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Special Alerts
Rituximab: Additional Report of Progressive Multifocal Leukoencephalopathy (PML) - September 2008
In conjunction with the U.S. Food and Drug Administration (FDA), Genentech, Inc has issued a “Dear Healthcare Professional” letter informing of an additional case of fatal PML, reported in a patient who had received rituximab for the treatment of rheumatoid arthritis (RA). In this case, PML was diagnosed 18 months after the last rituximab dose; confounding factors include a long history of immunosuppressant therapy and treatment with a tumor necrosis factor (TNF) antagonist for RA, plus development of oropharyngeal cancer (subsequently treated with chemotherapy and radiation therapy [after rituximab therapy, but 9 months prior to the diagnosis of PML]).
PML has previously been associated with rituximab use, although previous reports were confined to patients treated for hematologic malignancies and an unapproved use, systemic lupus erythematosus (SLE). The product labeling, which previously contained warnings regarding PML, has been updated to reflect this new report. Any new-onset neurological changes should be evaluated promptly; consider neurology consultation, brain MRI, and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.
Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm094994.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Rituxan® may be confused with Remicade®
RiTUXimab may be confused with bevacizumab, inFLIXimab
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The rituximab dose for rheumatoid arthritis is a flat dose (1000 mg) and is not based on body surface area (BSA).
Pronunciation
(ri TUK si mab)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of low-grade or follicular CD20-positive, B-cell non-Hodgkin's lymphoma (NHL); treatment of diffuse large B-cell CD20-positive NHL; treatment of moderately- to severely-active rheumatoid arthritis (RA) in combination with methotrexate
Use: Unlabeled/Investigational
Treatment of autoimmune hemolytic anemia (AIHA) in children; chronic immune thrombocytopenic purpura (ITP); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); pemphigus vulgaris, Waldenström's macroglobulinemia (WM); treatment of systemic autoimmune diseases (other than rheumatoid arthritis); treatment of refractory chronic graft-versus-host disease (GVHD)
Pregnancy Risk Factor
C
Pregnancy Considerations
Animal studies have demonstrated adverse effects including decreased (reversible) B-cells and immunosuppression. There are no adequate and well-controlled studies in pregnant women. IgG molecules are known to cross the placenta (rituximab is an engineered IgG molecule) and rituximab has been detected in the serum of infants exposed in utero. B-Cell lymphocytopenia lasting <6 months may occur in exposed infants. Use during pregnancy only if clearly needed.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if rituximab is excreted in human milk. However, human IgG is excreted in breast milk, and therefore, rituximab may also be excreted in milk. The manufacturer recommends discontinuing breast-feeding until circulating levels of rituximab are no longer detectable.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Warnings/Precautions
Boxed warnings:
• Infusion reactions: See “Concerns related to adverse effects” below.
• Mucocutaneous reactions: See “Concerns related to adverse effects” below.
• Progressive multifocal leukoencephalopathy: See “Concerns related to adverse effects” below.
• Tumor lysis syndrome: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Bowel obstruction/perforation: Have been reported, with an average onset of symptoms of ?6 days; complaints of abdominal pain should be evaluated, especially if early in the treatment course.
• Infusion reactions: [U.S. Boxed Warning]: Severe (occasionally fatal) infusion-related reactions have been reported, usually with the first infusion; fatalities have been reported within 24 hours of infusion; monitor closely and discontinue with grades 3 or 4 infusion reactions. Reactions usually occur within 30-120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylaxis. Risk factors associated with fatal outcomes include chronic lymphocytic leukemia, female gender, mantle cell lymphoma, or pulmonary infiltrates. Closely monitor patients with a history of prior cardiopulmonary reactions or with pre-existing cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (>25,000/mm3). Discontinue infusion for severe reactions and serious or life-threatening cardiac arrhythmias; subsequent doses should include cardiac monitoring during and after the infusion. Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, corticosteroids) should be available for immediate use; treatment is symptomatic. Mild-to-moderate infusion-related reactions (eg, chills, fever, rigors) occur frequently and are typically managed through slowing or interrupting the infusion. Infusion may be resumed at a 50% infusion rate reduction upon resolution of symptoms. Due to the potential for hypotension, consider withholding antihypertensives 12 hours prior to treatment.
