Rituximab, a chimeric human-murine anti-human antigen CD20 monoclonal antibody, is an antineoplastic agent.1
Rituximab is used alone or in combination with other chemotherapy regimens for the treatment of B-cell non-Hodgkin's lymphoma (NHL)1 and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this cancer.6
Relapsed or Refractory Low-grade or Follicular Non-Hodgkin's Lymphoma
Rituximab is used as a single agent for the treatment of relapsed or refractory low-grade or follicular, antigen CD20-positive, B-cell NHL.1, 2, 7, 9, 12 Treatment of advanced-stage or relapsed low-grade NHL generally is palliative, and many therapeutic options have been employed, including single-agent chemotherapy, combination chemotherapy and/or radiation therapy, and aggressive management with combination chemotherapy and bone marrow or peripheral stem cell transplantation.2, 9, 12 Although most patients with relapse of low-grade or follicular NHL initially achieve an objective clinical response to treatment, further relapse eventually occurs, and subsequent therapy is associated with lower response rates and shorter durations of remission.2, 9, 10 The optimal management of indolent recurrent NHL has not been established, and new therapies are continually being evaluated.9
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).54 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.54 According to multivariate analysis, overall response rate was higher in patients with International Working Formulation (IWF) histologic lymphoma subtypes B, C, or D than in those with subtype A (58 versus 12%).54 In addition, overall response rate was higher in patients whose largest lesion was less than 5 cm versus greater than 7 cm (maximum, 21 cm) in greatest diameter (53 versus 38%), and in patients with chemosensitive versus chemoresistant relapse (defined as duration of response of less than 3 months) (53 versus 36%).54 Response rates did not differ according to age, presence of extranodal disease or bone marrow involvement, or history of prior anthracycline therapy.54 The overall response rate in patients receiving rituximab who had been treated previously with autologous bone marrow transplantation was 78%.1, 7
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 Treatment with 8 weekly doses of rituximab was associated with a higher overall incidence of grade 3 and 4 adverse effects compared with a regimen of 4 weekly doses (70 versus 57%).54
Rituximab appears to have activity in patients with relapsed or refractory low-grade NHL who have bulky disease (single lesion exceeding 10 cm in diameter) but is associated with an increased incidence of clinically important adverse events, including neutropenia, anemia, dyspnea, hypotension, and abdominal pain, in such patients.54 In pooled data from multiple studies, 39 patients with relapsed or refractory, bulky disease, 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 Among the 60 patients, 55 patients received their second course of rituximab, 3 patients received their third course, and 2 patients received both their second and third course of rituximab in the study.54 The incidence of grade 3 or 4 adverse effects was similar in patients retreated with rituximab and patients receiving initial treatment with rituximab (58 and 57%, respectively).54
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.29, 30, 31 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.29 In another 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 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab-CHOP for relapsed or resistant follicular NHL compared with those receiving induction chemotherapy alone.31
Radioimmunotherapy with Rituximab and Ibritumomab
Rituximab is used as a required component of a therapeutic regimen with ibritumomab tiuxetan (ibritumomab tiuxetan therapeutic regimen) for the treatment of relapsed or refractory low-grade or follicular B-cell NHL, including follicular NHL that is refractory to rituximab therapy.1, 18 Limited evidence indicates that the overall response rate is higher in such patients receiving the ibritumomab tiuxetan therapeutic regimen compared with standard rituximab immunotherapy; comparative effects on survival have not been established.18 The regimen consists of an initial rituximab dose (administered on day 1) and a second rituximab dose (administered on day 7, 8, or 9) followed within 4 hours by a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.18 For additional information on the use of rituximab as part of the ibritumomab tiuxetan therapeutic regimen for NHL, see Ibritumomab Tiuxetan 10:00.
Rituximab in Combination with Bendamustine
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 has 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 one 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
Previously Untreated Follicular Non-Hodgkin's Lymphoma
Rituximab is used in combination with chemotherapy for the treatment of previously untreated follicular, antigen CD20-positive, B-cell NHL.1, 9, 14, 56
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 Among patients receiving rituximab, 85% received the maximum dosage (a total of 8 doses).1, 20 The median age of the patients was 52 years, and 26% of the patients were 60 years of age or older.1, 54 Most of the patients had stage III or IV disease, 50% had an International Prognostic Index score of at least 2, and the diagnosis of follicular NHL was centrally confirmed in 95% of the patients.1, 54
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 (hazard ratio: 0.44, range: 0.29-0.65) in patients receiving the rituximab-containing regimen.1 Patients receiving rituximab and CVP experienced higher incidences of neutropenia (8 versus 3%) and infusion-related toxicity, including rash (17 versus 5%), cough (15 versus 6%), flushing (14 versus 3%), rigors (10 versus 2%), pruritus (10 versus 1%), and chest tightness (7 versus 1%) than those receiving CVP alone.1
Radioimmunotherapy with Rituximab and Ibritumomab
Rituximab is used as a required component of a therapeutic regimen with ibritumomab tiuxetan (ibritumomab tiuxetan therapeutic regimen) for consolidation treatment of newly diagnosed follicular NHL in patients who have achieved partial or complete response to first-line induction chemotherapy.18, 55 Data from a phase 3, open-label study indicate that median progression-free survival is longer in such patients receiving consolidation therapy with the ibritumomab tiuxetan therapeutic regimen compared with those receiving no further treatment; comparative effects on survival have not been established.18 The regimen consists of an initial rituximab dose (administered on day 1) and a second rituximab dose (administered on day 7, 8, or 9) followed within 4 hours by a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.18 For additional information on the use of rituximab as part of the ibritumomab tiuxetan therapeutic regimen for NHL, see Ibritumomab Tiuxetan 10:00.
