Version April 2023
Rituximab administration can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue rituximab infusion for severe reactions and provide medical treatment for grade 3 or 4 infusion-related reactions.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products.
Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation.
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products.
Note: Patient should be under the care of a clinician experienced with using rituximab for the specific indication. Pretreatment screening: Avoid use in patients with severe active infection. Screen for hepatitis B virus before starting therapy; additional pretreatment screening (eg, hepatitis C, HIV, tuberculosis) may be warranted. For patients with latent or active infection, consult infectious disease or other appropriate specialists before initiating therapy (Ref). Pretreatment immunizations: Administer appropriate immunizations prior (eg, ≥4 weeks) to starting therapy when feasible. Antimicrobial prophylaxis: Refer to institutional protocols and manufacturer's labeling; prophylaxis against opportunistic infection and/or viral reactivation may be warranted during and up to 12 months after completion of rituximab therapy. Premedication: Manufacturer's labeling recommends premedicating ~30 minutes prior to administration with acetaminophen, an antihistamine, and methylprednisolone 100 mg IV (or equivalent) for adults. For uses requiring concomitant administration with a glucocorticoid (eg, some oncology uses), administer glucocorticoid component of the chemotherapy regimen prior to rituximab infusion. Premedication practice may vary; refer to institutional protocols. For oncology uses, antihyperuricemic therapy and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes ≥25,000/mm3).
Dosage forms note: In the United States, Riabni (rituximab-arrx), Ruxience (rituximab-pvvr), and Truxima (rituximab-abbs) are approved biosimilars to Rituxan (rituximab). In Canada, Riximyo, Ruxience, and Truxima are approved biosimilars to Rituxan (rituximab); refer to Canadian product monographs for biosimilar-specific labeled indications.
Acute lymphoblastic leukemia, B-cell precursor, CD20-positive (off-label use):
GRAALL 2005-R: Adults <60 years of age: IV: 375 mg/m2 on days 1 and 7 of induction (and days 1 and 7 of salvage cycle, if needed), on days 1 and 29 of consolidation 1 and 2, on days 1 and 7 of late intensification, on days 1 and 29 of consolidation 3, and on day 1 of reinductions 1, 3, 5, 7, 9, and 11 of the maintenance phase for a total of 16 to 18 rituximab doses. Note: Administer rituximab after hydration and before chemotherapy; administer rituximab after steroids, if both are administered on the same day. If the initial WBC is >30,000/mm3 on day 1 after the steroid prophase, split rituximab administration into 100 mg/m2 on days 1 and 2, followed by 175 mg/m2 on day 3 (total dose: 375 mg/m2). Refer to protocol for further information regarding concomitant chemotherapy agents, dosing, and administration (Ref).
Rituximab in combination with hyper-CVAD: Adults <60 years of age: IV: 375 mg/m2 on days 1 and 11 of hyper-CVAD cycles (cyclophosphamide, mesna, dexamethasone, doxorubicin, and vincristine) and on days 1 and 8 of high-dose methotrexate and cytarabine cycles, for a total of 8 rituximab doses over the first 4 courses; rituximab was also administered with early and late hyper-CVAD intensifications during months 6 and 18 of maintenance therapy (on days 1 and 11). Refer to protocol for further information regarding concomitant chemotherapy agents, dosing, and administration (Ref).
Antibody-mediated rejection, treatment (adjunctive agent) (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols. Administer as part of an appropriate combination regimen. If plasmapheresis is utilized, administer after completion of plasmapheresis (Ref).
Heart transplantation (off-label use): IV: 375 mg/m2 once weekly for 1 to 4 doses (Ref).
Kidney transplantation (off-label use): Note: For use in patients with evidence of microvascular inflammation on biopsy (Ref).
IV: 375 mg/m2 once weekly for 1 to 4 doses (Ref). Some experts administer a single dose of 200 to 375 mg/m2 (Ref).
Lung transplantation (off-label use): IV: 375 mg/m2 once; may administer a second dose of 375 mg/m2 after ~2 weeks if donor-specific antibodies are still present (Ref).
Pancreas transplantation (off-label use): IV: 375 mg/m2 administered in 2-week intervals for a total of 1 to 4 doses (Ref).
Burkitt lymphoma (off-label use): IV: 375 mg/m2 on days 1 and 11 of cycles 1 and 3 and days 2 and 8 of cycles 2 and 4 (Ref) or 375 mg/m2 at the start of each chemotherapy cycle, followed by 2 additional doses 3 and 6 weeks after the completion of chemotherapy (Ref) or 50 mg/m2 on day 8 and 375 mg/m2 on days 10 and 12 of cycle 2 followed by 375 mg/m2 on day 8 of cycles 3 to 7 (Ref).
Chronic lymphocytic leukemia
Rituxan and rituximab biosimilars: IV: 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 to 6 (in combination with fludarabine and cyclophosphamide).
Off-label chronic lymphocytic leukemia (CLL) combinations:
Previously untreated chronic lymphocytic leukemia: IV: 375 mg/m2 on the day prior to bendamustine in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine) (Ref) or 375 mg/m2 on days 1 and 4 of cycle 1 (or 50 mg/m2 on day 1, followed by 325 mg/m2 on day 3, followed by 375 mg/m2 on day 5 of cycle 1), then 375 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with fludarabine; refer to protocol for rituximab dosing and infusion parameters) (Ref) or 50 mg/m2 on day 1 of cycle 2, followed by 325 mg/m2 on day 2 of cycle 2, followed by 500 mg/m2 on day 1 of cycles 3 to 7 (in combination with ibrutinib in patients <70 years of age with IGHV-unmutated CLL without 17p deletion) (Ref).
Relapsed or refractory chronic lymphocytic leukemia: IV: 375 mg/m2 on day 1, followed by 500 mg/m2 every 14 days for 4 doses and then 500 mg/m2 every 28 days for 3 doses (in combination with idelalisib) (Ref) or 375 mg/m2 on the day prior to bendamustine in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine) (Ref) or 375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine and ibrutinib) (Ref) or 375 mg/m2 on day 1 of cycle 1 (following completion of dose ramp-up for venetoclax), then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6 (in combination with venetoclax) (Ref).
Dermatomyositis and polymyositis, refractory disease (alternative agent) (off-label use):
Note: For use in patients who do not respond sufficiently to conventional induction regimens (eg, systemic glucocorticoids plus azathioprine or methotrexate). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses (Ref).
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (off-label use):
Note: For use in patients with severe disease (in combination with glucocorticoids) to initiate disease remission or to re-induce remission following relapse. May also be considered as alternative maintenance therapy in patients with severe disease (if remission was induced with rituximab) or in those who are unable to receive first-line therapies (Ref).
IV: 375 mg/m2 once weekly for 4 doses or 1 g once every 2 weeks for 2 doses (Ref).
Granulomatosis with polyangiitis or microscopic polyangiitis (Rituxan and rituximab biosimilars):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on disease severity, organ system(s) involved, and institutional protocols.
Induction therapy: Note: For use in patients with active, severe disease; may also be used to re-induce remission in patients with severe disease relapse or in patients with refractory disease. In patients with nonsevere disease, rituximab may be used as alternative induction therapy (Ref).
IV: 375 mg/m2 once weekly for 4 doses (manufacturer’s labeling) or 1 g once every 2 weeks for 2 doses (Ref); for either dosing regimen, administer in combination with a systemic glucocorticoid.
Maintenance therapy (after achieving disease control with induction): Note: For use in patients with severe disease, or as alternative to first-line agents in patients with nonsevere disease if remission was induced with rituximab or cyclophosphamide (Ref). If induction for active disease was with rituximab, begin rituximab maintenance therapy within 4 to 6 months of the last rituximab induction dose. If induction therapy was cyclophosphamide-based, begin rituximab maintenance therapy within 1 month following WBC recovery. Duration varies according to risk of relapse and may range from 6 months to indefinite use (Ref).
IV: 500 mg once every 2 weeks for 2 doses, then 500 mg or 1 g once every 4 to 6 months (Ref). Alternatively, some experts prefer to omit 500 mg once every 2 weeks for 2 doses and proceed with 500 mg or 1 g once every 4 to 6 months; other experts only re-dose intermittently with 500 mg or 1 g when peripheral CD19+ lymphocyte count reconstitutes and ANCA titers become positive (Ref).
Hodgkin lymphoma, nodular lymphocyte-predominate, advanced (off-label use): IV: 375 mg/m2 once weekly for 4 weeks (Ref) or 375 mg/m2 once weekly for 4 weeks followed by maintenance dosing of 375 mg/m2 once weekly for 4 weeks every 6 months for 2 years (Ref). May be administered as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or for relapsed disease, in combination with ifosfamide, carboplatin and etoposide (RICE) (Ref).