• Mucocutaneous reactions: [U.S. Boxed Warning]: Severe and sometimes fatal mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis and vesiculobullous dermatitis) have been reported, occurring from 1-13 weeks following exposure. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of re-exposure following mucocutaneous reactions has not been evaluated.
• Progressive multifocal leukoencephalopathy: [U.S. Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) due to JC virus infection has been reported with rituximab use. Cases were reported in patients with hematologic malignancies receiving rituximab either with combination chemotherapy, or with hematopoietic stem cell transplant. Cases were also reported in patients receiving rituximab for autoimmune diseases who had received concurrent or prior immunosuppressant therapy. Onset may be delayed, although most cases were diagnosed within 12 months of the last rituximab dose. Evaluate any neurological change promptly; consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.
• Renal toxicity: May cause renal toxicity in patients with hematologic malignancies; consider discontinuation with increasing serum creatinine or oliguria.
• Tumor lysis syndrome: [U.S. Boxed Warning]: Tumor lysis syndrome leading to acute renal failure requiring dialysis may occur 12-24 hours following the first dose. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Consider prophylaxis (allopurinol, hydration) in patients at high risk (high numbers of circulating malignant cells ?25,000/mm3 or high tumor burden).
• Viral infections: Rarely, reactivation of hepatitis B (with fulminant hepatitis and hepatic failure) has been reported in association with use; screen high-risk patients prior to therapy initiation. Other serious and potentially fatal viral infections, either new or reactivated, associated with use include cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. Viral infections may be delayed; occurring up to 1 year after discontinuation of therapy.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease or prior cardiopulmonary events.
• Respiratory disease: Use with caution in patients with pre-existing pulmonary disease, or prior cardiopulmonary events.
Concurrent drug therapy issues:
• Biologic agents: Safety and efficacy of rituximab in combination with biologic agents have not been established.
• Disease-modifying antirheumatic drugs (DMARD): Safety and efficacy of rituximab in combination DMARD other than methotrexate have not been established.
• Immunizations: Live vaccines should not be given concurrently with rituximab; there is no data available concerning secondary transmission of live vaccines with or following rituximab treatment. RA patients should be brought up to date with nonlive immunizations (following current guidelines) before initiating therapy; evaluate risks of therapy delay versus benefit (of nonlive vaccines) for NHL patients.
Special populations:
• Elderly: Use with caution in the elderly; higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis).
• Pediatrics: Not approved for use in children.
• Rheumatoid arthritis (RA) patients: Monitor closely RA patients during and after each infusion; increased risk of cardiovascular events. Safety and efficacy of retreatment for RA have not been established.
Adverse Reactions
Note: Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions.
>10%:
Central nervous system: Fever (5% to 53%), chills (3% to 33%), headache (19%), pain (12%)
Dermatologic: Rash (15%; grades 3/4: 1%), pruritus (5% to 14%), angioedema (11%; grades 3/4: 1%)
Gastrointestinal: Nausea (8% to 23%), abdominal pain (2% to 14%)
Hematologic: Cytopenias (grades 3/4: ?48%; may be prolonged), lymphopenia (48%; grades 3/4: 40%; median duration 14 days), leukopenia (14%; grades 3/4: 4%), neutropenia (14%; grades 3/4: 6%; median duration 13 days), thrombocytopenia (12%; grades 3/4: 2%)
Neuromuscular & skeletal: Weakness (2% to 26%)
Respiratory: Cough (13%), rhinitis (3% to 12%)
Miscellaneous: Infusion-related reactions (lymphoma: first dose 77%; decreases with subsequent infusions; may include angioedema, bronchospasm, chills, dizziness, fever, headache, hyper-/hypotension, myalgia, nausea, pruritus, rash, rigors, urticaria, and vomiting; reactions reported are lower [first infusion: 32%] in RA); infection (31%; grades 3/4: 4%; bacterial: 19%; viral 10%; fungal: 1%), night sweats (15%)
1% to 10%:
