RiTUXimab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Rituxan: 100 mg/10 mL (10 mL) [contains polysorbate 80]

Rituxan: 10 mg/mL (50 mL) [contains mouse (murine) and/or hamster protein, polysorbate 80]

Rituxan: 10 mg/mL (10 mL) [contains polysorbate 80]

Ruxience: rituximab-pvvr 100 mg/10 mL (10 mL); rituximab-pvvr 500 mg/50 mL (50 mL) [contains edetate disodium dihydrate, polysorbate 80]

Truxima: rituximab-abbs 100 mg/10 mL (10 mL); rituximab-abbs 500 mg/50 mL (50 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

Rheumatoid arthritis: 3.1 L.

Granulomatosis with polyangiitis/microscopic polyangiitis:

Children ≥6 years and Adolescents ≤17 years: Median: 2.28 L (range: 1.43 to 3.17 L).

Adults: Median: 3.12 L (range: 2.42 to 3.91 L).

Excretion

Clearance:

Rheumatoid arthritis: 0.335 L/day.

Granulomatosis with polyangiitis/microscopic polyangiitis:

Children ≥6 years and Adolescents ≤17 years: 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).

Onset of Action

Immune thrombocytopenia: Initial response: 7 to 56 days; Peak response: 14 to 180 days (Neunert 2011)

NHL: B-cell depletion: Within 3 weeks.

Rheumatoid arthritis (RA): B-cell depletion: Within 2 weeks.

Duration of Action

NHL: 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

RA: B-cell depletion persists for at least 6 months.

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).

Rheumatoid arthritis: Mean terminal half-life: 18 days (range: 5 to 78 days).

Granulomatosis with polyangiitis/microscopic polyangiitis:

Children ≥6 years and Adolescents ≤17 years: Median: 22 days (range: 11 to 42 days).

Adults: Median: 25 days (range: 11 to 52 days).

Use: Labeled Indications

Chronic lymphocytic leukemia (Rituxan and rituximab biosimilar): Treatment of previously untreated or previously treated CD20-positive chronic lymphocytic leukemia (CLL) in adults (in combination with fludarabine and cyclophosphamide).

Note: Other medications have approval for use in combination with rituximab (eg, idelalisib, venetoclax, ibrutinib) for the treatment of relapsed or refractory CLL.

Granulomatosis with polyangiitis (Rituxan and rituximab biosimilar): Treatment of granulomatosis with polyangiitis (Wegener granulomatosis) (in combination with glucocorticoids) in adults (Rituxan and rituximab biosimilar) and pediatric patients ≥2 years of age (Rituxan only).

Microscopic polyangiitis (Rituxan and rituximab biosimilar): Treatment of microscopic polyangiitis (in combination with glucocorticoids) in adults (Rituxan and rituximab biosimilar) and pediatric patients ≥2 years of age (Rituxan only).

Non-Hodgkin lymphomas (Rituxan and rituximab biosimilar): 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 if 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)

Pemphigus vulgaris (Rituxan only): Treatment of moderate to severe pemphigus vulgaris in adults.

Rheumatoid arthritis (Rituxan and rituximab biosimilar): 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: Truxima (rituximab-abbs) has been approved as a biosimilar to Rituxan (rituximab).

Use: Off Label

Antibody-mediated rejection in cardiac transplantation (treatment)yes

Based on the American Heart Association's Scientific Statement for Antibody-Mediated Rejection in Cardiac Transplantation and the International Society of Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients, rituximab, usually in combination with other immune therapies, may be a reasonable option for the secondary treatment of patients with AMR of the cardiac allograft. ISHLT guidelines state rituximab may be added to the current regimen to reduce the risk of recurrent rejection. There are currently no large randomized trials evaluating treatments for AMR in cardiac transplantation; recommendations are based on consensus.

Autoimmune hemolytic anemia (refractory)b

Data from a meta-analysis of 21 observational studies with a total of 409 patients support the use of rituximab in the management of refractory autoimmune hemolytic anemia (AIHA) Reynaud 2015. Data from a small prospective multicenter study support the use of low-dose rituximab (in combination with prednisone) in patients with newly diagnosed or refractory AIHA Barcellini 2012. Data from a retrospective study in patients with refractory AIHA also support the use of rituximab for refractory AIHA Roumier 2014. Data from another small retrospective study which included patients with refractory AIHA also support the use of rituximab in its management Gobert 2011. Additionally, clinical experience also suggests the utility of rituximab in the treatment of refractory autoimmune hemolytic anemia in patients who are not candidates for splenectomy or refractory to splenectomy Lechner 2010.