IgG4-related disease (adjunctive agent) (off-label use):
Note: IgG4-related disease commonly presents as type 1 (IgG4-related) autoimmune pancreatitis; IgG4-related sclerosing cholangitis; major salivary gland enlargement or sclerosing sialadenitis; orbital disease, often with proptosis; and retroperitoneal fibrosis, frequently with chronic periaortitis. Consider for use in patients who have incomplete response to induction or are unable to sufficiently reduce glucocorticoid therapy (Ref).
IV: 1 g once every 15 days for 2 doses (Ref).
Immune thrombocytopenia (alternative agent) (off-label use):
Note: May be used as a single agent for patients who do not have an adequate platelet count response to glucocorticoids. Use in combination with other therapies has also been reported. Optimal dose, frequency, and duration have not been established and vary based on institutional protocols.
IV: 375 mg/m2 once weekly for 4 doses (Ref).
Lupus nephritis, diffuse or focal, resistant (off-label use):
Note: Consider for use in patients who are resistant to initial therapy (eg, glucocorticoids in combination with mycophenolate or cyclophosphamide). May use rituximab in combination with mycophenolate, a calcineurin inhibitor, or cyclophosphamide. Optimal dose, frequency, and duration of therapy are unknown and vary based on institutional protocols (Ref).
IV: 1 g on days 0 and 15 (Ref) or 375 mg/m2 once weekly for 4 doses (Ref).
Membranous nephropathy, primary (off-label use):
Note: May be used in patients with normal kidney function who are at high or very high risk for progression and select moderate-risk patients (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses (Ref); alternative dosing regimens include 375 mg/m2 once weekly for 4 doses (Ref) or 375 mg/m2 once followed by a second dose of 375 mg/m2 if ≥5 circulating B cells per mcL are detected by flow cytometry 1 week after the initial dose (Ref).
Minimal change disease, frequently relapsing disease (alternative agent) (off-label use):
Note: For use in patients with frequently relapsing disease despite glucocorticoid therapy or who are glucocorticoid dependent. Initiate after remission is induced by glucocorticoids (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses; alternative regimens include 375 mg/m2 once weekly for 4 doses or 375 mg/m2 once followed by a second dose of 375 mg/m2 if ≥5 circulating B cells per mcL are detected by flow cytometry 1 week after the initial dose (Ref).
Mixed cryoglobulinemia syndrome, moderate to severe disease (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses (Ref) or 375 mg/m2 once weekly for 4 doses (Ref); usually administer in combination with a systemic glucocorticoid and, if due to HIV or hepatitis B virus infections, with antiviral therapy (Ref).
Mucosa-associated lymphoid tissue lymphoma (gastric), advanced (off-label use): IV: 375 mg/m2 once weekly for 4 doses (Ref).
Multiple sclerosis (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses; then repeat 1 g once every 6 to 12 months (Ref). Alternatively, may administer 500 mg to 1 g once every 6 to 12 months (Ref).
Myasthenia gravis, refractory or muscle-specific tyrosine kinase antibody-positive (off-label use):
Note: Recommended as an early option in patients with muscle-specific tyrosine kinase antibody-positive disease, or in refractory myasthenia gravis when response to other agents is insufficient or limited by toxicity (Ref). Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses or 375 mg/m2 once weekly for 4 weeks; may repeat full or partial course at preplanned intervals (eg, 6 months) or as clinically indicated based on symptoms and lymphocyte recovery (Ref).
Neuromyelitis optica, relapse prevention (alternative therapy) (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established. Dosing regimens vary based on institutional protocols.
IV: 1 g once every 2 weeks for 2 doses or 375 mg/m2 once weekly for 4 weeks; then repeat 1 g once every 6 months or earlier if CD19+ lymphocytes become detectable (Ref).
Non-Hodgkin lymphomas
Diffuse large B-cell, previously untreated (Rituxan and rituximab biosimilars): IV: 375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses (in combination with CHOP chemotherapy [or other anthracycline-based regimen]). For patients ≤60 years of age with limited stage aggressive B-cell lymphoma and a favorable prognosis, a randomized trial demonstrated noninferiority with 4 cycles of rituximab-CHOP chemotherapy when compared to 6 cycles (Ref).
Diffuse large B-cell, relapsed or refractory (off-label combination): IV: 375 mg/m2 on day 1 of each 21-day chemotherapy cycle for up to 6 cycles (in combination with bendamustine and polatuzumab) (Ref).
Follicular, CD20-positive, B-cell, previously untreated (Rituxan and rituximab biosimilars): IV: 375 mg/m2 on day 1 of each chemotherapy cycle for up to 8 doses (in combination with first-line chemotherapy).
Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy): Note: Begin 8 weeks after completion of rituximab in combination with chemotherapy. IV: 375 mg/m2 once every 8 weeks for 12 doses (Ref).
Nonprogressing, low-grade, CD20-positive, B-cell, after 6 to 8 cycles of first-line CVP are completed (Rituxan and rituximab biosimilars): IV: 375 mg/m2 once weekly for 4 doses every 6 months for a maximum of 16 doses (as a single agent).
Relapsed/Refractory, low-grade or follicular CD20-positive, B-cell (Rituxan and rituximab biosimilars): IV: 375 mg/m2 once weekly for 4 or 8 doses (as a single agent). Re-treatment following disease progression: 375 mg/m2 once weekly for 4 doses.
Follicular lymphoma, relapsed (single-agent therapy; off-label dosing): IV: 375 mg/m2 once weekly for 4 doses followed by 375 mg/m2 once every 2 months for 4 additional doses (Ref).
Follicular lymphoma, relapsed/refractory, maintenance therapy (as a single agent, in patients with response to induction therapy; off-label dosing): IV: 375 mg/m2 every 3 months until relapse or for maximum duration of 2 years (Ref).
Follicular lymphoma, relapsed/refractory (off-label combination): IV: 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1 (28-day cycle), followed by 375 mg/m2 on day 1 every 28 days of cycles 2 to 5 (in combination with lenalidomide) (Ref).
Rituxan and rituximab biosimilars: Combination therapy with ibritumomab: IV: 250 mg/m2 IV day 1; repeat in 7 to 9 days with ibritumomab (also see Ibritumomab monograph).
Splenic marginal zone lymphoma (off-label use): IV: 375 mg/m2 once weekly for 6 weeks followed by 375 mg/m2 once every 2 months for 1 to 2 years (Ref) or 375 mg/m2 once weekly for 4 weeks as monotherapy or 375 mg/m2 on day 1 of each chemotherapy cycle for up to 6 cycles; 1 to 2 additional cycles of rituximab monotherapy may be administered for consolidation or to improve response (Ref).
Pemphigus vulgaris (labeled use [Rituxan only] for moderate to severe; off-label use for mild) or pemphigus foliaceus (off-label use for mild, moderate, or severe):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
Initial dose: IV: 1 g once every 2 weeks for 2 doses in combination with a systemic glucocorticoid, followed by a maintenance dose (Ref). For patients with complete remission who initially presented with severe disease or who have persistently elevated anti-desmoglein (Dsg) antibodies after 3 months, consider another dose of 500 mg to 1 g administered 6 months after initial therapy (Ref).
Maintenance dose (if complete remission is achieved with initial therapy): IV: 500 mg once 12 months after initial therapy, then every 6 months thereafter or based on clinical evaluation, but no sooner than every 16 weeks (Ref).
Treatment of relapse: Note: Consider in patients whose last rituximab dose was ≥4 to 6 months ago or in patients who did not previously receive rituximab as initial therapy; administer in combination with a systemic glucocorticoid (Ref).
IV: 1 g once every 2 weeks for 2 doses (Ref) or 1 g administered one time only (manufacturer's labeling).
Posttransplant lymphoproliferative disorder (off-label use):
Note: Used in monomorphic and polymorphic CD20+ disease in conjunction with reduction of immunosuppression. May be used as a single agent or in combination with chemotherapy and/or radiation (Ref). Optimal dose, frequency, and duration of therapy have not been established and vary based on type of lymphoproliferative disease and institutional protocols.
IV: 375 mg/m2 once weekly for 4 doses alone (Ref) or 375 mg/m2 once weekly for 4 doses followed 4 weeks later with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (Ref).