Previously Untreated Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma
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
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 rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (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 rituximab in combination with cyclophosphamide, vincristine, and prednisone [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
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
Nonprogressing Low-grade Non-Hodgkin's Lymphoma
Rituximab is used as a single agent for the treatment of nonprogressing (including stable disease) low-grade, antigen CD20-positive, B-cell NHL following first-line combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP).1 This indication 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; 59% of the patients received the maximum dosage of rituximab.1, 54 The median age of patients receiving rituximab was 58 years; 37% of the patients in the study were 60 years of age or older.1, 54 Most of the patients had stage III or IV disease, 63% had an International Prognostic Index score of at least 2, and the diagnosis of low-grade NHL was centrally confirmed in 62% of the patients.1
The risk of disease progression, relapse, or death was reduced (estimated hazard ratio: 0.36-0.49) in patients receiving the rituximab-containing regimen.1 Patients receiving rituximab following CVP experienced higher incidences of grade 3 or 4 neutropenia (4 versus 1%) than those receiving no further treatment; other adverse effects that occurred more frequently in patients receiving rituximab included fatigue (39 versus 14%), anemia (35 versus 20%), peripheral sensory neuropathy (30 versus 18%), infection (19 versus 9%), pulmonary toxicity (18 versus 10%), hepatobiliary toxicity (17 versus 7%), rash and/or pruritus (17 versus 5%), arthralgia (12 versus 3%), and weight gain (11 versus 4%).1
Previously Untreated Diffuse Large B-cell Non-Hodgkin's Lymphoma
Rituximab is used in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based regimens for the treatment of previously untreated diffuse large B-cell, antigen CD20-positive, NHL.1, 9, 14 This indication 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 (hazard ratio: 0.69) 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 (hazard ratio: 0.60) 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
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 (hazard ratio: 0.45) in patients receiving the rituximab-containing regimen.1
Patients with diffuse large B-cell NHL receiving rituximab and CHOP in clinical trials experienced a higher incidence of certain adverse effects.1 Grade 3 or 4 thrombocytopenia (9 versus 7%) and grade 3 or 4 lung disorder (6 versus 3%) occurred more frequently in patients receiving rituximab-CHOP than in those receiving CHOP alone.1 Other adverse effects that occurred more frequently in patients 60 years of age or older who received rituximab and CHOP included pyrexia (56 versus 46%), lung disorder (31 versus 24%), cardiac disorder (29 versus 21%), and chills (13 versus 4%).1 In the second randomized trial, the higher incidence of cardiac disorders in patients receiving rituximab and CHOP was caused mainly by increased frequency of supraventricular arrhythmias or tachycardia (4.5 versus 1%).1 Other severe adverse effects that occurred more frequently in patients receiving rituximab and CHOP than in those receiving CHOP alone (in one or more studies) were viral infection, neutropenia, and anemia.1
Responses to rituximab therapy have been observed in patients with recurrent aggressive antigen CD20-positive NHL†.9
Rituximab is used in combination with fludarabine and cyclophosphamide (R-FC) for the treatment of previously untreated and previously treated antigen CD20-positive chronic lymphocytic leukemia (CLL).1 Rituximab is designated an orphan drug by FDA for the treatment of this cancer.6
Previously Untreated Chronic Lymphocytic Leukemia
Rituximab is used in combination with fludarabine and cyclophosphamide (R-FC) for the treatment of previously untreated antigen CD20-positive chronic lymphocytic leukemia (CLL).1 This indication 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, 38, 51 The median age of patients in this study was 61 years,38 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.38 More than 99% of patients had an ECOG performance status of 0-1.1
At a median follow-up of 37.7 months, patients receiving R-FC experienced prolonged median progression-free survival (51.8 versus 32.8 months), a higher overall response rate (95 versus 88%), a higher complete response rate (44 versus 22%), and a higher overall survival rate (84 versus 79%, although median survival has not been reached) compared with patients receiving FC.38 In patients receiving R-FC, the largest benefit on progression-free survival, overall response, and complete response was observed in those with Binet stage A or stage B CLL; in addition, only patients with Binet stage A or stage B CLL experienced an improved benefit in overall survival.38 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, 51
Patients receiving R-FC experienced higher incidences of adverse hematologic effects (i.e., neutropenia, leukopenia, febrile neutropenia, pancytopenia) compared with those receiving FC;38, 51 however, this was not associated with an increase in infection rate.38 Patients receiving R-FC also experienced a higher incidence of infusion-related effects.51 The treatment-related mortality rate was similar (2%) in patients receiving R-FC compared with those receiving FC.38
Previously Treated Chronic Lymphocytic Leukemia
Rituximab is used in combination with fludarabine and cyclophosphamide (R-FC) for the treatment of previously treated antigen CD20-positive chronic lymphocytic leukemia (CLL).1 This indication 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 Approximately 9, 60, or 31% of patients in this study had Binet stage A, stage B, or stage C disease, respectively.39, 51 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, 51 No difference in overall survival has been observed with the R-FC regimen compared with the FC regimen.39
Patients receiving R-FC experienced higher incidences of grade 3 or 4 neutropenia; however, this was not associated with an increase in the overall incidence of infections or grade 3 or 4 infections.39 Hepatitis B (primary infection and reactivation) was reported in 3% of patients receiving R-FC and in less than 1% of those receiving FC.39
Rituximab in combination with methotrexate is used 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 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
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 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 Approximately 57% of patients receiving rituximab in combination with methotrexate had no progression of structural damage after 2 years of therapy.1
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 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 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
