Rituximab

Several rituximab biosimilars are available.69, 70, 71 Biosimilarity of these products has been demonstrated for the indications described in Table 1.69, 70, 71 Biosimilarity to originator rituximab is additionally supported by comparative clinical studies in patients with non-Hodgkin lymphoma (rituximab-abbs, rituximab-arrx, rituximab-pvvr) and rheumatoid arthritis (rituximab-abbs, rituximab-arrx, rituximab-pvvr).72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83

Table 1. Rituximab Biosimilar Products and FDA licensed Indications.1, 69, 70, 71

FDA labeled indication	NHL	CLL	RA	GPA/MPA	PV
Rituximab-abbs (Truxima^®)	X^a	X	X	X^b	X
Rituximab-arrx (Riabni^®)	X^a	X	X	X^b	X
Rituximab-pvvr (Ruxience^®)	X^a	X	X	X^b	X

^aOriginator rituximab is labeled for use in adults and pediatric patients ≥6 months of age with certain types of NHL; biosimilars are only labeled for use in adults with NHL.

^bOriginator rituximab is labeled for use in adults and pediatric patients ≥2 years of age with GPA/MPA; biosimilars are only labeled for use in adults with GPA/MPA.

^cCOP, cyclophosphamide, Oncovin^® (vincristine), prednisone; COPDAM, cyclophosphamide, Oncovin^® (vincristine), prednisolone, Adriamycin^® (doxorubicin), methotrexate; CYM, cytarabine plus methotrexate; CYVE, cytarabine plus veposide (VP16); LMB, Lymphome Malin B.

Non-Hodgkin Lymphoma

Rituximab and its biosimilars are used as single agents for the treatment of adults with relapsed or refractory, low-grade or follicular, CD20-positive B-cell non-Hodgkin lymphoma (NHL).1, 69, 70, 71 Rituximab is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.6 Rituximab/hyaluronidase is used as a single agent for the treatment of adults with relapsed or refractory follicular lymphoma, and is designated an orphan drug by FDA for the treatment of this cancer.6, 68 Rituximab/hyaluronidase should only be initiated after patients have received at least 1 full dose of a rituximab product by IV infusion.68

Rituximab and its biosimilars are used in combination with first-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product plus chemotherapy, as single-agent maintenance therapy for the treatment of adults with previously untreated follicular, CD20-positive B-cell NHL.1, 69, 70, 71 Rituximab/hyaluronidase is used in combination with first-line chemotherapy and, in patients achieving a complete or partial response to a rituximab product plus chemotherapy, as single-agent maintenance therapy for the treatment of adults with previously untreated follicular lymphoma; it is designated an orphan drug by FDA for this use.6, 68 Rituximab/hyaluronidase should only be initiated after patients have received at least 1 full dose of a rituximab product by IV infusion.68

Rituximab and its biosimilars are used as single agents after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy for the treatment of adults with nonprogressing (including stable disease), low-grade, CD20-positive B-cell NHL.1, 69, 70, 71 Rituximab/hyaluronidase is used as a single agent after first-line CVP chemotherapy for the treatment of adults with nonprogressing (including stable disease) follicular lymphoma; it is designated an orphan drug by FDA for this use.6, 68 Rituximab/hyaluronidase should only be initiated after patients have received at least 1 full dose of a rituximab product by IV infusion.68

Rituximab and its biosimilars are used in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens for the treatment of adults with previously untreated, CD20-positive diffuse large B-cell NHL.1, 69, 70, 71 Rituximab/hyaluronidase is used in combination with CHOP or other anthracycline-based chemotherapy regimens for the treatment of adults with previously untreated diffuse large B-cell lymphoma; it is designated an orphan drug by FDA for this use.6, 68 Rituximab/hyaluronidase should only be initiated after patients have received at least 1 full dose of a rituximab product by IV infusion.68

Rituximab is used in combination with chemotherapy for the treatment of pediatric patients ≥6 months of age with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia.1 Rituximab is designated an orphan drug by FDA for the treatment of these cancers.6

Clinical Experience

Rituximab for Relapsed or Refractory Low-grade or Follicular Non-Hodgkin Lymphoma

The current indication for use of rituximab in the treatment of relapsed or refractory low-grade or follicular NHL is based on data from noncomparative studies.1, 2, 7 The use of rituximab for the treatment of relapsed or refractory low-grade or follicular B-cell NHL has been investigated in clinical studies, including a total of 296 patients receiving rituximab regimens of 4 or 8 once-weekly doses administered as initial treatment, initial treatment of bulky disease, or retreatment.1

In a multicenter, open-label, single-arm study, 166 patients with relapsed or refractory low-grade or follicular B-cell NHL who received rituximab 375 mg/m² as an IV infusion once weekly for 4 weeks had an overall response rate of 48% (6% complete responses, 42% partial responses).1, 7 Patients with bulky disease (tumor masses greater than 10 cm) or with greater than 5000 lymphocytes/mm³ in the peripheral blood were excluded from the study.1, 7 The median time to onset of response was 50 days, and the median duration of response was 11.2 months (range: 1.9-42.1 or more months).1 Resolution of disease-related signs and symptoms was reported in 64% (25/39) of patients with such manifestations (including B symptoms) at the time of study entry.1

Rituximab also has been administered once weekly in an 8-week regimen.1, 16 In a multicenter, single-arm study, 37 patients with relapsed or refractory low-grade NHL who received rituximab 375 mg/m² as an IV infusion once weekly for 8 weeks had an overall response rate of 57% (14% complete responses, 43% partial responses).1, 16 The projected median duration of response was 13.4 months (range: 2.5-36.5 or more months).1, 16

In pooled data from multiple studies, 39 patients with relapsed or refractory, bulky disease (single lesion >10 cm), low-grade NHL who received rituximab 375 mg/m² as an IV infusion once weekly for 4 weeks had an overall response rate of 36% (3% complete responses, 33% partial responses) and a median duration of response of 6.9 months (range: 2.8-25 or more months).1

Responses also have been observed in patients with NHL receiving additional courses of rituximab for refractory disease or for relapse of disease that initially responded to the drug.1, 2, 17 In a multicenter, single-arm study, an overall response rate of 38% (10% complete responses, 28% partial responses) and a projected median duration of response of 15 months (range: 3-25.1 or more months) were reported in 60 patients receiving retreatment with rituximab 375 mg/m² once weekly for 4 weeks for relapsed or refractory, low-grade or follicular B-cell NHL following an objective clinical response to one or more prior courses of rituximab at a median of 14.5 months prior to retreatment.1, 17

Maintenance therapy with rituximab following induction chemotherapy (with or without rituximab) has been shown to offer benefit in patients with relapsed or refractory indolent NHL.30, 31, 84, 85 In a phase 3 randomized trial, progression-free survival was prolonged in patients receiving 2 years of maintenance therapy with rituximab following chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) for advanced indolent NHL compared with those receiving CVP alone.84 In a randomized trial, duration of response was prolonged in patients receiving maintenance therapy with rituximab following salvage chemotherapy (with or without rituximab) for recurring or refractory follicular or mantle cell lymphoma compared with those receiving induction chemotherapy alone.30 In a phase 3 randomized trial, median progression-free survival and median overall survival were prolonged in patients receiving maintenance therapy with rituximab following chemotherapy with either CHOP or rituximab-CHOP (R-CHOP) for relapsed or resistant follicular NHL compared with those receiving induction chemotherapy alone.31, 85

Rituximab for Previously Untreated Follicular Non-Hodgkin Lymphoma

The current indication for rituximab in the treatment of previously untreated follicular NHL is based on data from randomized trials.1 In an open-label, multicenter, randomized trial, 322 patients with previously untreated follicular B-cell NHL received either rituximab with cyclophosphamide, vincristine, and prednisone (CVP) or CVP alone.1, 20 CVP was administered in eight 3-week cycles; in the combined modality regimen, rituximab 375 mg/m² was administered on day 1 of each cycle of CVP.1, 20 Approximately 26% of the patients were 60 years of age or older;1 99% of the patients had stage III or IV disease, and 50% had an International Prognostic Index score of at least 2.1 Median progression-free survival was prolonged in patients with advanced follicular NHL receiving rituximab with CVP (2.4 years) compared with those receiving CVP alone (1.4 years).1 The risk of disease progression, relapse, or death was reduced in patients receiving the rituximab-containing regimen.1

An additional open-label, multicenter, randomized trial enrolled 1018 patients with previously untreated follicular NHL who achieved a complete or partial response to rituximab plus chemotherapy.1, 86, 87 In this trial, patients were randomized to receive single-agent rituximab 375 mg/m² every 8 weeks for up to 12 doses or to observation.1, 86 Rituximab was initiated 8 weeks after completion of chemotherapy.1, 86 Approximately 40% of patients in this trial were 60 years of age or older, 70% had stage IV disease, 96% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 42% had an International Prognostic Index score of 3-5.1 Prior to randomization, most patients (75%) had received rituximab in combination with R-CHOP for their chemotherapy, while 22% had received rituximab in combination with cyclophosphamide, vincristine, and prednisone (R-CVP) and 3% had received rituximab in combination with fludarabine, cyclophosphamide, and mitoxantrone (R-FCM).1 Most patients (71%) had demonstrated a complete or unconfirmed complete response to the initial chemotherapy regimen.1 The primary outcome measure, progression-free survival, was prolonged among patients who received single-agent rituximab maintenance therapy.1, 86 At a median follow-up of 36 months, the median time to disease progression was not reached in the rituximab maintenance group and 48.3 months in the observation group.86 The final progression-free survival analysis, performed after 9 years of follow-up, found a median progression-free survival of 4.1 years in the observation group and 10.5 years in the rituximab maintenance group.87

Rituximab and Hyaluronidase for Previously Untreated Follicular Lymphoma

The efficacy of rituximab/hyaluronidase for the treatment of previously untreated, CD20-positive follicular lymphoma was assessed in the randomized, open-label, multicenter, SABRINA study.68, 88 In this study, 410 patients with previously untreated grade 1, 2, or 3a follicular lymphoma were enrolled.68, 88 Patients were randomized to receive an IV rituximab product at a dosage of 375 mg/m² for 8 cycles or an IV rituximab product at a dosage of 375 mg/m² for 1 cycle followed by 7 cycles of subcutaneous rituximab/hyaluronidase at a dosage of 1400 mg rituximab and 23,400 units hyaluronidase.68, 88 Rituximab treatments were administered every 3 weeks in conjunction with a total of 6-8 cycles of CHOP or 8 cycles of CVP.68, 88 After 4 cycles of treatment, patients underwent interim staging; patients receiving R-CHOP with complete response, unconfirmed complete response, partial response, or stable disease at the interim assessment could receive either 4 more cycles of R-CHOP or 2 cycles of R-CHOP followed by 2 cycles of monotherapy with rituximab or rituximab/hyaluronidase (according to their assigned treatment group).68 Patients with at least a partial response after combination treatment with chemotherapy continued single-agent maintenance treatment with rituximab or rituximab/hyaluronidase (according to their assigned treatment group) every 8 weeks for 24 months.68, 88

The median age of patients enrolled in the SABRINA trial was 57 years (range: 28-86 years); 53% were female, 86% were white, 45% had high-risk disease (based on their International Prognostic Index score), 34% had intermediate-risk disease (based on their International Prognostic Index score), and 54% had Ann Arbor stage IV disease.68 Most patients (90%) completed all 8 cycles of combination treatment with chemotherapy, and 70% of patients completed all 20 cycles of therapy (8 cycles of combination treatment with chemotherapy and 12 cycles of single-agent maintenance therapy).68 The median treatment duration was 27.1 months.68, 88 At the end of combination treatment with chemotherapy, the overall response rate was 84.4% among patients who received rituximab/hyaluronidase and 84.9% among patients who received IV rituximab.68, 88 Complete responses were achieved in 32.2% of patients in each treatment group.68, 88 At the end of single-agent maintenance treatment, the overall response rate was 77.9% among patients who received rituximab/hyaluronidase and 78.1% among patients who received IV rituximab; complete response rates were 50.6 and 56.2% in the rituximab/hyaluronidase and IV rituximab groups, respectively.68, 88 Progression-free survival and overall survival were similar between treatment groups.68, 88

Rituximab for Nonprogressing Low-grade Non-Hodgkin Lymphoma

The current indication for rituximab in the treatment of nonprogressing (including stable disease) low-grade NHL following first-line chemotherapy with CVP is based on data from an open-label, multicenter, randomized trial in which 322 patients with previously untreated low-grade B-cell NHL (IWF histologic subtype A, B, or C) received 6 or 8 cycles of CVP followed by rituximab or no further treatment.1 In the combined modality regimen, patients received rituximab 375 mg/m² once weekly for 4 weeks (4 doses total) every 6 months for up to 16 doses total.1

Approximately 37% of the patients in the study were 60 years of age or older;1 99% of the patients had stage III or IV disease, and 63% had an International Prognostic Index score of at least 2.1 The risk of disease progression, relapse, or death was reduced in patients receiving the rituximab-containing regimen.1

Rituximab for Previously Untreated Diffuse Large B-cell Non-Hodgkin Lymphoma

The current indication for rituximab in combination with CHOP or other anthracycline-based regimens for the treatment of previously untreated CD20-positive diffuse large B-cell NHL is based on data from 3 open-label, multicenter, randomized trials involving a total of 1854 patients who received rituximab with combination chemotherapy (CHOP or other anthracycline-based regimen) or combination chemotherapy alone for previously untreated diffuse large B-cell NHL.1, 21, 22, 23 The addition of rituximab to chemotherapy was shown to offer benefit in older patients with advanced-stage disease21, 22 as well as younger patients with early-stage disease.23, 28

In the first randomized trial (the NCI-sponsored E4494 trial), 632 patients (60 years of age or older) with diffuse large B-cell NHL (IWF histologic subtype F, G, or H B-cell NHL or diffuse large B-cell NHL, including primary mediastinal B-cell lymphoma according to the Revised European-American Lymphoma [REAL] classification) received 6 or 8 cycles of CHOP with or without rituximab 375 mg/m² (2 doses preceding the first 21-day cycle of chemotherapy and then 1 dose preceding cycles 3, 5, and 7 for a total of 4 or 5 doses).1, 21 Most of the patients (73%) had stage III or IV disease, 30% had extranodal disease in at least 2 sites, 56% had an International Prognostic Index score of at least 2, 86% had an ECOG performance status less than 2, and the diagnosis of diffuse large B-cell NHL was centrally confirmed in 62% of the patients.1 Median progression-free survival was prolonged in patients with diffuse large B-cell NHL receiving rituximab and CHOP (3.1 years) compared with those receiving CHOP alone (1.6 years).1 The risk of disease progression, relapse, or death was reduced in patients receiving the rituximab-containing regimen.1 Patients with disease that responded to treatment with rituximab and CHOP then received either additional rituximab therapy or no further therapy.1 The statistical evaluation of the data for induction therapy with rituximab was designed to exclude the effect of additional rituximab therapy; additional rituximab therapy did not affect survival.1

In the second randomized trial (the Groupe d'Etude des Lymphomes de l'Adulte trial), 399 patients (60 years of age or older, median age: 69 years) with diffuse large B-cell NHL received up to 8 cycles of CHOP with or without rituximab 375 mg/m² on day 1 of each 21-day cycle.1, 22 Most of the patients (80%) had stage III or IV disease, 52% had extranodal disease in at least 2 sites, 60% had an age-adjusted International Prognostic Index score of at least 2, and 80% had an ECOG performance status less than 2.1 Median event-free survival was prolonged in patients with diffuse large B-cell NHL receiving rituximab and CHOP (2.9 years) compared with those receiving CHOP alone (1.1 years).1 The risk of disease progression, relapse, change in therapy, or death from any cause was reduced in patients receiving the rituximab-containing regimen.1 Estimated overall survival at 5 years was 58% for patients receiving rituximab-CHOP versus 46% for patients receiving CHOP alone.1, 27 Estimated overall survival at 10 years was 43.5% for patients receiving R-CHOP versus 27.6% for patients receiving CHOP alone.89

In the third randomized trial (the MabThera International Trial M39045), 823 patients (18-60 years of age) with diffuse large B-cell NHL received an anthracycline-containing chemotherapy regimen with or without rituximab.1, 23 Among all patients, 28% had stage III or IV disease, 49% had bulky disease, and 34% had extranodal disease; 100% had an International Prognostic Index score of 1 or less, and 99% had an ECOG performance status less than 2.1 The main end point of the study was time to treatment failure.1 The risk of disease progression, failure to achieve a complete response, relapse, or death was reduced in patients receiving the rituximab-containing regimen.1 After a median follow-up of 72 months, 6-year event-free survival was 74.3% for patients who received chemotherapy plus rituximab versus 55.8% for patients who received chemotherapy alone.90

Rituximab and Hyaluronidase for Previously Untreated Diffuse Large B-cell Lymphoma

The efficacy of rituximab/hyaluronidase in combination with CHOP or other anthracycline-based regimens for the treatment of previously untreated diffuse large B-cell lymphoma was assessed in the randomized, open-label MabEase study.68, 91 The MabEase study enrolled 576 patients with previously untreated CD20-positive diffuse large B-cell lymphoma.68, 91 Patients were randomized to receive an IV rituximab product at a dosage of 375 mg/m² for 8 cycles or an IV rituximab product at a dosage of 375 mg/m² for 1 cycle followed by 7 cycles of subcutaneous rituximab/hyaluronidase at a dosage of 1400 mg rituximab and 23,400 units hyaluronidase.68, 91 Rituximab treatments were administered in combination with up to 6-8 cycles of CHOP chemotherapy every 14 days (CHOP-14) or every 21 days (CHOP-21).68, 91