Burkitt lymphomaa

Data from a large multicenter study support the use of rituximab (in combination with chemotherapy) in the treatment of Burkitt lymphoma Hoelzer 2014. Results from CALGB 10 022, a phase II study in patients with Burkitt leukemia/lymphoma also support the use of rituximab in combination with chemotherapy for the treatment of this disease Rizzieri 2014. A small study evaluated the addition of rituximab to HyperCVAD chemotherapy for the treatment of Burkitt lymphoma; the results support the use of rituximab added to the chemotherapy regimen Thomas 2006.

CNS lymphomab

Data from 2 retrospective studies support the use of rituximab (in combination with high-dose methotrexate) for the treatment of newly diagnosed primary CNS lymphoma Gregory 2013, Holdhoff 2014. Data from a prospective multicenter trial support the addition of rituximab to methotrexate-based chemotherapy and whole brain radiotherapy for the management of newly diagnosed primary CNS lymphoma in immunocompetent patients Shah 2007. Data from a limited number of patients in a small study suggest that rituximab (in combination with temozolomide) may be beneficial for the treatment of refractory primary CNS lymphoma Wong 2004.

Graft-versus-host disease (chronic, steroid-refractory)byes

Data from a small study suggest that rituximab may be beneficial in the treatment of chronic graft-versus-host disease (GVHD) that is refractory to systemic corticosteroid treatment Cutler 2006.

Based on the American Society for Blood and Marrow Transplant (ASBMT) Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease, the use of rituximab is considered a second-line treatment option for chronic, steroid-refractory GVHD; patients with cutaneous or musculoskeletal chronic GVHD manifestations have a higher likelihood of response Wolff 2011.

Hodgkin lymphoma (nodular lymphocyte-predominant), advancedb

Data from phase II studies support the use of rituximab in the treatment of nodular lymphocyte-predominant Hodgkin lymphoma Advani 2014, Ekstrand 2003, Schulz 2008. Clinical experience suggests that rituximab may be used for advanced disease (either as a single agent or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or for relapsed disease in combination with ifosfamide, carboplatin and etoposide [ICE]), but not for newly diagnosed early stage disease Advani 2013.

Idiopathic membranous nephropathy (resistant)b

Data from a randomized controlled phase III study support the use of rituximab for the treatment of severe membranous nephropathy which has not responded to nonimmunosuppressive antiproteinuric therapy Dahan 2016. Data from other small studies (including follow up data) support the use of rituximab in the management of severe, persistent or refractory idiopathic or primary membranous nephropathy Fervenza 2008, Fervenza 2010, Ruggenenti 2012, Ruggenenti 2015.

Immune thrombocytopenia (refractory)cyes

Evidence from meta-analyses including randomized controlled trials and observational studies suggest that rituximab demonstrates benefit (as complete or partial response) in the management of refractory or relapsed immune thrombocytopenia (ITP) in nonsplenectomized patients Augur 2012, Chugh 2015.

According to American Society of Hematology guidelines and an international consensus report, rituximab is considered second-line therapy for ITP

Lupus nephritis (refractory)byes

Data from a pilot study and a retrospective study in patients with lupus nephritis refractory to initial standard therapy suggested that rituximab may be beneficial for the treatment of refractory lupus nephritis Melander 2009, Vigna-Perez 2006. In a pooled analysis of patients who received rituximab for the treatment of lupus nephropathy, second-line therapy with rituximab was effective, particularly in patients with severe or refractory disease or with an exacerbation after immunosuppressive treatment Diaz-Largares 2012.

Based on guidelines from the American College of Rheumatology and the Joint European League Against Rheumatism and European Renal Association- European Dialysis and Transplant Association, rituximab may be a treatment option for the management of refractory lupus nephritis after failure with other treatments, including 6 months of one induction therapy or cyclophosphamide and mycophenolate Bertsias 2012, Hahn 2012.

Mucosa-associated lymphoid tissue lymphoma (gastric) (advanced)b

Data from a small study support the use of rituximab in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, which was either H. pylori negative or persistent following standard H. pylori treatment Martinelli 2005. Based on an analysis of the SEER-Medicare database, survival was not improved if rituximab was added to systemic therapy for gastric MALT compared to rituximab alone in elderly patients receiving initial therapy for their disease. Rituximab monotherapy produces durable remissions and may be an option for elderly patients Olszewski 2013.

Myasthenia gravis (refractory)b

Data from a small study in patients with myasthenia gravis unresponsive to first-line prednisone and other second-line immunosuppressants suggest that rituximab may be useful in the management of refractory myasthenia gravis, particularly in patients who are MuSK (muscle specific tyrosine kinase) antibody-positive Diaz-Manera 2012. A systematic review of rituximab analyzing a large number of case reports determined that rituximab was effective and safe in the management of myasthenia gravis, particularly in MuSK antibody-positive and refractory disease Tandan 2017.