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 does of 500 mg each), rituximab 2 g (given as 2 separate does of 1 g each), or placebo.1 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 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 After a minimum of 24 weeks, patients with ongoing disease activity were permitted to receive retreatment with additional courses of their assigned treatment.1 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 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 Despite the demonstrated efficacy in patients who had an inadequate response to DMARDs and in methotrexate-naive patients, a favorable risk-benefit ratio has not been established for the use of rituximab in these patient populations; therefore, the use of rituximab for RA in patients with disease that has no prior inadequate response to one or more TNF antagonists currently is not recommended.1
Adverse effects during the 24-hour period following the first infusion, such as acute infusion reactions, occurred more frequently in patients receiving rituximab-methotrexate than in those receiving placebo-methotrexate (overall adverse effects: 32 versus 23%, acute infusion reactions: 27 versus 19%).1
Rituximab has been used in the treatment of other forms of NHL, including lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia)†.9 Rituximab also has been used in the treatment of relapsed or refractory hairy cell leukemia†.32
Rituximab has been used for the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura)† in adult patients.33 Results of a meta-analysis indicated an overall response (platelet counts exceeding 50,000/mm3) or complete response (platelet counts exceeding 150,000/mm3) rate of approximately 63 or 46%, respectively; however, because of the lack of controlled randomized studies, efficacy of rituximab compared with standard treatments for ITP cannot be determined, and indiscriminate use of rituximab for the treatment of ITP in adult patients should be avoided .33 Rituximab also has been used in children with severe chronic ITP refractory to standard therapy†.34 However, because of the low response rate (30-60%) and potentially serious adverse effects (including progressive multifocal leukoencephalopathy [PML]), some experts recommend that rituximab be reserved for pediatric patients with chronic ITP who have failed splenectomy.40
Rituximab and immune globulin IV has been used in the treatment of refractory pemphigus vulgaris†.36
Reconstitution and Administration
Rituximab is administered by IV infusion.1 Rituximab solutions should not be administered undiluted nor by rapid IV injection.1, 11
Rituximab for injection concentrate must be diluted prior to IV infusion.1, 11 For IV infusion, the appropriate dose of rituximab for injection concentrate should be withdrawn and diluted in the appropriate volume of 0.9% sodium chloride or 5% dextrose injection to yield a final rituximab concentration of 1-4 mg/mL.1 Aseptic technique should be used, and the IV bag should be gently inverted to mix the solution.1 Any unused solution remaining in the vial should be discarded.1 No other drug should be added to or administered in the same IV line with rituximab infusion.1 Prior to administration, rituximab solutions should be inspected visually for particulate matter and discoloration.1 If particulate matter or discoloration is evident, the solution should not be used.1
The initial rituximab dose should be infused at an initial 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, 11 In patients who tolerate the first infusion well, subsequent rituximab 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
Patients with previously untreated follicular non-Hodgkin's lymphoma (NHL) or previously untreated diffuse large B-cell NHL who are receiving rituximab in combination with a glucocorticoid-containing chemotherapy regimen may receive the second rituximab 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.56, 64 In such patients, the second rituximab 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.56, 64 Those who tolerate this 90-minute infusion may receive subsequent rituximab doses (through cycle 6 or 8) at the same 90-minute infusion rate.56, 64 Patients should receive the glucocorticoid component of the chemotherapy regimen prior to each rituximab infusion to reduce the incidence and severity of infusion reactions.56, 64 Patients with clinically important cardiovascular disease (i.e., uncontrolled hypertension, myocardial infarction [MI], unstable angina, New York Heart Association [NYHA] functional class II or greater congestive heart failure [CHF], ventricular arrhythmia requiring medication within the past year, NYHA class II or greater peripheral vascular disease) or with a high circulating lymphocyte count (5000/mm3 or greater) before cycle 2 should not receive rituximab over 90 minutes, as these patients were excluded from the phase 3 noncomparative trial (RATE) evaluating this infusion rate.56, 64, 67
To minimize the risk of infusion-related events (see Cautions: Infusion-Related Effects) associated with rituximab, premedication with acetaminophen and an antihistamine is recommended before each infusion of the drug.1 Because transient hypotension may occur during administration of rituximab, it may be appropriate to withhold antihypertensive therapy during the 12-hour period preceding each rituximab infusion.54
Immunotherapy for Relapsed or Refractory Low-grade or Follicular Non-Hodgkin's Lymphoma
For the treatment of relapsed or refractory low-grade or follicular, antigen CD20-positive, B-cell NHL, the recommended dosage of rituximab is 375 mg/m2 administered by IV infusion once weekly for 4 weeks1, 7, 12 or 8 weeks.1, 16 Patients who subsequently develop progressive disease following response to previous rituximab therapy may receive an additional course of rituximab 375 mg/m2 by IV infusion once weekly for 4 weeks.1
Radiotherapy for Relapsed or Refractory Low-grade or Follicular Non-Hodgkin's Lymphoma
When used in conjunction with ibritumomab as a component of a radioimmunotherapeutic regimen for relapsed or refractory low-grade or follicular B-cell NHL, rituximab 250 mg/m2 should be infused on day 1 and then again on day 7, 8, or 9; the second dose of rituximab should be followed within 4 hours by a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.18 For additional dosage information regarding the use of rituximab as part of the ibritumomab tiuxetan therapeutic regimen, see Ibritumomab Tiuxetan 10:00.
Combination Therapy for Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma
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
Previously Untreated Follicular Non-Hodgkin's Lymphoma
For the treatment of previously untreated follicular, antigen CD20-positive, B-cell NHL, the recommended dosage of rituximab is 375 mg/m2 administered by IV infusion on day 1 of each cycle of chemotherapy for up to 8 doses.1, 56
When used in conjunction with ibritumomab as a component of a radioimmunotherapeutic regimen for consolidation treatment of follicular NHL in patients who have achieved partial or complete response to first-line induction chemotherapy, rituximab 250 mg/m2 should be infused on day 1 and then again on day 7, 8, or 9; the second dose of rituximab should be followed within 4 hours by a therapeutic dose of yttrium Y 90 ibritumomab tiuxetan.18 For additional dosage information regarding the use of rituximab as part of the ibritumomab tiuxetan therapeutic regimen, see Ibritumomab Tiuxetan 10:00.