The median age of patients enrolled in the MabEase study was 64 years (range: 18-80 years); 54% were male, 79% were white, and 42% had Ann Arbor stage IV disease.68 Based on International Prognostic Index scores, 31, 30, 24, and 15% of patients had low risk, low intermediate risk, high intermediate risk, or high risk disease, respectively.68 Most patients (82%) received 8 cycles of treatment, and the median duration of treatment exposure was 4.9 months in both groups.68 Over a median observation time of approximately 28 months, complete response rates were 47 and 42% for patients receiving rituximab/hyaluronidase and IV rituximab, respectively.68 Progression-free survival was similar between groups, with 27 and 23% of patients experiencing disease progression, relapse, or death in the rituximab/hyaluronidase and IV rituximab groups, respectively.68 Overall survival was also similar between groups, with 17 and 15% of patients receiving rituximab/hyaluronidase and IV rituximab, respectively, experiencing death from any cause.68

Rituximab for Previously Untreated Non-Hodgkin Lymphoma in Pediatric Patients

The current indication for rituximab in the treatment of pediatric patients ≥6 months of age with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia is based principally on the results of a multicenter, open-label, randomized trial.1, 92 For the purposes of this trial, “advanced stage” disease was defined as stage III disease with lactate dehydrogenase levels greater than 2 times the upper limit of normal or stage IV B-cell NHL or mature B-cell acute leukemia.1, 92 Patients were randomized to receive Lymphome Malin B (LMB) chemotherapy alone or in combination with rituximab.1 The LMB chemotherapy protocol utilizes corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple-drug intrathecal therapy with methotrexate, cytarabine, and corticosteroids; the specific administration protocol was determined based on the patient's clinical group classification.1 Patients randomized to receive rituximab in addition to LMB chemotherapy received 6 IV infusions of rituximab 375 mg/m², including 2 doses during each of the 2 chemotherapy induction courses and 1 dose during each of the 2 chemotherapy consolidation courses.1, 92

The trial had a planned enrollment of 600 patients; however, the trial was stopped early for efficacy after 362 patients had been enrolled.1, 92 A total of 328 patients were included in the efficacy analyses.1, 92 The median age was 8 years in the rituximab group (range: 2-17 years) and 7 years in the chemotherapy alone group (range: 1-17 years).1 Most patients in the trial were 3 years of age or older, and the majority of patients (71%) were 3 to less than 12 years of a only 1 patient less than 3 years of age was enrolled in the rituximab group.1 Burkitt or Burkitt-like NHL was the most common disease type (occurring in 55-56% of patients in each group), followed by mature B-cell acute leukemia (34-37% of patients in each group) and diffuse large B-cell lymphoma (8% of patients in each group).1 Bone marrow involvement was documented in 45% of patients in each group, and CNS involvement was documented in 27% of patients in each group.1

Efficacy was assessed using an endpoint of event-free survival, where an “event” was defined as the occurrence of progressive disease, relapse, second malignancy, death from any cause, or non-response (as evidenced by detection of viable cells in residue after the second course of cytarabine and etoposide).1, 92 At a median follow-up of 3.1 years, there were 28 events in the chemotherapy alone group and 10 events in the rituximab plus chemotherapy group, indicating improved event-free survival with rituximab plus chemotherapy.1, 92 Overall survival was also improved with rituximab plus chemotherapy compared with chemotherapy alone; during the follow-up period, 20 deaths were reported in the chemotherapy alone group and 8 deaths were reported in the rituximab plus chemotherapy group.1, 92

Rituximab in Combination with Bendamustine for Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

Efficacy and safety of rituximab in combination with bendamustine† for the treatment of relapsed or refractory indolent NHL or relapsed or refractory mantle cell lymphoma† in patients who had received up to 3 prior treatment regimens have been studied in 2 open-label, phase 2 studies.10002, 10003

In both studies, patients received rituximab 375 mg/m² IV on day 1, followed by bendamustine hydrochloride 90 mg/m² daily as an IV infusion on days 2 and 3, administered on a 28-day cycle for a total of 4 cycles.10002, 10003 An additional dose of rituximab was administered 1 week prior to the first rituximab-bendamustine treatment cycle and repeated at 28 days following the last rituximab-bendamustine treatment cycle.10002, 10003 Patients achieving a response between the second and fourth treatment cycles were permitted to receive an additional 2 cycles of rituximab-bendamustine treatment in the second study.10003 Overall response rates in the 2 studies were similar (90-92%), with 41-60% of patients exhibiting complete responses.10002, 10003 Overall and complete response rates were higher in patients with no prior exposure to rituximab (100 and 48%, respectively) than in those with prior rituximab exposure (86 and 35%, respectively).10003 Median progression-free survival was similar in both studies (24 and 23 months).10002, 10003 At the time of the data analysis, median duration of survival had not been reached in the first study; however, the actuarial 48-month survival rate was 55%.10002

Small numbers of patients in each study (16 and 12, respectively) had relapsed or refractory mantle cell lymphoma.10002, 10003 Overall and complete response rates for these patients were 75-92 and 42-50%, respectively.10002, 10003 Median progression-free survival was 18 months in the first study;10002 median response duration was 19 months in the second study.10003

Based on current evidence and because of the favorable toxicity profile,10002, 10003 combination therapy with rituximab and bendamustine is recommended (accepted) for use in the treatment of relapsed or refractory indolent NHL or mantle cell lymphoma.10020

Efficacy and safety of rituximab in combination with bendamustine† for the treatment of previously untreated advanced-stage indolent NHL or previously untreated advanced-stage mantle cell lymphoma† have been studied in two phase 3 studies (Study Group Indolent Lymphomas [StiL] NHL 1-2003 and BRIGHT).10001, 10018, 10021

In the StiL NHL 1-2003 study in 514 patients with previously untreated mantle cell lymphoma or CD20-positive indolent NHL, rituximab in combination with bendamustine was noninferior to R-CHOP in terms of progression-free survival; median progression-free survival was 69.5 and 31.2 months in patients receiving rituximab in combination with bendamustine and those receiving R-CHOP, respectively.10001 Overall response rates were similar in patients receiving rituximab in combination with bendamustine and those receiving R-CHOP (93 versus 91%, respectively); however, the complete response rate was higher in the rituximab-bendamustine group (40 versus 30%).10001 Although median overall survival had not been reached in either group at the time of analysis, substantial differences were not observed between the treatment groups.10001

In the BRIGHT study in 447 patients with previously untreated mantle cell lymphoma or CD20-positive indolent NHL, rituximab in combination with bendamustine was noninferior to standard combination chemotherapy (R-CHOP or R-CVP) for attainment of complete response; complete response was achieved in 31% of patients receiving rituximab in combination with bendamustine and 25% of those receiving R-CHOP or R-CVP.10018 Although complete response rates in patients with indolent NHL (mainly follicular lymphoma) tended to favor the rituximab-bendamustine regimen over R-CHOP or R-CVP, subset analysis failed to establish noninferiority of the rituximab-bendamustine regimen in patients with indolent NHL or follicular lymphoma.10018 In the subset of patients with mantle cell lymphoma, complete response rates were higher in patients receiving rituximab in combination with bendamustine compared with those receiving R-CHOP or R-CVP.10018 Overall response rates were higher in patients receiving rituximab in combination with bendamustine compared with those receiving R-CHOP or R-CVP (97 versus 91%).10018 In a long-term follow-up analysis, 5-year progression-free survival rates were substantially greater with the rituximab-bendamustine regimen (65.5 versus 55.8%).^[r10021] No substantial differences in overall survival were observed at 5 years.10018

Based on current evidence,10001, 10018 use of rituximab in combination with bendamustine may be considered a reasonable choice (accepted, with possible conditions) for the treatment of previously untreated advanced-stage indolent NHL or mantle cell lymphoma; however, the histologic subtype of NHL should be considered when selecting a combination chemotherapy regimen.10019

Clinical Perspective

The non-Hodgkin lymphomas are a heterogenous group of lymphoproliferative malignancies; these malignancies may be indolent (e.g., follicular lymphoma grades 1-3a; lymphoplasmacytic lymphoma [Waldenstrom macroglobulinemia]; marginal zone lymphoma) or aggressive (e.g., diffuse large B-cell lymphoma; primary mediastinal large B-cell lymphoma; follicular lymphoma grade 3b; mantle cell lymphoma; Burkitt lymphoma; B-cell lymphoblastic lymphoma).3002, 3003, 3004 Rituximab is commonly utilized in recommended chemotherapy regimens for the treatment of follicular lymphoma (including relapsed/refractory disease) and diffuse large B-cell lymphoma in adults.3000, 3001 It has also been utilized in various treatment regimens for other types of NHL, including Burkitt lymphoma† (in adults† and pediatric patients), mantle cell lymphoma†, marginal zone lymphoma†, lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)†, and primary mediastinal B-cell lymphoma†.3000, 3001, 3002

Chronic Lymphocytic Leukemia

Rituximab and its biosimilars are used in combination with fludarabine and cyclophosphamide (FC) for the treatment of adults with previously untreated and previously treated antigen CD20-positive chronic lymphocytic leukemia (CLL).1, 69, 70, 71 Rituximab is designated an orphan drug by FDA for the treatment of this cancer.6 Rituximab/hyaluronidase is used in combination with FC for the treatment of adults with previously untreated and previously treated CLL, and is designated an orphan drug by FDA for this use.6, 68 Rituximab/hyaluronidase should only be initiated after patients have received at least 1 full dose of an IV rituximab product.68

Clinical Experience

Rituximab for Previously Untreated Chronic Lymphocytic Leukemia

The indication for rituximab in combination with fludarabine and cyclophosphamide (R-FC) for the treatment of previously untreated antigen CD20-positive chronic lymphocytic leukemia (CLL) is based principally on the results of a multicenter, open-label, randomized study (CLL8) in which 817 adult patients with previously untreated CLL were randomized to receive 6 cycles of either FC (fludarabine 25 mg/m² and cyclophosphamide 250 mg/m², administered IV on days 1-3 of each 28-day cycle) or FC in combination with rituximab (rituximab 375 mg/m² administered by IV infusion on day 0 during the first FC cycle, followed by rituximab 500 mg/m² IV on day 1 during subsequent FC cycles).1, 93, 94 The median age of patients in this study was 61 years,^[r93] and 30% of the patients were 65 years of age or older.1 Approximately 5, 64, or 31% of patients in this study had Binet stage A, stage B, or stage C disease, respectively.93 More than 99% of patients had an ECOG performance status of 0-1.1

At a median follow-up of 3.1 years,94 patients receiving R-FC experienced prolonged median progression-free survival (51.8 versus 32.8 months), a higher overall response rate (90 versus 80%), a higher complete response rate (44 versus 22%), and a higher overall survival rate (87 versus 83%) compared with patients receiving FC.93 In patients receiving R-FC, the largest benefit on progression-free survival and overall survival was observed in those with Binet stage A or stage B CLL.93 Based on results of an exploratory analysis (stratified by age), the addition of rituximab to FC resulted in no additional benefit in progression-free survival in patients 70 years of age or older.1 After a median follow-up of 5.9 years, median progression-free survival remained prolonged among patients who received R-FC (56.8 versus 32.9 months); overall survival was not reached in the R-FC group and was 86 months in the FC group.94

Rituximab for Previously Treated Chronic Lymphocytic Leukemia

The indication for rituximab in combination with fludarabine and cyclophosphamide (R-FC) for the treatment of previously treated antigen CD20-positive chronic lymphocytic leukemia (CLL) is based principally on the results of a multicenter, open-label, randomized study (REACH) in which 552 adult patients with previously treated CLL were randomized to receive 6 cycles of either FC (fludarabine 25 mg/m² and cyclophosphamide 250 mg/m², administered IV on days 1-3 of each 28-day cycle) or FC in combination with rituximab (rituximab 375 mg/m² administered by IV infusion on day 0 during the first FC cycle, followed by 500 mg/m² IV on day 1 during subsequent FC cycles).1, 39 The median age in this study was 63 years,39 and 44% of the patients were 65 years of age or older.1 Most patients (82%) had received previous treatment with an alkylating agent (27% alkylator refractory, 55% alkylator sensitive), and 17% had previously received (and demonstrated response to) fludarabine; fludarabine-refractory patients or patients who had received previous treatment with interferon, rituximab, other monoclonal antibodies, or stem-cell transplantation were excluded from the study.39 All patients had an ECOG performance status of 0-1.1

At a median follow-up of 25 months, patients receiving R-FC experienced prolonged median progression-free survival (27 versus 21.9 months), a higher overall response rate (61 versus 49%), and a higher complete response rate (9 versus 3%) compared with patients receiving FC.39 Among patients receiving R-FC, improved progression-free survival was observed in patients across all Binet stages as well as in patients with high lymphocyte counts, poor renal function, or poor prognostic factors (e.g., del11q, unmutated IgVH, positive ZAP-70).39 Based on results of an exploratory analysis (stratified by age), the addition of rituximab to FC resulted in no additional benefit in progression-free survival in patients 65 years or older.1 No difference in overall survival has been observed with the R-FC regimen compared with the FC regimen.39

Rituximab and Hyaluronidase for Previously Untreated Chronic Lymphocytic Leukemia

The efficacy of rituximab/hyaluronidase in combination with R-FC for the treatment of previously untreated CLL was assessed in the randomized, open-label SAWYER study.68, 95 The SAWYER study enrolled 176 patients with previously untreated CLL.68, 95 Patients were randomized to receive IV rituximab or subcutaneous rituximab/hyaluronidase in combination with 6 cycles of FC chemotherapy.68, 95 In the IV rituximab group, patients received IV rituximab 375 mg/m² in cycle 1 followed by IV rituximab 500 mg/m² for up to 5 additional cycles; in the subcutaneous rituximab/hyaluronidase group, patients received IV rituximab 375 mg/m² in cycle 1 followed by subcutaneous rituximab/hyaluronidase at a dose of 1600 mg rituximab and 26,800 units hyaluronidase for up to 5 additional cycles.68, 95

The median age of patients in the SAWYER study was 60 years; 62% had Binet stage B disease.68 Overall response rates were 85.2 and 80.7% among patients in the rituximab/hyaluronidase and IV rituximab groups, respectively; complete response rates were 27.3 and 31.8%, respectively.68 Progression-free survival events occurred in 34.1% of patients receiving rituximab/hyaluronidase and 42% of patients receiving IV rituximab.68

Clinical Perspective

Chronic lymphocytic leukemia (CLL) is often managed in a conservative manner, because it is not curable, progresses slowly, and occurs in older populations.3007 Asymptomatic patients or patients who are minimally affected by the disease are typically managed with observation only, and treatment is considered only when symptom progression becomes evident.3007 Historically, R-FC was used for the initial treatment of young, fit patients with low-risk CLL; however, R-FC is no longer recommended in most patients, because it has been associated with prolonged immunosuppression and increased risk of secondary cancers (e.g., myelodysplasia, acute myeloid leukemia).3005, 3006 Targeted therapies such as venetoclax/obinutuzumab, acalabrutinib (with or without obinutuzumab), and zanubrutinib are generally preferred when treatment of CLL is necessary.3005, 3006

Rheumatoid Arthritis

Rituximab and its biosimilars are used in combination with methotrexate for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults with disease that has shown an inadequate response to therapy with at least one tumor necrosis factor (TNF; TNF-α) antagonist.1, 69, 70, 71

Clinical Experience

This indication is based mainly on data from 2 randomized, double-blind, placebo-controlled studies in patients at least 18 years of age who had a diagnosis of RA according to American College of Rheumatology (ACR) criteria and had active disease (at least 8 swollen joints and 8 tender joints).1, 24, 98

In the first randomized study, patients received an IV infusion of either rituximab 1 g or placebo on days 1 and 15 (for a total of 2 doses) in combination with continued therapy with oral or parenteral methotrexate 10-25 mg weekly for 24 weeks.1, 24, 96, 97 Patients were permitted to receive additional courses of rituximab (given as 2 separate doses of 1 g each) in combination with methotrexate in an open-label extension study at intervals determined by clinical evaluation, but no sooner than 16 weeks after the previous dose of rituximab.1 IV glucocorticoid was administered prior to each rituximab infusion, and oral glucocorticoid was administered on a tapering schedule from baseline through day 14.1, 24 At 24 weeks, the number of patients achieving a response measured as a percentage improvement (20%, 50%, or 70%) in disease symptoms according to ACR criteria was higher for those receiving rituximab and methotrexate compared with those receiving placebo and methotrexate (ACR 20: 51 versus 18%, ACR 50: 27 versus 5%, ACR 70: 12 versus 1%).1, 24 Favorable responses were noted for all components of the ACR response including reduced counts for swollen and tender joints, improvement according to physician and patient global assessments, reduced pain, reduced disability, and reduced serum C-reactive protein (CRP) concentrations.1, 24 Although all patients experienced similar benefits at week 4 following a brief course of IV and oral glucocorticoids, the number of patients experiencing ACR responses (at all levels) from week 8 through week 24 was higher among those receiving rituximab and methotrexate.1 Results of the open-label extension study indicate that the combination of rituximab and methotrexate is more effective than methotrexate alone in delaying radiographic progression of structural damage (defined as changes in the Genant-modified total Sharp score [TSS], erosion score [ES], and joint space narrowing [JSN] score) after one year of therapy; progression of structural damage was further delayed following 2 years of therapy.1, 96, 97 Approximately 57% of patients receiving rituximab in combination with methotrexate had no progression of structural damage after 2 years of therapy.1, 97