Neuromyelitis optica (relapse prevention)b

Data from a multicenter retrospective study in patients who received treatment with azathioprine, mycophenolate, and/or rituximab support the use of rituximab in preventing relapses of neuromyelitis optica Mealy 2014. A systematic review and meta-analysis of studies of rituximab in patients with neuromyelitis optica determined that rituximab reduces the frequency of neuromyelitis optica relapses Damato 2016.

Pemphigus vulgaris (refractory)b

Data from a small prospective study support the use of rituximab (in combination with IV immune globulin) in patients with pemphigus vulgaris that was refractory to multiple lines of therapy, including systemic corticosteroids and with minimal response to IV immune globulin alone Ahmed 2006. Clinical experience and data from retrospective studies also suggest the utility of rituximab in the management of refractory pemphigus vulgaris Cholera 2016, El Tal 2006, Kasperkiewicz 2011.

Post-transplant lymphoproliferative disorderb

Data from 2 international multicenter phase II studies support the use of rituximab (either followed by CHOP chemotherapy or as monotherapy) for the treatment of posttransplant lymphoproliferative disorder Choquet 2006, Trappe 2012.

Splenic marginal zone lymphomac

Data from 3 retrospective studies suggest the utility of rituximab (either as a single agent or in combination with chemotherapy) in the management of splenic marginal zone lymphoma Else 2012, Kalpadakis 2013, Tsimberdou 2006.

Thrombotic thrombocytopenic purpura (acquired)b

There are no randomized trials evaluating the use of rituximab with plasma exchange in the management of acquired thrombotic thrombocytopenic purpura (TTP). Data are limited to several case reports, case series, and a phase 2 trial demonstrating significant reductions in ADAMTS13 autoantibodies and increases in ADAMTS13 activity, with low relapse rates (~10%).

Waldenström macroglobulinemiabyes

Data from a randomized multicenter phase III study support the use of rituximab (in combination with ibrutinib) for the treatment of Waldenström macroglobulinemia Dimopoulos 2018. Data from a phase II multicenter study support the use of rituximab (in combination with cyclophosphamide and dexamethasone) for the treatment of Waldenström macroglobulinemia Dimopoulos 2007. Data from phase II studies also support the use of rituximab, either as a single agent, or in combination with bortezomib, bortezomib and dexamethasone, bendamustine, or carfilzomib and dexamethasone for the treatment of Waldenström macroglobulinemia Dimopoulos 2002, Dimopoulos 2013, Ghobrial 2010, Rummel 2005, Treon 2009, Treon 2014.

Based on recommendations from the Eighth International Workshop on Waldenström Macroglobulinemia (IWWM), rituximab either alone (avoid single-agent rituximab in patients with high IgM levels) or in combination with chemotherapy may be used for the treatment of Waldenström macroglobulinemia.

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Truxima (rituximab-abbs) has been approved as a biosimilar to Rituxan (rituximab).

Premedicate with acetaminophen and an antihistamine prior to infusion. 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).

In patients with chronic lymphocytic leukemia (CLL), Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment) as appropriate.

In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis, PCP prophylaxis is recommended during and for at least 6 months after rituximab treatment; consider PCP prophylaxis during and after rituximab treatment in patients with pemphigus vulgaris.

Consider antiviral prophylaxis to prevent hepatitis B reactivation for all patients receiving rituximab (oncology and non-oncology indications) with resolved hepatitis B virus infection (Bath 2018).

Antibody-mediated rejection in cardiac transplantation, treatment (off-label use): IV: 375 mg/m² once weekly for 1 to 4 doses (AHA [Colvin 2015]; ISHLT [Costanzo 2010]) or 1,000 mg on days 7 and 21 or on days 7 and 22 (AHA [Colvin 2015]).

Autoimmune hemolytic anemia, refractory (off-label use): IV: 375 mg/m² once weekly for 4 doses (may continue systemic corticosteroids); a second course may be administered for relapse (Gobert 2011; Reynaud 2015; Roumier 2014).

Burkitt lymphoma (off-label use): IV: 375 mg/m² on day 1 and 11 of cycles 1 and 3 and days 2 and 8 of cycles 2 and 4 (Thomas 2006) 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 (Hoelzer 2014) 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 (Rizzieri 2014).

Chronic lymphocytic leukemia (Rituxan and rituximab biosimilar): 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).

Chronic lymphocytic leukemia (off-label combinations): IV:

Previously untreated chronic lymphocytic leukemia: 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) (Eichhorst 2016) 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) (Byrd 2003) 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 and without 17p deletion CLL) (Shanafelt 2019).

Relapsed or refractory chronic lymphocytic leukemia: 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) (Furman 2014) 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) (Fischer 2011) or 375 mg/m² on day 1 in cycle 1, then 500 mg/m² on day 1 (every 28 days) of cycles 2 to 6 (in combination with bendamustine and ibrutinib) (Chanan-Khan 2016) 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) (Seymour 2018).