Primary CNS lymphoma (off-label use):
Newly diagnosed: IV: 375 mg/m2 on day 3 every 14 days (in combination with high-dose methotrexate) until disease progression or unacceptable toxicity, or for 2 doses beyond a complete response followed by monthly treatments for up to a total of 1 year (Ref) or 500 mg/m2 on day 1 of each cycle for 5 to 7 induction cycles (in combination with high-dose methotrexate, vincristine, and procarbazine, followed by whole-brain radiotherapy and cytarabine consolidation) (Ref) or 375 mg/m2 once per week beginning on day 3 of remission induction and continuing for 6 doses (in combination with high-dose methotrexate, leucovorin, and temozolomide and followed by etoposide and cytarabine consolidation therapy) (Ref).
Refractory disease: IV: 375 mg/m2 on day 1 every 28 days (in combination with temozolomide) for 4 cycles, followed by temozolomide monotherapy (Ref).
Rheumatoid arthritis (Rituxan and rituximab biosimilars) (alternative agent):
Note: For use in patients who have not met treatment goals despite maximally tolerated methotrexate therapy, and either an inadequate response to TNF inhibitor therapy or a history of lymphoproliferative disorder for which rituximab is an approved therapy. May be administered in combination with methotrexate, another conventional synthetic disease-modifying antirheumatic drug, or as monotherapy if other treatment options are not tolerated (Ref). Patients should be under the care of a clinician experienced with use of rituximab for this condition.
IV: Initial: 1 g once every 2 weeks for 2 doses; subsequent courses of 1 g once every 2 weeks for 2 doses may be administered every 24 weeks or as indicated based on clinical evaluation, but no sooner than every 16 weeks. Note: In patients who initially respond, may consider a lower dose of 1 g once per subsequent course or 500 mg given twice (2 weeks apart) per course (Ref).
Thrombotic thrombocytopenic purpura, acquired (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
Acute treatment for initial therapy or for refractory or relapsing disease: IV: 375 mg/m2 once weekly for 4 doses, typically in combination with a systemic glucocorticoid and plasma exchange; administer immediately following plasma exchange and allow ≥24 hours after rituximab before the next plasma exchange (Ref).
Prophylactic therapy during remission (following treatment and recovery from an acute episode) with persistently low ADAMTS13 activity (eg, <20%) but normal platelet count: Note: The decision to treat prophylactically should be based on shared decision making to consider patient preferences regarding remission versus potential rituximab toxicity.
IV: 375 mg/m2 once weekly for 1 to 4 doses depending on follow-up measurements of ADAMTS13 activity (Ref). Some experts may administer a single dose of 375 mg/m2 approximately once every 3 months to maintain remission in patients with multiple relapses and severe ADAMTS13 deficiency (Ref).
Waldenström macroglobulinemia (off-label use):
In combination with cyclophosphamide and dexamethasone: IV: 375 mg/m2 on day 1 every 21 days for 6 cycles (Ref).
In combination with cyclophosphamide and fludarabine: IV: 375 mg/m2 on day 1 every 28 days for up to 6 cycles (Ref).
In combination with bortezomib: IV: 375 mg/m2 on days 1, 8, 15, and 22 every 28 days during cycles 1 and 4; treatment is continued for 6 cycles, with a total of 8 rituximab doses (Ref).
In combination with bortezomib and dexamethasone: IV: 375 mg/m2 on days 1, 8, 15, and 22 every 35 days during cycles 2 and 5; treatment is administered for 6 cycles, with a total of 8 rituximab doses (Ref) or 375 mg/m2 on day 11 every 21 days for 4 cycles (induction); after a 12-week break, 4 additional maintenance cycles (spaced 12 weeks apart) were administered (Ref).
In combination with bendamustine: IV: 375 mg/m2 on day 1 every 28 days for 4 cycles; single rituximab doses were also administered 1 week prior to the first cycle and 4 weeks after the last cycle (for a total of 6 rituximab doses) (Ref) or 375 mg/m2 on day 1 every 28 days for up to 6 cycles (Ref).
In combination with carfilzomib and dexamethasone: IV: 375 mg/m2 on days 2 and 9 every 21 days for 6 induction cycles, followed by 375 mg/m2 on day 2 every 8 weeks for 8 maintenance cycles (Ref).
In combination with ibrutinib: IV: 375 mg/m2 once weekly during weeks 1 to 4 and weeks 17 to 20 (Ref).
Warm autoimmune hemolytic anemia (off-label use):
Note: Optimal dose, frequency, and duration of therapy have not been established and vary based on institutional protocols.
IV: 375 mg/m2 once weekly for 4 doses in combination with a systemic glucocorticoid (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Kidney impairment prior to treatment initiation:
Note: Theoretically, rituximab’s large molecular weight (145,000 Daltons) precludes the drug from being efficiently filtered at the glomerulus or by dialysis filters; hence, in general, dose adjustments for kidney dysfunction and/or renal replacement therapies should be unnecessary (Ref). In patients with nephrotic syndrome, urinary rituximab losses and altered pharmacokinetics have been observed, but the dosing implications of these findings are uncertain (Ref).
Altered kidney function: IV: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2): Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post trauma or major surgery are at highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients (Ref).
IV: No dosage adjustment necessary (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (Ref):
IV: No dosage adjustment or supplemental dose necessary (Ref).
Peritoneal dialysis: In general, unlikely to be significantly dialyzed (expert opinion); however, significant amounts reported to be dialyzed in a patient with nephrotic syndrome (Ref):
IV: No dosage adjustment necessary (Ref).
CRRT:
IV: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration):
IV: No dosage adjustment necessary (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Rituximab (intravenous) including biosimilars: Pediatric drug information")
Prior to rituximab therapy, patients should be brought up to date with all nonlive vaccination if possible; any nonlive vaccines should be administered ≥4 weeks prior to first rituximab dose. Pretreatment with acetaminophen and an antihistamine (diphenhydramine typically used in pediatric trials) is recommended for all indications.
For oncology uses: A uricostatic agent (eg, allopurinol) and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3) and dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol. Screen all patients for hepatitis B virus (HBV) infection (measure hepatitis B surface antigen [HBsAg] and hepatitis B core antibody [anti-HBc]) (see "Monitoring Parameters"); consider antiviral prophylaxis to prevent hepatitis B reactivation for all patients receiving rituximab (oncology and nononcology indications) with resolved HBV infection (Ref).
Acute lymphoblastic leukemia, mature B-cell, CD 20+ (B-ALL); relapsed/refractory: Limited data available: Children ≥5 years and Adolescents: IV infusion: 375 mg/m2 administered on days 1 and 3 of courses 1 and 2 and on day 1 only of course 3; used in combination with ifosfamide, carboplatin, and etoposide (ICE) (Ref).
Autoimmune hemolytic anemia: Limited data available: Infants ≥4 months, Children, and Adolescents: IV infusion: 375 mg/m2 once weekly for 4 doses (Ref).
Graft-versus-host disease, chronic (cGVHD); steroid-refractory: Limited data available: Children and Adolescents: IV: 375 mg/m2 once weekly for 4 doses followed by monthly infusions has been reported; in preliminary data, GVHD musculoskeletal and dermal manifestations were observed to respond better than ophthalmic, hepatic, or gastrointestinal manifestations (Ref).
Granulomatosis with polyangiitis (GPA, Wegener granulomatosis): Note: In addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent). Patients should receive Pneumocystis jirovecii pneumonia (PCP) prophylaxis during rituximab therapy and for at least 6 months following the last rituximab dose.
Children ≥2 years and Adolescents:
Induction (active GPA): IV: 375 mg/m2 once weekly for 4 doses.
Note: Use rituximab in combination with corticosteroids (ie, methylprednisolone or oral corticosteroid taper). Prior to the first dose of rituximab, methylprednisolone should be administered for 3 days (30 mg/kg/dose once daily; maximum dose: 1,000 mg/dose) followed by oral corticosteroid taper per usual clinical practice and patient response.
Maintenance (once disease control achieved): IV: 250 mg/m2 every 2 weeks for 2 doses, followed by 250 mg/m2 every 6 months based upon clinical response. Begin maintenance regimen within 16 to 24 weeks of last rituximab induction dose. If rituximab was not part of induction regimen, begin rituximab within 4 weeks of achieving disease control.
Immune thrombocytopenic purpura, chronic: Limited data available: Children and Adolescents: IV infusion: 375 mg/m2 once weekly for 4 doses (Ref).
Leukemia, acute B-cell; CD20+; advanced stage, previously untreated: Infants ≥6 months, Children, and Adolescents: IV infusion: 375 mg/m2/dose in combination with systemic Lymphome Malin B (LMB) chemotherapy regimen; administer 2 doses during each induction course (day −2 and day 1), and 1 dose on day 1 of each of the 2 consolidation cycles (6 doses total).
Microscopic polyangiitis (MPA): Note: In addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent). Patients should receive PCP prophylaxis during rituximab therapy and for at least 6 months following the last rituximab dose.