In the second randomized study, all patients received the first course of rituximab (2 separate doses of 1 g each) in combination with methotrexate.1, 98 Patients who experienced ongoing disease activity were randomized to receive either a second course of rituximab (2 separate doses of 1 g each) in combination with methotrexate or placebo in combination with methotrexate, generally between weeks 24-28.1, 98 At week 48, 54, 29, or 14% of patients receiving rituximab in combination with methotrexate achieved ACR 20, ACR 50, or ACR 70, respectively, compared with 45, 26, or 13%, respectively, of those receiving methotrexate alone.1, 98

Efficacy of rituximab has been established in 4 controlled studies in patients with RA who had an inadequate response to nonbiologic disease-modifying antirheumatic drugs (DMARDs) and in one controlled study in methotrexate-naive patients; however, a favorable risk-benefit ratio has not been established for the use of rituximab in these patient populations.1 In one of the 4 controlled studies, 342 adult patients with moderately to severely active RA who had an inadequate response to methotrexate were randomized to receive methotrexate in combination with either rituximab 1 g (given as 2 separate doses of 500 mg each), rituximab 2 g (given as 2 separate doses of 1 g each), or placebo.1, 101 At 24 weeks, more patients receiving methotrexate in combination with rituximab 2 g had clinically meaningful improvement in physical function, as reflected by improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI) score, than patients receiving methotrexate with placebo (58 versus 48%).1 In addition, patients receiving methotrexate in combination with rituximab experienced greater improvement from baseline in HAQ-DI score at 24 weeks than did patients receiving methotrexate with placebo.1 These improvements were maintained at 48 weeks.1 Improvements in HAQ-DI score observed with the 2 rituximab dosages (1 g or 2 g) were similar; however, radiographic responses were not assessed.1 In another randomized study, 161 patients with active RA despite treatment with methotrexate received one of the following regimens: oral methotrexate (at least 10 mg weekly), rituximab (1 g IV on days 1 and 15), rituximab (same dosage) and cyclophosphamide (750 mg IV on days 3 and 17), or rituximab (same dosage) and methotrexate (at least 10 mg weekly).25 At week 24, the proportion of patients achieving an ACR 50 response was greater in those receiving rituximab-methotrexate (43%) or rituximab-cyclophosphamide (41%) than in those receiving methotrexate alone (13%).25 Responses at all levels of improvement (i.e., ACR 20, 50, and 70 responses) were maintained at week 48 in the rituximab-methotrexate group.25

Efficacy of rituximab also has been established in one randomized, double-blind, placebo-controlled study in methotrexate-naive patients.1, 99, 100 In this study, patients with moderately to severely active RA were randomized to receive methotrexate (7.5 mg weekly initially, then titrated up to 20 mg weekly by week 8) in combination with either rituximab 1 g (500 mg IV on days 1 and 15), rituximab 2 g (1 g IV on days 1 and 15), or placebo.1, 99 After a minimum of 24 weeks, patients with ongoing disease activity were permitted to receive retreatment with additional courses of their assigned treatment.1, 99 Following one year of therapy, the proportion of patients achieving ACR 20, ACR 50, or ACR 70 was similar among those receiving methotrexate with either dose of rituximab, which was higher than the proportion of patients receiving methotrexate with placebo.1, 99 However, only the combination of methotrexate with high dose rituximab (2 g) was shown to be more effective than methotrexate alone in delaying radiographic progression of structural damage (as assessed by TSS).1, 99, 100

Clinical Perspective

The ACR issued guidelines for the treatment of rheumatoid arthritis in 2021.2003 Disease-modifying treatments for rheumatoid arthritis include conventional disease-modifying antirheumatic drugs (DMARDs; e.g., hydroxychloroquine, leflunomide, methotrexate, sulfasalazine), biologic DMARDs (e.g., tumor necrosis factor [TNF] blocking agents, abatacept, tocilizumab, sarilumab, rituximab), and/or targeted synthetic DMARDs (e.g., Janus kinase inhibitors).2003 Specific agents for rheumatoid arthritis treatment are selected according to current disease activity, prior therapies used, and the presence of comorbidities.2003 A “treat-to-target” approach is typically employed, with the goal of achieving a predefined target of low disease activity or remission.2003

TNF blocking agents used in the treatment of rheumatoid arthritis include adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab.2003 Methotrexate monotherapy is strongly recommended over biologic DMARD monotherapy and conditionally recommended over the combination of methotrexate and a TNF blocking agent for DMARD-naive patients with moderate to high disease activity, because many patients will achieve their treatment goal with methotrexate alone, and combination therapy with TNF blocking agents may be associated with additional risks and costs.2003 Biologic DMARDs (including TNF blocking agents) and targeted synthetic DMARDs are conditionally recommended as add-on therapy for patients who are taking maximally tolerated dosages of methotrexate and are not at target.2003 Rituximab is only recommended for patients who have had an inadequate response to TNF inhibitors or for patients who have a history of a lymphoproliferative disorder for which rituximab is indicated.2003 Recommendations for the use and selection of biologic DMARDs in rheumatoid arthritis vary based on the presence of certain comorbidities (e.g., heart failure, previous serious infection, nontuberculous mycobacterial lung disease).2003 Consult the ACR guidelines for additional details.2003

Granulomatosis with Polyangiitis and Microscopic Polyangiitis

Rituximab and its biosimilars are used in combination with glucocorticoids for the treatment of granulomatosis with polyangiitis (GPA; also referred to as Wegener's granulomatosis) and microscopic polyangiitis (MPA); rituximab is used in adults and pediatric patients ≥2 years of age, while rituximab biosimilars are used in adults only.1, 69, 70, 71 Rituximab is designated an orphan drug by FDA for this use.6

Clinical Experience

The indication for rituximab in the treatment of GPA and MPA is based principally on the results of 2 randomized controlled trials in adults and a small single-arm study in pediatric patients.1, 102, 103, 104, 105

One randomized, double-blind, multicenter, non-inferiority trial enrolled 197 patients 15 years of age or older with active, severe GPA or MPA.1, 102 The study was conducted in 2 phases: a 6-month remission induction phase and a 12-month remission maintenance phase.1, 102 Patients were randomized to receive IV rituximab 375 mg/m² once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3-6 months during the remission induction phase.1, 102 Patients were premedicated with an antihistamine and acetaminophen prior to rituximab infusion.1 Patients in both arms received 1000 mg IV methylprednisolone per day for 1-3 days within 14 days prior to the initial infusion; following IV corticosteroid administration, all patients received oral prednisone (1 mg/kg per day, with a maximum of 80 mg/kg per day) with prespecified tapering.1 Once remission was achieved (or at the end of the 6-month remission induction period), patients in the cyclophosphamide group received azathioprine to maintain remission.1, 102 The rituximab group did not receive additional therapy to maintain remission.1 The primary outcome was the achievement of complete remission at 6 months (defined as a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis [BVAS/GPA] of 0 with no ongoing corticosteroid therapy).1, 102

The majority of patients in the trial (75%) were diagnosed with GPA; 24% were diagnosed with MPA and 1% had an unknown vasculitis type.1 Approximately half of the patients were being treated for new disease (49%), and 51% had relapsing disease.1, 102 Complete remission at 6 months was achieved in 64% of patients who received rituximab and 53% of patients who received cyclophosphamide, demonstrating noninferiority between treatments.1 Complete remission at 6 and 12 months was achieved in 44% of patients treated with rituximab and 38% of patients treated with cyclophosphamide (with azathioprine maintenance), while complete remission at months 6, 12, and 18 was achieved by 38% of patients treated with rituximab and 31% of patients treated with cyclophosphamide.1 Based on investigator judgment, 15 patients in the rituximab group received a second course of treatment for relapse of disease activity at 8-17 months after the induction treatment course.1

Another randomized, open-label, multicenter trial enrolled 115 patients 21 years of age or older with GPA, MPA, or renal-limited antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in disease remission.1, 103 Remission of active disease was achieved with a combination of glucocorticoids and cyclophosphamide.1, 103 Within a maximum of 1 month after the last cyclophosphamide dose, eligible patients (i.e., those with a BVAS of 0) were randomized to receive azathioprine or rituximab as maintenance therapy.1, 103 Rituximab was administered as two 500-mg IV infusions separated by 2 weeks followed by a 500-mg IV infusion every 6 months for 18 months.1, 103 Azathioprine was administered orally at a dosage of 2 mg/kg per day for 12 months, then 1.5 mg/kg per day for 6 months, and finally 1 mg/kg per day for 4 months; treatment was discontinued after 22 months.1, 103 Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg/day) for at least 18 months after randomization; prednisone dose tapering and the decision to stop prednisone treatment after 18 months were left to the investigator's discretion.1, 103 Patients were followed for 28 months (10 or 6 months after the last rituximab infusion or the last dose of azathioprine, respectively).1, 103 The primary endpoint was the occurrence of major relapse through month 28 (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity that could lead to organ failure or damage, or could be life-threatening).1

Of the 115 patients enrolled in the trial, 86 had GPA, 24 had MPA, and 5 had renal-limited ANCA-associated vasculitis.1 Most patients (80%) had newly-diagnosed disease, while 20% had relapsing disease.1 By month 28, 5% of patients maintained on rituximab had experienced major relapse, compared with 29% of patients maintained on azathioprine.1, 103 Between month 28 and month 60 (end of follow-up), 11 additional patients in the azathioprine group (19%) and 13 additional patients in the rituximab group (23%) had major relapses.104 Therefore, at month 60, 49.4% of patients receiving azathioprine and 71.9% of patients receiving rituximab remained major relapse-free.104

A multicenter, open-label, single-arm study examined the efficacy of rituximab in 25 patients 6-17 years of age with active GPA and MPA.1, 105 This study consisted of an initial 6-month remission induction phase and a minimum 12-month follow-up phase (with a maximum follow-up of 54 months).1, 105 Patients received a minimum of 3 doses of IV methylprednisolone (30 mg/kg per day, up to a maximum of 1 g/day) prior to the first rituximab dose; if clinically indicated, up to 3 additional daily doses of methylprednisolone could be administered.1, 105 For remission induction, patients received 4 once-weekly infusions of rituximab 375 mg/m² in combination with oral prednisolone or prednisone (1 mg/kg per day [up to a maximum of 60 mg/day], tapered to 0.2 mg/kg per day [up to a maximum of 10 mg/day] by month 6).1, 105 After the remission induction phase, patients could receive subsequent rituximab infusions on or after month 6 to maintain remission and disease control.1, 105 Patients who had not achieved remission by month 6 or who had progressive disease or flare that could not be controlled by glucocorticoids alone received additional treatment with rituximab and/or other therapies (at the discretion of the investigator).1 Efficacy outcomes in this study were considered exploratory and primarily assessed using the Pediatric Vasculitis Activity Score (PVAS).1, 105 Remission was defined as a PVAS score of 0 with successful tapering of glucocorticoids to 0.2 mg/kg per day (or 10 mg/day, whichever is lower), or a PVAS score of 0 on 2 consecutive visits at least 4 weeks apart (irrespective of glucocorticoid dose).1, 105

The median age of patients enrolled in the study was 14 years, and 80% of patients were female; 76% of patients had GPA, 24% had MPA, and 72% had newly diagnosed disease.1 Remission was achieved in 56% of patients by month 6, 92% of patients by month 12, and 100% of patients by month 18.1, 105 Approximately half of the patients (14 patients; 56%) received additional rituximab treatment between month 6 and month 18.1 Five patients received 4 once-weekly doses of IV rituximab 375 mg/m² approximately every 6 months, 5 patients received a single 375 mg/m² dose of rituximab every 6 months, and 4 patients received various other rituximab doses/regimens.1 Of the 14 patients who received follow-up treatment between month 6 and month 18, 4 patients achieved their first remission between months 6 and 12 and 1 patient achieved their first remission between months 12 and 18; the remaining 9 patients achieved remission by month 6 but required additional follow-up treatment.1

Clinical Perspective

GPA and MPA are types of ANCA-associated vasculitis that lead to necrotizing inflammation of small blood vessels.1990, 1991 Recommendations for the treatment of ANCA-associated vasculitis are provided by the ACR and the Kidney Disease: Improving Global Outcomes (KDIGO) workgroup.1990, 1991

The ACR conditionally recommends rituximab over cyclophosphamide for remission induction in patients with active, severe GPA or MPA.1990 Either IV pulsed glucocorticoids or high-dose oral glucocorticoids may be prescribed as part of initial therapy for severe disease; the dose of glucocorticoids should be individualized, but a reduced-dose glucocorticoid regimen is conditionally recommended over a standard-dose regimen to reduce toxicities associated with glucocorticoid use.1990 Once a patient with severe disease has entered remission, maintenance treatment with rituximab is conditionally recommended over maintenance treatment with methotrexate or azathioprine.1990 For patients who relapse with severe disease manifestations, remission reinduction should be performed with rituximab (if the patient is not already receiving rituximab maintenance therapy) or cyclophosphamide (if the patient is receiving rituximab maintenance therapy).1990

The KDIGO guideline recommends glucocorticoids in combination with rituximab or cyclophosphamide for the initial treatment of new-onset ANCA-associated vasculitis.1991 The choice between rituximab and cyclophosphamide for induction therapy should be based on patient-specific factors such as patient age, disease characteristics, and access to treatment.1991 For patients with markedly reduced or rapidly declining glomerular filtration rate, KDIGO recommends cyclophosphamide plus glucocorticoids or a combination of rituximab and cyclophosphamide.1991 For maintenance therapy, KDIGO recommends either rituximab or azathioprine plus low-dose corticosteroids; the choice of therapy should be based on patient-specific factors.1991 Patients with relapsing disease should be reinduced, preferably with rituximab.1991 Consult the KDIGO guideline for additional information.1991

The ACR also states that rituximab may be used (typically in conjunction with glucocorticoids) for remission induction in patients with active, severe eosinophilic GPA†.1990

Pemphigus Vulgaris

Rituximab and its biosimilars are used for the treatment of adults with moderate to severe pemphigus vulgaris.1, 69, 70, 71 Rituximab is designated an orphan drug by FDA for this use.6

Clinical Experience

The indication for rituximab in the treatment of pemphigus vulgaris is based principally on the results of 2 randomized controlled trials.1, 106, 107, 108, 109

In one randomized, open-label, multicenter study, 90 adults with newly-diagnosed, moderate-to-severe pemphigus vulgaris or pemphigus foliaceus were randomized to receive rituximab plus short-term prednisone therapy or long-term prednisone monotherapy.1, 106 Patients in the rituximab group received an initial IV infusion of rituximab 1000 mg on day 1, followed by another 1000 mg infusion on day 15 and maintenance IV infusions of 500 mg at months 12 and 18.1, 106 Patients were premedicated with an antihistamine, acetaminophen, and methylprednisolone prior to each rituximab infusion.1 Patients in the rituximab group also received oral prednisone (0.5 mg/kg per day tapered off over 3 months for moderate disease or 1 mg/kg per day tapered off over 6 months for severe disease).1, 106 Patients in the rituximab group who relapsed could receive an additional infusion of rituximab 1000 mg in combination with reintroduced or escalated prednisone; maintenance and relapse infusions could not be administered within 16 weeks of a previous rituximab infusion.1 Patients in the prednisone monotherapy group received oral prednisone 1 mg/kg per day tapered off over 12 months if they had moderate disease or 1.5 mg/kg per day tapered off over 18 months if they had severe disease.1, 106 The primary endpoint of the study was complete remission (defined as complete epithelialization and absence of new and/or established lesions) at month 24 without the use of prednisone therapy for at least 2 months.1, 106

Of the 90 patients included in the trial, 74 patients had pemphigus vulgaris and 16 had pemphigus foliaceus.1 Patients were 19-79 years of age, and most had severe disease at baseline.1 Among the patients with pemphigus vulgaris, complete remission rates at month 24 were 90% in the rituximab group and 28% in the prednisone group.1, 107 In a long-term follow-up analysis of the overall trial population, after a median follow-up of 7.3 years, rituximab plus prednisone was found to decrease the relapse rate by more than 2-fold compared with prednisone alone.108

An additional randomized, double-blind, multicenter study enrolled 135 patients with moderate-to-severe pemphigus vulgaris; patients in this study were receiving 60-120 mg/day oral prednisone (or equivalent) at study entry, and were tapered down to a prednisone dose of 60 or 80 mg/day by day 1 of study treatment.1, 109 Patients were randomized to receive 52 weeks of treatment with IV rituximab (1000 mg on day 1, day 15, week 24, and week 26) or oral mycophenolate mofetil (1 g/day initially with titration to a goal dosage of 2 g/day by week 2).1, 109 Patients continued 60 or 80 mg/day oral prednisone initially, with a goal of tapering and discontinuing prednisone by week 24.1, 109 Of the 135 patients enrolled, only 125 patients were included in the primary efficacy analysis.1, 109 The primary efficacy endpoint was the proportion of patients achieving sustained complete remission (defined as healing of lesions with no new active lesions and no oral glucocorticoid use) for at least 16 consecutive weeks.1, 109 Sustained complete remission was achieved in 40.3% of patients treated with rituximab and 9.5% of patients treated with mycophenolate mofetil.1 Disease flare (defined as the appearance of 3 or more new lesions a month that do not heal spontaneously within 1 week or extension of established lesions in a patient who had achieved disease control) was also less common among patients treated with rituximab.1