CNS lymphoma (off-label use): IV:

Newly diagnosed: 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 (Holdhoff 2014) 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) (Shah 2007).

Refractory disease: 375 mg/m² on day 1 every 28 days (in combination with temozolomide) for 4 cycles, then followed by temozolomide monotherapy (Wong 2004).

Graft-versus-host disease, chronic, refractory (off-label use): IV: 375 mg/m² once weekly for 4 doses; a second course of 4 weekly doses may be administered 8 weeks after initial therapy for lack of or incomplete response (Cutler 2006) or 375 mg/m² once weekly for 4 to 8 doses (Wolff 2011).

Granulomatosis with polyangiitis (Wegener granulomatosis) (Rituxan and rituximab biosimilar): IV:

Induction therapy (for active granulomatosis with polyangiitis): 375 mg/m² once weekly for 4 doses. Administer in combination with methylprednisolone IV for 1 to 3 days followed by prednisone/prednisone taper per clinical practice recommendations. Corticosteroid therapy should begin within 14 days prior to or with rituximab initiation; may continue during and after the 4-week course of rituximab induction treatment.

Follow-up therapy (after achieving disease control with induction): 500 mg as two infusions separated by 2 weeks, followed by 500 mg once every 6 months thereafter (based on clinical evaluation). If induction for active disease was with rituximab, begin rituximab follow-up therapy within 24 weeks of the last rituximab induction dose (or based on clinical evaluation), but no sooner than 16 weeks following the last rituximab induction dose. If induction therapy for active disease was with another agent (not rituximab), then initiate rituximab follow-up therapy within the 4-week period following achievement of disease control. Premedication with methylprednisolone 100 mg IV is recommended 30 minutes prior to each rituximab dose.

Hodgkin lymphoma, nodular lymphocyte-predominate, advanced (off-label use): IV: 375 mg/m² once weekly for 4 weeks (Ekstrand 2003; Schulz 2008) 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 (Advani 2014). 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) (Advani 2013).

Idiopathic membranous nephropathy, resistant (off-label use): IV: 375 mg/m² once weekly for 4 doses; repeat cycle at 6 months (Fervenza 2010) or 1,000 mg (flat dose) on days 1 and 15; may repeat cycle at 6 months (Fervenza 2008) or 375 mg/m² once weekly for 2 doses (Dahan 2016) or 375 mg/m² once weekly for 4 doses (Ruggenenti 2012; Ruggenenti 2015) or 375 mg/m² as a single dose and repeated at least 1 week later only if circulating B-cells >5/mm³ were detected (Ruggenenti 2012; Ruggenenti 2015).

Immune thrombocytopenia, refractory (off-label use): IV: 375 mg/m² once weekly for 4 doses (Arnold 2007; Godeau 2008; Provan 2010) or some patients may have a response with a dose of 100 mg (flat dose) once weekly for 4 weeks (Zaja 2010).

Lupus nephritis, refractory (off-label use): IV: 375 mg/m² once weekly for 4 doses (Diaz-Largares 2012; Melander 2009) or 1,000 mg (flat dose) on days 0 and 15 (Diaz-Largares 2012) or 500 to 1,000 mg (flat dose) on days 1 and 15 (Vigna-Perez 2006).

Microscopic polyangiitis (Rituxan and rituximab biosimilar): IV:

Induction therapy (for active microscopic polyangiitis): 375 mg/m² once weekly for 4 doses. Administer in combination with methylprednisolone IV for 1 to 3 days followed by prednisone/prednisone taper per clinical practice recommendations. Corticosteroid therapy should begin within 14 days prior to or with rituximab initiation; may continue during and after the 4-week course of rituximab induction treatment.

Follow-up therapy (after achieving disease control with induction): 500 mg as two infusions separated by 2 weeks, followed by 500 mg once every 6 months thereafter (based on clinical evaluation). If induction for active disease was with rituximab, begin rituximab follow-up therapy within 24 weeks of the last rituximab induction dose (or based on clinical evaluation), but no sooner than 16 weeks following the last rituximab induction dose. If induction therapy for active disease was with another agent (not rituximab), then initiate rituximab follow-up therapy within the 4-week period following achievement of disease control. Premedication with methylprednisolone 100 mg IV is recommended 30 minutes prior to each rituximab dose.

Mucosa-associated lymphoid tissue lymphoma (gastric), advanced (off-label use): IV: 375 mg/m² once weekly for 4 doses (Martinelli 2005).

Myasthenia gravis, severe, refractory (off-label use): IV: 375 mg/m² once weekly for 4 weeks, then once a month for 2 months; repeat if symptomatic (Diaz-Manera 2012) or 375 mg/m² once weekly for 4 weeks; may repeat if clinically indicated (Tandan 2017).