Children ≥2 years and Adolescents:
Induction (active MPA): IV: 375 mg/m2 once weekly for 4 doses.
Note: Use rituximab in combination with corticosteroids (ie, methylprednisolone or oral corticosteroid taper). Prior to the first dose of rituximab, methylprednisolone should be administered for 3 days (30 mg/kg/dose once daily; maximum dose: 1,000 mg/dose) followed by oral corticosteroid taper per usual clinical practice and patient response.
Maintenance (once disease control achieved): IV: 250 mg/m2 every 2 weeks for 2 doses, followed by 250 mg/m2 every 6 months based upon clinical response. Begin maintenance regimen within 16 to 24 weeks of last rituximab induction dose. If rituximab was not part of induction regimen, begin rituximab within 4 weeks of achieving disease control.
Nephrotic syndrome, steroid-dependent: Limited data available; use should be reserved for patients with frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing therapy or intolerance to therapy (Ref). Children and Adolescents: IV infusion: 375 mg/m2 once weekly for 1 to 4 doses; a maximum dose of 500 mg/dose has been reported in some, but not all, reports; dosing based on small trials, case series, and retrospective analyses (Ref).
Non-Hodgkin lymphoma B-cell, CD 20+; relapsed and refractory: Limited data available: Children ≥11 years and Adolescents: IV infusion: 375 mg/m2 administered on days 1 and 3 of courses 1 and 2 and on day 1 only of course 3; used in combination with ICE (Ref).
Non -Hodgkin lymphoma; CD20+, diffuse large B-cell (DLBCL), Burkitt lymphoma, Burkitt-like lymphoma; previously untreated, advanced stage: Infants ≥6 months, Children, and Adolescents: IV infusion: 375 mg/m2/dose in combination with systemic Lymphome Malin B (LMB) chemotherapy regimen; administer 2 doses during each induction course (day −2 and day 1), and 1 dose on day 1 of each of the 2 consolidation cycles (6 doses total).
Posttransplant lymphoproliferative disorder: Limited data available: Infants ≥11 months, Children, and Adolescents: IV infusion: 375 mg/m2 once weekly for 3 to 4 doses (Ref).
Primary mediastinal large B-cell lymphoma: Limited data available: Children and Adolescents: IV: 375 mg/m2 every 21 to 28 days for 6 to 8 doses; use in combination with multi-agent chemotherapy (Ref).
Systemic lupus erythematosus; refractory: Limited data available; various dosing regimens reported in small open-labeled trials and case series; experts suggest rituximab as an option in nonresponders if more than one initial therapy has failed (Ref): Children ≥6 years and Adolescents: IV infusion: Usual regimen: Initial dose: 187.5 mg/m2 once (day 1) followed by 375 mg/m2 once weekly for 1 to 3 doses (days 8, 15, 22) (Ref); other reports omit the lower initial dose and administer 375 mg/m2 once weekly beginning on day 1 for 2 to 4 doses (days 8, 15, 22) (Ref). Others have reported a higher dose regimen of 750 mg/m2 on days 1 and 15 (maximum dose: 1,000 mg/dose) (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (ASCO [Griggs 2021]).
Note: Adjustments for concomitant chemotherapy may also be necessary.
Cardiac arrhythmia (severe or life-threatening): Discontinue rituximab infusion.
Hepatitis B virus reactivation: Discontinue rituximab (and concomitant medications) and initiate antiviral therapy.
Hepatitis (viral): Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral hepatitis; initiate antiviral therapy.
Infection (serious): Discontinue rituximab and initiate appropriate anti-infective treatment.
Infusion reaction: Interrupt infusion or slow infusion rate. Temporarily or permanently discontinue infusion (depending on the severity of the reaction and required interventions).
Mild infusion reaction: After symptoms resolve, infusion may be resumed with at least a 50% infusion rate reduction.
Severe infusion reaction: Discontinue rituximab; provide medical treatment for grade 3 or 4 infusion-related reactions.
Progressive multifocal leukoencephalopathy: Discontinue rituximab; also consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.
Severe mucocutaneous reaction: Discontinue rituximab.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Riabni: rituximab-arrx 100 mg/10 mL (10 mL); rituximab-arrx 500 mg/50 mL (50 mL) [contains polysorbate 80]
Rituxan: 100 mg/10 mL (10 mL [DSC]); 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Ruxience: rituximab-pvvr 100 mg/10 mL (10 mL); rituximab-pvvr 500 mg/50 mL (50 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
Truxima: rituximab-abbs 100 mg/10 mL (10 mL); rituximab-abbs 500 mg/50 mL (50 mL) [contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Concentrate, Intravenous:
Riabni: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Rituxan: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Riximyo: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]
Ruxience: 10 mg/mL (10 mL, 50 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
Solution, Intravenous:
Truxima: 100 mg/10 mL (10 mL); 500 mg/50 mL (50 mL) [contains polysorbate 80]
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Riabni: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761140s001lbl.pdf#page=41
Rituxan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103705s5465lbl.pdf#page=56
Ruxience: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761103s005lbl.pdf#page=42
Truxima: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761088s018lbl.pdf#page=49
Note: Refer to specific protocol for administration rate guidelines.
IV: For IV administration only. Do not administer IV push or bolus. Do not administer IV rituximab subcutaneously. If an infusion-related reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate. Discontinue infusion in the event of serious or life-threatening cardiac arrhythmias.
Initial infusion: Start infusion at a rate of 50 mg/hour; if there is no infusion-related reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.
Subsequent infusions:
Standard infusion rate: If patient tolerated initial infusion, start at 100 mg/hour; if there is no infusion-related reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.
Accelerated infusion rate (90 minutes): For adult patients with previously untreated follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid as part of their combination chemotherapy regimen, have a circulating lymphocyte count <5,000/mm3, or have no significant cardiovascular disease. After tolerance has been established (no grade 3 or 4 infusion-related event) at the recommended infusion rate in cycle 1, a rapid infusion rate may be 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 over the first 30 minutes and the remaining 80% is given over 60 minutes (Ref). If the 90-minute infusion in cycle 2 is tolerated, the same rate may be used for the remainder of the treatment regimen (through cycles 6 or 8).
IV infusion: Must be diluted prior to administration; do not administer undiluted or as an IV push or rapid injection. Premedicate with acetaminophen, an antihistamine, with/without corticosteroid as indicated. For oncology uses in pediatric patients, in addition to prednisone which is part of the chemotherapeutic regimen, premedicate 30 to 60 minutes prior to the rituximab infusion with acetaminophen and an H1 antihistamine (eg, diphenhydramine). For granulomatosis with polyangiitis, microscopic polyangiitis, and Wegener granulomatosis, in addition to an antihistamine and acetaminophen, patients should also be premedicated 30 minutes prior to each infusion with methylprednisolone (eg, 100 mg IV in adults or equivalent).
In pediatric trials, described infusion rates vary and are indication specific. One retrospective report (Ref) evaluated rituximab infusion in 67 pediatric patients for multiple uses (mostly autoimmune disease [58%] and oncology uses [36%]) and used a 2 mg/mL concentration. In the trial, patients were premedicated with intravenous diphenhydramine (1 mg/kg up to 50 mg/dose) and oral acetaminophen (10 mg/kg up to 650 mg/dose); corticosteroid premedication was at prescriber discretion. Overall, infusions were well tolerated; 5 (2.7% incidence) infusion related reactions were reported and were grade 1 or 2 severity). Infusions were administered with the following:
First dose: Initial rate: 0.5 mg/kg/hour (maximum rate: 50 mg/hour) for 1 hour; if tolerated, then rate increase in 0.5 mg/kg/hour increments every 30 minutes up to a maximum 400 mg/hour (Ref). If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate.
Subsequent doses (if first dose well tolerated): Initial rate: 1 mg/kg/hour (maximum rate: 50 mg/hour [per the manufacturer]; 100 mg/hour has been reported (Ref)) for 1 hour; if tolerated, then increase rate in 1 mg/kg/hour increments every 30 minutes up to a maximum 400 mg/hour (Ref). If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate.
Refer to specific protocols for administration rate guidelines.
Indication-specific information: Limited data available: Infusion data reported from experience in pediatric trials. If hypersensitivity or infusion-related reactions occur, slow or interrupt the infusion. If symptoms completely resolve, resume infusion at 50% of the previous rate (manufacturer's labeling).
Acute leukemia: 0.5 mg/kg/hour for the first hour; if tolerated, rate was increased every 30 minutes to maximum rate of 400 mg/hour in trials (Ref); in some oncology trials, doses were infused over 6 to 8 hours (Ref).
Autoimmune hemolytic anemia: Doses were infused over 5 hours (Ref).