Cardiovascular: Hypotension (10%), peripheral edema (8%), hypertension (6% to 8%), flushing (5%), edema (<5%)
Central nervous system: Dizziness (10%), anxiety (2% to 5%), agitation (<5%), depression (<5%), hypoesthesia (<5%), insomnia (<5%), malaise (<5%), nervousness (<5%), neuritis (<5%), somnolence (<5%), vertigo (<5%), migraine (RA: 2%)
Dermatologic: Urticaria (2% to 8%)
Endocrine & metabolic: Hyperglycemia (9%), hypoglycemia (<5%), hypercholesterolemia (2%)
Gastrointestinal: Diarrhea (10%), vomiting (10%), dyspepsia (3%), anorexia (<5%), weight loss (<5%)
Hematologic: Anemia (8%; grades 3/4: 3%)
Local: Pain at the injection site (<5%)
Neuromuscular & skeletal: Back pain (10%), myalgia (10%), arthralgia (6% to 10%), paresthesia (2%), arthritis (<5%), hyperkinesia (<5%), hypertonia (<5%), neuropathy (<5%)
Ocular: Conjunctivitis (<5%), lacrimation disorder (<5%)
Respiratory: Throat irritation (2% to 9%), bronchospasm (8%), dyspnea (7%), upper respiratory tract infection (RA: 7%), sinusitis (6%)
Miscellaneous: LDH increased (7%)
Postmarketing and/or case reports: Acute renal failure, anaphylactoid reaction/anaphylaxis, angina, aplastic anemia, ARDS, arrhythmia, bowel obstruction, bronchiolitis obliterans, cardiac failure, cardiogenic shock, disease progression (Kaposi's sarcoma), fatal infusion-related reactions, fulminant hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, hepatitis, hepatitis B reactivation, hyperviscosity syndrome (in Waldenström's macroglobulinemia), hypogammaglobulinemia, hypoxia, interstitial pneumonitis, lichenoid dermatitis, lupus-like syndrome, marrow hypoplasia, MI, neutropenia (late-onset occurring >40 days after last dose), optic neuritis, pancytopenia (prolonged), paraneoplastic pemphigus (uncommon), pleuritis, pneumonia, pneumonitis, polyarticular arthritis, progressive multifocal leukoencephalopathy (PML), pure red cell aplasia, renal toxicity, serum sickness, Stevens-Johnson syndrome, supraventricular arrhythmia, systemic vasculitis, toxic epidermal necrolysis, tumor lysis syndrome, urticaria, uveitis, vasculitis with rash, ventricular fibrillation, ventricular tachycardia, vesiculobullous dermatitis, viral reactivation (includes JC virus, cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C)
Drug Interactions
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
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. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid echinacea (may diminish the therapeutic effect of immunosuppressants). Avoid hypoglycemic herbs, including alfalfa, aloe, bilberry, bitter melon, burdock, celery, damiana, fenugreek, garcinia, garlic, ginger, ginseng (American), gymnema, marshmallow, and stinging nettle (may enhance the hypoglycemic effect of rituximab).
Storage
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Protect vials from direct sunlight. Solutions for infusion are stable at 2°C to 8°C (36°F to 46°F) for 24 hours and at room temperature for an additional 24 hours.
Reconstitution
Withdraw necessary amount of rituximab and dilute to a final concentration of 1-4 mg/mL with 0.9% sodium chloride or 5% dextrose in water. Gently invert the bag to mix the solution. Do not shake.
Mechanism of Action
Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. B-cells are believed to play a role in the development and progression of rheumatoid arthritis. Signs and symptoms of RA are reduced by targeting B-cells and the progression of structural damage is delayed.
Pharmacodynamics/Kinetics
Duration: Detectable in serum 3-6 months after completion of treatment; B-cell recovery begins ?6 months following completion of treatment; median B-cell levels return to normal by 12 months following completion of treatment
Absorption: I.V.: Immediate and results in a rapid and sustained depletion of circulating and tissue-based B cells
Distribution: 4.3 L (following two 1000 mg doses for rheumatoid arthritis)
Half-life elimination:
Cancer: Proportional to dose; wide ranges reflect variable tumor burden and changes in CD20 positive B-cell populations with repeated doses:
>100 mg/m2: 4.4 days (range: 1.6-10.5 days)
375 mg/m2:
Following first dose: Mean half-life: 3.2 days (range: 1.3-6.4 days)
Following fourth dose: Mean half-life: 8.6 days (range: 3.5-17 days)
RA: Mean terminal half-life: 19 days
Excretion: Uncertain; may undergo phagocytosis and catabolism in the reticuloendothelial system (RES)
Dosage
Note: Pretreatment with acetaminophen and an antihistamine is recommended.
