likely to be delivered to the marrow (eg, percent marrow occupied by lymphoma) (Borghaei et al, 2004). Therefore, ibritumomab tiuxetan should not be administered to patients with 25% or greater lymphoma marrow involvement and/or impaired bone marrow reserve (prior myeloablative therapies); platelet count less than 100,000 cells/cubic millimeter (mm(3)); neutrophil count less than 1500 cells/mm(3); bone marrow with 15% or less cellularity or marked reduction in bone marrow precursors; or patients with a history of failed stem cell collection. Ibritumomab tiuxetan therapy should not be considered in patients with a platelet count of less than 100,000 cells/cubic millimeter (mm(3)); dose reduction is required in patients with platelet counts of 100,000 to 150,000 cells/mm(3) (Prod Info ZEVALIN(R) IV kit, 2007).
    c) In heavily-pretreated patients, myelosuppression has correlated with pretreatment tumor marrow involvement and platelet counts, but not Y-90 pharmacokinetics or marrow/whole-body absorbed radiation doses (Witzig et al, 1999a; Witzig, 2000a; Wiseman et al, 2001a; White et al, 2001a). Grade 4 thrombocytopenia has occurred in up to 15% of patients (Witzig, 2000a). However, hematologic toxicity is transient and reversible, with recovery generally evident with two or three weeks.
    d) These adverse hematologic effects have also been reported during rituximab monoimmunotherapy; the contributing role of rituximab pretreatment to myelosuppression in these studies is unclear.
    e) In a phase I/II study, median nadirs (times to nadirs) in patients receiving 0.4 mCi/kg were 50,000/mm(3) for platelets (43 days), 1100/mm(3) for absolute granulocyte count (50 days), and 9.9 g/dL for hemoglobin (time unspecified). The median time to recovery was about 2 weeks (which includes patients who had nadirs below 10 g/dL for hemoglobin, 1000/mm(3) for granulocytes, or 50,000/mm(3) for platelets and recovered to values above these levels). Grade 4 platelet nadirs (less than 25,000/mm(3)) were seen in all patients with greater than 20% marrow-tumor involvement; the frequency of grade 4 nadirs was 46% in patients with less than 20% involvement and 8% in those with no involvement; similar trends were seen for hemoglobin and granulocyte nadirs. Hospitalization for infection was only required in a few patients in this study (n=51) (Witzig et al, 1999a).
    f) Based on research to date, the risk of developing myelodysplastic syndrome and/or acute myelogenous leukemia following ibritumomab therapy is comparable to conventional therapy with a risk of 1% to 1.5% per year, 2 to 10 years after the initiation of therapy (Otte & Dierckx, 2005).
    D) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) INCIDENCE: Based on safety data collected on 349 patients in multiple clinical trials receiving ibritumomab tiuxetan therapy, the overall incidence of serious infection was 7%. Of those patients, 26% (6 of 23) were related to febrile neutropenia. The highest rate of infection occurred in the first 12 weeks after treatment (Borghaei et al, 2004).
    E) ECCHYMOSIS
    1) WITH THERAPEUTIC USE
    a) Ecchymosis (all grades) was reported in 7% of patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma treated with ibritumomab tiuxetan (n=349); additionally, less than 1% of reported ecchymosis was grade 3 or 4 (Prod Info ZEVALIN(R) IV kit, 2007).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CUTANEOUS HYPERSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Severe cutaneous and mucocutaneous reactions, some fatal, have been reported during the postmarketing use of ibritumomab tiuxetan. Stevens-Johnson syndrome, erythema multiforme, bullous dermatitis, toxic epidermal necrolysis, and exfoliative dermatitis have been observed. The onset of these reactions has been both acute (days) and delayed (3 to 4 months) (Prod Info ZEVALIN(R) IV kit, 2007).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Severe cutaneous and mucocutaneous reactions (some fatal), including Stevens-Johnson syndrome, have been reported during the postmarketing use of ibritumomab tiuxetan. The onset of these reactions has been both acute (days) and delayed (3 to 4 months) (Prod Info ZEVALIN(R) IV kit, 2007).
    C) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Severe cutaneous and mucocutaneous reactions (some fatal), including erythema multiforme, have been reported during the postmarketing use of ibritumomab tiuxetan. The onset of these reactions has been both acute (days) and delayed (3 to 4 months) (Prod Info ZEVALIN(R) IV kit, 2007).
    D) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) Extravasation injury has been reported with yttrium-90-ibritumomab tiuxetan therapy and consists of slowly progressing injury with moist desquamation. Symptoms may be delayed up to a month after administration (Prod Info ZEVALIN(R) IV kit, 2007). Significant tissue injury with minimal healing was observed in postmarketing experience in two patients (Williams et al, 2006; Siebeneck, 2008). Surgical intervention was likely indicated in both cases, but not performed due to rapidly progressing underlying disease.
    b) CASE REPORT: A 64-year-old man with B-cell non-Hodgkin's lymphoma had no response to two cycles of standard multidrug chemotherapy and was enrolled in a clinical trial to receive yttrium-90-ibritumomab tiuxetan. During the procedure, an estimated 1 cc of a 1.22 GBq (32.9 mCi) dose infiltrated the antecubital fossa, which represented an estimated dose of 20 to 40 Gy. Tenderness was noted about 14 days after exposure with a bulla forming in the area. Grade 3 dermatitis with moist desquamation was observed on day 29 with dressing changes required 3 times daily. Plastic surgery was consulted for treatment (silver sulfadiazine cream applied daily) and possible skin grafting. The patient died 3 months after presentation from persistent disease (Williams et al, 2006).