Granulomatosis with polyangiitis and microscopic polyangiitis: Note: Although an FDA-approved indication, administration to pediatric patients is not described in the manufacturer's labeling.
Initial infusions: In the clinical trial (n=25, age range: 6 to 17 years), infusions were initiated at a rate of 25 mg/hour. If no hypersensitivity or infusion-related reactions occurred, infusion rates were increased in 25 mg/hour increments every 30 minutes to a maximum infusion rate of 200 mg/hour as tolerated (Ref). Note: In the clinical trial utilizing these rates of administration, the youngest patient enrolled was 6 years of age.
Nephrotic syndrome: Doses were infused over 3 to 4 hours (Ref).
Non-Hodgkin lymphoma: 0.5 mg/kg/hour for the first hour; if tolerated, rate was increased every 30 minutes to maximum rate of 400 mg/hour in trials (Ref).
Posttransplant lymphoproliferative disorder: Doses were infused over 2 to 8 hours (Ref).
Systemic lupus erythematosus: Doses of 187.5 mg/m2 were infused over 4 hours (Ref); doses of 375 mg/m2 were infused over 6 to 8 hours (Ref); the infusion time of the higher 750 mg/m2 doses was not reported.
Rapid rate infusions: Children and Adolescents: Multiple regimens have been reported and most experience reported with nononcologic uses of rituximab (Ref). Note: Rapid infusion rates should not be used for initial infusions, in unstable patients, patients at risk for tumor lysis syndrome or with an absolute lymphocyte count >5,000/mm3 (Ref).
90-minute infusion: IV: Infuse 20% of the dose over the first 30 minutes; if tolerated, increase rate to deliver the remaining 80% of the dose over 60 minutes (Ref). Infusion protocol reported in 17 pediatric and young adult patients (age range: 2 to 23 years of age) for 37 infusions (majority of doses were 375 mg/m2); patients were premedicated with diphenhydramine and acetaminophen (doses not reported); concentration of infusion not reported. The results showed one grade 1 infusion related reaction (hypotension) in a single patient who also took amlodipine on the morning prior to infusion (which was not recommended) (Ref).
60-minute infusion: Reported only in nononcologic uses and for doses of 375 mg/m2: IV: Infuse dose over 60 minutes (Ref). Infusion protocol reported in 20 pediatric patients (mean age: 10.2 years; range: 4 months to 14 years) for 64 pediatric infusions with mostly autoimmune cytopenias, Epstein-Barr viremia, and graft-vs-host disease; patients were premedicated with diphenhydramine and acetaminophen (doses not reported); corticosteroids were administered according to clinician discretion and protocols (4 of the 20 patients did not receive corticosteroids nor have infusion-related reactions); 2 adverse events were observed; 1 resolved and the other lead to therapy discontinuation; concentration of infusion not reported (Ref).
Chronic lymphocytic leukemia (Rituxan and rituximab biosimilars): Treatment of previously untreated or previously treated CD20-positive chronic lymphocytic leukemia (CLL) in adults (in combination with fludarabine and cyclophosphamide).
Note: Other medications (eg, idelalisib, venetoclax, ibrutinib) have approval for use in combination with rituximab for the treatment of relapsed or refractory CLL.
Granulomatosis with polyangiitis (Rituxan and rituximab biosimilars): Treatment of granulomatosis with polyangiitis (in combination with glucocorticoids) in adults (Rituxan and rituximab biosimilars) and pediatric patients ≥2 years of age (Rituxan only).
Microscopic polyangiitis (Rituxan and rituximab biosimilars): Treatment of microscopic polyangiitis (in combination with glucocorticoids) in adults (Rituxan and rituximab biosimilars) and pediatric patients ≥2 years of age (Rituxan only).
Non-Hodgkin lymphomas:
Rituxan and rituximab biosimilars: Treatment of CD20-positive non-Hodgkin lymphomas (NHL) in adults with:
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 in patients achieving a complete or partial response to rituximab with chemotherapy).
Nonprogressing (including stable disease), low-grade B-cell NHL (as a single agent after first-line cyclophosphamide, vincristine, and prednisone [CVP] treatment).
Diffuse large B-cell NHL, previously untreated (in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] chemotherapy or other anthracycline-based regimen).
Rituxan only: Treatment of CD20-positive NHLs in pediatric patients ≥6 months of age with:
Previously untreated, advanced stage diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia (in combination with chemotherapy).
Pemphigus vulgaris (Rituxan only): Treatment of moderate to severe pemphigus vulgaris in adults.
Rheumatoid arthritis (Rituxan and rituximab biosimilars): Treatment of moderately to severely active rheumatoid arthritis (in combination with methotrexate) in adults with inadequate response to one or more tumor necrosis factor-antagonist therapies.
Note: In the United States, Riabni (rituximab-arrx), Ruxience (rituximab-pvvr), and Truxima (rituximab-abbs) have been approved as biosimilars to Rituxan (rituximab). In Canada, Riximyo, Ruxience, and Truxima are approved as biosimilars to Rituxan (rituximab); refer to Canadian product monographs for biosimilar-specific labeled indications.
Acute lymphoblastic leukemia, B-cell precursor, CD20-positive; Antibody-mediated rejection, treatment, heart transplantation; Antibody-mediated rejection, treatment, kidney transplantation; Antibody-mediated rejection, treatment, lung transplantation; Antibody-mediated rejection, treatment, pancreas transplantation; Burkitt lymphoma; Dermatomyositis and polymyositis, refractory disease; Eosinophilic granulomatosis with polyangiitis (Churg-Strauss); Graft-versus-host disease, chronic, steroid-refractory; Hodgkin lymphoma, nodular lymphocyte-predominant, advanced; IgG4-related disease; Immune thrombocytopenia; Lupus nephritis, diffuse or focal, resistant; Membranous nephropathy, primary; Minimal change disease, frequently relapsing disease; Mixed cryoglobulinemia syndrome, moderate to severe disease; Mucosa-associated lymphoid tissue lymphoma (gastric), advanced; Multiple sclerosis; Myasthenia gravis, refractory, or muscle-specific tyrosine kinase antibody-positive; Neuromyelitis optica, relapse prevention; Non-Hodgkin lymphomas: Splenic marginal zone lymphoma; Pemphigus foliaceus, moderate to severe; Posttransplant lymphoproliferative disorder; Primary CNS lymphoma; Thrombotic thrombocytopenic purpura, acquired; Waldenström macroglobulinemia; Warm autoimmune hemolytic anemia
Rituxan may be confused with Remicade, Rituxan Hycela
RiTUXimab may be confused with bevacizumab, brentuximab vedotin, dinutuximab, inFLIXimab, obinutuzumab, ofatumumab, polatuzumab vedotin, ramucirumab, rituximab and hyaluronidase, ruxolitinib, siltuximab, ustekinumab
This medication is in a class the Institute for Safe Medication Practices includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Rituximab is for intravenous (IV) administration only. Do not substitute rituximab and hyaluronidase (SubQ) for rituximab (IV). Use caution during product selection, preparation, and administration.
The rituximab dose for rheumatoid arthritis is a flat dose (1,000 mg) and is not based on body surface area (BSA). Follow-up dosing for granulomatosis with polyangiitis and microscopic polyangiitis are flat doses and not based on BSA.
Exacerbation of hepatitis B virus (HBV) may occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death (Ref). Reactivation has occurred in patients who are hepatitis B surface antigen (HBsAg) positive (typical reactivation) as well as in those who are HBsAg negative but are anti-HBc positive (reverse seroconversion) (Ref).
Mechanism: In the immune system control of HBV infection, B-cells may act as antigen-presenting cells and prime cytotoxic T-cells for lysis of HBV-infected hepatocytes (Ref). Rituximab causes B-cell depletion (Ref), which therefore may impair control of HBV infection.
Onset: Varied; typical reactivation: 3 to 6 months. Reverse seroconversion: 12 to 36 months (Ref).
Risk factors:
• Chronic HBV (HBsAg positive) or past HBV (HBsAg negative and anti-HBc positive with either negative or positive anti-HBs) infection (Ref)
• Hematologic malignancy (Ref)
• History of stem cell transplantation (Ref)
• Presence of other risk factor for HBV infection (eg, high-prevalence region, household contact, high-risk behavior) (Ref)
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab-based therapy (Ref). Infections have been reported in some patients with prolonged hypogammaglobulinemia. New or reactivated viral infections have included CMV viremia, herpes simplex infection, parvovirus B19 seroconversion, varicella zoster infection, West Nile virus, and hepatitis C and B.
Mechanism: Dose-related; immunosuppression due to B-cell depletion, hypogammaglobulinemia, and neutropenia (Ref).