Children: AIHA, chronic ITP (unlabeled uses): I.V.: 375 mg/m2 once weekly for 2-4 doses
Adults: I.V. infusion (refer to individual protocols):
NHL (relapsed/refractory, low-grade or follicular CD20-positive, B-cell): 375 mg/m2 once weekly for 4 or 8 doses
Retreatment following disease progression: 375 mg/m2 once weekly for 4 doses
NHL (diffuse large B-cell): 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses
NHL (follicular, CD20-positive, B-cell, previously untreated): 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses
NHL (nonprogressing, low-grade, CD20-positive, B-cell, after first line CVP): 375 mg/m2 once weekly for 4 doses every 6 months for up to 4 cycles (initiate after 6-8 cycles of chemotherapy are completed)
Rheumatoid arthritis: 1000 mg on days 1 and 15 in combination with methotrexate
Note: Premedication with a corticosteroid (eg, methylprednisolone 100 mg I.V.) 30 minutes prior to each rituximab dose is recommended. In clinical trials, patients received oral corticosteroids on a tapering schedule from baseline through day 16.
CLL/SLL (unlabeled use): 100 mg day 1, then 375 mg/m2 3 times/week for 11 doses
Refractory pemphigus vulgaris (unlabeled use): 375 mg/m2 once weekly of weeks 1, 2, and 3 of a 4-week cycle, repeat for 1 additional cycle, then 1 dose per month for 4 months (total of 10 doses in 6 months)
Refractory chronic GVHD, Waldenström's macroglobulinemia (unlabeled uses): 375 mg/m2 once weekly for 4 weeks
Combination therapy with ibritumomab: 250 mg/m2 I.V. day 1; repeat in 7-9 days with ibritumomab (also see Ibritumomab monograph):
Dosage: Combination Regimens
Leukemia, chronic lymphocytic:
Fludarabine-Cyclophosphamide-Rituximab (CLL)
Fludarabine-Rituximab (CLL)
OFAR (CLL)
PCR
Lymphoma, non-Hodgkin's:
Bendamustine-Rituximab
Fludarabine-Cyclophosphamide-Mitoxantrone-Rituximab
Fludarabine-Cyclophosphamide-Rituximab (NHL-Follicular)
Fludarabine-Mitoxantrone-Dexamethasone-Rituximab
Fludarabine-Mitoxantrone-Rituximab
Gemcitabine-Oxaliplatin-Rituximab (NHL)
Rituximab-CHOP
R-CVP
RICE
Lymphoma, non-Hodgkin's: (Mantle Cell):
Bendamustine-Rituximab
Hyper-CVAD + Rituximab
Administration: I.V.
Do not administer I.V. push or bolus.
Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.
Subsequent infusions: If patient did not tolerate initial infusion follow initial infusion guidelines. If patient tolerated initial infusion, start at 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.
Note: If a reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate.
In patients with NHL who are receiving a corticosteroid as part of their combination chemotherapy regimen and after tolerance has been established at the recommended infusion rate in cycle 1, a rapid infusion rate has been used beginning with cycle 2. The daily corticosteroid, acetaminophen, and diphenhydramine are administered prior to treatment, then the rituximab dose is administered over 90 minutes, with 20% of the dose administered in the first 30 minutes and the remaining 80% is given over 60 minutes (Sehn, 2007).
Administration: I.V. Detail
Discontinue infusions in the event of serious or life-threatening cardiac arrhythmias.
pH: 6.5
Monitoring Parameters
CBC with differential and platelets, peripheral CD20+ cells; HAMA/HACA titers (high levels may increase the risk of allergic reactions); renal function, fluid balance; vital signs; monitor for infusion reactions, cardiac monitoring during and after infusion in rheumatoid arthritis patients and in patients with pre-existing cardiac disease or if arrhythmias develop during or after subsequent infusions
Screen for hepatitis B in high-risk patients prior to initiation of rituximab therapy (the NCCN NHL guidelines recommend screening all NHL patients prior to therapy). In addition, carriers and patients with evidence of recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV infection during therapy and for up to a year following completion of treatment. High-risk patients should be screened for hepatitis C (per NCCN guidelines).
Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment. Signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits). If PML is suspected, obtain brain MRI scan and lumbar puncture.