Clinical Perspective

Pemphigus is a group of life-threatening autoimmune bullous diseases characterized by flaccid blisters and erosions of the mucous membranes and/or skin.1992 The primary goal of pemphigus treatment is to control and heal bullous skin and/or mucous lesions while minimizing adverse effects of treatment.1992 Rituximab is generally considered a first-line treatment for moderate or severe pemphigus vulgaris; it is typically administered with systemic corticosteroids initially, although it may be administered alone or with topical corticosteroids in patients with absolute contraindications to systemic corticosteroids.1992 If rituximab is contraindicated or not available, therapeutic options include systemic corticosteroid therapy alone or systemic corticosteroids in conjunction with a corticosteroid-sparing immunosuppressive agent (e.g., azathioprine, mycophenolate mofetil).1992 Rituximab has also been used for the treatment of mild pemphigus vulgaris† and pemphigus foliaceus†.1992

Antibody-mediated Organ Transplant Rejection

Although evidence is limited, rituximab has been used for the treatment of hyperacute and acute antibody-mediated rejection in heart transplant recipients†.1993 Rituximab has also been used in conjunction with IV immunoglobulin and plasma exchange for the treatment of refractory acute antibody-mediated rejection in liver transplant recipients† who do not respond adequately to initial therapy with high-dose corticosteroids and immunosuppressants.1994 Rituximab has also been used to treat acute antibody-mediated rejection in kidney transplant recipients†.1995

Autoimmune Hemolytic Anemia

Rituximab has been used for the treatment of primary warm autoimmune hemolytic anemia†.119, 2109 It is typically used second line in patients with an inadequate response to corticosteroids, but it may be used for first-line treatment (in combination with corticosteroids) in patients with severe disease or elderly patients with comorbidities.2109 Rituximab may also be useful for the treatment of warm autoimmune hemolytic anemia secondary to CLL, systemic lupus erythematosus, or common variable immunodeficiency†.2109

Rituximab is considered a first-line treatment for primary cold agglutinin disease (cold agglutinin-mediated autoimmune hemolytic anemia)†; it may be given alone or in combination with bendamustine.2109 Rituximab has also been used in combination with bendamustine or fludarabine for the second-line treatment of primary cold agglutinin disease.2109

Dermatomyositis and Polymyositis

Rituximab has been used for the treatment of dermatomyositis† in adults and pediatric patients and polymyositis† in adults.110 Although other therapies (e.g., high-dose glucocorticoids, conventional DMARDs) are typically recommended first line, rituximab is an option for refractory disease.1996, 1997 Rituximab may be particularly useful for juvenile-onset disease, patients with a positive myositis autoantibody profile, and patients with a lower burden of disease damage.1996 Rituximab may also be useful to manage rapidly-progressing interstitial lung disease (in conjunction with high-dose glucocorticoids) or treatment-resistant chronic interstitial lung disease associated with dermatomyositis/polymyositis.1996

Graft-versus-host Disease

Based on limited evidence, rituximab has been used for the treatment of chronic graft-versus-host disease †.1998 It may be considered as a second-line treatment option for patients with refractory musculoskeletal or cutaneous manifestations of chronic graft-versus-host disease; it may also be considered as a third-line option for patients with chronic graft-versus-host disease involving other organs.1998

Immune Checkpoint Inhibitor Toxicity

Rituximab has been used for the management of adverse events related to immune checkpoint inhibitors†.2107, 2108 A guideline published by the American Society of Clinical Oncology (ASCO) states that rituximab may be useful for various manifestations of immune checkpoint inhibitor toxicity, including grade 3 or 4 bullous pemphigoid, grade 3 or 4 myositis that does not respond adequately to first-line treatments, grade 3 or 4 myasthenia gravis refractory to IV immunoglobulin or plasmapheresis, selected types of encephalitis (including refractory disease), grade 4 hemolytic anemia that is severe and/or does not respond to corticosteroids, grade 3 or 4 acquired thrombotic thrombocytopenic purpura, grade 3 or 4 immune thrombocytopenia (if previous treatment with corticosteroids and/or IV immunoglobulin was unsuccessful), and grade 2-4 acquired hemophilia A.2107 Another guideline from the Society for Immunotherapy of Cancer (SITC) states that rituximab may be useful for grade ≥2 pemphigus or bullous pemphigoid, vasculitis, primary myositis, corticosteroid-refractory encephalitis, or severe/corticosteroid-refractory immune thrombocytopenia related to immune checkpoint inhibitor therapy.2108 Consult the guidelines for additional information.2107, 2108

Immune Thrombocytopenia

Rituximab has been used for the treatment of immune thrombocytopenia (ITP; also known as idiopathic thrombocytopenic purpura and immune thrombocytopenic purpura)† in adult patients.111, 112, 1999 Rituximab also has been used in pediatric patients with ITP refractory to standard therapy†.113, 1999

The American Society of Hematology has published a guideline on the treatment of ITP.1999 According to this guideline, rituximab is typically reserved for the second-line treatment of ITP; however, for adults with newly-diagnosed ITP, combination therapy with rituximab and corticosteroids may be considered over corticosteroids alone if high value is placed on the possibility for remission over concerns for potential adverse effects.1999 Options for second-line therapy of ITP in adults who are corticosteroid-dependent or who do not respond to corticosteroids include splenectomy, thrombopoietin receptor agonists, and rituximab.1999 In general, rituximab is suggested over splenectomy, and thrombopoietin receptor agonists are suggested over rituximab.1999 Choice of therapy should be individualized based on duration of ITP, frequency of bleeding episodes requiring hospitalization or rescue medication, comorbidities, patient age, medication adherence, medical and social support networks, patient values and preferences, cost, and availability.1999 For pediatric patients with ITP, second-line therapy options are similar to those available for adults; the American Society of Hematology generally suggests thrombopoietin receptor agonists over rituximab or splenectomy and rituximab over splenectomy in this setting.1999

Interstitial Lung Disease

Rituximab has been used for the treatment of interstitial lung disease (ILD)† associated with systemic autoimmune rheumatic diseases (SARD; e.g., systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective tissue disease, Sjogren disease).2100 A guideline from the ACR lists rituximab as one of several options for first-line or second-line treatment of SARD-associated ILD, including rapidly progressive disease.2100 Consult the guideline for further information.2100

Lupus Nephritis and Systemic Lupus Erythematosus

Anti-CD20 agents, including rituximab, have been used for the management of non-responsive or refractory lupus nephritis†.2101, 2104 These agents are typically reserved for last-line therapy and used in conjunction with glucocorticoids and other immunosuppressants (e.g., mycophenolate mofetil, belimumab, calcineurin inhibitors).2101

Anti-CD20 agents, including rituximab, have also been used for the management of certain hematologic, neuropsychiatric, cardiopulmonary, and vascular manifestations of systemic lupus erythematosus (SLE)† that are refractory to initial hydroxychloroquine therapy.2102 A guideline from the ACR provides recommendations for the management of SLE, including recommendations for various organ-specific manifestations.2102 For patients with symptomatic thrombocytopenia (i.e., active significant bleeding) or symptomatic autoimmune hemolytic anemia (i.e., with ischemic manifestations and/or hemodynamic instability) attributed to SLE, the guideline conditionally recommends initial glucocorticoid therapy plus IV immunoglobulin and/or anti-CD20 therapy.2102 For patients with active lupus optic neuritis, lupus acute confusional state, or active lupus mononeuritis multiplex, the guideline conditionally recommends initial therapy with pulse/high-dose glucocorticoid taper plus immunosuppressive therapy with IV cyclophosphamide, mycophenolate mofetil, or anti-CD20 therapy.2102 For active lupus psychosis, a conditional recommendation is made for adding glucocorticoids, IV cyclophosphamide, mycophenolate mofetil, or anti-CD20 therapy to antipsychotic therapy.2102 For patients with seizures attributed to active SLE, the guideline conditionally recommends administering glucocorticoids, cyclophosphamide, mycophenolate mofetil, azathioprine, or anti-CD20 therapy alongside antiseizure medications.2102 For severe vasculitis attributed to SLE, the guideline conditionally recommends IV cyclophosphamide or anti-CD20 therapy over other immunosuppressant therapies for initial treatment.2102 For patients with acute and/or worsening lupus myocarditis, the guideline conditionally recommends adding IV cyclophosphamide, mycophenolate mofetil, anti-CD20 therapy, and/or IV immunoglobulin to glucocorticoid treatment.2102 Consult the guideline for additional details.2102

Membranous Nephropathy

Rituximab has been used for the treatment of membranous nephropathy†.2103 A guideline from KDIGO provides recommendations for the treatment of membranous nephropathy based on the patient's risk for progressive loss of kidney function (as determined by factors such as current symptoms, estimated glomerular filtration rate [eGFR], proteinuria, serum albumin, antibodies against the M-type phospholipase A2 receptor, and various other urinary biomarkers).2103 Rituximab is a recommended option for patients at moderate or high risk of progressive loss of kidney function.2103 For patients at moderate risk of progressive loss of kidney function, recommended treatment options include rituximab or calcineurin inhibitors, with or without glucocorticoids.2103 For patients at high risk of progressive loss of kidney function, options include rituximab, cyclophosphamide plus glucocorticoids, or rituximab plus a calcineurin inhibitor.2103 Rituximab is also used in patients who relapse after initial therapy for membranous nephropathy and certain patients with treatment-resistant disease.2103 Consult the guideline for additional information.2103

Minimal Change Disease

Rituximab has been used for the treatment of frequently relapsing/steroid-dependent minimal change disease†.2103 According to a guideline from KDIGO, high-dose oral glucocorticoids are recommended for initial treatment of minimal change disease in adults; for patients who cannot receive glucocorticoids, other immunosuppressants (cyclophosphamide, calcineurin inhibitors, mycophenolate mofetil) are recommended first line.2103 For patients with frequently relapsing/steroid-dependent minimal change disease, recommended treatment options include rituximab, cyclophosphamide, calcineurin inhibitors, or mycophenolate mofetil.2103

Multiple Sclerosis

Rituximab has been used for the treatment of relapsing forms of multiple sclerosis†.114, 115 In one randomized controlled trial of adults with early relapsing-remitting multiple sclerosis or clinically isolated syndrome, rituximab was found to reduce the risk of relapse over 24 months compared with dimethyl fumarate.115 A Cochrane review concluded that rituximab compares favorably with a number of approved disease-modifying therapies for preventing relapses in patients with relapsing forms of multiple sclerosis; however, it is unclear whether rituximab prevents disability worsening in this setting.114

Myasthenia Gravis

Rituximab has been used for the treatment of myasthenia gravis†, although data from randomized controlled trials are limited.116, 2105 A Cochrane review including 2 small randomized controlled trials concluded that rituximab likely reduces the number of relapses requiring rescue therapy over a 9-month period compared with placebo.116 Its effects on symptom severity and functional ability in the long-term remain uncertain.116 A guideline from a group of international experts recommends rituximab as an early therapeutic option for patients with muscle-specific kinase (MuSK) antibody-positive myasthenia gravis who have an unsatisfactory response to initial immunotherapy.2105 Rituximab can also be considered for patients with refractory acetylcholine receptor (AChR) antibody-positive myasthenia gravis who have failed or did not tolerate other immunosuppressive agents.2105

Neuromyelitis Optica

Rituximab has been used for the treatment of neuromyelitis optica spectrum disorders†, although data from randomized controlled trials to support this use are limited.117, 118 In one randomized controlled trial of 38 Japanese patients with neuromyelitis optica spectrum disorders who were seropositive for aquaporin 4 (AQP4) antibody, rituximab was more effective for preventing disease relapse than placebo over the 72-week follow-up period.117 Another randomized controlled trial in 86 patients with neuromyelitis optica spectrum disorders found that rituximab reduced the annualized relapse rate and expanded disability extended scale (EDSS) score more effectively than azathioprine.118

Thrombotic Thrombocytopenic Purpura

Rituximab has been used for the treatment of immune thrombotic thrombocytopenic purpura (iTTP)†.2106 Combination therapy with rituximab, corticosteroids, and therapeutic plasma exchange is a recommended treatment strategy for patients experiencing a first acute iTTP event or acute relapse.2106 In patients with iTTP who are in remission but still have low plasma ADAMTS-13 activity, rituximab may be useful for relapse prevention.2106

Other Hematologic Cancers

Rituximab also has been used in the treatment of CD20-positive B-cell acute lymphoblastic leukemia (ALL)†, nodular lymphocyte-predominant Hodgkin lymphoma†, hairy cell leukemia†, and primary CNS lymphoma†.3008, 3009, 3010, 3011

Dosage and Administration ⬆ ⬇

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential prior to initiating therapy.1, 68
Screen all patients for hepatitis B infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibodies (anti-HBc) prior to initiating therapy.1, 68
Obtain CBC (including platelets) prior to initiating therapy.1
Review the patient's vaccination history and administer any necessary immunizations prior to initiating therapy.1 Administer non-live vaccines at least 4 weeks prior to course of rituximab therapy.1

Patient Monitoring

In patients with lymphoid malignancies, obtain CBC with differential and platelet counts prior to each course of rituximab.1 During treatment with rituximab and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias.1
In patients with rheumatoid arthritis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or pemphigus vulgaris, obtain CBC with differential and platelet counts at 2-4 month intervals during therapy.1 Monitor for cytopenias after the final dose and until resolution.1
Monitor for signs and symptoms of infusion-related reactions or administration reactions, especially in patients with pre-existing cardiac or pulmonary conditions, patients who have experienced prior cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (≥25,000 cells/mm³).1, 68
Monitor patients with evidence of current or prior hepatitis B infection for clinical and laboratory signs of hepatitis or hepatitis B reactivation during and for several months following therapy.1, 68
Perform cardiac monitoring during and after all rituximab administrations in patients who develop clinically significant cardiac arrhythmias or who have a history of arrhythmia or angina.1, 68
Monitor closely for signs of renal failure.1, 68
If biologic agents or disease-modifying antirheumatic drugs (DMARDs) are used concomitantly with rituximab, monitor closely for signs of infection.1

Premedication and Prophylaxis

Premedicate with acetaminophen and an antihistamine prior to each IV rituximab infusion and each administration of rituximab/hyaluronidase.1, 68 For pediatric patients with mature B-cell non-Hodgkin lymphoma (NHL)/mature B-cell acute leukemia, premedicate with acetaminophen and an H₁ antihistamine (diphenhydramine or equivalent) 30-60 minutes prior to the start of each IV rituximab infusion.1
For patients receiving rituximab/hyaluronidase, consider additional premedication with a glucocorticoid.68
For adults receiving IV rituximab as a 90-minute infusion, administer the glucocorticoid component of their chemotherapy regimen prior to infusion.1
For patients with rheumatoid arthritis, GPA, MPA, or pemphigus vulgaris, administer methylprednisolone 100 mg IV or its equivalent 30 minutes prior to each IV rituximab infusion.1
In patients with chronic lymphocytic leukemia (CLL), provide prophylactic treatment for Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections during treatment and for up to 12 months after the last dose as appropriate.1, 68
In patients with GPA or MPA, provide prophylactic treatment for PCP during treatment and for at least 6 months after the last dose.1
In patients with pemphigus vulgaris, consider PCP prophylaxis during and following treatment.1
Administer aggressive IV hydration and anti-hyperuricemic therapy in patients at high risk for tumor lysis syndrome.1, 68

Dispensing and Administration Precautions

The Institute for Safe Medication Practices (ISMP) includes riTUXimab and inFLIXimab, and Rituxan^® and Rituxan Hycela^® on their List of Confused Drug Names, and recommends using special safeguards to ensure the accuracy of prescriptions for these drugs.555
To prevent medication errors, check vial labels to ensure that the drug being prepared and administered is the intended rituximab product (IV rituximab or subcutaneous rituximab/hyaluronidase); do not administer rituximab/hyaluronidase IV.68

Other General Considerations

All patients must receive at least 1 full dose of an IV rituximab product without experiencing severe adverse reactions prior to starting treatment with rituximab/hyaluronidase.68 Do not switch to rituximab/hyaluronidase if the patient is not able to receive 1 full dose of IV rituximab; continue subsequent cycles with an IV rituximab product until a full IV dose is successfully administered.68

Administration

Rituximab and its biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) are administered by IV infusion.1, 69, 70, 71 These products should not be administered by rapid IV injection.1

Rituximab/hyaluronidase is administered by subcutaneous injection only; it should not be administered by IV infusion.68

Rituximab and rituximab/hyaluronidase should only be administered by healthcare professionals with the medical support necessary to manage severe infusion-related reactions.1, 68

IV Administration (Rituximab and Biosimilars)

Rituximab and its biosimilars are supplied in preservative-free vials containing 10 mg/mL solutions.1, 69, 70, 71 Store unopened vials of rituximab products under refrigeration at 2-8°C; protect the vials from direct sunlight and do not freeze or shake.1, 69, 70, 71