Neuromyelitis optica, relapse prevention (off-label use): IV: 1,000 mg once every 2 weeks for 2 doses, repeat every 6 months or when monthly CD19 cells counts are >0.1% of total lymphocytes (Damato 2016; Mealy 2014; Trebst 2014) or 375 mg/m² once weekly for 4 weeks, repeat every 6 months (Damato 2016, Trebst 2014).

Non-Hodgkin lymphoma (relapsed/refractory, low-grade or follicular CD20-positive, B-cell) (Rituxan and rituximab biosimilar): 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/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 (van Oers 2010).

Follicular lymphoma, relapsed/refractory (off-label combination): IV: 375 mg/m² on days 1, 8, 15, and 22 in cycle 1 (28-day cycle), followed by 375 mg/m² on day 1 every 28 days in cycles 2 to 5 (in combination with lenalidomide) (Leonard 2019).

Non-Hodgkin lymphoma (diffuse large B-cell)(Rituxan and rituximab biosimilar): IV: 375 mg/m² given on day 1 of each chemotherapy cycle for up to 8 doses (in combination with CHOP chemotherapy [or other anthracycline-based regimen]).

Non-Hodgkin lymphoma (follicular, CD20-positive, B-cell, previously untreated)(Rituxan and rituximab biosimilar): IV: 375 mg/m² given 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; begin 8 weeks after completion of rituximab in combination with chemotherapy): IV: 375 mg/m² once every 8 weeks for 12 doses.

Non-Hodgkin lymphoma (nonprogressing, low-grade, CD20-positive, B-cell, after 6 to 8 cycles of first-line CVP are completed)(Rituxan and rituximab biosimilar): IV: 375 mg/m² once weekly for 4 doses every 6 months for a maximum of 16 doses (as a single agent).

Non-Hodgkin lymphoma(Rituxan and rituximab biosimilar): Combination therapy with ibritumomab: IV: 250 mg/m² IV day 1; repeat in 7 to 9 days with ibritumomab (also see Ibritumomab monograph).

Pemphigus vulgaris (Rituxan only): IV: 1,000 mg once every 2 weeks for 2 doses (in combination with a tapering course of glucocorticoids), followed by maintenance of rituximab 500 mg at months 12 and 18 (Joly 2017) and every 6 months thereafter or based on clinical evaluation. Upon relapse, administer rituximab 1,000 mg and consider resuming or increasing the glucocorticoid dose based on clinical evaluation. Administer subsequent rituximab infusions no sooner than 16 weeks following the previous rituximab infusion. Premedication with methylprednisolone 100 mg IV is recommended 30 minutes prior to each rituximab dose.

Pemphigus vulgaris, refractory (off-label): IV: 375 mg/m² once weekly for 4 doses (some patients also continued immunosuppressant therapy); may repeat a second time (based on response) if needed (Cholera 2016; El Tal 2006; Kasperkiewicz 2011) or 375 mg/m² once weekly of weeks 1, 2, and 3 of a 4-week cycle, repeat for 1 additional cycle, then 1 dose per month for 4 months (total of 10 doses in 6 months), in combination with IV immune globulin (Ahmed 2006) or 1,000 mg once every 2 weeks for 2 doses (some patients also continued immunosuppressant therapy) (Cholera 2016; Kasperkiewicz 2011).

Posttransplant lymphoproliferative disorder (off-label use): IV: 375 mg/m² once weekly for 4 doses (Choquet 2006) or 375 mg/m² once weekly for 4 doses, followed 4 weeks later with 4 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (Trappe 2012).

Rheumatoid arthritis (Rituxan and rituximab biosimilar): IV: 1,000 mg on days 1 and 15 (in combination with methotrexate); subsequent courses may be administered every 24 weeks (or based on clinical evaluation), but no sooner than every 16 weeks. Premedication with methylprednisolone 100 mg IV is recommended 30 minutes prior to each rituximab dose.

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 (Kalpadakis 2013) 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 (Else 2012).

Thrombotic thrombocytopenic purpura (acquired) (off-label use): IV: 375 mg/m² once weekly for 4 doses (in combination with plasma exchange); up to 4 additional doses may be administered for ADAMTS13 levels remaining below normal or for persistently detectable anti-ADAMTS13 IgG antibodies (Scully 2007; Scully 2011). Rituximab should be timed to be administered immediately following plasma exchange; allow 24 hours after rituximab before the next plasma exchange (McDonald 2010; Sayani 2015).

Waldenström macroglobulinemia (off-label use): IV:

Single-agent rituximab: 375 mg/m² once weekly for 4 weeks as a single agent; may repeat cycle one time after 12 weeks (Dimopoulos 2002).

In combination with cyclophosphamide and dexamethasone: 375 mg/m² on day 1 every 21 days for 6 cycles (Dimopoulos 2007).

