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Special Alerts
Rituximab (Rituxan®): Fatal Infusion Related Reactions in patients with Rheumatoid Arthritis (RA)
June 2011
Hoffmann-La Roche Limited, in collaboration with Health Canada, has notified healthcare professionals and the public of four fatalities that may be associated with rituximab infusions. The fatalities occurred in patients receiving rituximab for the treatment of RA.
Review of safe administration practices may be helpful in preventing further events. Premedicate (analgesic/antipyretic, antihistamine, and glucocorticoid) patients 30 minutes prior to the rituximab infusion, have resuscitation equipment immediately available when rituximab is administered, monitor closely during infusion and immediately stop the infusion with suspected anaphylaxis or other severe hypersensitivity or infusion reactions, and closely monitor patients with pre-existing cardiac conditions or those with previous cardiopulmonary adverse events after completion of the infusion.
It is not known if the patients with fatal infusion reactions were properly premedicated, although all RA patients should receive methylprednisolone 100 mg I.V. 30 minutes prior to the initiation of each rituximab infusion (in addition to acetaminophen and diphenhydramine).
Further information may be found on Health Canada's website at http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2011/rituxan_6_hpc-cps-eng.php
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.
Pronunciation
(ri TUK si mab)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM169892.pdf, must be dispensed with this medication.
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of CD20-positive non-Hodgkin's lymphomas (NHL):
Relapsed or refractory, low-grade or follicular B-cell NHL (as a single agent)
Follicular B-cell NHL, previously untreated (in combination with first-line chemotherapy, and as single-agent maintenance therapy if response to first-line rituximab with chemotherapy)
Nonprogressing, low-grade B-cell NHL (as a single agent after first-line CVP treatment)
Diffuse large B-cell NHL, previously untreated (in combination with CHOP chemotherapy [or other anthracycline-based regimen])
Treatment of CD20-positive chronic lymphocytic leukemia (CLL) (in combination with fludarabine and cyclophosphamide)
Treatment of moderately- to severely-active rheumatoid arthritis (in combination with methotrexate) in adult patients with inadequate response to one or more TNF antagonists
Treatment of Wegener's granulomatosis (WG) (in combination with glucocorticoids)
Treatment of microscopic polyangiitis (MPA) (in combination with glucocorticoids)
Use: Unlabeled
Treatment of Burkitt's lymphoma, central nervous system lymphoma, Hodgkin's lymphoma (lymphocyte predominant); mucosal associated lymphoid tissue (MALT) lymphoma (gastric and nongastric), splenic marginal zone lymphoma; Waldenström's macroglobulinemia (WM); post-transplant lymphoproliferative disorder (PTLD); autoimmune hemolytic anemia (AIHA) in children; chronic immune thrombocytopenic purpura (ITP); refractory pemphigus vulgaris; treatment of steroid-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. 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. Retrospective case reports of inadvertent pregnancy during rituximab treatment (often combined with concomitant teratogenic therapies) describe premature births, and infant hematologic abnormalities and infections; no specific pattern of birth defects has been observed (limited data). Effective contraception should be used during and for 12 months following treatment. Healthcare providers are encouraged to enroll women with rheumatoid arthritis exposed to rituximab during pregnancy in the OTIS AutoImmune Diseases Study by contacting the Organization of Teratology Information Specialists (877-311-8972).
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 FDA-approved manufacturer's labeling.
Canadian labeling (not in U.S. labeling): Type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML)
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: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1-77 days); complaints of abdominal pain should be evaluated, especially if early in the treatment course.
• Infections: Use is not recommended if severe active infection is present; serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and up to 1 year after completing rituximab. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Rarely, reactivation of hepatitis B (with fulminant hepatitis, hepatic failure, and death) has been reported in association with use; median time to hepatitis diagnosis was ~4 months after initiation of therapy and 1 month following last dose; screen high-risk patients prior to therapy initiation; monitor for several months following completion of therapy. Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral hepatitis and initiate antiviral therapy. Discontinue rituximab in patients who develop other serious infections and initiate appropriate anti-infective treatment.
• 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 during infusion; 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). Prior to infusion, premedicate patients with acetaminophen and an antihistamine (and methylprednisolone for patients with RA). 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; may be fatal. 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. A retrospective analysis of patients (n=57) diagnosed with PML following rituximab therapy, found a median of 16 months (following rituximab initiation), 5.5 months (following last rituximab dose), and 6 rituximab doses preceded PML diagnosis. Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Carson, 2009). Promptly evaluate any patient presenting with neurological changes; 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 fatal renal toxicity in patients with hematologic malignancies. Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome. Monitor for signs of renal failure; discontinue rituximab 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 when used as a single agent in the treatment of NHL. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (allopurinol, hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities; monitor renal function and hydration status.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease or prior cardiopulmonary events. Discontinue with serious cardiac arrhythmia.