Dilution

Rituximab products are supplied as injection concentrates and must be diluted prior to IV infusion.1, 69, 70, 71 For IV infusion, the appropriate dose should be withdrawn and diluted in the appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield a final concentration of 1-4 mg/mL.1, 69, 70, 71 Aseptic technique should be used, and the IV bag should be gently inverted to mix the solution.1, 69, 70, 71 Any unused solution remaining in the vial should be discarded.1, 69, 70, 71 No other drug should be added to or administered in the same IV line.1, 69, 70, 71 Prior to administration, solutions should be inspected visually for particulate matter and discoloration.1, 69, 70, 71 If particulate matter or discoloration is evident, the solution should not be used.1, 69, 70, 71

Diluted solutions of rituximab and rituximab-abbs may be stored under refrigeration at 2-8°C for 24 hours and are stable for an additional 24 hours at room temperature.1, 71 Diluted solutions of rituximab-arrx made with 0.9% sodium chloride may be stored under refrigeration at 2-8°C for up to 7 days with protection from light; diluted solutions made with 5% dextrose may be stored under refrigeration at 2-8°C for up to 24 hours.69 Diluted solutions of rituximab-pvvr made with 0.9% sodium chloride may be stored under refrigeration at 2-8°C for up to 16 days; diluted solutions made with 5% dextrose may be stored under refrigeration at 2-8°C for up to 24 hours.70 No incompatibilities with polyvinylchloride or polyethylene bags have been observed for diluted solutions of rituximab, rituximab-arrx, and rituximab-abbs; no incompatibilities with polyvinylchloride bags have been observed for diluted solutions of rituximab-pvvr.1, 69, 70, 71

Rate of Administration

Initial infusions should be started at a rate of 50 mg/hour; if infusion-related events do not occur, the infusion rate may be increased in increments of 50 mg/hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1, 69, 70, 71 In patients who tolerate the first infusion well, subsequent infusions may be administered at an initial infusion rate of 100 mg/hour; the rate of infusion may be increased in increments of 100 mg/hour every 30 minutes as tolerated to a maximum infusion rate of 400 mg/hour.1, 69, 70, 71

For pediatric patients with mature B-cell NHL or mature B-cell acute leukemia, infusions should be started at a rate of 0.5 mg/kg per hour (maximum of 50 mg/hour); if infusion-related events do not occur, the infusion rate may be increased in increments of 0.5 mg/kg per hour every 30 minutes to a maximum infusion rate of 400 mg/hour.1 In patients who tolerate the first infusion well, subsequent infusions may be administered at an initial infusion rate of 1 mg/kg per hour (maximum of 50 mg/hour); the rate of infusion may be increased in increments of 1 mg/kg per hour every 30 minutes as tolerated to a maximum infusion rate of 400 mg/hour.1

Patients with previously untreated follicular non-Hodgkin lymphoma (NHL) or previously untreated diffuse large B-cell NHL who are receiving rituximab or a rituximab biosimilar in combination with a glucocorticoid-containing chemotherapy regimen may receive the second rituximab product dose at an accelerated infusion rate if they tolerate the first dose (administered at the standard rate) without experiencing grade 3 or 4 infusion-related events.1, 69, 70, 71 In such patients, the second rituximab product infusion may be administered over a total infusion time of 90 minutes, with 20% of the total dose administered over the first 30 minutes and the remaining 80% of the total dose administered over the next 60 minutes.1, 69, 70, 71 Those who tolerate this 90-minute infusion may receive subsequent doses (through cycle 6 or 8) at the same 90-minute infusion rate.1, 69, 70, 71 Patients should receive the glucocorticoid component of the chemotherapy regimen prior to each rituximab product infusion to reduce the incidence and severity of infusion reactions.1, 69, 70, 71 Patients with clinically important cardiovascular disease or with a high circulating lymphocyte count (5000 cells/mm³ or greater) before cycle 2 should not receive infusions of rituximab products over 90 minutes.1, 69, 70, 71

Subcutaneous Administration (Rituximab/Hyaluronidase)

Rituximab/hyaluronidase is administered subcutaneously by a healthcare professional.68 Dilution of rituximab/hyaluronidase is not required prior to administration.68

Rituximab/hyaluronidase is supplied in single-dose vials containing 1400 mg rituximab/23,400 units hyaluronidase per 11.7 mL or 1600 mg rituximab/26,800 units hyaluronidase per 13.4 mL.68 Store unopened vials of rituximab/hyaluronidase under refrigeration at 2-8°C in the original carton to protect from light; do not freeze.68

Use a sterile needle and syringe to prepare rituximab/hyaluronidase for administration.68 Rituximab/hyaluronidase is compatible with polypropylene and polycarbonate syringe material and stainless steel transfer and injection needles.68 Using a 20 mL syringe, withdraw the required volume from the vial with a narrow (e.g., 25-30 gauge) needle of any length.68 Label the syringe with the provided peel-off label.68 Change the needle to a 1/2” to 5/8” long, narrow gauge needle (e.g., 25-30 gauge) immediately prior to subcutaneous administration to avoid needle clogging.68 Visually inspect the solution for particulate matter and discoloration prior to administration; if particulate matter or discoloration is present, do not use the solution.68

Use the prepared rituximab/hyaluronidase solution immediately; if it is not used immediately, it may be stored under refrigeration at 2-8°C for up to 48 hours and subsequently for 8 hours at room temperature up to 30°C in diffuse light.68

Inject rituximab/hyaluronidase into the subcutaneous tissue of the abdomen; do not inject into areas where the skin is red, bruised, tender, or hard, or areas with moles or scars.68 If administering a dose of 11.7 mL rituximab/hyaluronidase, administer over approximately 5 minutes; if administering a dose of 13.4 mL of rituximab/hyaluronidase, administer over approximately 7 minutes.68 If administration is interrupted, continue administration at the same site or at a different site on the abdomen.68 Do not administer other medications at the same sites as rituximab/hyaluronidase.68

Observe patients for at least 15 minutes following rituximab/hyaluronidase administration.68

Dosage

Adults

Non-Hodgkin Lymphoma - IV Rituximab and Biosimilars

For the treatment of relapsed or refractory low-grade or follicular, CD20-positive, B-cell NHL, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion once weekly for 4 weeks or 8 weeks.1, 69, 70, 71 Patients who subsequently develop progressive disease following response to previous IV rituximab product therapy may receive an additional course of 375 mg/m² by IV infusion once weekly for 4 weeks.1, 69, 70, 71

For the treatment of previously untreated follicular, CD20-positive, B-cell NHL, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion on day 1 of each cycle of chemotherapy for up to 8 doses.1, 69, 70, 71 In patients with complete or partial response, maintenance therapy with single-agent IV rituximab (or biosimilar) should be initiated 8 weeks after completion of combination therapy with an IV rituximab product and chemotherapy.1, 69, 70, 71 Rituximab maintenance therapy is administered at a dosage of 375 mg/m² every 8 weeks for a total of 12 doses.1, 69, 70, 71

For the treatment of nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL following first-line therapy with 6-8 cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP), the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion once weekly for 4 doses every 6 months for up to a maximum of 16 doses.1, 69, 70, 71

For the treatment of previously untreated diffuse large B-cell NHL, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion on day 1 of each cycle of chemotherapy (such as cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) for up to 8 doses total.1, 69, 70, 71

When rituximab has been used in combination with bendamustine† in adults with relapsed or refractory indolent NHL or relapsed or refractory mantle cell lymphoma†, rituximab 375 mg/m² has been administered by IV infusion on day 1, followed by IV infusion (over 30-60 minutes) of bendamustine hydrochloride 90 mg/m² on days 2 and 3.10002, 10003 The bendamustine-rituximab regimen has been administered on a 28-day cycle for a total of 4-6 cycles.10002, 10003 An additional dose of rituximab has been administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10002, 10003

When rituximab has been used in combination with bendamustine† in adults with previously untreated advanced-stage indolent NHL or previously untreated advanced-stage mantle cell lymphoma†, rituximab 375 mg/m² has been administered by IV infusion on day 1, followed by IV infusion (over 30-60 minutes) of bendamustine hydrochloride 90 mg/m² on days 1 and 2.10001, 10018 The bendamustine-rituximab regimen has been administered on a 28-day cycle for up to 8 cycles.10001, 10018

Non-Hodgkin Lymphoma - Rituximab/Hyaluronidase

For the treatment of relapsed or refractory follicular lymphoma, the recommended dosage of rituximab/hyaluronidase is 1400 mg rituximab/23,400 units hyaluronidase administered subcutaneously once weekly for 3 or 7 weeks following a full dose of an IV rituximab product at week 1 (i.e., 4 or 8 weeks in total).68 Patients who subsequently develop progressive disease following response to previous therapy may receive an additional course of 1400 mg rituximab/23,400 units hyaluronidase administered once weekly for 3 weeks following a full dose of an IV rituximab product at week 1 (i.e., 4 weeks in total).68

For the treatment of previously untreated follicular lymphoma, the recommended dosage of rituximab/hyaluronidase is 1400 mg rituximab/23,400 units hyaluronidase administered subcutaneously on day 1 of cycles 2-8 of chemotherapy (every 21 days) for up to 7 cycles following a full dose of an IV rituximab product on day 1 of cycle 1 of chemotherapy (i.e., up to 8 cycles in total).68 In patients with complete or partial response, maintenance therapy with single-agent rituximab/hyaluronidase should be initiated 8 weeks after completion of combination therapy with rituximab/hyaluronidase and chemotherapy.68 Maintenance therapy is administered at a dosage of 1400 mg rituximab/23,400 units hyaluronidase subcutaneously every 8 weeks for a total of 12 doses.68

For the treatment of nonprogressing (including stable disease) follicular lymphoma following first-line therapy with 6-8 cycles of CVP chemotherapy and a full dose of an IV rituximab product at week 1, the recommended dosage of rituximab/hyaluronidase is 1400 mg rituximab/23,400 units hyaluronidase subcutaneously once weekly for 3 weeks (i.e., 4 weeks total) every 6 months for up to a maximum of 16 doses.68

For the treatment of previously untreated diffuse large B-cell lymphoma, the recommended dosage of rituximab/hyaluronidase is 1400 mg rituximab/23,400 units hyaluronidase subcutaneously on day 1 of cycles 2-8 of CHOP chemotherapy for up to 7 cycles following a full dose of an IV rituximab product on day 1 of cycle 1 of CHOP chemotherapy (i.e., up to 6-8 cycles total).68

Chronic Lymphocytic Leukemia - IV Rituximab and Biosimilars

For the treatment of previously untreated antigen CD20-positive CLL, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion on day 0 (one day prior to initiation of the first cycle of chemotherapy with fludarabine and cyclophosphamide [FC]), followed by 500 mg/m² administered by IV infusion on day 1 of subsequent FC cycles (cycles 2-6, administered every 28 days), for up to 6 doses total.1, 69, 70, 71

For the treatment of previously treated antigen CD20-positive CLL, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² administered by IV infusion on day 0 (one day prior to initiation of the first cycle of chemotherapy with FC), followed by 500 mg/m² administered by IV infusion on day 1 of subsequent FC cycles (cycles 2-6, administered every 28 days), for up to 6 doses total.1, 69, 70, 71

Chronic Lymphocytic Leukemia - Rituximab/Hyaluronidase

For the treatment of previously untreated CLL, the recommended dosage of rituximab/hyaluronidase is 1600 mg rituximab/26,800 units hyaluronidase administered subcutaneously on day 1 of FC cycles 2-6 (every 28 days), for a total of 5 cycles following a full dose of an IV rituximab product on day 1 of FC cycle 1 (i.e., 6 cycles in total).68

For the treatment of previously treated CLL, the recommended dosage of rituximab/hyaluronidase is 1600 mg rituximab/26,800 units hyaluronidase administered subcutaneously on day 1 of FC cycles 2-6 (every 28 days), for a total of 5 cycles following a full dose of an IV rituximab product on day 1 of FC cycle 1 (i.e., 6 cycles in total).68

Rheumatoid Arthritis - IV Rituximab and Biosimilars

For the treatment of rheumatoid arthritis, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) in combination with methotrexate is 1 g administered as an IV infusion on days 1 and 15 (for a total of 2 doses per course).1, 69, 70, 71 Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.1, 69, 70, 71

Granulomatosis with Polyangiitis and Microscopic Polyangiitis - IV Rituximab and Biosimilars

For induction treatment of active GPA/MPA in adults, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 375 mg/m² by IV infusion once weekly for 4 weeks; rituximab should be administered in combination with glucocorticoids (i.e., methylprednisolone 1000 mg IV per day for 1-3 days followed by oral prednisone).1, 69, 70, 71 The glucocorticoid regimen should begin within 14 days prior to or with the initiation of the IV rituximab product and may continue during and after the 4-week induction course.1, 69, 70, 71

In patients with GPA/MPA who achieve disease control with induction treatment, the recommended maintenance dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 500 mg by IV infusion on days 1 and 15 followed by a 500 mg infusion every 6 months thereafter based on clinical evaluation.1, 69, 70, 71 If induction treatment was performed with a rituximab product, initiate maintenance treatment within 24 weeks after the last induction infusion or based on clinical evaluation (but no sooner than 16 weeks after the last induction infusion).1, 69, 70, 71 If induction treatment was performed with another standard of care immunosuppressant, initiate rituximab product maintenance treatment within the 4-week period that follows achievement of disease control.1, 69, 70, 71

Pemphigus Vulgaris - IV Rituximab and Biosimilars

For the treatment of pemphigus vulgaris, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 1 g by IV infusion on days 1 and 15 in combination with a tapering course of glucocorticoids.1, 69, 70, 71 For maintenance treatment, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 500 mg by IV infusion at month 12 and every 6 months thereafter or based on clinical evaluation.1, 69, 70, 71 For treatment of relapse, the recommended dosage of IV rituximab or biosimilars (rituximab-abbs, rituximab-arrx, and rituximab-pvvr) is 1 g by IV infusion on relapse, with consideration of resuming or increasing the glucocorticoid dose based on clinical evaluation.1, 69, 70, 71 Subsequent infusions of rituximab products may be administered no sooner than 16 weeks following the previous infusion.1, 69, 70, 71

Antibody-mediated Organ Transplant Rejection - IV Rituximab

For antibody-mediated rejection in heart transplant recipients†, a regimen of rituximab 375 mg/m² IV once weekly for 1-4 weeks has been used.1993

Autoimmune Hemolytic Anemia - IV Rituximab

For warm autoimmune hemolytic anemia†, a regimen of rituximab 1 g IV on days 1 and 15 or 375 mg/m² IV weekly for 4 weeks has been used in conjunction with corticosteroids.2109

For primary cold agglutinin disease (cold agglutinin-mediated autoimmune hemolytic anemia)†, a dosage of rituximab 375 mg/m² IV weekly for 4 weeks has been used.2109

Immune Checkpoint Inhibitor Toxicity - IV Rituximab

For the treatment of adverse events related to immune checkpoint inhibitors†, the typical dosage of IV rituximab is 375 mg/m² once a week for 4 weeks.2107

Interstitial Lung Disease - IV Rituximab

For the treatment of interstitial lung disease (ILD)† associated with systemic autoimmune rheumatic diseases (e.g., systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective tissue disease, Sjogren disease), the typical dosage of IV rituximab is 1 g every 2 weeks for 2 doses; this course of treatment may be repeated every 24 weeks as necessary.2100

Lupus Nephritis and Systemic Lupus Erythematosus - IV Rituximab

For the treatment of systemic lupus erythematosus (SLE)†, the typical dosage of IV rituximab is 1 g on days 1 and 15.2102

Membranous Nephropathy - IV Rituximab

For the treatment of membranous nephropathy†, dosage regimens of rituximab 1 g IV administered twice within 2 weeks and rituximab 375 mg/m² IV once weekly for 1-4 weeks have been used.2102

Minimal Change Disease - IV Rituximab

For the treatment of minimal change disease†, several rituximab induction regimens have been used.2103 These regimens include: rituximab 375 mg/m² IV weekly for 4 doses; a single dose of rituximab 375 mg/m² IV with a repeat dose administered after one week if the patient's CD19 cells are >5 cells/mm³; and rituximab 1 g IV for 2 doses, with doses administered 2 weeks apart.2103 For patients with relapse after induction, single doses of rituximab 375 mg/m² or rituximab 1 g have been administered.2103

Pediatric Patients

Non-Hodgkin Lymphoma - IV Rituximab

For the treatment of pediatric patients ≥6 months of age with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia, the recommended dosage of IV rituximab (in conjunction with systemic Lymphome Malin B [LMB] chemotherapy) is 375 mg/m².1 A total of 6 IV rituximab infusions are administered: 2 infusions are administered during each of the 2 induction courses of LMB, and 1 infusion is administered during each of the 2 consolidation courses of LMB (see Table 2).1

Table 2. Administration Schedule for Rituximab in Conjunction with LMB Chemotherapy in Pediatric Mature B-cell NHL and Mature B-cell Acute Leukemia1

Chemotherapy Cycle	Day of Treatment	Administration Details
Prephase (COP)	No rituximab administered
Induction courses 1 and 2 (COPDAM1 and COPDAM2)	Day -2 and Day 1 of each course	During the first induction course, administer the prednisone component of the chemotherapy regimen prior to rituximab Administer the second rituximab infusion 48 hours after the first infusion in each course
Consolidation courses 1 and 2 (CYM/CYVE)	Day 1 of each course

Chemotherapy Cycle

Day of Treatment

Administration Details

Prephase (COP)

No rituximab administered

Induction courses 1 and 2 (COPDAM1 and COPDAM2)

Day -2 and Day 1 of each course

During the first induction course, administer the prednisone component of the chemotherapy regimen prior to rituximab

Administer the second rituximab infusion 48 hours after the first infusion in each course

Consolidation courses 1 and 2 (CYM/CYVE)

Day 1 of each course

Abbreviations: COP: cyclophosphamide, Oncovin^® (vincristine), prednisone; COPDAM: cyclophosphamide, Oncovin^® (vincristine), prednisolone, Adriamycin^® (doxorubicin), methotrexate; CYM: cytarabine plus methotrexate; CYVE: cytarabine plus veposide (VP16); LMB: Lymphome Malin B.