In combination with bortezomib: 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 (Ghobrial 2010).

In combination with bortezomib and dexamethasone: 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 (Dimopoulos 2013) 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 (Treon 2009).

In combination with bendamustine: 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 cycles (for a total of 6 rituximab doses) (Rummel 2005).

In combination with carfilzomib and dexamethasone: 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 (Treon 2014).

In combination with ibrutinib: 375 mg/m² once weekly during weeks 1 to 4 and weeks 17 to 20 (Dimopoulos 2018).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Prior to rituximab therapy, patients should be brought up to date with all nonlive vaccination if possible; any nonlive vaccines should be administered at least 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 is 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 (Bath 2018).

Acute lymphoblastic leukemia, mature B-cell, CD 20+ (B-ALL): 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) (Griffin 2009).

Autoimmune hemolytic anemia: Limited data available: Infants ≥4 months, Children, and Adolescents: IV infusion: 375 mg/m² once weekly for 4 doses (Ducassou 2017; Ladogana 2017; Rodrigo 2015; Zecca 2003).

Graft-versus-host disease (GVHD), steroid-refractory; chronic: 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 (Kim 2010).

Granulomatosis with polyangiitis (GPA, Wegener's 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 (Bennett 2006; Parodi 2009; Tamminga 2006; Wang 2005).

Leukemia, acute B-cell; CD20+; Stage III/IV: Limited data available: Children and Adolescents: IV infusion: 375 mg/m² administered every 14 days for 4 doses; use in combination with multi-agent chemotherapy (Samochatova 2014).

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 (KDIGO 2012). 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 (Guigonis 2008; Gulati 2010; Iijima 2014; Kamei 2009; Prytuła 2010; Van Horebeek 2017).

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 (Griffin 2009).

Non-Hodgkin lymphoma, mature B-cell Stage III/IV: Limited data available: Children and Adolescents: IV infusion: 375 mg/m²; a maximum dose of 500 mg/dose has been reported; timing of doses variable; some protocols vary administration and number of doses based on regimen phase (ie, induction or consolidation): Usually administered for a total of 6 doses as follows: Induction 1 and 2: On days -2 and 0 of each phase (4 doses); consolidation 1 and 2: On day 1 of each phase (2 doses) (Goldman 2013); other protocols administer every 14 days for 4 doses (Samochatova 2014); use in combination with multi-agent chemotherapy regimens.

Posttransplant lymphoproliferative disorder: Infants ≥11 months, Children, and Adolescents: IV infusion: 375 mg/m² once weekly for 3 to 4 doses (Milpied 2000; Serinet 2002).

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 (García-Suárez 2007; Giulino-Roth 2017).

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 (KDIGO 2012): 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) (Nwobi 2008; Pereira 2011); 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) (Willems 2006). Others have reported a higher dose regimen of 750 mg/m² on days 1 and 15 (maximum dose: 1,000 mg/dose) (Marks 2005; Podolskaya 2008).

Dosing: Adjustment for Toxicity

Dosage adjustments for rituximab are not recommended; however, adjustments for concomitant chemotherapy may be necessary.

Reconstitution

IV: Withdraw necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL with NS or D5W. Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other medications. Compatible in polyvinyl chloride (PVC) and polyethylene bags.

Administration

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 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 (Sehn 2007). 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).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Protect vials from direct sunlight. Solutions diluted for infusion in NS or D5W may be stored at 2°C to 8°C (36°F to 46°F) for 24 hours and are stable at room temperature for an additional 24 hours (although because there is no preservative, the manufacturer recommends storing refrigerated).

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

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.

>10%:

Cardiovascular: Cardiac disorder (5% to 29%), peripheral edema (8% to 16%), flushing (5% to 14%), hypertension (6% to 12%)

Central nervous system: Fatigue (13% to 39%), chills (3% to 33%), peripheral sensory neuropathy (30%), headache (17% to 19%), insomnia (14%), pain (12%)

Dermatologic: Pruritus (≤17%), skin rash (≤17%), night sweats (15%)

Endocrine & metabolic: Hypophosphatemia (12% to 21%), weight gain (11%)

Gastrointestinal: Nausea (8% to 23%), diarrhea (10% to 17%), abdominal pain (14%)

Genitourinary: Urinary tract infection

Hematologic & oncologic: Hypogammaglobulinemia (27% to 58%), neutropenia (8% to 49%; grades 3/4: 4% to 49%; prolonged lasting up to 42 days: 25%; late-onset occurring >42 days after last dose: 15% to 39%), lymphocytopenia (48%; grades 3/4: 40%; median duration: 14 days), anemia (8% to 35%; grades 3/4: 3%), leukopenia (10% to 23%; grades 3/4: 4% to 23%), febrile neutropenia (grades 3/4: 9% to 15%), thrombocytopenia (12%; grades 3/4: 2% to 11%)