    c) CASE REPORT: A 83-year-old man with diffuse large B-cell non-Hodgkins lymphoma was treated with 2 courses of rituximab and ibritumomab tiuxetan for chemotherapy-resistant disease. One week after the second infusion, the patient developed erythema at the injection site which gradually grew to 15 cm by 25 cm by 4 weeks along with moderate pain. Positive radiation levels were observed in the extravasated arm following Geiger counter scanning. Moist desquamation occurred at 5 weeks with skin sloughing. Despite treatment with silver sulfadine cream, no wound healing was observed up to 15 weeks after injury. Tissue granulation slowly began after four months with a dime size area of necrotic tissue. No further treatment was provided because of the patient's rapidly progressing disease (Siebeneck, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=349), the following musculoskeletal adverse events were reported (% all grades, % grade 3/4): back pain (8%, 1%), arthralgia (7%, 1%), myalgia (7%, less than 1%) (Prod Info ZEVALIN(R) IV kit, 2007).
    b) Back pain and arthralgia have been described by some non-Hodgkin's lymphoma patients (less than 10%) during or following the radioimmunotherapy protocol (Witzig et al, 1999a). These effects have been reported with rituximab monoimmunotherapy, and the contributing role of rituximab pretreatment is unclear.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Serious hypersensitivity reactions, including anaphylaxis, have been reported with ibritumomab tiuxetan use. Allergic reactions were reported in 2% of patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma treated with ibritumomab tiuxetan (n=349); additionally, 1% of reported allergic reactions were considered severe or life-threatening. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA); patients with evidence of HAMA may be at increased risk of serious reactions (Prod Info ZEVALIN(R) IV kit, 2007).
    b) CASE REPORT: A 45-year-old man with follicular non-Hodgkin lymphoma with extensive lymphadenopathy was treated initially with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) in 1999, followed by multiple recurrences which was treated with rituximab and ibritumomab in 2004. In 2006, ibritumomab was administered for another recurrence. Shortly after the second dose of therapy, the patient developed an anaphylactic episode, which included sudden shortness of breath, hypotension, tachycardia. The patient was successfully resuscitated. A human antimouse antibody (HAMA) level was 618 ng/mL (reference range: 0 to 188 ng/mL) (Jankowitz et al, 2008).
    B) ANTIBODY DEVELOPMENT
    1) WITH THERAPEUTIC USE
    a) In clinical trials, 3.8% of patients who received ibritumomab tiuxetan therapy and were followed for 90 days had evidence of human antimouse antibodies (HAMA) or human antichimeric antibodies (HACA) at some point during the study. Evidence of immunogenicity may be masked in patients who are lymphopenic (Prod Info ZEVALIN(R) IV kit, 2007). HAMA and HACA were observed in 1.4% and 0.5% of non-Hodgkin's lymphoma patients, respectively, receiving the rituximab/ibritumomab tiuxetan protocol in one analysis (n=211) (Goldenberg, 2001a). A higher incidence of HAMA responses has been observed when ibritumomab was used as the pretreatment antibody (Witzig et al, 1999a). No clinical consequences of antibody formation have been reported; it is capable of altering murine-based immunoassays and biodistribution/targeting.
    C) TRANSFUSION REACTION DUE TO SERUM PROTEIN REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 47-year-old woman with follicular lymphoma was enrolled in a clinical trial using standard chemotherapy which included rituximab followed by radioimmunotherapy (RIT) with ibritumomab tiuxetan. Approximately one week after RIT the patient developed evidence of serum sickness which included a fever, chills, myalgia and arthralgia. Although the patient remained in remission, the patient had recurrent symptoms of diffuse myalgias and arthralgias with an elevated sedimentation rate and C-reactive protein. Symptoms finally resolved following combination therapy with prednisone and indomethacin. Serum testing was inconclusive. The authors suggested that although the causative agent could not be determined, theoretically ibritumomab, a pure murine molecule, may have been responsible for the effects observed (DeMonaco & Jacobs, 2007).
    D) INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) In clinical trials (n=349), 29% of patients developed infections during the first 3 months after receiving ibritumomab tiuxetan therapy. Serious infections developed in 3% of patients and life-threatening infections developed in 2% of patients. In long-term follow-up (from 3 months to 4 years after ibritumomab tiuxetan therapy), infections occurred in 6% of patients treated with ibritumomab tiuxetan, with 2% and 1% being serious and life-threatening infections, respectively (Prod Info ZEVALIN(R) IV kit, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Ibritumomab tiuxetan is classified as FDA pregnancy category D. Although there are no adequate and well-controlled studies in pregnant women, ibritumomab tiuxetan may cause fetal harm.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ibritumomab tiuxetan is classified by the manufacturer as FDA pregnancy category D (Prod Info ZEVALIN(R) intravenous injection, 2013).
    2) Ibritumomab tiuxetan may cause fetal harm based on its radioactivity. Additionally, immunoglobulins are known to cross the placenta (Prod Info ZEVALIN(R) intravenous injection, 2013).
    3) Advise women of childbearing potential to use adequate contraception for a minimum of 12 months. Apprise women who become pregnant during treatment of the potential risks to the fetus (Prod Info ZEVALIN(R) intravenous injection, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Because of the potential effects to the nursing infant, nursing women should either discontinue this drug or breastfeeding, taking into account the importance of this drug to the mother (Prod Info ZEVALIN(R) intravenous injection, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No long-term studies to assess the potential carcinogenicity of ibritumomab tiuxetan have been performed; however, radiation is a potential carcinogen