Onset: Delayed; infection may occur at any time; risk may be higher in the 3 to 6 months after initiation (Ref).
Risk factors:
Hypogammaglobulinemia:
• More than 1 dose of rituximab (Ref)
• Maintenance regimens (Ref)
• Older age (Ref)
• Low pre-treatment immunoglobulin levels (Ref)
• Exposure to mycophenolate or purine analogues (Ref)
Infection:
• Malignant versus non-malignant indications (Ref)
• Higher number of rituximab courses (Ref)
• Prolonged low levels of IgG (Ref)
• G-CSF use (Ref)
• Glucocorticoid use (Ref)
• Chronic lung disease and/or cardiac insufficiency (Ref)
• Older patients (Ref)
• Extra-articular involvement in patients with rheumatic arthritis (Ref)
Serious (including fatal) infusion-related reactions have been reported with rituximab. Reactions may include angioedema, bronchospasm, cough, hypotension, hypoxia, throat irritation, urticaria, and in more severe cases, acute respiratory distress syndrome, pulmonary infiltrates, acute myocardial infarction, ventricular fibrillation, and cardiogenic shock (Ref).
Mechanism: Dose-related; may produce human antichimeric antibodies and human antihuman antibodies (Ref).
Onset: Rapid; usually occur within 30 to 120 minutes after starting the infusion.
Risk factors:
• First infusion (~80% of fatal infusion reactions occurred in association with the first infusion)
• Rapid infusion (Ref)
• High tumor burden with treatment-sensitive malignant disease (Ref)
• History of prior cardiopulmonary reactions
• Preexisting cardiac or pulmonary conditions
Progressive multifocal leukoencephalopathy (PML) due to John Cunningham (JC) virus infection has been reported with rituximab and 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 (Ref). Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Ref).
Mechanism: Non–dose-related; reactivation of the JC virus (Ref).
Onset: Delayed; 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 six rituximab doses preceded PML diagnosis (Ref). In a series of rheumatologic cases, a median of 12 months (range 1 to 57 months following rituximab initiation), and 5 months (range 0 to 29 months following last rituximab dose), and two rituximab courses preceded PML diagnosis (Ref).
Risk factors:
• Systemic lupus erythematosus (SLE) (Ref)
• Undiagnosed HIV (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions. Most reported adverse reactions are from studies in which rituximab was given concomitantly with chemotherapeutic agents, glucocorticoid steroids, or methotrexate. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Cardiac disorder (5% to 29%), flushing (5% to 14%), hypertension (6% to 12%) (table 1), peripheral edema (8% to 16%)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
12% |
Cyclophosphamide plus glucocorticoids: 5% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids |
|
6% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
|
8% |
Placebo plus methotrexate: 5% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
Dermatologic: Night sweats (15%), pruritus (≤17%) (table 2), skin rash (≤17%) (table 3)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
17% |
No further therapy: 5% |
375 mg/m² once weekly for 4 doses every 6 months for up to 16 doses |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma, maintenance therapy |
N/A |
N/A |
In patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP); described as "rash and/or pruritus" |
|
10% |
Cyclophosphamide, vincristine, prednisone (CVP): 1% |
N/A |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
N/A |
N/A |
Rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) |
|
14% |
N/A |
Most patients received 375 mg/m2 weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
|
5% |
Placebo plus methotrexate: 1% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
10% |
Cyclophosphamide plus glucocorticoids: 17% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids |
|
17% |
Cyclophosphamide, vincristine, and prednisone (CVP): 5% |
N/A |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
N/A |
N/A |
Rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) |
|
17% |
No further therapy: 5% |
375 mg/m² once weekly for 4 doses every 6 months for up to 16 doses |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
N/A |
N/A |
In patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP); described as "rash and/or pruritus" |
|
15% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell non-Hodgkin lymphoma |
356 |
N/A |
N/A |
Endocrine & metabolic: Hypophosphatemia (12% to 21%), weight gain (11%)
Gastrointestinal: Abdominal pain (14%), diarrhea (10% to 17% grades 3/4: 1%), nausea (8% to 23%; grades 3/4: 1%)
Hematologic & oncologic: Anemia (8% to 35%; grades 3/4: 3%), febrile neutropenia (grades 3/4: 9% to 15%), hypogammaglobulinemia (<1% to 58%; including IgA, IgG, or IgM below the lower limit of normal, can be prolonged) (table 4), leukopenia (10% to 14%; grades 3/4: 4% to 23%), lymphocytopenia (48%; grades 3/4: 40%), neutropenia (8% to 14%; grades 3/4: 4% to 49%; may be prolonged neutropenia [lasting up to 42 days] or late onset [occurring >42 days after last dose]), thrombocytopenia (12%; grades 3/4: 2% to 11%)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
58% |
Cyclophosphamide plus glucocorticoids: 50% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids; Low IgG level |
|
51% |
Cyclophosphamide plus glucocorticoids: 46% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids; Low IgM level |
|
27% |
Cyclophosphamide plus glucocorticoids: 25% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids; Low IgA level |
|
16% |
Mycophenolate mofetil (MMF) plus oral corticosteroids: N/A |
1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeks |
Pemphigus vulgaris |
67 |
N/A |
Rituximab plus oral corticosteroids; prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months); IgG or IgM |
|
10% |
Placebo plus methotrexate: N/A |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate; Low IgM level |
|
3% |
Placebo plus methotrexate: N/A |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate; Low IgG level |
|
0.8% |
Placebo plus methotrexate: N/A |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate; Low IgA level |
Hepatic: Hepatobiliary disease (17%), increased serum alanine aminotransferase (13%)
Hypersensitivity: Angioedema (11%)
Immunologic: Antibody development (1% to 32%)
Infection: Bacterial infection (19%; including cellulitis), infection (19% to 63%%; including CMV viremia, herpes simplex infection, parvovirus B19 seroconversion, varicella zoster infection, hepatitis C, and lower respiratory tract infection) (table 5), serious infection (2% to 11%; including sepsis)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
62% |
Cyclophosphamide plus glucocorticoids: 47% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids |
|
63% |
Mycophenolate mofetil (MMF) plus oral corticosteroids: N/A |
1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeks |
Pemphigus vulgaris |
67 |
N/A |
Rituximab plus oral corticosteroids |
|
37% |
Observation: 22% |
375 mg/m² once weekly for 8 weeks for up to 12 doses |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma; maintenance therapy |
N/A |
N/A |
Initiated 8 weeks following completion of chemotherapy in patients who achieved a response with rituximab plus chemotherapy |
|
19% |
No further therapy: 9% |
375 mg/m² once weekly for 4 doses every 6 months for up to 16 doses |
Previously untreated, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma; maintenance therapy |
N/A |
N/A |
In patients who did not progress after 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP) |
|
31% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
|
39% |
Placebo plus methotrexate: 34% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
Nervous system: Chills (3% to 33%), fatigue (13% to 39%), headache (15% to 19%), insomnia (14%), pain (12%), peripheral sensory neuropathy (30%)
Neuromuscular & skeletal: Arthralgia (6% to 13%), asthenia (2% to 26%), muscle spasm (17%)
Respiratory: Bronchitis, cough (13% to 15%) (table 6), epistaxis (11%), nasopharyngitis (≤16%), pulmonary disease (31%), pulmonary toxicity (18%), rhinitis (3% to 12%), upper respiratory tract infection (≤16%)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
13% |
Cyclophosphamide plus glucocorticoids: 11% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids |
|
15% |
Cyclophosphamide, vincristine, and prednisone (CVP): 6% |
N/A |
Previously untreated, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin lymphoma |
N/A |
N/A |
Rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) |
|
13% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
Miscellaneous: Fever (5% to 56%), infusion related reaction (first dose: 12% to 77%; including cytokine release syndrome and nonimmune anaphylaxis; reactions can be acute; decreases with subsequent infusions) (table 7)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
59% |
Fludarabine plus cyclophosphamide (FC): N/A |
375 mg/m² as an initial infusion, followed by 500 mg/m² for up to 5 doses |
Chronic lymphocytic leukemia |
N/A |
N/A |
Rituximab plus fludarabine and cyclophosphamide (R-FC) |
|
12% |
Cyclophosphamide plus glucocorticoids: 11% |
375 mg/m² once weekly for 4 weeks |
Granulomatosis with polyangiitis and microscopic polyangiitis; induction therapy |
99 |
98 |