Patient Education
This medication is only administered by infusion. You may experience a reaction during the infusion of this medication, including high fever, chills, respiratory difficulty, or congestion. You will be closely monitored and comfort measures provided. Maintain adequate hydration during entire course of therapy unless instructed to restrict fluid intake. You will be susceptible to infection and people may wear masks and gloves while caring for you to protect you as much as possible (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). If you have diabetes, monitor glucose levels closely; this medication may impact glucose control. May cause dizziness or trembling (use caution until response to medication is known); nausea, vomiting, or loss of appetite (small, frequent meals and frequent mouth care may help); diarrhea (increase dietary fiber, buttermilk, or yogurt); bone or muscle pain (ask prescriber for appropriate analgesic). Report immediately any unusual abdominal pain; skin rash or redness, persistent dizziness, swelling of extremities, unusual weight gain, respiratory difficulty, chest pain or tightness; symptoms of respiratory infection (wheezing, bronchospasms, or difficulty breathing); unresolved GI disturbance (nausea, vomiting); opportunistic infection (sore or irritated throat; unusual and persistent fatigue, chills, fever, unhealed sores, white plaques in mouth or genital area; unusual bruising or bleeding); CNS changes (confusion, agitation, insomnia); pain, tingling, loss of sensation in extremities, or loss of coordination); or other unusual effects related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness or depression
Mental Health: Effects on Psychiatric Treatment
Leukopenia is common; avoid concurrent use with clozapine or carbamazepine
Nursing: Physical Assessment/Monitoring
Assess patient history with mouse antibodies prior to beginning therapy. Assess other pharmacological or herbal products patient may be taking for potential interactions (eg, anything that may increase hypotensive effects of this drug). Evaluate results of laboratory tests prior to, during, and following therapy. Patient must be monitored closely during and following each infusion; severe infusion reactions can occur. Pretreatment with acetaminophen and diphenhydramine is recommended (corticosteroid when used to treat RA). Emergency equipment and medications (epinephrine, antihistamines, corticosteroids) should be immediately available during infusion. In the event of severe infusion reaction, infusion should be stopped and prescriber notified immediately. Evaluate patient response closely after each dose and following discontinuation of therapy (eg, abdominal pain [bowel obstruction and perforation], hyper-/hypertension, CNS changes, hyper-/hypoglycemia, rash); bowel obstruction and perforation can occur early in therapy; acute tumor lysis syndrome leading to acute renal failure can occur 12-24 hours after first dose; severe mucocutaneous reactions can occur from 1-13 weeks following treatment; and new or reactivated serious viral infection may occur up to one year following discontinuation of therapy. Teach patient possible side effects/appropriate interventions and importance of reporting adverse reactions.
Oncology: Emetic Potential
Very low (<10%)
Oncology: Vesicant
No
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Rituxan®: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Pricing: U.S. (www.drugstore.com)
Concentrate (Rituxan)
10 mg/mL (10): $631.85
References
Ahmed AR, Spigelman Z, Cavacini LA, et al, “Treatment of Pemphigus Vulgaris With Rituximab and Intravenous Immune Globulin,” N Engl J Med, 2006, 355(17):1772-9.
Avivi I, Robinson S, and Goldstone A, “Clinical Use of Rituximab in Haematological Malignancies,” Br J Cancer, 2003, 89(8):1389-94.
Boye J, Elter T, and Engert A, “An Overview of the Current Clinical Use of the Anti-CD20 Monoclonal Antibody Rituximab,” Ann Oncol, 2003, 14(4):520-35.
Byrd JC, Murphy T, Howard RS, et al, “Rituximab Using a Thrice Weekly Dosing Schedule in B-Cell Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Demonstrates Clinical Activity and Acceptable Toxicity,” J Clin Oncol, 2001, 19(8):2153-64.
Coiffier B, “State-of-the-Art Therapeutics: Diffuse Large B-Cell Lymphoma,” J Clin Oncol, 2005, 23(26): 6387-93.
Coiffier B, Haioun C, Ketterer N, et al, “Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients With Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study,” Blood, 1998, 92(6):1927-32.
Coiffier B, Lepage E, Briere J, “CHOP Chemotherapy Plus Rituximab Compared With CHOP Alone in Elderly Patients With Diffuse Large-B-Cell Lymphoma,” N Engl J Med, 2002, 346(4):235-42.
Cutler C, Miklos D, Kim HT, et al, “Rituximab for Steroid-Refractory Chronic Graft-Versus-Host Disease,” Blood, 2006, 108(2):756-62.