Hepatic: Hepatobiliary disease (17%), increased serum alanine aminotransferase (13%)

Hypersensitivity: Angioedema (11%)

Immunologic: Antibody development (1% to 23%)

Infection: Infection (19% to 62%), bacterial infection (19%), serious infection (2% to 11%)

Neuromuscular & skeletal: Asthenia (2% to 26%), muscle spasm (17%), arthralgia (6% to 13%)

Respiratory: Pulmonary disease (31%), pulmonary toxicity (18%), cough (13% to 15%), rhinitis (3% to 12%), epistaxis (11%), bronchitis, nasopharyngitis

Miscellaneous: Infusion related reaction (first dose: 12% to 77%; decreases with subsequent infusions), fever (5% to 56%)

1% to 10%:

Cardiovascular: Hypotension (10%), chest tightness (7%), significant cardiovascular event (2%)

Central nervous system: Dizziness (10%), rigors (10%), anxiety (2% to 5%), migraine (2%), paresthesia (2%)

Dermatologic: Urticaria (2% to 8%)

Endocrine & metabolic: Hyperglycemia (9%), increased lactate dehydrogenase (7%), hyperuricemia (2%)

Gastrointestinal: Vomiting (10%), dyspepsia (3%), upper abdominal pain (2%)

Hematologic & oncologic: Pancytopenia (grades 3/4: 3%)

Hepatic: Hepatitis B (grades 3/4: 2%)

Infection: Viral infection (10%), fungal infection (1%)

Neuromuscular & skeletal: Back pain (10%), myalgia (10%)

Respiratory: Dyspnea (7% to 10%), throat irritation (2% to 9%), bronchospasm (8%), upper respiratory tract infection (7%), sinusitis (6%)

Frequency not defined:

Infection: Influenza, lower respiratory tract infection

<1%, postmarketing and/or case reports: Acute mucocutaneous toxicity, acute myocardial infarction, acute renal failure, acute respiratory distress syndrome, anaphylactoid shock, anaphylaxis, arthritis (polyarticular), bone marrow depression, bronchiolitis obliterans, cardiac arrhythmia, cardiac failure, cardiogenic shock, fulminant hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, hepatitis, hypoxia, increased serum immunoglobulins (hyperviscosity syndrome in Waldenstrom’s macroglobulinemia), interstitial pneumonitis, intestinal obstruction, intestinal perforation, Kaposi sarcoma (progression), lichenoid dermatitis, lupus-like syndrome, nephrotoxicity, optic neuritis, pemphigus (paraneoplastic), pleurisy, pneumonia, pneumonitis, progressive multifocal leukoencephalopathy, pure red cell aplasia, reactivation of HBV, reversible posterior leukoencephalopathy syndrome, serum sickness, Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, toxic epidermal necrolysis, tumor lysis syndrome, uveitis, vasculitis (systemic; with rash), ventricular fibrillation, ventricular tachycardia, vesiculobullous dermatitis

Warnings/Precautions

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.
• Cardiovascular effects: Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock, may occur in patients receiving rituximab products. Discontinue infusion for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after the infusion in patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.
• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment. Monitor blood counts; continue to monitor for cytopenias after the final rituximab dose and until resolution.
• Hepatitis B virus reactivation: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with rituximab products and in some cases may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection prior to treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation. Screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc); monitor patients for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment. If viral hepatitis develops, initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported up to 24 months after discontinuation. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during rituximab treatment. The safety of resuming rituximab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management.

- American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for HBV reactivation. Screen for HBV infection with HBsAg and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, IV drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg positive/anti-HBc positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

- A systematic review of treatment-induced hepatitis B reactivations suggests antiviral prophylaxis to prevent hepatitis B reactivation be administered to all patients receiving rituximab therapy (oncology and non-oncology indications) with previously resolved HBV infection (Bath 2018).