• 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) at least 4 weeks 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).
• 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. Rituximab is not recommended for use in RA patients who have not had prior inadequate response to TNF antagonists.
• Wegener's granulomatosis (WG)/microscopic polyangiitis (MPA): The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with WG or MPA after rituximab-induced B-cell depletion. There are only limited data on subsequent courses of rituximab for WG or MPA; safety and efficacy of retreatment has not been established.
Adverse Reactions
Note: Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions.
>10%:
Cardiovascular: Peripheral edema (8% to 16%), hypertension (6% to 12%)
Central nervous system: Fever (5% to 53%), fatigue (13% to 39%), chills (3% to 33%), headache (17% to 19%), insomnia (≤14%), pain (12%)
Dermatologic: Rash (10% to 17%; grades 3/4: 1%), pruritus (5% to 17%), angioedema (11%; grades 3/4: 1%)
Gastrointestinal: Nausea (8% to 23%), diarrhea (10% to 17%), abdominal pain (2% to 14%), weight gain (11%)
Hematologic: Cytopenias (grades 3/4: ≤48%; may be prolonged), lymphopenia (48%; grades 3/4: 40%; median duration 14 days), anemia (8% to 35%; grades 3/4: 3%), leukopenia (NHL: 14%; grades 3/4: 4%; CLL: grades 3/4: 23%; WG/MPA: 10%), neutropenia (NHL: 14%; grades 3/4: 4% to 6%; median duration 13 days; CLL: grades 3/4: 30% to 49%), neutropenic fever (CLL: grades 3/4: 9% to 15%), thrombocytopenia (12%; grades 3/4: 2% to 11%)
Hepatic: ALT increased (≤13%)
Neuromuscular & skeletal: Neuropathy (≤30%), weakness (2% to 26%), muscle spasm (≤17%), arthralgia (6% to 13%)
Respiratory: Cough (13%), rhinitis (3% to 12%), epistaxis (≤11%)
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; CLL: 59%; grades 3/4: 7% to 9%; WG/MPA: 12%); infection (19% to 62%; grades 3/4: 4%; bacterial: 19%; viral 10%; fungal: 1%), human antichimeric antibody (HACA) positive (1% to 23%), night sweats (15%)
1% to 10%:
Cardiovascular: Hypotension (10%; grades 3/4: 2%), flushing (5%)
Central nervous system: Dizziness (10%), anxiety (2% to 5%), migraine (RA: 2%)
Dermatologic: Urticaria (2% to 8%)
Endocrine & metabolic: Hyperglycemia (9%)
Gastrointestinal: Vomiting (10%), dyspepsia (RA: 3%)
Neuromuscular & skeletal: Back pain (10%), myalgia (10%), paresthesia (2%)
Respiratory: Dyspnea (≤10%), 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/perforation, bronchiolitis obliterans, cardiac failure, cardiogenic shock, disease progression (Kaposi's sarcoma), encephalomyelitis, 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, laryngeal edema, lichenoid dermatitis, lupus-like syndrome, marrow hypoplasia, MI, mucositis, mucocutaneous reaction, neutropenia (late-onset occurring >40 days after last dose), optic neuritis, pancytopenia (prolonged), paraneoplastic pemphigus (uncommon), pleuritis, pneumonia, pneumonitis, polyarticular arthritis, polymyositis, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), pure red cell aplasia, renal toxicity, reversible posterior leukoencephalopathy syndrome (RPLS), serum sickness, Stevens-Johnson syndrome, supraventricular arrhythmia, systemic vasculitis, toxic epidermal necrolysis, tuberculosis reactivation, tumor lysis syndrome, 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), wheezing
Metabolism/Transport Effects
None known.
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
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Risk X: Avoid combination
Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
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
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. 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). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. 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.
Compatibility
Stable in NS, D5W
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: RA: 3.1 L; WG/MPA: 4.5 L
Half-life elimination:
CLL: Median terminal half-life: 32 days (range: 14-62 days)
NHL: Median terminal half-life: 22 days (range: 6-52 days)
RA: Mean terminal half-life: 18 days (range: 5-78 days)
WG/MPA: 23 days (range: 9-49 days)
Excretion: Uncertain; may undergo phagocytosis and catabolism in the reticuloendothelial system (RES)
Dosage
Note: Details concerning dosing in combination regimens should also be consulted. Pretreatment with acetaminophen and an antihistamine is recommended for all indications. For oncology uses, a uricostatic agent (eg, allopurinol) and aggressive hydration is recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3). In patients with CLL, Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment). In patients with WG and MPA, PCP prophylaxis is recommended during and for 6 months after rituximab treatment. For patients with RA, premedication with methylprednisolone 100 mg I.V. (or equivalent) is recommended 30 minutes prior to each dose.