Dimopoulos MA, Kyle RA, Anagnostopoulos A, et al, “Diagnosis and Management of Waldenstrom's Macroglobulinemia,” J Clin Oncol, 2005, 23(7):1564-77.
Edwards JC, Szczepanski L, Szechinski J, et al, “Efficacy of B-Cell-Targeted Therapy With Rituximab in Patients With Rheumatoid Arthritis,” N Engl J Med, 2004, 350(25):2572-81.
Garcia-Suarez J, de Miguel D, Krsnik I, et al, “Changes in the Natural History of Progressive Multifocal Leukoencephalopathy in HIV-Negative Lymphoproliferative Disorders: Impact of Novel Therapies,” Am J Hematol, 2005, 80(4):271-81.
Goldberg SL, Pecora AL, Alter RS, et al, “Unusual Viral Infections (Progressive Multifocal Leukoencephalopathy and Cytomegalovirus Disease) After High-Dose Chemotherapy With Autologous Blood Stem Cell Rescue and Peritransplantation Rituximab,” Blood, 2002, 99(4):1486-8.
Gottenberg JE, Guillevin L, Lambotte O, et al, “Tolerance and Short Term Efficacy of Rituximab in 43 Patients With Systemic Autoimmune Diseases,” Ann Rheum Dis, 2005, 64(6):913-20.
Grillo-Lopez AJ, “Rituximab (Rituxan/MabThera): The First Decade (1993-2003),” Expert Rev Anticancer Ther, 2003, 3(6):767-79.
Higashida J, Wun T, Schmidt S, et al, “Safety and Efficacy of Rituximab in Patients With Rheumatoid Arthritis Refractory to Disease Modifying Antirheumatic Drugs and Anti-Tumor Necrosis Factor-Alpha Treatment,” J Rheumatol, 2005, 32(11):2109-15.
Johnson P and Glennie M, “The Mechanisms of Action of Rituximab in the Elimination of Tumor Cells,” Semin Oncol, 2003, 30(1 Suppl 2):3-8.
Keating MJ, O'Brien S, Albitar M, et al, “Early Results of a Chemoimmunotherapy Regimen of Fludarabine, Cyclophosphamide, and Rituximab as Initial Therapy for Chronic Lymphocytic Leukemia,” J Clin Oncol, 2005, 23(18):4079-88.
Maloney DG, Smith B, and Rose A, “Rituximab: Mechanism of Action and Resistance,” Semin Oncol, 2002, 29(1 Suppl 2):2-9.
Marcus R, Imrie K, Belch A, et al, “CVP Chemotherapy Plus Rituximab Compared With CVP as First-Line Treatment for Advanced Follicular Lymphoma,” Blood, 2005, 105(4):1417-23.
McLaughlin P, Grillo-Lopez AJ, Link BK, et al, “Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program,” J Clin Oncol, 1998, 16(8):2825-33.
Moore J, Ma D, Will R, et al, “A phase II Study of Rituximab in Rheumatoid Arthritis Patients With Recurrent Disease Following Haematopoietic Stem Cell Transplantation,” Bone Marrow Transplant, 2004, 34(3):241-7
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Non-Hodgkin's Lymphomas,” V.3.2008. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf
Ng CM, Bruno R, Combs D, et al, “Population Pharmacokinetics of Rituximab (Anti-CD20 Monoclonal Antibody) in Rheumatoid Arthritis Patients During a Phase II Clinical Trial,” J Clin Pharmacol, 2005, 45(7):792-801
Panayi GS, “B Cell-Directed Therapy in Rheumatoid Arthritis - Clinical Experience,” J Rheumatol Suppl, 2005, 73:19-24.
Sehn LH, Donaldson J, Filewich A, et al, “Rapid Infusion Rituximab in Combination With Corticosteroid-Containing Chemotherapy or as Maintenance Therapy is Well Tolerated and Can Safely be Delivered in the Community Setting,” Blood, 2007, 109(10):4171-3.
Wang J, Wiley JM, Luddy R, et al, “Chronic Immune Thrombocytopenic Purpura in Children: Assessment of Rituximab Treatment,” J Pediatr, 2005, 146(2):217-21.
Zecca M, Nobili B, Ramenghi U, et al, “Rituximab in the Treatment of Refractory Autoimmune Hemolytic Anemia in Children,” Blood, 2003, 101(10): 3857-61.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2009
Content last modified September 2009
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