Combination Therapy for Previously Untreated Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma
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
Nonprogressing, Low-grade Non-Hodgkin's Lymphoma
For the treatment of nonprogressing (including stable disease), low-grade, antigen 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 rituximab is 375 mg/m2 administered by IV infusion once weekly for 4 doses every 6 months for up to 16 doses total.1
Previously Untreated Diffuse Large B-cell Non-Hodgkin's Lymphoma
For the treatment of previously untreated diffuse large B-cell NHL, the recommended dosage of rituximab 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
For patients receiving rituximab in combination with fludarabine and cyclophosphamide for chronic lymphocytic leukemia, prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP) (i.e., co-trimoxazole) and herpes virus infection (i.e., acyclovir/valacyclovir) is recommended during treatment and for up to 12 months following discontinuance of therapy.1, 39
Previously Untreated Chronic Lymphocytic Leukemia
For the treatment of previously untreated antigen CD20-positive chronic lymphocytic leukemia, the recommended dosage of rituximab is 375 mg/m2 administered by IV infusion on day 0 of the first cycle of chemotherapy with fludarabine and cyclophosphamide (FC, administered on days 1-3 of each 28-day cycle), 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, 38
Previously Treated Chronic Lymphocytic Leukemia
For the treatment of previously treated antigen CD20-positive chronic lymphocytic leukemia, the recommended dosage of rituximab is 375 mg/m2 administered by IV infusion on day 0 of the first cycle of chemotherapy with fludarabine and cyclophosphamide (FC, administered on days 1-3 of each 28-day cycle), 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, 39
For patients receiving rituximab for rheumatoid arthritis, glucocorticoid (methylprednisolone 100 mg IV or its equivalent) should be administered 30 minutes prior to each infusion to reduce the incidence and severity of infusion reactions.1
When used in combination with methotrexate to reduce the signs and symptoms 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, rituximab 1 g is administered as an IV infusion on days 1 and 15 (for a total of 2 doses per course).1 Subsequent courses of rituximab and methotrexate may be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.1
Dosage Modification for Toxicity and Contraindications for Continued Therapy
Depending on the severity of the symptoms, the manufacturer recommends temporary or permanent discontinuance of rituximab when severe adverse effects occur; slower infusion rates should be employed when rituximab therapy is reinitiated following interruption of the infusion because of severe drug-related reactions (e.g., infusion-related effects).1
In patients experiencing signs and symptoms of a severe infusion reaction (e.g., urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events), appropriate medications and supportive care (e.g., epinephrine, glucocorticoids, oxygen, bronchodilators) should be provided as clinically indicated.1 Depending on the severity of the infusion reaction and the required interventions, rituximab infusion should be temporarily or permanently discontinued.1 Once manifestations of infusion reactions have resolved, the infusion may be resumed but the rate of infusion should be reduced by at least 50%.1
In the event of a severe mucocutaneous reaction, rituximab should be discontinued, and the patient should undergo prompt medical evaluation.1, 15 (See Cautions: Mucocutaneous and Dermatologic Effects and also see Mucocutaneous and Dermatologic Effects under Cautions: Precautions and Contraindications.) Skin biopsy may be useful to diagnose the mucocutaneous reaction and guide treatment.15, 54 The safety of readministration of rituximab in patients who have experienced a severe mucocutaneous reaction to the drug has not been determined.1, 15
Progressive Multifocal Leukoencephalopathy
In patients who develop progressive multifocal leukoencephalopathy (PML), rituximab therapy should be discontinued and reductions or discontinuance of any concomitant chemotherapy or immunosuppressive therapy should be considered.1, 35, 41 (See Cautions: Progressive Multifocal Leukoencephalopathy and also see Nervous System Effects under Cautions: Precautions and Contraindications.)
Hepatitis B Virus Reactivation
In patients with reactivation of hepatitis B virus (HBV) infection, rituximab therapy and any concomitant chemotherapy should be discontinued, and appropriate treatment, including antiviral therapy, should be initiated.1, 19, 56, 57 It has not been established whether rituximab can be safely readministered in patients who develop HBV reactivation.1, 19, 56, 57 Clinicians with expertise in managing HBV infection should be consulted regarding resumption of rituximab therapy once control of the reactivated infection has been achieved.56 (See Cautions: Hepatitis B Virus Reactivation and also see Hepatic Effects under Cautions: Precautions and Contraindications.)
In patients who develop severe infections, rituximab therapy should be discontinued, and appropriate anti-infective therapy should be initiated.1 (See Cautions: Infectious Complications and also see Infectious Complications under Cautions: Precautions and Contraindications.)
Rituximab infusion should be discontinued in the event of clinically important adverse cardiac events or serious or life-threatening cardiac arrhythmias.1 In patients who develop serious arrhythmias during rituximab therapy, or who have a history of arrhythmia or angina, cardiac monitoring should be instituted during and following all infusions of rituximab.1, 11 (See Cautions: Cardiovascular Effects and also see Cardiovascular Effects under Cautions: Precautions and Contraindications.)
Rituximab therapy should be discontinued in patients who experience oliguria or increases in serum creatinine concentrations.1 (See Cautions: Renal Effects.)
Some clinicians recommend discontinuance of rituximab if interstitial lung disease is suspected.45 The manufacturer states the safety of continuing or reinitiating rituximab therapy in patients who have experienced pneumonitis or bronchiolitis obliterans has not been established.54 (See Cautions: Respiratory Effects and also see Respiratory Effects under Cautions: Precautions and Contraindications.)