Granulomatosis with Polyangiitis and Microscopic Polyangiitis - IV Rituximab

For induction treatment of active GPA/MPA in pediatric patients ≥2 years of age, the recommended dosage of IV rituximab is 375 mg/m² by IV infusion once weekly for 4 weeks.1 Prior to the first rituximab infusion, administer IV methylprednisolone 30 mg/kg (not to exceed 1 g/day) once daily for 3 days; then, begin oral glucocorticoid therapy as per clinical practice.1

In pediatric patients with GPA/MPA who achieve disease control with induction treatment, the recommended maintenance dosage of IV rituximab is 250 mg/m² by IV infusion on days 1 and 15 followed by a 250 mg/m² infusion every 6 months thereafter based on clinical evaluation.1 If induction treatment was performed with rituximab, initiate maintenance treatment within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation (but no sooner than 16 weeks after the last induction infusion).1 If induction treatment was performed with other standard of care immunosuppressants, initiate rituximab maintenance treatment within the 4-week period that follows achievement of disease control.1

Lupus Nephritis and Systemic Lupus Erythematosus - IV Rituximab

For the treatment of systemic lupus erythematosus (SLE)†, a dosage of 375 mg/m² (maximum: 1 g/dose) IV weekly for 4 doses or a dosage of 750 mg/m² (maximum: 1 g/dose) IV every 2 weeks for 2 doses may be used.2102

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Depending on the severity of the symptoms, temporary or permanent discontinuance of rituximab-containing products may be warranted when severe adverse effects occur.1, 68 Dosage reductions of rituximab/hyaluronidase are not recommended; when rituximab/hyaluronidase is given in combination with chemotherapy, reduce the dosage of the chemotherapeutic drugs to manage adverse reactions.68

Infusion- and Administration-related Reactions

Depending on the severity of the infusion reaction and the required interventions, IV rituximab should be temporarily or permanently discontinued.1 Once manifestations of infusion reactions have resolved, the IV infusion may be resumed but the rate of infusion should be reduced by at least 50%.1

If signs of a severe reaction and/or cytokine release syndrome are observed during rituximab/hyaluronidase administration, the injection should be interrupted immediately and aggressive symptomatic treatment should be initiated.68

Mucocutaneous Effects

In the event of a severe mucocutaneous reaction, rituximab-containing products should be discontinued, and the patient should undergo prompt medical evaluation.1, 68 The safety of readministration of rituximab-containing products in patients who have experienced a severe mucocutaneous reaction to the drug has not been determined.1, 68

Progressive Multifocal Leukoencephalopathy

In patients who develop progressive multifocal leukoencephalopathy (PML), rituximab-containing product therapy should be discontinued and reductions or discontinuance of any concomitant chemotherapy or immunosuppressive therapy should be considered.1, 68

Hepatitis B Virus Reactivation

In patients with reactivation of hepatitis B virus infection, rituximab-containing products and any concomitant chemotherapy should be discontinued, and appropriate treatment, including antiviral therapy, should be initiated.1, 68 It has not been established whether rituximab-containing products can be safely readministered in patients who develop hepatitis B reactivation.1, 68 Clinicians with expertise in managing hepatitis B infection should be consulted regarding resumption of rituximab-containing product therapy once control of the reactivated infection has been achieved.1, 68

Infectious Complications

In patients who develop severe infections, rituximab-containing products should be discontinued, and appropriate anti-infective therapy should be initiated.1, 68

Cardiovascular Effects

Rituximab-containing products should be discontinued in the event of serious or life-threatening cardiac arrhythmias.1, 68

Renal Effects

Rituximab-containing products should be discontinued in patients who experience oliguria or increases in serum creatinine concentrations.1, 68

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1, 68

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1, 68

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1, 68

Cautions ⬆ ⬇

Contraindications

None.1, 68

Warnings/Precautions

Warnings

Infusion-related Reactions

A boxed warning about the risk of infusion-related reactions is included in the prescribing information for IV rituximab.1 Rituximab can cause infusion-related reactions that may be severe or fatal.1 Infusion-related reactions reported with rituximab include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid reactions, and death.1 Severe reactions typically occur during the first infusion, with a time to onset of 30-120 minutes.1

Premedication with an antihistamine and acetaminophen is recommended prior to each rituximab infusion.1 For patients being treated for rheumatoid arthritis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or pemphigus vulgaris, administration of methylprednisolone 100 mg IV (or equivalent) is recommended 30 minutes prior to each rituximab infusion.1 For pediatric patients being treated for mature B-cell non-Hodgkin lymphoma (NHL) or mature B-cell acute leukemia, the manufacturer recommends administering prednisone as part of the chemotherapy regimen prior to the rituximab infusion during induction and as needed for subsequent cycles.1

Closely monitor patients with pre-existing cardiac or pulmonary conditions, patients who have experienced previous cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (≥25,000 cells/mm³).1 If an infusion-related reaction occurs, institute appropriate medical management (e.g., corticosteroids, epinephrine, bronchodilators, oxygen) as needed.1 Depending on the severity of the reaction, temporary or permanent discontinuation of rituximab may be required.1 If rituximab is resumed following resolution of symptoms, reduce the infusion rate by at least 50%.1

Severe Mucocutaneous Reactions

A boxed warning about the risk of severe mucocutaneous reactions is included in the prescribing information for rituximab and rituximab/hyaluronidase.1, 68 Mucocutaneous reactions, including fatal reactions, have been reported in patients receiving rituximab.1, 68 These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis.1, 68 The onset of mucocutaneous reactions has been variable; in some cases, these reactions have occurred on the first day of rituximab exposure.1

Rituximab and rituximab/hyaluronidase should be discontinued in patients who experience severe mucocutaneous reactions.1, 68 The safety of re-administration of rituximab-containing products to patients with severe mucocutaneous reactions has not been determined.1, 68

Hepatitis B Reactivation

A boxed warning about the risk of hepatitis B reactivation is included in the prescribing information for rituximab and rituximab/hyaluronidase.1, 68 Hepatitis B reactivation is defined as an abrupt increase in hepatitis B virus replication, manifesting as a rapid increase in serum hepatitis B virus DNA levels or detection of hepatitis B surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive.1, 68 Reactivation of hepatitis B is often followed by hepatitis (i.e., increased transaminase levels); in severe cases, increased bilirubin levels, liver failure, and death can occur.1, 68

Hepatitis B reactivation has been reported in patients receiving CD20-directed cytolytic antibodies, including rituximab-containing products; in some cases, hepatitis B reactivation led to fulminant hepatitis, hepatic failure, and death.1, 68 Reactivation has occurred in patients who were HBsAg positive as well as in patients who were HBsAg negative but positive for anti-HBc.1 Cases have also been reported in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).1

All patients should be screened for hepatitis B infection before initiation of any rituximab-containing product; HBsAg and anti-HBc should both be measured.1, 68 For patients showing evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative with positive anti-HBc), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy before and/or during treatment with a rituximab-containing product.1, 68 Monitor patients with evidence of current or prior hepatitis B infection for clinical and laboratory signs of hepatitis or hepatitis B reactivation during and for several months after completion of rituximab product therapy.1, 68 Reactivation has been reported up to 24 months following completion of rituximab therapy.1, 68

If hepatitis B reactivation occurs, immediately discontinue the rituximab-containing product and any concomitant chemotherapy, and institute appropriate treatment.1, 68 The safety of resuming rituximab product therapy in patients whose hepatitis B reactivation has resolved is unknown; consult a physician with expertise in managing hepatitis B infection before resuming rituximab product therapy in such patients.1, 68

Progressive Multifocal Leukoencephalopathy

A boxed warning about the risk of progressive multifocal leukoencephalopathy (PML) is included in the prescribing information for rituximab and rituximab/hyaluronidase.1, 68 JC virus infection resulting in PML and death can occur in patients with hematologic malignancies or autoimmune diseases receiving rituximab-containing products.1, 68 The majority of rituximab-treated patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant.1 Patients with autoimmune diseases who were diagnosed with PML on rituximab therapy had received prior or concurrent immunosuppressive therapy.1 Most cases of PML were diagnosed within 12 months of the last rituximab infusion.1

A diagnosis of PML should be considered in any patient presenting with new-onset neurologic manifestations.1, 68 Evaluation for PML includes (but is not limited to) consultation with a neurologist, brain MRI, and lumbar puncture.1, 68 Discontinue rituximab-containing products and consider discontinuation or dosage reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.1, 68

Other Warnings/Precautions

Hypersensitivity and Other Subcutaneous Administration Reactions

Patients must receive at least 1 full dose of an IV rituximab product before receiving rituximab/hyaluronidase due to the higher risk of hypersensitivity and other acute reactions during the first infusion.68 Beginning therapy with an IV product allows for management of hypersensitivity and other administration reactions by slowing or stopping the infusion.68

Rituximab-containing products, including rituximab/hyaluronidase, are associated with hypersensitivity and other administration reactions, which may be related to release of cytokines and/or other chemical mediators.68 Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.68 These reactions may occur irrespective of the route of administration of the rituximab-containing product.68

Severe infusion-related reactions with fatal outcome have been reported with IV rituximab products, with the time of onset ranging from 30 minutes to 2 hours after the start of the infusion.68 These reactions were characterized by pulmonary events in addition to fever, chills, rigors, hypotension, urticaria, angioedema, and other symptoms.68 Anaphylactic and other hypersensitivity reactions can also occur; in contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting the infusion.68

Severe cytokine release syndrome is characterized by severe dyspnea (often associated with bronchospasm and hypoxia), fever, chills, rigors, urticaria, and angioedema.68 This syndrome may lead to acute respiratory failure and death.68 Cytokine release syndrome may occur within 1-2 hours of initiating the infusion.68 Patients with a history of pulmonary insufficiency or those with pulmonary tumor infiltration may be at a greater risk of poor outcome.68 If cytokine release syndrome occurs, immediately interrupt rituximab product administration and initiate aggressive symptomatic treatment.68

Premedicate patients with an antihistamine and acetaminophen prior to each injection of rituximab/hyaluronidase.68 Premedication with glucocorticoids should also be considered.68 Observe patients for at least 15 minutes following rituximab/hyaluronidase administration; a longer observation period may be appropriate in patients with an increased risk of hypersensitivity reactions.68 Closely monitor patients with pre-existing cardiac or pulmonary conditions, patients with a history of prior cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (≥25,000 cells/mm³).68 If signs of a severe reaction are observed during rituximab/hyaluronidase administration, immediately interrupt the injection and initiate aggressive symptomatic treatment.68

Local cutaneous reactions, including injection site reactions, have also been reported in patients receiving rituximab/hyaluronidase.68 Symptoms include pain, swelling, induration, hemorrhage, erythema, pruritus, and rash.68 Some local reactions occurred more than 24 hours after injection.68 The incidence of local cutaneous reactions following rituximab/hyaluronidase administration was 16%; these reactions were mild or moderate and resolved without specific treatment.68 Local cutaneous reactions were most common during the first cycle of rituximab/hyaluronidase, with the incidence decreasing with subsequent injections.68

Tumor Lysis Syndrome

Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after administration of a rituximab-containing product.1, 68 Patients with a high number of circulating malignant cells (≥25,000 cells/mm³) or high tumor burden are at increased risk of tumor lysis syndrome.1, 68

Administer aggressive IV hydration and anti-hyperuricemic therapy in patients at high risk for tumor lysis syndrome.1, 68 Correct any electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis if indicated.1, 68

Infections

Serious and sometimes fatal bacterial, fungal, and viral infections (including new or reactivated viral infections) can occur during and following completion of rituximab-containing therapy.1, 68 New or reactivated viral infections may include cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C.1, 68 Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure).1, 68 The incidence of infections with rituximab/hyaluronidase versus IV rituximab (both in combination with chemotherapy) was 56 versus 49%, respectively, in patients with chronic lymphocytic leukemia (CLL) and 46 versus 41%, respectively, in patients with follicular lymphoma/diffuse large B-cell lymphoma.68

Use of rituximab is not recommended for patients with severe active infections.1 If serious infection develops during rituximab-containing product therapy, discontinue the rituximab-containing product and institute appropriate anti-infective therapy.1, 68

Cardiovascular Adverse Reactions

Cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock, may occur in patients receiving rituximab-containing products.1, 68

Perform cardiac monitoring during and after all administrations of rituximab-containing products in patients who develop clinically significant cardiac arrhythmias or who have a history of arrhythmia or angina.1, 68 If serious or life-threatening cardiac arrhythmias occur, discontinue the rituximab-containing product.1, 68

Renal Toxicity

Severe, sometimes fatal, renal toxicity can occur after administration of a rituximab-containing product in patients with NHL.1, 68 Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials.1, 68 The combination of cisplatin and rituximab or rituximab/hyaluronidase is not an approved treatment regimen.1, 68

Monitor closely for signs of renal failure and discontinue rituximab-containing products in patients with rising serum creatinine levels or oliguria.1, 68

Bowel Obstruction and Perforation

Abdominal pain, bowel obstruction, and perforation, sometimes leading to death, can occur in patients receiving rituximab-containing products in combination with chemotherapy.1, 68 In post-marketing reports, the mean time to documented GI perforation was 6 days (range: 1-77 days) in patients with NHL.1, 68

Evaluate patients if symptoms of obstruction (e.g., abdominal pain, repeated vomiting) occur.1, 68

Immunization

The effect of rituximab on immune responses to non-live vaccines was assessed in a randomized controlled trial in patients with rheumatoid arthritis.1 In this study, the antibody titer response to pneumococcal vaccination (a T-cell independent antigen) was lower among patients who received rituximab plus methotrexate compared with methotrexate alone.1 The antibody titer response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar among patients treated with rituximab plus methotrexate and patients treated with methotrexate alone.1 Most patients in the rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization; the clinical implications of these findings are not known.1

Review the patient's vaccination status and bring patients up-to-date with all recommended immunizations prior to initiating rituximab, if possible.1 Non-live vaccines should be administered at least 4 weeks prior to a course of rituximab.1

The safety of immunization with live viral vaccines following rituximab-containing product therapy has not been studied; therefore, vaccination with live virus vaccines is not recommended before or during treatment.1, 68

Fetal/Neonatal Morbidity and Mortality

Based on human data, rituximab-containing products can cause adverse developmental outcomes, including B-cell lymphocytopenia, in infants exposed to the drug in utero.1, 68 Post-marketing data indicate that B-cell lymphocytopenia following in utero rituximab exposure generally lasts less than 6 months.1 Rituximab has been detected in the serum of infants exposed to rituximab in utero.1 There are no available data on the use of rituximab/hyaluronidase during pregnancy; however, animal studies indicate that subcutaneous hyaluronidase was associated with reduced fetal weight and increased fetal lethality when administered at a dose >2700 times higher than the recommended human dose.68 Comparable systemic exposure levels could occur in a pregnant patient following accidental IV administration of an entire vial of rituximab/hyaluronidase.68

Advise pregnant women of the potential risk to a fetus.1, 68 Verify pregnancy status in females of reproductive potential prior to initiating rituximab-containing products.1, 68 Advise females of reproductive potential to use effective contraception during treatment with rituximab-containing products and for 12 months after the last dose.1, 68 If exposure occurs, monitor newborns and infants for signs of infection and manage accordingly.1, 68

Concomitant Use with Other Agents in Rheumatoid Arthritis, Granulomatosis with Polyangiitis, Microscopic Polyangiitis, and Pemphigus Vulgaris

Limited data are available on the safety of the use of biologic agents or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in rheumatoid arthritis patients exhibiting peripheral B-cell depletion following rituximab treatment.1 Use of concomitant immunosuppressants other than corticosteroids has not been studied in patients with GPA/MPA or pemphigus vulgaris exhibiting peripheral B-cell depletion following rituximab treatment.1

If biologic agents and/or DMARDs are used concomitantly with rituximab, observe patients closely for signs of infection.1

Use in Rheumatoid Arthritis Patients Without Prior Inadequate Response to Tumor Necrosis Factor Antagonists

Use of rituximab in patients with rheumatoid arthritis who have not had a prior inadequate response to 1 or more tumor necrosis factor (TNF) antagonists is not recommended.1 A favorable risk-benefit profile has not been established in methotrexate-naive patients or patients with prior inadequate responses to non-biologic DMARDs.1

Immunogenicity

Using an enzyme-linked immunosorbent assay (ELISA), anti-rituximab antibodies were detected in 1.1% of patients with low-grade or follicular NHL receiving single-agent rituximab.1 Most of these patients (3 of 4) had an objective clinical response to rituximab.1