• Infections: Rituximab use is not recommended in patients with severe, active infection. Serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and after completing rituximab-based therapy. Infections have been observed in patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia >11 months after rituximab exposure. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. In patients with chronic lymphocytic leukemia, Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment) as appropriate. In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), PCP prophylaxis is recommended during and for at least 6 months after rituximab treatment; PCP prophylaxis should be considered for patients with pemphigus vulgaris (PV) during and after rituximab therapy. Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral hepatitis and initiate antiviral therapy. Discontinue rituximab in patients who develop other serious infections and initiate appropriate anti-infective treatment.
• Infusion-related reactions: [US Boxed Warning]: Serious (including fatal) infusion-related reactions have been reported, usually with the first infusion; fatalities have been reported within 24 hours of infusion; monitor closely during infusion; discontinue for severe reactions and provide medical intervention for grades 3 or 4 infusion-related reactions. Reactions usually occur within 30 to 120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and, in more severe cases, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylactoid events. Closely monitor patients with a history of prior cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (≥25,000/mm³). Prior to infusion, premedicate patients with acetaminophen and an antihistamine (and methylprednisolone for patients with GPA, MPA, rheumatoid arthritis [RA], and PV). Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, corticosteroids, oxygen) should be available for immediate use; treatment is symptomatic. If infusion-related reaction occurs, temporarily or permanently discontinue infusion (depending on the severity of the reaction and required interventions). After symptoms resolve, infusion may be resumed with at least a 50% infusion rate reduction.
• Mucocutaneous reactions: [US Boxed Warning]: Severe and sometimes fatal mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, and vesiculobullous dermatitis) have been reported; onset has been variable but has occurred as early as the first day of exposure. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of reexposure following mucocutaneous reactions has not been evaluated.
• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) due to John Cunningham virus infection has been reported with rituximab products; may be fatal. Cases were reported in patients with hematologic malignancies receiving rituximab either with combination chemotherapy or with hematopoietic stem cell transplant. Cases were also reported in patients receiving rituximab for autoimmune diseases who had received concurrent or prior immunosuppressant therapy. Onset may be delayed, although most cases were diagnosed within 12 months of the last rituximab dose. A retrospective analysis of patients (n=57) diagnosed with PML following rituximab therapy found a median of 16 months (following rituximab initiation), 5.5 months (following last rituximab dose), and 6 rituximab doses preceded PML diagnosis. Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Carson 2009). Promptly evaluate any patient presenting with neurological changes; consider neurology consultation, brain MRI, and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.
• Renal toxicity: May cause fatal renal toxicity in patients with 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. Monitor for signs of renal failure; discontinue rituximab with increasing serum creatinine or oliguria.
• 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; monitor renal function and hydration status, and administer supportive care as indicated.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Immunizations: Live vaccines should not be given before or during rituximab treatment; the safety of live vaccines following rituximab treatment has not been studied. 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.

Special populations:

• Elderly: Use with caution in the elderly. There is a higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis), and the incidence of serious infections and/or grade 3 or 4 adverse reactions are higher in elderly patients.
• Granulomatosis with polyangiitis (Wegener granulomatosis)/microscopic polyangiitis: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with GPA or MPA after rituximab-induced B-cell depletion.
• Pemphigus vulgaris: The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with PV 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.

Monitoring Parameters

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, electrolytes (in patients at risk for TLS), renal function (in patients at risk for TLS), fluid/hydration status balance; blood pressure, vital signs.

Screen all patients for hepatitis B virus (HBV) infection prior to therapy initiation (eg, hepatitis B surface antigen [HBsAG] and anti-HBc measurements). 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. HBV screening recommendations (ASCO provisional clinical opinion update [Hwang 2015]): Screen for HBV infection with HBsAG and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Monitor for infusion-related reactions; signs of active hepatitis B infection (during and for up to 12 months after therapy completion); cardiac monitoring during and after infusion (in rheumatoid arthritis patients and in patients with pre-existing cardiac disease or if arrhythmias develop during or after subsequent infusions); monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting); 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; signs/symptoms of TLS and/or mucocutaneous skin reactions.

Pregnancy

Pregnancy Considerations

Rituximab crosses the placenta and can be detected in the newborn. 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).

B-cell lymphocytopenia lasting <6 months may occur in exposed infants. 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 a case series has also been published (Das 2018; De Cock 2017).

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 the pregnancy (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, the cytotoxic portion of the regimen should not be administered within 3 weeks prior to anticipated delivery (Lishner 2016).

Other agents are preferred for treating lupus nephritis in pregnant women (Hahn 2012). When treating rheumatoid arthritis, it is recommended to discontinue use and switch to a safer medication prior to conception unless no other pregnancy compatible medication is able to control maternal disease (Götestam Skorpen 2016).

Effective contraception should be used in women of reproductive potential during therapy and for 12 months following treatment with rituximab.

Data collection to monitor pregnancy and infant outcomes following exposure to rituximab is ongoing. A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

What is this drug used for?

• It is used to treat types of leukemia and lymphoma.
• It is used to treat rheumatoid arthritis.
• It is used to treat Wegener's granulomatosis.
• It is used to treat microscopic polyangiitis.
• It is used to treat a skin problem called pemphigus vulgaris.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Abdominal pain
• Nausea
• Vomiting
• Diarrhea
• Runny nose
• Muscle spasms
• Back pain
• Sore throat
• Flushing
• Anxiety
• Muscle pain
• Joint pain
• Trouble sleeping
• Night sweats

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, difficulty speaking, change in balance, or vision changes
• Infusion reaction
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Bowel problems like black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; diarrhea
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Severe dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Severe headache
• Bruising
• Bleeding
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.