Serious adverse effects, sometimes fatal, have occurred in patients receiving rituximab.1 Severe or fatal infusion-related reactions; tumor lysis syndrome associated with fatal renal failure; severe or fatal mucocutaneous reactions; progressive multifocal leukoencephalopathy causing death; hepatitis B reactivation with fulminant hepatitis, hepatic failure, and death; other severe or fatal, bacterial, fungal, and viral infections; serious or life-threatening cardiac arrhythmias; severe or fatal renal toxicity; and fatal bowel obstruction and perforation have occurred in patients receiving rituximab.1
Adverse effects, including serious adverse effects, commonly occur with rituximab therapy.1 In clinical studies of rituximab in patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL), adverse effects were reported in 99% of patients, and grade 3 or 4 adverse effects were reported in 57% of patients.1 The most common adverse effects reported in 25% or more of patients in clinical studies are infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia.1
The incidence of adverse effects in patients with NHL is based on data collected from clinical trials involving 1606 patients receiving rituximab alone or in combination with chemotherapy, including data collected from 356 patients (median age: 57 years) with relapsed or refractory, low-grade NHL during a 12-month observation period following use of rituximab as a single agent in nonrandomized, single-arm clinical studies.1, 26 Most patients with NHL received rituximab 375 mg/m2 IV, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.1 Unless otherwise specified for a particular adverse effect in the following discussion, incidence rates for adverse effects in patients with NHL are based mainly on the data for patients receiving single-agent rituximab for relapsed or refractory low-grade or follicular NHL.1, 26 Many adverse effects of rituximab in patients with NHL generally were mild or moderate in severity; the incidence of grade 3 or 4 adverse effects often was 1% or less with the exception of a smaller subset of certain adverse effects that occurred more frequently with greater severity (e.g., grade 3 or 4 lymphopenia in 40%, grade 3 or 4 neutropenia in 6%).1
The incidence of adverse effects in patients with chronic lymphocytic leukemia (CLL) is based on data from clinical trials involving 676 patients receiving rituximab in combination with chemotherapy.1 The most common adverse effects reported in 25% or more of patients are infusion-related reactions and neutropenia.1
Incidence rates for adverse effects in patients with rheumatoid arthritis (RA) are based mainly on data from 2578 patients receiving methotrexate with either rituximab or placebo in phase 2 and 3 studies.1 The most common adverse effects reported in 10% or more of patients are upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis; other important adverse effects include infusion-related effects, serious infections, and cardiovascular events.1
Severe infusion-related effects, sometimes fatal, have been reported in patients receiving rituximab.1 Severe reactions typically occurred during the first infusion, with time to onset of 30-120 minutes.1 Fatal reactions have occurred within 24 hours of infusion, approximately 80% of which was associated with the first infusion.1 Manifestations and sequelae of an infusion-related reaction include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.1 (See Infusion-related Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Infusion-related Effects under Cautions: Precautions and Contraindications.) Acute infusion-related reactions observed with rituximab result from the release and/or activation of cytokines during B-cell depletion, often referred to as cytokine-release syndrome.51, 52 Reported risk factors for cytokine-release syndrome and subsequent infusion-related reactions induced by rituximab include older age, high tumor burden, elevated cytokine or complement levels, and B-lymphocyte aggregation or tumor cell agglutination at baseline.51, 52
The manufacturer reports that approximately 70 cases of serious infusion-related events, 8 of which were fatal, have been reported out of an estimated 12,000-14,000 patients worldwide who received rituximab therapy between November 1997 and December 1998.13 In 7 of the 8 fatal cases, manifestations developed during the initial infusion of rituximab, and death in most cases was preceded by severe bronchospasm, dyspnea, hypotension, and/or angioedema.13 Severe respiratory events, including hypoxia, pulmonary infiltrates, and adult respiratory distress syndrome, contributed to 6 of the 8 deaths.13 In some cases, manifestations worsened over time, while in others, initial improvement was followed by clinical deterioration.13 Therefore, patients experiencing any severe infusion-related manifestation should be monitored closely until complete resolution occurs.13 (See Infusion-related Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Infusion-related Effects under Cautions: Precautions and Contraindications.)
Among patients receiving rituximab for NHL, the incidence of infusion reactions was 77% during the first infusion and decreased with each subsequent infusion.1 Manifestations of infusion-related reactions in these patients included fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, and hypertension.1 These reactions generally occurred within 30-120 minutes of starting the first rituximab infusion and usually resolved with slowing or interruption of the infusion and administration of supportive care, including diphenhydramine, acetaminophen, and IV sodium chloride injection.1
Among patients with previously untreated follicular NHL or previously untreated diffuse large B-cell NHL who did not experience a grade 3 or 4 infusion-related reaction to rituximab during the first treatment cycle and who received rituximab as a 90-minute infusion during subsequent treatment cycles, the incidence of grade 3 or 4 infusion-related reactions was 1.1% during cycle 2 and 2.8% during cycles 2-8.56, 64 During cycle 2, the incidence of grade 3 or 4 infusion-related reactions was 3.5% among patients with follicular NHL receiving rituximab in combination with cyclophosphamide, vincristine, and prednisone (CVP) and 0% among patients with diffuse large B-cell NHL receiving rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).56, 64
Among patients receiving rituximab in combination with fludarabine and cyclophosphamide (FC) for CLL, grade 3 and 4 infusion reactions (defined as nausea, pyrexia, chills, hypotension, vomiting, or dyspnea occurring during or within 24 hours after initiation of rituximab infusion) occurred in 9 or 7% of previously untreated or previously treated patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, adverse effects occurred during the 24-hour period following the infusion in 32% of patients following the first infusion and in 11% of patients following the second infusion.1 Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria, rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) occurred in 27% of patients following the first infusion and in 9% of patients following the second infusion.1 Serious acute infusion reactions occurred in less than 1% of patients.1 Dosage modification of rituximab (stopping, slowing, or interrupting the infusion) for infusion-related toxicity was required after the first course of therapy in 10% of patients receiving rituximab and methotrexate.1 The percentage of patients experiencing acute infusion reactions decreased with subsequent courses of rituximab.1 Although the administration of IV glucocorticoids prior to rituximab infusions reduced the incidence and severity of acute infusion reactions, the administration of oral glucocorticoids provided no clear benefit in preventing such reactions.1 Antihistamines and acetaminophen also were administered prior to rituximab infusions to prevent infusion-related effects.1
Tumor lysis syndrome, consisting of rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, occurring within 12-24 hours of completion of the initial infusion of rituximab, has been reported in patients with NHL and sometimes has been fatal.1 The risk of tumor lysis syndrome is increased in patients with a high number of circulating malignant cells (25,000/mm3 or greater) or a large tumor burden.1 (See Tumor Lysis Syndrome under Cautions: Precautions and Contraindications.)