Approximately 11% of patients with rheumatoid arthritis tested positive for anti-rituximab antibodies at any time after receiving rituximab.1 Anti-rituximab antibodies were not associated with increased rates of infusion-related reactions or other adverse events.1

Approximately 23% of adults with GPA/MPA developed anti-rituximab antibodies within 18 months of starting treatment with rituximab; the clinical relevance of this finding is unknown.1 Approximately 19% of pediatric patients with GPA/MPA developed anti-rituximab antibodies within 18 months of starting rituximab therapy.1

Using a new ELISA assay, 56% of patients with pemphigus vulgaris who were treated with rituximab in one study tested positive for anti-rituximab antibodies by 18 months.1 In another study, 32% of rituximab-treated patients with pemphigus vulgaris tested positive for anti-rituximab antibodies by week 52.1 The clinical relevance of these findings is unknown.1

In a study of patients with previously-untreated follicular lymphoma, the incidence of treatment-induced/enhanced anti-rituximab antibodies was similar among patients treated with rituximab/hyaluronidase and IV rituximab (2 versus 1.9%).68 The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 15% in the rituximab/hyaluronidase group and 8% in the rituximab group.68 No patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies.68 The clinical relevance of these findings is unknown.68

In a study of patients with previously-untreated CLL, the incidence of treatment-induced/enhanced anti-rituximab antibodies was 12% among patients receiving rituximab/hyaluronidase and 15% among patients receiving IV rituximab.68 The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 11% in the rituximab/hyaluronidase group; no patients tested positive for neutralizing antibodies.68 The clinical relevance of these findings is unknown.68

Specific Populations

Pregnancy

There are no available data on the use of rituximab/hyaluronidase during pregnancy; however, animal studies indicate that subcutaneous hyaluronidase was associated with reduced fetal weight and increased fetal lethality when administered at a dose >2700 times higher than the recommended human dose.68 Comparable systemic exposure levels could occur in a pregnant patient following accidental IV administration of an entire vial of rituximab/hyaluronidase.68

Advise pregnant women of the potential risk to the fetus.1, 68 Verify pregnancy status in females of reproductive potential prior to initiating rituximab-containing products.1, 68 If exposure occurs, monitor newborns and infants for signs of infection and manage accordingly.1, 68

Lactation

Data regarding the presence of rituximab in human breast milk and the effect on the breast-fed child are limited; there are no data regarding the effect of rituximab on milk production.1, 68 Rituximab has been detected in the milk of lactating cynomolgus monkeys, and maternal immunoglobulin G is present in human breast milk.1, 68 Rituximab has also been reported to be excreted at low concentrations in human breast milk.1, 68 The clinical significance of these findings for breast-fed children is not known.1, 68 There are no data on the presence of human hyaluronidase in human breast milk.68

Advise women not to breast-feed during treatment with rituximab-containing products and for 6 months after the last dose due to the potential for serious adverse reactions in the breast-fed child.1, 68

Females and Males of Reproductive Potential

Rituximab-containing products may cause fetal harm if administered to a pregnant woman.1, 68 Verify pregnancy status in females of reproductive potential prior to initiating rituximab-containing products.1, 68 Advise females of reproductive potential to use effective contraception during treatment with rituximab-containing products and for 12 months after the last dose.1, 68

Pediatric Use

The safety and efficacy of IV rituximab in combination with chemotherapy for the treatment of previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, and mature B-cell acute leukemia have been established in pediatric patients ≥6 months of age.1 Use of rituximab for this indication is supported by evidence from an adequate and well-controlled study in pediatric patients ≥1 year of age with extrapolation to patients 6 months to <1 year of age based on pharmacokinetic modeling and the expectation that the course of advanced disease is similar between pediatric patients 6 months to <1 year of age and pediatric patients ≥1 year of age.1 Patients <3 years of age had a higher incidence of infections compared with older pediatric patients.1

The safety and efficacy of IV rituximab for the treatment of GPA/MPA have been established in pediatric patients ≥2 years of age.1 Use of rituximab in pediatric patients ≥6 years of age is supported by evidence from adequate and well-controlled studies of rituximab in adults with GPA/MPA, a trial in pediatric patients ≥6 years of age with active GPA/MPA, and population pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric patients 6-17 years of age.1 Use of rituximab in pediatric patients 2 to <6 years of age is supported by pharmacokinetic modeling in patients 2 years of age and older and safety data from pediatric patients <6 years of age treated with rituximab.1

The safety and effectiveness of IV rituximab have not been established in pediatric patients with CLL, pemphigus vulgaris, or rheumatoid arthritis.1 Rituximab has not been studied in pediatric patients with polyarticular juvenile idiopathic arthritis due to concerns for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system.1

The safety and effectiveness of rituximab/hyaluronidase have not been established in pediatric patients.68

Geriatric Use

Among patients with diffuse large B-cell NHL evaluated in 3 randomized controlled trials of IV rituximab, 43% were ≥65 years of age and 13% were ≥75 years of age.1 No overall differences in effectiveness were observed between these patients and younger patients; however, cardiac adverse reactions (mostly supraventricular arrhythmias) occurred more frequently among geriatric patients.1 Serious pulmonary adverse reactions were also more common among the geriatric patients, including pneumonia and pneumonitis.1

Among patients with previously untreated follicular NHL evaluated in one randomized study of IV rituximab, 24% of patients were ≥65 years of age.1 No overall differences in safety or effectiveness were observed between these patients and younger patients.1 Other clinical studies in low-grade or follicular, CD20-positive B-cell NHL did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger subjects.1

Among patients with CLL evaluated in 2 randomized controlled trials of IV rituximab, 36% were ≥65 years of age and 15% were ≥70 years of age.1 In exploratory analyses of these randomized controlled trials, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients ≥70 years of age in either study; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients ≥65 years of age in one of the studies.1 The incidence of several grade 3 or 4 adverse reactions was higher among patients receiving rituximab with fludarabine and cyclophosphamide who were ≥70 years of age compared with younger patients; these adverse reactions included neutropenia (44 versus 31% in study 1 and 56 versus 39% in study 2), anemia (5 versus 2% in study 1 and 21 versus 10% in study 2), thrombocytopenia (19 versus 8% in study 2 only), pancytopenia (7 versus 2% in study 1 and study 2), and infections (30 versus 14% in study 2 only).1

Among patients with rheumatoid arthritis evaluated in clinical studies of IV rituximab, 12% were 65-75 years of age and 2% were ≥75 years of age.1 The incidences of adverse reactions were similar between older and younger patients; however, the rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events, were higher in older patients.1

Among the 99 patients with GPA/MPA in a clinical trial of IV rituximab, 36% were ≥65 years of age, and 8% were ≥75 years of age.1 No overall differences in efficacy were observed between older and younger patients; however, the overall incidence of serious adverse events was higher in patients ≥65 years of age.1 The study did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.1 In a second study of patients with GPA/MPA, 26% of patients were ≥65 years of a this study did not include a sufficient number of patients ≥65 years of age to determine whether they respond differently from younger patients.1

Among 46 patients with pemphigus vulgaris treated with IV rituximab in a clinical study, 33% were ≥65 years of age.1 The clinical study did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients.1

Among the patients treated with rituximab/hyaluronidase in 3 clinical studies, 37% were ≥65 years of age and 10% were ≥75 years of age.68 No overall differences in safety or effectiveness were observed between these patients and younger patients.68 Other reported clinical experience has not identified differences in responses between geriatric and younger patients, but greater sensitivity of some older patients cannot be ruled out.68

Hepatic Impairment

No formal studies have been conducted to examine the effects of hepatic impairment on rituximab or rituximab/hyaluronidase pharmacokinetics.1, 68

Renal Impairment

No formal studies have been conducted to examine the effects of renal impairment on rituximab or rituximab/hyaluronidase pharmacokinetics.1, 68

Common Adverse Effects

In adults receiving IV rituximab for the treatment of NHL, the most common adverse reactions (≥25%) were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia.1

In pediatric patients receiving IV rituximab for diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia, the most common adverse reactions (grade 3 or higher, >15%) were febrile neutropenia, stomatitis, enteritis, sepsis, elevated alanine aminotransferase, and hypokalemia.1

In adults receiving IV rituximab for the treatment of CLL, the most common adverse reactions (≥25%) were infusion-related reactions and neutropenia.1

In adults receiving IV rituximab for the treatment of rheumatoid arthritis, the most common adverse reactions (≥10%) were upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis; other important adverse reactions included infusion-related reactions, serious infections, and cardiovascular events.1

In patients receiving IV rituximab for the treatment of GPA/MPA, the most common adverse reactions (≥15%) were infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, and infusion-related reactions.1

In patients receiving IV rituximab for the treatment of pemphigus vulgaris, the most common adverse reactions (≥15%) were infusion-related reactions, depression, upper respiratory tract infection/nasopharyngitis, and headache; other important adverse reactions included infections.1

In patients receiving rituximab/hyaluronidase for the treatment of follicular lymphoma, the most common adverse reactions (≥20%) were infections, neutropenia, nausea, constipation, cough, and fatigue.68

In patients receiving rituximab/hyaluronidase for the treatment of diffuse large B-cell lymphoma, the most common adverse reactions (≥20%) were infections, neutropenia, alopecia, nausea, and anemia.68

In patients receiving rituximab/hyaluronidase for the treatment of CLL, the most common adverse reactions (≥20%) were infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema.68

Drug Interactions ⬆ ⬇

Formal drug interaction studies of rituximab and rituximab/hyaluronidase have not been conducted.1, 68

Antirheumatic Agents

The safety of concomitant use of rituximab with biologic agents or nonbiologic disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients with rheumatoid arthritis (RA) exhibiting peripheral B cell depletion following treatment with rituximab has not been established.1 Such patients should be monitored closely for signs of infection if biologic agents and/or DMARDs are used concomitantly.1 In clinical trials, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetic disposition of rituximab in patients with RA.1

Cisplatin

Renal toxicity has been reported in patients receiving cisplatin in combination with rituximab for NHL in clinical studies.1 The combination of rituximab or rituximab/hyaluronidase and cisplatin is not an approved treatment regimen.1, 68

Cyclophosphamide

Concomitant administration of rituximab with cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) did not alter systemic exposure to cyclophosphamide.1

Fludarabine

Concomitant administration of rituximab with fludarabine in patients with CLL did not alter systemic exposure to fludarabine.1

Vaccines

The safety of immunization with live viral vaccines following rituximab-containing product therapy has not been established.1, 68 The manufacturer states that use of vaccines containing live virus is not recommended prior to or during rituximab-containing product therapy.1, 68 Non-live vaccines should be administered at least 4 weeks prior to a course of rituximab therapy.1

Other Information ⬆ ⬇

Description

Rituximab, a chimeric human-murine anti-human antigen CD20 monoclonal antibody, is an antineoplastic agent.1 Rituximab binds specifically to antigen CD20 located on pre-B and mature B lymphocytes.1 CD20 antigen is involved in the regulation of cell cycle initiation and differentiation and also may function as a calcium ion channel.1, 3, 4 Following binding of the Fab domain of rituximab to the CD20 antigen on B lymphocytes, the Fc domain triggers a host immune response causing lysis of normal and malignant B cells;1, 3 the exact mechanism of cell lysis has not been fully elucidated but is thought to involve complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).1, 2, 3, 4 Inhibition of cellular proliferation and induction of apoptosis by rituximab have been demonstrated in some non-Hodgkin lymphoma (NHL) cell lines.1, 5 Rituximab also has been shown to increase the in vitro sensitivity of certain chemoresistant human lymphoma cell lines to some cytotoxic agents, including doxorubicin.5 B cells may contribute to the pathogenesis of rheumatoid arthritis and associated chronic synovitis by involvement in the production of rheumatoid factor and other autoantibodies, presentation of antigen, activation of T cells, and/or production of inflammatory cytokines.1

Hyaluronidase, a component of rituximab/hyaluronidase, is a recombinant human endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.68 Hyaluronidase temporarily depolymerizes hyaluronan, a polysaccharide found in the extracellular matrix of subcutaneous tissue; this leads to increased permeability of subcutaneous tissues.68 Hyaluronidase acts transiently and locally; the effects are reversible, and the permeability of the subcutaneous tissue is restored within 24-48 hours.68 Hyaluronidase was shown to increase the absorption rate of a rituximab product in animal studies.68

Rapid and sustained depletion of circulating and tissue-based B cells occurs as a result of the lysis of B cells induced by rituximab.1, 16 Depletion of circulating B cells lasted for up to 6-9 months in 83% of patients receiving IV rituximab for NHL in a clinical study.1 Following completion of IV rituximab therapy, recovery of B cells begins at approximately 6 months, and levels of B cells generally return to normal within 12 months, although in some patients it may take longer.1 Repletion of B-cells following rituximab/hyaluronidase treatment in patients with follicular lymphoma occurs on a similar timeline, with B-cell repletion beginning after 6 months of stopping treatment; however, in some patients, this may take longer.68 In patients with chronic lymphocytic leukemia (CLL) receiving rituximab/hyaluronidase, 28% were B-cell-depleted prior to the cycle 2 dose; by cycle 6, 96% of patients were B-cell-depleted.68 Patients remained B-cell-depleted until the month 9 follow-up visit, where signs of repletion were seen.68 In patients with rheumatoid arthritis, nearly complete depletion of peripheral B lymphocytes (CD19 counts below the lower limit of quantification [20/µL]) occurred within 2 weeks following the first dose of IV rituximab.1 In most patients, depletion of circulating B cells lasted for at least 6 months.1 A small number of patients (approximately 4%) experienced prolonged peripheral B-cell depletion (more than 3 years) after a single course of treatment.1 Rituximab therapy also was associated with the reduction of certain biologic markers of inflammation, including interleukin-6, C-reactive protein, serum amyloid protein, S100 A8/S100 A9 heterodimer complex, anti-citrullinated peptide, and rheumatoid factor.1 In a clinical study of IV rituximab in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), peripheral blood CD19 B-cells remained depleted in most patients (84%) through month 6; by month 12, 81% of patients demonstrated signs of B-cell return, and by month 18, 87% of patients had recovered from B-cell depletion.1 In another clinical study of patients with GPA/MPA treated with IV rituximab, 70% of patients had undetectable CD19 peripheral B-cells at month 24.1

Rituximab/hyaluronidase is administered subcutaneously; in pharmacokinetic studies of rituximab/hyaluronidase, the absolute bioavailability of rituximab following rituximab/hyaluronidase administration was 64.6 and 63.4% in patients with follicular lymphoma and CLL, respectively.68

In a study of 203 patients with non-Hodgkin lymphoma (NHL) receiving rituximab 375 mg/m² by IV infusion once weekly for 4 weeks, rituximab was detected in the serum of patients 3-6 months after completion of treatment.1 The pharmacokinetic disposition of rituximab when administered in conjunction with 6 cycles of combination chemotherapy with CHOP (i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone) is similar to that observed with rituximab alone.1

In a study of 35 pediatric patients ≥3 years of age with diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia, the maximum serum rituximab concentration was highest after the fourth infusion (cycle 2 of induction therapy).1 Pharmacokinetic parameters were similar in these patients and adult patients with NHL.1 No pharmacokinetic data are available for pediatric patients <3 years of age.1

Based on a population pharmacokinetic analysis of data in 298 patients with NHL receiving IV rituximab once weekly or once every 3 weeks, the estimated median terminal elimination half-life was 22 days (range: 6.1-52 days).1 In 21 patients with CLL receiving IV rituximab 375 mg/m² approximately every 28 days, the estimated median terminal half-life was 32 days (range: 14-62 days).1 Based on a population pharmacokinetic analysis of data in 2005 patients with rheumatoid arthritis, the mean terminal elimination half-life of IV rituximab was 18 days (range: 5.17-77.5 days).1 Based on a population pharmacokinetic analysis of data from 97 adult patients with GPA/MPA and 25 pediatric patients with GPA/MPA, the median terminal elimination half-life of IV rituximab was 25 days (range: 11-52 days) in adult patients and 22 days (range: 11-42 days) in pediatric patients.1 In a population pharmacokinetic study of 67 adults with pemphigus vulgaris, the median terminal elimination half-life of IV rituximab was 21.1 days (range: 9.3-36.2 days) after the first cycle of treatment and 26.2 days (range: 16.4-42.8 days) after the second cycle of treatment.1 The median terminal elimination half-life of rituximab in pediatric patients with diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia was 25.7 days (range: 18-31 days) in patients ≥3 to <12 years of age and 26.3 days (range: 16.9-31.9 days) in patients ≥12 to <18 years of age.1 The mean terminal elimination half-life of rituximab following administration of subcutaneous rituximab/hyaluronidase was 34.1 days in patients with follicular lymphoma and 32 days in patients with CLL.68

Patients with NHL and a higher CD19-positive cell count or larger measurable tumor lesions at pretreatment had a higher rate of rituximab clearance.1 Age and gender had no effect on the pharmacokinetics of rituximab in patients with NHL.1 Age, weight, and gender had no effect on the pharmacokinetics of rituximab in patients with rheumatoid arthritis.1