Rituximab plus glucocorticoids |
|
77% |
N/A |
N/A |
Non-Hodgkin lymphoma |
N/A |
N/A |
First infusion |
|
22% |
N/A |
1,000 mg on days 1, 15, week 24, and week 26 for up to 52 weeks |
Pemphigus vulgaris |
67 |
N/A |
N/A |
|
32% |
Placebo plus methotrexate: 23% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
1% to 10%:
Cardiovascular: Chest tightness (7%), hypotension (10%), significant cardiovascular event (2%)
Dermatologic: Urticaria (2% to 8%) (table 8)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
8% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
|
2% |
Placebo plus methotrexate: <1% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
Endocrine & metabolic: Hyperglycemia (9%), hyperuricemia (2%), increased lactate dehydrogenase (7%)
Gastrointestinal: Dyspepsia (3%), oral candidiasis (9%), upper abdominal pain (2%), vomiting (10%; grades 3/4: 1%)
Genitourinary: Urinary tract infection (8%)
Hematologic & oncologic: Pancytopenia (grades 3/4: 3%; can be prolonged)
Hepatic: Exacerbation of hepatitis B (grades 3/4: 2%)
Infection: Fungal infection (1%), viral infection (10%; including herpes zoster)
Nervous system: Anxiety (2% to 5%), dizziness (6% to 10%), migraine (2%), paresthesia (2%), rigors (10%)
Neuromuscular & skeletal: Back pain (9% to 10%), myalgia (10%)
Respiratory: Bronchospasm (8%), dyspnea (7% to 10%), sinusitis (6%), throat irritation (2% to 9%) (table 9)
|
Drug (Rituximab) |
Comparator |
Dose |
Indication |
Number of Patients (Rituximab) |
Number of Patients (Comparator) |
Comments |
|---|---|---|---|---|---|---|
|
9% |
N/A |
Most patients received 375 mg/m² weekly for 4 doses |
Relapsed or refractory, low-grade or follicular, CD-20 positive, B-cell, non-Hodgkin lymphoma |
356 |
N/A |
N/A |
|
2% |
Placebo plus methotrexate: 0% |
2 x 1,000 mg |
Rheumatoid arthritis |
540 |
398 |
Rituximab plus methotrexate |
<1%: Hematologic & oncologic: Hemolytic anemia, pure red cell aplasia
Postmarketing:
Cardiovascular: Acute myocardial infarction (Kasi 2012), cardiac tamponade (Cohen 2006), cardiogenic shock (Kasi 2012), heart failure (Kasi 2012), Kawasaki syndrome (Sato 2020), myocarditis (Ghielmini 2004), vasculitis (systemic; with rash) (Kim 2009), ventricular fibrillation (Kasi 2012), ventricular tachycardia (Kasi 2012),
Dermatologic: Epidermolysis bullosa (Wu 2020), lichenoid dermatitis (Scheinfeld 2006), pemphigus (paraneoplastic) (Scheinfeld 2006), pyoderma gangrenosum (including genital presentation) (Georgakopoulos 2018, Maloney 2018), Stevens-Johnson syndrome (Scheinfeld 2006), toxic epidermal necrolysis (Scheinfeld 2006), vesiculobullous dermatitis (Scheinfeld 2006)
Gastrointestinal: Crohn’s disease (Cavalcanti 2020), enterocolitis (including ileocolitis, ulcerative colitis, microscopic colitis) (Tsuzuki 2021), intestinal obstruction (Kasi 2012), intestinal perforation (mean onset: 6 days [range: 1 to 77 days in patients with non-Hodgkin lymphoma]) (Cornejo 2009, Kollmar 2002)
Hematologic & oncologic: Bone marrow depression (Kasi 2012), increased serum immunoglobulins (hyperviscosity syndrome in Waldenström's macroglobulinemia), Kaposi sarcoma (including new onset and progression) (Billon 2018, Geller 2018), sarcoidosis (children: Scar sarcoidosis) (Vesely 2020), tumor lysis syndrome (Yang 1999)
Hepatic: Fulminant hepatitis (Evens 2011), hepatic failure (Evens 2011)
Hypersensitivity: Anaphylaxis (Liccioli 2020), serum sickness (Fouda 2020)
Infection: Reactivation of HBV (Evens 2011)
Nervous system: Progressive multifocal leukoencephalopathy (Carson 2009, Molloy 2012), reversible posterior leukoencephalopathy syndrome (Mustafa 2019)
Neuromuscular & skeletal: Arthritis (polyarticular), lupus-like syndrome (Chessa 2021)
Ophthalmic: Optic neuritis, uveitis
Renal: Nephrotoxicity
Respiratory: Acute respiratory distress syndrome (Kasi 2012), bronchiolitis obliterans (Shen 2012), hypoxia (Kasi 2012), interstitial pulmonary disease (Wagner 2007), pleurisy, pneumonia, pulmonary infiltrates (Kasi 2012)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known 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); patients with severe, active infections
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 to 77 days); evaluate abdominal pain or repeated vomiting.
• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment.
• Renal toxicity: May cause fatal renal toxicity in patients with non-Hodgkin lymphomas (NHL). 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.
• Tumor lysis syndrome: Tumor lysis syndrome leading to acute renal failure requiring dialysis (sometimes fatal) may occur within 12 to 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 (antihyperuricemic therapy, aggressive hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities and administer supportive care as indicated.
Special populations:
• Older adult: There is a higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis), and the incidence of grade 3 or 4 adverse reactions are higher in patients ≥65 years of age.
• Granulomatosis with polyangiitis/microscopic polyangiitis: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with granulomatosis with polyangiitis or microscopic polyangiitis after rituximab-induced B-cell depletion.
• Pemphigus vulgaris: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with pemphigus vulgaris after rituximab-induced B-cell depletion.
• Rheumatoid arthritis: There are limited data on the safety of other biologics or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients with rheumatoid arthritis (RA) with B-cell depletion following rituximab treatment. Monitor patients closely for infection if biologic agents or DMARDs are used concomitantly. The use of rituximab is not recommended in RA patients who have not had prior inadequate response to one or more tumor necrosis factor antagonists.
Dosage form specific issues:
• Administration: Rituximab is for IV administration only. Do not substitute rituximab and hyaluronidase (SUBQ) for rituximab (IV). Use caution during product selection, preparation, and administration.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Immunizations: In the oncology setting, live vaccines should not be given before or during rituximab treatment; the safety of live vaccines following rituximab treatment has not been studied. When using for the treatment of multiple sclerosis, avoid live-attenuated vaccines in patients who currently receive or have recently discontinued rituximab; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]). Review vaccination status for all patients, and if possible, bring up to date with all immunizations (following current immunization guideline recommendations) prior to rituximab initiation and administer nonlive vaccines at least 4 weeks prior to initiating a rituximab course of therapy. Response to some immunizations may be lower in some patients receiving rituximab.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid combination
Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccines: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of COVID-19 Vaccines. Management: Administer COVID-19 vaccine 2 to 4 weeks prior to the next scheduled dose of anti-CD20 therapy, if used chronically for the treatment of autoimmune disease. Revaccinate 6 months after completion of anti-CD20 therapy if used over a limited period. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines 2 weeks prior to starting anti-CD20 B-cell depleting therapies. Vaccination of patients treated with these agents in the past 6 months is not recommended. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Mumps- Rubella- or Varicella-Containing Live Vaccines: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Poliovirus Vaccine (Live/Trivalent/Oral): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation or 6 months after anti-CD20 B-cell depleting therapies. If vaccinated prior to B cell recovery, consider assessing immune response to vaccination. Risk D: Consider therapy modification
Vaccines (Live): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation in patients who may become pregnant.
The manufacturer recommends patients who may become pregnant use effective contraception during therapy and for 12 months following the last rituximab dose.
Based on limited information, use of rituximab may be continued through conception in patients with rheumatic and musculoskeletal diseases who are planning a pregnancy and not able to use alternative therapies; use should be discontinued once pregnancy is confirmed. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).
Rituximab has been evaluated off-label for neuromyelitis optica spectrum disorder (NMOSD). Use of rituximab prior to pregnancy may prevent pregnancy-related attacks (Borisow 2018; Kim 2020).
Based on limited information, use of rituximab may be continued in patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).
Rituximab crosses the placenta and can be detected in the newborn.
Rituximab is a humanized monoclonal antibody (IgG1). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009). In one infant born at 41 weeks' gestation, in utero exposure occurred from week 16 to 37; rituximab concentrations were higher in the neonate at birth (32,095 ng/mL) than the mother (9,750 ng/mL) and still measurable at 18 weeks of age (700 ng/mL infant; 500 ng/mL mother) (Friedrichs 2006).