Mucocutaneous and Dermatologic Effects
Severe mucocutaneous reactions, sometimes fatal, have been reported in patients receiving rituximab.1, 15 Severe mucocutaneous reactions associated with rituximab therapy include paraneoplastic pemphigus (an uncommon disorder which is a manifestation of the underlying malignancy),1 Stevens-Johnson syndrome,1, 47 lichenoid dermatitis,1 vesiculobullous dermatitis,1 and toxic epidermal necrolysis.1, 15 The onset of severe mucocutaneous reactions is variable but has occurred as early as the first day of rituximab administration.1, 15 (See Mucocutaneous Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Mucocutaneous and Dermatologic Effects under Cautions: Precautions and Contraindications.)
Adverse effects involving the skin or appendages were reported in 44% of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 2% of patients.1 Rash,1, 7, 16 night sweats,1 pruritus,1, 7, 16, 17 and urticaria1, 7, 16 were reported in 15, 15, 14, and 8% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, pruritus occurred in 5%, and urticaria in 2%, of patients.1
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) secondary to JC infection, sometimes fatal, has been reported in patients receiving rituximab for hematologic malignancies or autoimmune diseases (e.g., RA, systemic lupus erythematosus [SLE]†).1, 35, 42, 43, 46 Most patients with hematologic malignancies who were diagnosed with PML had received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplantation.1, 35 Patients with autoimmune diseases who developed PML had received prior or concurrent immunosuppressive therapy.1 Most cases of PML were diagnosed within 12 months of the last infusion of rituximab.1, 35 PML usually causes death or severe disability, and no therapy is known to prevent, treat, or cure this condition.1, 41
In a report from the Research on Adverse Drug Events and Reports (RADAR) project, 52 cases of PML were identified in patients with B-cell lymphoid malignancy (e.g., CLL, NHL); all of these patients had received prior therapies that affect immune function (e.g., alkylating agents, purine analogs, corticosteroids, drugs that prevent allogeneic stem cell or solid organ graft rejection).46 Reported manifestations of PML, which progressed over weeks to months, included confusion, mental status changes, focal motor weakness, hemiparesis, loss of motor coordination, and speech and vision changes.46 According to the report, a median of 6 rituximab doses was administered prior to diagnosis of PML, and the median time to diagnosis of PML was 5.5 months following the last dose of rituximab.46 The case-fatality rate of PML derived from this report was 90%, with a median time to death of 2 months after diagnosis of PML.46
Two fatal cases of PML have been reported in patients with RA receiving rituximab; these patients had possible risk factors for PML (e.g., prior chemotherapy and radiation therapy, long-standing lymphopenia).41 In addition, at least one case of PML has been reported in a patient with RA receiving rituximab who had not received prior therapy with a tumor necrosis factor (TNF) antagonist.41 The manufacturer states that the reported incidence of PML is rare (3 out of 100,000 patients); however, data suggest that patients with RA who receive rituximab are at increased risk of developing PML. 41 (See Progressive Multifocal Leukoencephalopathy under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Nervous System Effects under Cautions: Precautions and Contraindications.)
Hepatitis B Virus Reactivation
Reactivation of hepatitis B virus (HBV) infection has been reported in patients receiving anti-CD20 monoclonal antibodies, including rituximab, and has resulted in fulminant hepatitis, hepatic failure, and death.1, 19, 56, 57, 58, 59, 60, 65, 66 HBV reactivation has been reported in patients who are hepatitis B surface antigen-positive [HBsAg-positive]; HBsAg-negative and hepatitis B core antibody-positive [anti-HBc-positive]; or HBsAg-negative, anti-HBc-positive, and hepatitis B surface antibody-positive [anti-HBs-positive].56, 57
Following review of the Adverse Event Reporting System (AERS) database, the US Food and Drug Administration (FDA) identified 106 cases of fatal HBV-related acute liver injury in patients receiving rituximab (between November 1997 and August 2012) and 3 such cases in patients receiving ofatumumab (between October 2009 and August 2012); 32 of these case reports contained sufficient data to meet the criteria for HBV reactivation.57 In this review, acute liver injury was attributed to HBV reactivation if seroconversion of HBsAg from negative to positive occurred in those with either anti-HBc or a history of HBV, or if an increase in serum HBV DNA level occurred in those who were HBsAg-positive prior to therapy with an anti-CD20 monoclonal antibody (i.e., rituximab, ofatumumab).57 HBV reactivation was diagnosed by seroconversion of HBsAg in most (69%) cases.57 In this review, the duration of rituximab or ofatumumab therapy prior to diagnosis of HBV reactivation was highly variable, ranging from 63 days after initiation of the drug to 12 months following the last dose;57 however, delayed onset of HBV reactivation (up to 24 months following completion of rituximab therapy) has been reported.56, 58 All of the patients experiencing HBV reactivation had received recent or concomitant therapy with other immunosuppressive agents.57 Among patients with HBV reactivation, 10% received HBV antiviral prophylaxis and 28% received antiviral treatment for HBV reactivation.57 (See Hepatitis B Virus Reactivation under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Hepatic Effects under Cautions: Precautions and Contraindications.)