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).1, 68
Inform patients receiving IV rituximab about the signs and symptoms of infusion-related reactions.1 Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions, including urticaria, hypotension, angioedema, sudden cough, breathing problems, weakness, dizziness, palpitations, or chest pain.1
Inform patients receiving rituximab/hyaluronidase about the signs and symptoms of hypersensitivity and administration-related reactions.68 Advise patients to contact their healthcare provider immediately to report symptoms of administration-related reactions, including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain.68
Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the lips or mouth, blisters, peeling skin, rash, and pustules.1, 68
Advise patients to contact their healthcare provider immediately for symptoms of hepatitis, including worsening fatigue or yellow discoloration of skin or eyes.1, 68
Advise patients to contact their healthcare provider immediately for signs and symptoms of progressive multifocal leukoencephalopathy (PML), including new or changing neurological symptoms (e.g., confusion, dizziness, loss of balance), difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems.1, 68
Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome (e.g., nausea, vomiting, diarrhea, lethargy).1, 68
Advise patients of the increased risk of infections during and after treatment with rituximab.1, 68 Advise patients to contact their healthcare provider immediately for signs and symptoms of infections, including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, oral herpes simplex infection, and painful wounds with erythema.1, 68
Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock.1, 68 Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats.1, 68
Advise patients of the risk of renal toxicity, and inform patients of the need for healthcare providers to monitor kidney function.1, 68
Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting.1, 68
Advise females of reproductive potential to inform their clinician if they are or suspect they may be pregnant.1, 68 Advise pregnant women of the potential risk to the fetus1, 68 Advise females of reproductive potential to use effective contraception during treatment and for 12 months following the last dose.1, 68
Advise women to inform their clinician if they plan to breast-feed.1, 68 Advise women not to breast-feed during treatment and for 6 months after the last dose.1, 68
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1, 68
Advise patients of other important precautionary information.1, 68

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

riTUXimab

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion	10 mg/mL (100 and 500 mg)	Rituxan^®(single-dose vials)	Genentech

riTUXimab-abbs (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion	10 mg/mL (100 and 500 mg)	Truxima^®(single-dose vials)	Teva Pharmaceuticals

riTUXimab-arrx (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion	10 mg/mL (100 and 500 mg)	Riabni^®(single-dose vials)	Amgen

riTUXimab-pvvr (biosimilar)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection concentrate, for IV infusion	10 mg/mL (100 and 500 mg)	Ruxience^® (single-dose vials)	Pfizer

RiTUXimab and Hyaluronidase Human

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use only	1400 mg rituximab and 23,400 units/11.7 mL hyaluronidase (120 mg/2000 units/mL)	Rituxan Hycela^®(single-dose vials)	Genentech
	Injection, for subcutaneous use only	1600 mg rituximab and 26,800 units/13.4 mL hyaluronidase (120 mg/2000 units/mL)	Rituxan Hycela^®(single-dose vials)	Genentech

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

1. Genentech, Inc. Rituxan^® (rituximab) injection, solution prescribing information. South San Francisco, CA; 2021 Dec.

2. Maloney DG, Grillo-López AJ, White CA et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood . 1997; 90:2188-95. [PubMed 9310469]

3. Maloney DG, Liles TM, Czerwinski DK et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood . 1994; 84:2457-66. [PubMed 7522629]

4. Maloney DG, Grillo-López AJ, Bodkin DJ et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol . 1997; 15:3266-74. [PubMed 9336364]

5. Demidem A, Lam T, Alas S et al. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm . 1997; 12:177-86. [PubMed 10851464]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD. From FDA website. [Web]

7. McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol . 1998; 16:2825-33. [PubMed 9704735]

16. Piro LD, White CA, Grillo-Lopez AJ et al. Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol . 1999; 10:655-61. [PubMed 10442187]

17. Davis TA, Grillo-Lopez AJ, White CA et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol . 2000; 18:3135-43. [PubMed 10963642]

20. Marcus R, Imrie K, Belch A et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood . 2005; 105:1417-23. [PubMed 15494430]

21. Habermann TM, Weller EA, Morrison VA et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol . 2006; 24:3121-7. [PubMed 16754935]

22. Coiffier B, Lepage E, Briere J et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med . 2002; 346:235-42. [PubMed 11807147]

23. Pfreundschuh M, Trumper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol . 2006; 7:379-91. [PubMed 16648042]

24. Cohen SB, Emery P, Greenwald MW et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum . 2006; 54:2793-806. [PubMed 16947627]

25. Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med . 2004; 350:2572-81. [PubMed 15201414]

27. Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol . 2005; 23:4117-26. [PubMed 15867204]

28. Friedberg JW. Rituximab for early-stage diffuse large-B-cell lymphoma. Lancet Oncol . 2006; 7:357-9. [PubMed 16648037]

30. Forstpointner R, Unterhalt M, Dreyling M et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood . 2006; 108:4003-8. [PubMed 16946304]

31. van Oers MH, Klasa R, Marcus RE et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood . 2006; 108:3295-301. [PubMed 16873669]

39. Robak T, Dmoszynska A, Solal-Céligny P et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol . 2010; 28:1756-65. [PubMed 20194844]

64. Dakhil S, Hermann R, Schreeder MT et al. Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. Leuk Lymphoma . 2014; :. [PubMed 24471908]

68. Genentech, Inc. Rituxan Hycela^® (rituximab and hyaluronidase human) injection, solution prescribing information. South San Francisco, CA; 2021 Jun.

69. Amgen, Inc. Riabni^® (rituximab-arrx) injection, solution prescribing information. Thousand Oaks, CA; 2025 Jun.

70. Pfizer Inc. Ruxience^® (rituximab-pvvr) injection, solution prescribing information. New York, NY; 2025 Jun.

71. Teva Pharmaceuticals USA, Inc. Truxima^® (rituximab-abbs) injection, solution prescribing information. North Wales, PA; 2025 Jun.

72. Ogura M, Sancho JM, Cho SG, et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial. Lancet Haematol. 2018;5(11):e543-e553.

73. Kwak LW, Sancho JM, Cho SG, et al. Efficacy and Safety of CT-P10 Versus Rituximab in Untreated Low-Tumor-Burden Follicular Lymphoma: Final Results of a Randomized Phase III Study. Clin Lymphoma Myeloma Leuk. 2022;22(2):89-97.

74. Kim WS, Buske C, Ogura M, et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol. 2017;4(8):e362-e373.

75. Buske C, Jurczak W, Sancho JM, et al. Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study. Blood Adv. 2021;5(17):3354-3361.

76. Park W, Božić-Majstorović L, Milakovic D, et al. Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial. MAbs. 2018;10(6):934-943.

77. Suh CH, Yoo DH, Berrocal Kasay A, et al. Long-Term Efficacy and Safety of Biosimilar CT-P10 Versus Innovator Rituximab in Rheumatoid Arthritis: 48-Week Results from a Randomized Phase III Trial. BioDrugs. 2019;33(1):79-91.

78. Shim SC, Božić-Majstorović L, Berrocal Kasay A, et al. Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial. Rheumatology (Oxford). 2019;58(12):2193-2202.

79. Burmester G, Drescher E, Hrycaj P, Chien D, Pan Z, Cohen S. Efficacy and safety results from a randomized double-blind study comparing proposed biosimilar ABP 798 with rituximab reference product in subjects with moderate-to-severe rheumatoid arthritis. Clin Rheumatol. 2020;39(11):3341-3352.

80. Niederwieser D, Hamm C, Cobb P, et al. Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product. Target Oncol. 2020;15(5):599-611.

81. Sharman JP, Liberati AM, Ishizawa K, et al. A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera®) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL). BioDrugs. 2020;34(2):171-181.

82. Williams JH, Hutmacher MM, Zierhut ML, et al. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab. Br J Clin Pharmacol. 2016;82(6):1568-1579.

83. Cohen SB, Burgos-Vargas R, Emery P, Jin B, Cronenberger C, Vázquez-Abad MD. Extension Study of PF-05280586, a Potential Rituximab Biosimilar, Versus Rituximab in Subjects With Active Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2018;70(11):1598-1606.

84. Hochster H, Weller E, Gascoyne RD, et al. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009;27(10):1607-1614.

85. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28(17):2853-2858.

86. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51.

87. Bachy E, Seymour JF, Feugier P, et al. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019;37(31):2815-2824.

88. Davies A, Merli F, Mihaljević B, et al. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017;4(6):e272-e282.

89. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010;116(12):2040-2045.

90. Pfreundschuh M, Kuhnt E, Trümper L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12(11):1013-1022.

91. Lugtenburg P, Avivi I, Berenschot H, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017;102(11):1913-1922.

92. Minard-Colin V, Aupérin A, Pillon M, et al. Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children. N Engl J Med. 2020;382(23):2207-2219.

93. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174.

94. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.

95. Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016;3(3):e128-e138.

96. Keystone E, Emery P, Peterfy CG, et al. Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2009;68(2):216-221.

97. Cohen SB, Keystone E, Genovese MC, et al. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis. 2010;69(6):1158-1161.

98. Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol. 2010;37(5):917-927.

99. Tak PP, Rigby WF, Rubbert-Roth A, et al. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis. 2011;70(1):39-46.

100. Tak PP, Rigby W, Rubbert-Roth A, et al. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Ann Rheum Dis. 2012;71(3):351-357.

101. Emery P, Deodhar A, Rigby WF, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010;69(9):1629-1635.

102. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.

103. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-1780.

104. Terrier B, Pagnoux C, Perrodeau É, et al. Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides. Ann Rheum Dis. 2018;77(8):1150-1156.

105. Brogan P, Yeung RSM, Cleary G, et al. Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis. Arthritis Rheumatol. 2022;74(1):124-133.

106. Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031-2040.

107. Chen DM, Odueyungbo A, Csinady E, et al. Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect. Br J Dermatol. 2020;182(5):1111-1119.

108. Tedbirt B, Maho-Vaillant M, Houivet E, et al. Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy: Follow-Up of the Ritux 3 Trial. JAMA Dermatol. 2024;160(3):290-296.

109. Werth VP, Joly P, Mimouni D, et al. Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris. N Engl J Med. 2021;384(24):2295-2305.

110. Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65(2):314-324.

111. Chugh S, Darvish-Kazem S, Lim W, et al. Rituximab plus standard of care for treatment of primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2015;2(2):e75-e81.

112. Ghanima W, Khelif A, Waage A, et al. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9978):1653-1661.

113. Ayad N, Grace RF, Al-Samkari H. Thrombopoietin receptor agonists and rituximab for treatment of pediatric immune thrombocytopenia: A systematic review and meta-analysis of prospective clinical trials. Pediatr Blood Cancer. 2022;69(3):e29447.

114. Filippini G, Kruja J, Del Giovane C. Rituximab for people with multiple sclerosis. Cochrane Database Syst Rev. 2025;3(3):CD013874. Published 2025 Mar 11.

115. Svenningsson A, Frisell T, Burman J, et al. Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial. Lancet Neurol. 2022;21(8):693-703.

116. Dodd KC, Clay FJ, Forbes AM, et al. Rituximab for myasthenia gravis. Cochrane Database Syst Rev. 2025;7(7):CD014574. Published 2025 Jul 3.

117. Tahara M, Oeda T, Okada K, et al. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020;19(4):298-306.

118. Nikoo Z, Badihian S, Shaygannejad V, Asgari N, Ashtari F. Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. J Neurol. 2017;264(9):2003-2009.

119. Liu AP, Cheuk DK. Disease-modifying treatments for primary autoimmune haemolytic anaemia. Cochrane Database Syst Rev. 2021;3(3):CD012493. Published 2021 Mar 26.

169. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Considerations in demonstrating interchangeability with a reference product guidance for industry. Guidance for industry. From FDA website [Web]

170. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. Guidance for industry. From FDA website [Web]

171. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. From FDA website. [Web]

172. Food and Drug Administration. FDA Purple Book Database of Licensed Biological Products. Rockville, MD. From FDA website. Accessed 2026 Mar 17. [Web]

555. Institute for Safe Medication Practices (ISMP). ISMP List of Confused Drug Names. ISMP; 2024.

1990. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021;73(8):1366-1383.

1991. Kidney Disease: Improving Global Outcomes (KDIGO) ANCA Vasculitis Work Group. KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis. Kidney Int. 2024;105(3S):S71-S116.

1992. Joly P, Horvath B, Patsatsi A, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020;34(9):1900-1913.

1993. Velleca A, Shullo MA, Dhital K, et al. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023;42(5):e1-e141.

1994. Te HS, Agopian VG, Demetris AJ, et al. AASLD AST Practice Guideline on adult liver transplantation: Diagnosis and management of graft-related complications. Liver Transpl. 2026;32(3):444-490.

1995. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1-S155.

1996. Oldroyd AGS, Lilleker JB, Amin T, et al. British Society for Rheumatology guideline on management of paediatric, adolescent and adult patients with idiopathic inflammatory myopathy. Rheumatology (Oxford). 2022;61(5):1760-1768.

1997. Bellutti Enders F, Bader-Meunier B, Baildam E, et al. Consensus-based recommendations for the management of juvenile dermatomyositis. Ann Rheum Dis. 2017;76(2):329-340.

1998. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol. 2012;158(1):46-61.

1999. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866.

2003. Fraenkel L, Bathon JM, England BR et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2021; 73:924-939.

2100. Johnson SR, Bernstein EJ, Bolster MB, et al. 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis Rheumatol. 2024;76(8):1182-1200.

2101. Sammaritano LR, Askanase A, Bermas BL, et al. 2024 American College of Rheumatology (ACR) Guideline for the Screening, Treatment, and Management of Lupus Nephritis. Arthritis Rheumatol. 2025;77(9):1115-1135.

2102. Sammaritano LR, Askanase A, Bermas BL, et al. 2025 American College of Rheumatology (ACR) Guideline for the Treatment of Systemic Lupus Erythematosus. Arthritis Rheumatol. Published online November 4, 2025.

2103. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.

2104. Kidney Disease: Improving Global Outcomes (KDIGO) Lupus Nephritis Work Group. KDIGO 2024 Clinical Practice Guideline for the management of LUPUS NEPHRITIS. Kidney Int. 2024;105(1S):S1-S69.

2105. Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021;96(3):114-122.

2106. Zheng XL, Al-Housni Z, Cataland SR, et al. 2025 focused update of the 2020 ISTH guidelines for management of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2025;23(11):3711-3732.

2107. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021;39(36):4073-4126.

2108. Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435.

2109. Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648.

3000. Neelapu SS, Adkins S, Ansell SM, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma. J Immunother Cancer. 2020;8(2):e001235.

3001. Eyre TA, Cwynarski K, d'Amore F, et al. Lymphomas: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025;36(11):1263-1284.

3002. National Cancer Institute. Indolent B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. Revised May 14, 2025. Accessed 2026 Mar 23. [Web]

3003. National Cancer Institute. Aggressive B-Cell Non-Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. Revised May 12, 2025. Accessed 2026 Mar 23. [Web]

3004. National Cancer Institute. Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. Revised April 17, 2025. Accessed 2026 Mar 23. [Web]

3005. Soumerai JD, Barrientos J, Ahn I, et al. Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL or SLL. Blood Adv. 2025;9(5):1213-1229.

3006. Eichhorst B, Ghia P, Niemann CU, et al. ESMO Clinical Practice Guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukaemia. Ann Oncol. 2024;35(9):762-768.

3007. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment (PDQ®)-Health Professional Version. Revised April 25, 2025. Accessed 2026 Mar 23. [Web]

3008. National Cancer Institute. Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. Revised February 12, 2025. Accessed 2026 Mar 26. [Web]

3009. National Cancer Institute. Hairy Cell Leukemia Treatment (PDQ®)-Health Professional Version. Revised February 21, 2025. Accessed 2026 Mar 26. [Web]

3010. National Cancer Institute. Primary Central Nervous System Lymphoma Treatment (PDQ®)-Health Professional Version. Revised May 13, 2025. Accessed 2026 Mar 26. [Web]

3011. Boyiadzis MM, Aksentijevich I, Arber DA, et al. The Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia. J Immunother Cancer. 2020;8(2):e000810.

10001. Rummel MJ, Niederle N, Maschmeyer G et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet . 2013; 381:1203-10. [PubMed 23433739]

10002. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:3383-9. [PubMed 15908650]

10003. Robinson KS, Williams ME, van der Jagt RH et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008;26:4473-9. [PubMed 18626004]

10018. Flinn IW, van der Jagt R, Kahl BS et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood . 2014; 123:2944-52. [PubMed 24591201]

10019. AHFS final determination of medical acceptance: Off-label use of rituximab in combination with bendamustine for previously untreated indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Published May 24, 2016.

10020. AHFS final determination of medical acceptance: Off-label use of rituximab in combination with bendamustine for relapsed or refractory indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Published May 24, 2016.

10021. Flinn IW, van der Jagt R, Kahl B, et al. First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study. J Clin Oncol. 2019;37(12):984-991.

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Table 1. Rituximab Biosimilar Products and FDA licensed Indications.1, 69, 70, 71

Dosage and Administration ⬆ ⬇

Table 2. Administration Schedule for Rituximab in Conjunction with LMB Chemotherapy in Pediatric Mature B-cell NHL and Mature B-cell Acute Leukemia1

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

riTUXimab

riTUXimab-abbs (biosimilar)

riTUXimab-arrx (biosimilar)

riTUXimab-pvvr (biosimilar)

RiTUXimab and Hyaluronidase Human

Copyright ⬆ ⬇

References ⬆