Genotoxicity

    A) There have been no studies to determine the genetic potential of ibritumomab tiuxetan (Prod Info ZEVALIN(R) IV kit, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor serial CBC with differential and platelet count.
    E) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor serial CBC with differential and platelet count.
    E) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: In clinical trials, the administration of doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ibritumomab tiuxetan caused severe hematological toxicities. When single doses up to 50 mCi (1850 MBq) and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) were studied in a limited number of patients, autologous stem cell support was required in some patients to manage hematological toxicity.
    B) THERAPEUTIC: ADULT: MAXIMUM DOSE: 32 mCi (1184 MBq) infused over 10 minutes. CHILD: Safety and effectiveness in children have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The therapeutic regimen has two distinct steps:
    1) STEP 1: On day 1, infuse rituximab 250 mg/m(2) IV after premedication with oral acetaminophen 650 mg and diphenhydramine 50 mg (Prod Info ZEVALIN(R) intravenous injection, 2011).
    2) STEP 2: On day 7, 8, or 9, premedicate with acetaminophen and diphenhydramine and infuse rituximab 250 mg/m(2) IV (Prod Info ZEVALIN(R) intravenous injection, 2011).
    a) Within 4 hours, give yttrium-90 ibritumomab tiuxetan 0.4 mCi/kg (14.8 MBq/kg) of actual body weight for patients with normal platelets. Give 0.3 mCi/kg (11.1 MBq/kg) of actual body weight in relapsed or refractory patients with platelet count of 100,000 to 149,000 cells/mm(3). Infuse IV over 10 minutes (Prod Info ZEVALIN(R) intravenous injection, 2011).
    b) The maximum dose, regardless of body weight, is 32 mCi (1184 MBq) (Prod Info ZEVALIN(R) intravenous injection, 2011).
    c) Ibritumomab tiuxetan should not be administered to patients with platelet count less than 100,000 cells/mm(3) (Prod Info ZEVALIN(R) intravenous injection, 2011).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of ibritumomab tiuxetan therapy in pediatric patients have not been established (Prod Info ZEVALIN(R) intravenous injection, 2011).