Serious, including fatal, bacterial, fungal, and new or reactivated viral infections, have been reported during and following completion of rituximab-based therapy.1 Infections have been reported in some patients with prolonged hypogammaglobulinemia (i.e., hypogammaglobulinemia lasting longer than 11 months following rituximab therapy).56 New or reactivated viral infections include cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C.1 (See Infectious Complications under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Infectious Complications under Cautions: Precautions and Contraindications.) An increased incidence of fatal infections has been observed in patients receiving rituximab for HIV-associated lymphoma†.1
Infection was reported in 31% of patients receiving rituximab for NHL in clinical studies; severe (grade 3 or 4) infections, including sepsis, occurred in 4% of patients.1 The incidence of bacterial, viral, and fungal infections was 19, 10, and 1%, respectively; 6% of patients had infections of unknown etiology.1 In patients with NHL receiving rituximab monotherapy, B-cell depletion occurred in 70-80% of patients with NHL, and reduction in serum concentrations of IgG and IgM occurred in 14% of patients.1
Among patients receiving rituximab and methotrexate for RA in clinical studies, 39% of patients experienced an infection; the most common infections were nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, and sinusitis.1 Serious infection was reported in approximately 2% of patients with RA receiving rituximab; the most common serious infections were pneumonia, lower respiratory tract infection, cellulitis, and urinary tract infection.1 Fatal serious infections included pneumonia, sepsis, and colitis.1 The incidence of serious infection remained stable in patients receiving subsequent courses of rituximab.1 In 185 patients with active RA receiving rituximab, subsequent treatment with a biologic disease-modifying antirheumatic drug (DMARD) did not appear to increase the incidence of serious infection.1
JC virus infection causing progressive multifocal leukoencephalopathy (PML), sometimes fatal, has been reported in patients receiving rituximab.1, 35 (See Cautions: Progressive Multifocal Leukoencephalopathy.)
Myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or hypotension have occurred as severe manifestations and sequelae of infusion-related reactions and sometimes led to death in patients receiving rituximab.1, 13, 41, 42, 43 (See Cautions: Infusion-related Effects.) Other severe adverse cardiac effects, including rare instances of fatal cardiac failure1 with onset of manifestations weeks after rituximab therapy,26 have been reported. Cardiac arrhythmias1, 7 and angina1 also have been reported. (See Cardiovascular Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Cardiovascular Effects under Cautions: Precautions and Contraindications.)
Adverse cardiovascular effects were reported in about 25% of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 3% of patients.1 Hypotension,1, 7, 16 peripheral edema,1, 16 and hypertension1, 16 were reported in 10, 8, and 6% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, serious adverse cardiovascular effects, sometimes fatal, occurred in about 2% of patients; hypertension was reported in 8% of patients.1
Severe, including fatal, renal toxicity can occur after rituximab administration in patients with NHL.1 Acute renal failure requiring dialysis and sometimes resulting in death, has occurred in patients who experience tumor lysis syndrome.1 (See Cautions: Tumor Lysis Syndrome, and see Renal Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration, and also see Tumor Lysis Syndrome under Cautions: Precautions and Contraindications.)
Renal toxicity associated with rituximab also has occurred in patients with NHL receiving concomitant cisplatin therapy† during clinical studies.1 Combined therapy with rituximab and cisplatin currently is not approved by the US Food and Drug Administration (FDA).1
Abdominal pain, bowel obstruction, and bowel perforation, sometimes fatal, can occur in patients receiving rituximab in combination with chemotherapy.1 In postmarketing reports in patients with NHL, the mean time to documented GI perforation was 6 days (range: 1-77 days).1
Adverse GI effects were reported in about 37%1 of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 2% of patients.1 Nausea1, 7, 16 and vomiting1, 7 occurred in 23 and 10% of patients, respectively.1 Abdominal pain1 and diarrhea1, 7, 16 occurred in 14 and 10% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, nausea occurred in 8%, dyspepsia in 3%, and upper abdominal pain in 2% of patients.1
Patients receiving rituximab who have complaints suggestive of bowel obstruction, such as abdominal pain or repeated vomiting, should receive a diagnostic evaluation.56
Adverse respiratory effects, including acute respiratory distress syndrome, bronchospasm, dyspnea, hypoxia, and pulmonary infiltrates, have occurred as severe manifestations and sequelae of infusion-related reactions to rituximab and sometimes have been fatal.1, 13 Patients with preexisting pulmonary conditions should be closely monitored for possible infusion-related toxicity.1 (See Cautions: Infusion-related Effects and also see Infusion-related Effects under Cautions: Precautions and Contraindications.)
Delayed pulmonary toxicity (e.g., bronchiolitis obliterans [presenting during and up to 6 months following rituximab infusion], pneumonitis [including interstitial pneumonitis]), sometimes fatal, has been reported in patients receiving rituximab alone or in combination with other chemotherapeutic agents.1, 44, 45 In several reports evaluating cases of interstitial lung disease (i.e., interstitial pneumonitis), the most common manifestations observed included dyspnea, fever, and cough.45, 48 In these reports, if interstitial lung disease was suspected, immediate discontinuance of rituximab was required, and patients were managed with corticosteroid therapy (e.g., methylprednisolone, prednisolone, prednisone) and other clinically appropriate measures (e.g., antibiotics).44, 45, 48 The manufacturer states the safety of continuing or reinitiating rituximab therapy in patients experiencing pneumonitis or bronchiolitis obliterans has not been established.54 Interstitial pneumonitis reportedly recurred in a limited number of patients following rechallenge with rituximab.48 (See Respiratory Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Respiratory Effects under Cautions: Precautions and Contraindications.)