Children: I.V. infusion:
AIHA (unlabeled use): 375 mg/m2 once weekly for 2-4 doses (Zecca, 2003)
Chronic ITP (unlabeled use): 375 mg/m2 once weekly for 4 doses (Parodi, 2009; Wang, 2005)
Adults: I.V. infusion:
CLL: 375 mg/m2 on the day prior to fludarabine/cyclophosphamide in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2-6
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
Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy; begin 8 weeks after completion of combination chemotherapy): 375 mg/m2 every 8 weeks for 12 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)
NHL: Combination therapy with ibritumomab: 250 mg/m2 I.V. day 1; repeat in 7-9 days with ibritumomab (also see Ibritumomab monograph)
Canadian labeling: NHL, low grade or follicular:
Initial: 375 mg/m2 once weekly for 4 doses (as a single agent) or 375 mg/m2 on day 1 of each 21-day cycle for 8 cycles (in combination with CVP chemotherapy)
Maintenance (responding to induction therapy): 375 mg/m2 every 3 months until disease progression or up to a maximum of 2 years
Rheumatoid arthritis: 1000 mg on days 1 and 15 in combination with methotrexate; subsequent courses may be administered every 24 weeks (based on clinical evaluation), if necessary may be repeated no sooner than every 16 weeks
Wegener's granulomatosis (WG): 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone I.V. for 1-3 days followed by daily prednisone)
Microscopic polyangiitis (MPA): 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone I.V. for 1-3 days followed by daily prednisone)
Chronic GVHD, refractory (unlabeled use): 375 mg/m2 once weekly for 4 doses (Cutler, 2006)
Chronic ITP (unlabeled use): 375 mg/m2 once weekly for 4 doses (Arnold, 2007; Godeau, 2008)
Hodgkin's lymphoma (unlabeled use): 375 mg/m2 once weekly for 4 weeks (Ekstrand, 2003; Schulz, 2008)
Pemphigus vulgaris, refractory (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) (Ahmed, 2006)
Post-transplant lymphoproliferative disorder (unlabeled use): 375 mg/m2 once weekly for 4 doses (Choquet, 2006)
Waldenström's macroglobulinemia (unlabeled use): 375 mg/m2 once weekly for 4 doses (Dimopoulos, 2002)
Dosage: Combination Regimens
Leukemia, chronic lymphocytic:
Cyclophosphamide-Fludarabine-Alemtuzumab-Rituximab (CLL)
Fludarabine-Cyclophosphamide-Rituximab (CLL)
Fludarabine-Rituximab (CLL)
OFAR (CLL)
PCR
Lymphoma, non-Hodgkin's:
Bendamustine-Rituximab
EPOCH (Dose-Adjusted)-Rituximab (NHL)
EPOCH-Rituximab (NHL)
Fludarabine-Cyclophosphamide-Mitoxantrone-Rituximab
Fludarabine-Cyclophosphamide-Rituximab (NHL-Follicular)
Fludarabine-Mitoxantrone-Dexamethasone-Rituximab
Fludarabine-Mitoxantrone-Rituximab
Fludarabine-Rituximab (NHL-Follicular)
Gemcitabine-Oxaliplatin-Rituximab (NHL)
Rituximab-CHOP (NHL)
R-CVP
RICE
Lymphoma, non-Hodgkin's: (Mantle Cell):
Bendamustine-Rituximab
Hyper-CVAD + Rituximab
Primary CNS Lymphoma: Temozolomide-Rituximab (CNS Lymphoma)
Waldenstrom's Macroglobulinemia:
Bortezomib-Dexamethasone-Rituximab (Waldenstrom's Macroglobulinemia)
Bortezomib-Rituximab (Waldenstrom's Macroglobulinemia)
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 (obtain at weekly to monthly intervals and more frequently in patients with cytopenias, or at 2-4 month intervals in rheumatoid arthritis patients, WG and MPA), 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. If you have diabetes, monitor glucose levels closely; this medication may impact glucose control. May cause dizziness, trembling, nausea, vomiting, loss of appetite, diarrhea, or bone or muscle pain. 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, or loss of sensation in extremities; or loss of coordination.
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
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 patient assessed. Monitor patient closely for abdominal pain (bowel obstruction and perforation), hyper-/hypotension, CNS changes, hyper-/hypoglycemia, and rash after each dose and following discontinuation of therapy. 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.
Oncology: Emetic Potential
Very low (<10%)
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): $704.97
References
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Last full review/revision January 2012
Content last modified January 2012
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