Based on human data, in utero exposure to rituximab may cause fetal harm. B-cell lymphocytopenia generally lasting <6 months may occur in exposed infants; infants and newborns should be monitored for infection. Retrospective case reports of inadvertent pregnancy during rituximab treatment collected by the manufacturer (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) (Chakravarty 2011). Similar information from a British pregnancy registry and available case series have also been published (Das 2018; De Cock 2017; Perrotta 2021).
The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). Based on limited data, if pregnancy occurs during rituximab treatment, the pregnancy may continue provided rituximab treatment is withheld. In general, although the risk of B-cell depletion in the newborn is increased, if postponing rituximab treatment would significantly compromise maternal outcome in patients diagnosed with B-cell lymphoma during pregnancy, rituximab use is not discouraged during pregnancy (ESMO [Peccatori 2013]). An international consensus panel has published guidelines for hematologic malignancies during pregnancy. In patients with aggressive lymphomas, rituximab (as a component of the R-CHOP chemotherapy regimen) may be administered in the second and third trimesters, however, it should be avoided within 3 weeks of anticipated delivery (Lishner 2016).
Although approved for the treatment of rheumatoid arthritis, based on available information, rituximab should be discontinued once pregnancy is detected in patients treated for rheumatic and musculoskeletal diseases; treatment during pregnancy should only be considered for pregnant patients with life- or organ-threatening disease (ACR [Sammaritano 2020]).
Rituximab is used off-label for the treatment of primary immune thrombocytopenia (ITP). Although information specific to pregnancy is limited, use can be considered in pregnant patients with very severe ITP. Monitor for perinatal and neonatal immunosuppression and subsequent infection (Donohoe 2019; Provan 2019).
Rituximab has been evaluated off-label for neurological indications such as multiple sclerosis (Ciplea 2020; Das 2018; Smith 2020) and neuromyelitis optica spectrum disorder (NMOSD). Maternal NMOSD may be associated with adverse pregnancy outcomes, including miscarriage and preeclampsia. Information related to the treatment of NMOSD during pregnancy is limited; however, use of rituximab prior to pregnancy may prevent pregnancy-related attacks (Borisow 2018; Chang 2020; Kim 2020; Miranda-Acuña 2019; Munger 2020; Zhu 2020).
A long-term observational research study is collecting information about the diagnosis and treatment of cancer during pregnancy. For additional information about the pregnancy and cancer registry or to become a participant, contact Cooper Health (1-877-635-4499).
Rituximab is present in breast milk.
Rituximab 1,000 mg was administered for granulomatosis with polyangiitis to a woman within 6 months postpartum. Following infusion, milk and maternal serum concentrations were evaluated for 4 days, beginning 7 days after administration. Milk concentrations (0.4 to 0.6 mcg/mL) were significantly less than those in the maternal serum (110 to 130 mcg/mL). Corresponding serum concentrations were not available from the fully breastfed infant; however, serious infections were not observed and normal growth and development were noted (Bragnes 2017). Information is also available from a prospective study of nine lactating women with multiple sclerosis treated with rituximab. Breast milk samples were obtained prior to the infusion and at intervals up to 30 days following a 500 mg or 1,000 mg dose (30 samples obtained). The median maximum milk concentration of rituximab was 0.074 μg/mL (range: 0.061 to 0.12 μg/mL). Using the maximum milk concentrations from four women who provided serial samples, the authors of this study calculated the relative infant dose (RID) of rituximab to be 0.10% of the weight-adjusted maternal dose, providing an estimated daily infant dose via breast milk of 0.011 mg/kg/day. There were no serious infections reported in the five infants who were breastfed. In addition, they were reported to have normal growth and development up to 12 months of age (Krysko 2019). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).
According to the manufacturer, breastfeeding is not recommended during treatment and for 6 months after the last dose of rituximab. However, based on available information, rituximab is considered compatible with breastfeeding in patients treated for rheumatic and musculoskeletal diseases. In addition, rituximab is unlikely to be absorbed by the infant gastrointestinal tract following exposure via breast milk (ACR [Sammaritano 2020]).
CBC with differential and platelets (obtain prior to treatment and prior to each treatment course, and at weekly to monthly intervals and more frequently in patients with lymphoid malignancies, or at 2- to 4-month intervals in rheumatoid arthritis patients, granulomatosis with polyangiitis and microscopic polyangiitis); continue to monitor for cytopenias after the final rituximab dose and until resolution. Monitor electrolytes (in patients at risk for tumor lysis syndrome [TLS]), renal function (in patients at risk for TLS or nephrotoxicity), fluid/hydration status balance. Monitor BP and vital signs. Evaluate pregnancy status (prior to treatment initiation in patients who may become pregnant).
Hepatitis B virus reactivation screening: Screen all patients for hepatitis B virus (HBV) infection prior to therapy initiation (eg, hepatitis B surface antigen [HBsAG] and hepatitis B core antibody measurements). Screen patients for latent infections (eg, hepatitis C, HIV, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment. The American Society of Clinical Oncology HBV screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with HBsAg, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up. Monitor for signs of active hepatitis B infection.
Monitor closely for infusion-related reactions, especially in patients with a history of prior cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions or patients with high numbers of circulating malignant cells (≥25,000/mm3). Perform cardiac monitoring during and after rituximab infusion (in rheumatoid arthritis patients and in patients with preexisting cardiac disease, a history of arrhythmia or angina, or if clinically significant arrhythmias develop during or after subsequent infusions). Monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting), tumor lysis syndrome, and/or mucocutaneous skin reactions. Monitor for 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 progressive multifocal leukoencephalopathy is suspected, obtain brain MRI scan and lumbar puncture.
Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of 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 rheumatoid arthritis are reduced by targeting B-cells and the progression of structural damage is delayed.
Onset:
Immune thrombocytopenia: Initial response: 7 to 56 days; Peak response: 14 to 180 days (ASH [Neunert 2011]).
Non-Hodgkin lymphomas: B-cell depletion: Within 3 weeks.
Rheumatoid arthritis: B-cell depletion: Within 2 weeks.
Duration:
Non-Hodgkin lymphomas: Detectable in serum 3 to 6 months after completion of treatment; B-cell depletion is sustained for up to 6 to 9 months and B-cell recovery begins ~6 months following completion of treatment; median B-cell levels return to normal by 12 months following completion of treatment.
Rheumatoid arthritis: B-cell depletion persists for at least 6 months.
Distribution:
Pemphigus vulgaris: Median: 3.49 L (range: 2.48 to 5.22 L).
Rheumatoid arthritis: 3.1 L.
Granulomatosis with polyangiitis/microscopic polyangiitis:
Children ≥6 years of age and Adolescents ≤17 years of age: Median: 2.28 L (range: 1.43 to 3.17 L).
Adults: Median: 3.12 L (range: 2.42 to 3.91 L).
Half-life elimination:
Chronic lymphocytic leukemia: Median terminal half-life: 32 days (range: 14 to 62 days).
Non-Hodgkin lymphomas: Median terminal half-life: 22 days (range: 6 to 52 days).
Pemphigus vulgaris: Median terminal half-life: First cycle (1,000 mg on days 1, 15): 21.1 days (range: 9.3 to 36.2 days); second cycle (1,000 mg on days 168, 182): 26.2 days (range: 16.4 to 42.8 days).
Rheumatoid arthritis: Mean terminal half-life: 18 days (range: 5 to 78 days).
Granulomatosis with polyangiitis/microscopic polyangiitis:
Children ≥6 years of age and Adolescents ≤17 years of age: Median terminal half-life: 22 days (range: 11 to 42 days).
Adults: Median terminal half-life: 25 days (range: 11 to 52 days).
Excretion: Clearance:
Pemphigus vulgaris: Median: First cycle (1,000 mg on days 1, 15): 0.3 L/day (range: 0.16 to 1.51 L/day); second cycle (1,000 mg on days 168, 182): 0.24 L/day (range: 0.13 to 0.45 L/day).
Rheumatoid arthritis: 0.335 L/day.
Granulomatosis with polyangiitis/microscopic polyangiitis:
Children ≥6 years and Adolescents ≤17 years of age: Median: 0.222 L/day (range: 0.0996 to 0.381 L/day).
Adults: Median: 0.279 L/day (range: 0.133 to 0.653 L/day).
Solution (Riabni Intravenous)
100 mg/10 mL (per mL): $86.02
500 mg/50 mL (per mL): $86.02
Solution (Rituxan Intravenous)
100 mg/10 mL (per mL): $112.74
500 mg/50 mL (per mL): $112.74
Solution (Ruxience Intravenous)
100 mg/10 mL (per mL): $86.02
500 mg/50 mL (per mL): $86.02
Solution (Truxima Intravenous)
100 mg/10 mL (per mL): $101.47
500 mg/50 mL (per mL): $101.47
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