Minimum Lethal Exposure

    A) A minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) In clinical trials, the administration of doses as high as 0.52 mCi/kg (19.2 MBq/kg) of Y-90 ibritumomab tiuxetan caused severe hematological toxicities. When single doses up to 50 mCi (1850 MBq) and multiple doses of 20 mCi (740 MBq) followed by 40 mCi (1480 MBq) were studied in a limited number of patients, autologous stem cell support was required in some patients to manage hematological toxicity (Prod Info ZEVALIN(R) IV kit, 2007; Witzig, 2003).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ibritumomab tiuxetan does not bind selectively to neoplastic cells; cross-reactivity was observed in vitro on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, lymphoid follicles of the tonsil, and lymphoid nodules of other organs such as large and small intestines. Nonlymphoid tissues or gonadal tissues were not observed to bind ibritumomab tiuxetan (Prod Info ZEVALIN(R) IV kit, 2007).
    B) IgG and IgA median serum levels remained within the normal range throughout the period of B-cell depletion. (Prod Info ZEVALIN(R) IV kit, 2007).
    C) IgM median serum levels decreased (median 49 mg/dL, range 13 to 3990 mg/dL) after treatment and recovered to normal values by 6 months after treatment (Prod Info ZEVALIN(R) IV kit, 2007).
    D) Ibritumomab is a murine kappa immunoglobulin G1 (IgG1) monoclonal antibody. It is the parent murine antibody of the chimeric rituximab, and both antibodies are directed against the CD20 antigen, which is present on B cells in more than 90% of patients with B-cell non-Hodgkin's lymphoma (Goldenberg, 2001; Witzig, 2000; White et al, 1999).
    E) For clinical use, ibritumomab is linked to radionuclides for both imaging and radioimmunotherapy by the linker-chelate tiuxetan (MX-DTPA; 1,4-methyl-benzyl isothiocyanate diethylenetriamine pentaacetic acid); tiuxetan is attached to ibritumomab via a covalent urea-type bond (Wiseman et al, 1999; White et al, 2001). Ibritumomab tiuxetan is then reacted with indium-111 (In-111) (for imaging/dosimetry) or yttrium-90 (Y-90) for radioimmunotherapy; the radionuclides are chelated via the five carboxyl groups on tiuxetan (Wiseman et al, 2001; Wiseman et al, 1999). Y-90 is unsuitable for imaging, thus the In-111 linkage is required for this purpose (Wiseman et al, 2000).
    F) Y-90-Ibritumomab tiuxetan selectively targets radiation to B cells with the CD20 antigen; it does not react with T cells or other types of lymphocytes (Chinn et al, 1999; Wiseman et al, 1999). Similar to rituximab (White et al, 2000; Witzig, 2000), ibritumomab appears to also induce antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis in target cells (White et al, 2000; Witzig et al, 1999).
    G) In preclinical studies, biodistribution patterns of In-111-ibritumomab tiuxetan and Y-90-ibritumomab tiuxetan were similar (biodistribution is determined by the antibody); In-111-labeled antibody has thus been used in dosimetry studies to estimate radiation absorbed doses from Y-90-ibritumomab tiuxetan (Wiseman et al, 2000). In studies involving both animals and humans, estimated whole-body/normal-tissue radiation doses were below accepted safe limits (Chinn et al, 1999; Wiseman et al, 2000).

Toxicologic Mechanism

    A) It should be anticipated that an inadvertent exposure may result in significant myelosuppression, in particular thrombocytopenia.

Physicochemical

Physical Characteristics

    A) Ibritumomab is a clear, colorless solution which may contain translucent particles and that has an apparent affinity for the CD20 antigen between approximately 14 and 18 nanometers (Prod Info ZEVALIN(R) intravenous injection, 2011).

Molecular Weight

    A) 148 kD (Prod Info ZEVALIN(R) intravenous injection, 2011)

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