Adverse respiratory effects were reported in about 38% of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 4% of patients.1 Increased cough,1, 7 bronchospasm,1, 7 and dyspnea1, 7, 16 were reported in 13, 8, and 7% of patients, respectively.1 Rhinitis,1, 7 throat irritation,1 and sinusitis1 occurred in 12, 9, and 6% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, rhinitis occurred in 3%, and throat irritation in 2%, of patients.1
Metabolic and Electrolyte Effects
Among patients receiving single-agent rituximab for NHL, hyperglycemia1 and increases in LDH1 were reported in 9 and 7% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA in controlled clinical studies, hypophosphatemia and hyperuricemia were reported in 12 and 1.5% of patients, respectively.1 The majority of cases of hypophosphatemia occurred during the rituximab infusion and was considered transient; hypophosphatemia reportedly occurred more frequently in patients who received glucocorticoids.1
Adverse hematologic effects, mainly manifested by lymphopenia, occur frequently in patients receiving rituximab.1 Adverse hematologic or lymphatic system effects were reported in 67% of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 48% of patients.1 Lymphopenia1 was reported in 48% of patients and was grade 3 or 4 in severity in 40% of patients; the median duration of lymphopenia was 14 days (range: 1-588 days).1
Grade 3 and 4 cytopenias occurred in 48% of patients receiving single-agent rituximab for NHL in clinical studies.1 Neutropenia1, 7, 16, 17 and leukopenia1, 7, 16 each were reported in 14% of patients and were grade 3 or 4 in severity in 6 and 4% of patients, respectively.1 The median duration of neutropenia was 13 days (range: 2-116 days).1 Thrombocytopenia1, 7 occurred in 12% of patients and was grade 3 or 4 in severity in 2% of patients.1 Agranulocytosis has been reported in patients receiving rituximab.37
Anemia1, 7 was reported in 8% of patients receiving single-agent rituximab for NHL and was grade 3 or 4 in severity in 3% of patients.1 At least one case of transient aplastic anemia (pure red cell aplasia)1 and two cases of hemolytic anemia1 have been reported in patients receiving rituximab therapy for NHL.
Prolonged pancytopenia, marrow hypoplasia, late onset neutropenia, and hyperviscosity syndrome in lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia) have been reported in patients with hematologic malignancies receiving rituximab.1
Complete blood cell counts (CBC) and platelet counts should be monitored regularly during rituximab therapy with more frequent monitoring in patients who develop cytopenias.1 (See Hematologic Effects under Cautions: Precautions and Contraindications.) Cytopenias associated with rituximab may persist for an extended duration (i.e., months) following discontinuance of the drug.1
Administration of rituximab is associated with rapid and sustained depletion of B cells from the peripheral blood and tissues.1 (See Pharmacology.)
In patients with NHL, sustained and clinically important reductions in serum IgM and IgG concentrations were observed from 5 through 11 months following rituximab therapy; serum IgM and/or IgG concentrations below the normal range were observed in 14% of patients.1 In clinical studies of patients receiving rituximab for rheumatoid arthritis, total and individual serum immunoglobulin concentrations were reduced at 6 months with the greatest change observed in IgM concentrations.1 Following 24 weeks of therapy with rituximab, decreases in serum IgM, IgG, or IgA concentrations to below the lower limit of normal were observed in 10, 2.8, or 0.8% of patients, respectively; following repeated courses of rituximab, decreases in serum IgM, IgG, or IgA concentrations to below the lower limit of normal were observed in 23.3, 5.5, or 0.5% of patients, respectively.1 The clinical importance of decreased immunoglobulin concentrations in patients receiving rituximab for rheumatoid arthritis is uncertain.1
Adverse immunologic and/or autoimmune effects reported in patients receiving rituximab include uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash.1
Among 356 patients with low-grade or follicular NHL receiving single-agent rituximab in clinical studies, positive human antichimeric antibody (HACA) responses were detected in 4 patients (1.1%), 3 of whom achieved an objective clinical response.1
Among 2578 patients with RA receiving rituximab, positive HACA responses were detected in 273 patients (11%).1 Positive HACA responses typically were detected at any time after administration of rituximab and were not associated with increased infusion reactions or other adverse effects.1 Upon retreatment, the incidence of infusion reactions was similar between HACA-positive and HACA-negative patients; most infusion reactions were mild to moderate.1 Four HACA-positive patients with RA experienced serious infusion reactions; however, the temporal relationship between HACA positivity and infusion reaction was variable among these patients.1 The clinical importance of HACA formation in patients receiving rituximab is unclear.1
The immune response to various antigens have been evaluated in a randomized, controlled study in patients with RA receiving either rituximab in combination with methotrexate or methotrexate alone.1, 49 The proportion of patients demonstrating an immune response to pneumococcal vaccine (i.e., measured as an increase in antibody titers to at least 6 of 12 serotypes) was lower in patients receiving rituximab in combination with methotrexate (19%) than in patients receiving methotrexate alone (61%).1, 49 In addition, a smaller proportion of patients receiving rituximab in combination methotrexate developed detectable concentrations of anti-keyhole limpet hemocyanin (KLH) antibodies after vaccination compared with patients receiving methotrexate alone (47 versus 93%).1, 49 The immune response to tetanus toxoid (a recall antigen) and delayed-type hypersensitivity (DTH) response to a candida skin test, however, were similar in patients receiving rituximab in combination with methotrexate compared with patients receiving methotrexate alone.1, 49 Most patients receiving rituximab in combination with methotrexate 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
Adverse nervous system effects were reported in about one-third of patients receiving single-agent rituximab for NHL in clinical studies.1 Headache,1, 7, 16 dizziness,1, 7, 16 and anxiety1 were reported in 19, 10, and 5% of patients, respectively.1
Among patients receiving rituximab and methotrexate for RA, anxiety, migraine, and paresthesia each occurred in 2% of patients.1
PML secondary to JC infection, sometimes fatal, has been reported in patients receiving rituximab for hematologic malignancies or autoimmune diseases (e.g., RA, systemic lupus erythematosus [SLE]†).1, 35, 46 (See Cautions: Progressive Multifocal Leukoencephalopathy.)
Adverse musculoskeletal effects were reported in about 26% of patients receiving single-agent rituximab for NHL in clinical studies and were grade 3 or 4 in severity in 3% of patients.1 Back pain,1, 16 myalgia,1, 16 and arthralgia,1 each was reported in 10% of patients.1
Among patients receiving rituximab and methotrexate for RA, arthralgia occurred in 6% of patients.1
Fever1, 7, 16, 17 occurred in 53% of patients receiving rituximab monotherapy for NHL.1 Chills1, 7, 16, 17 were reported in 33% of patients with NHL and were grade 3 or 4 in severity in 3% of patients.1 Other adverse effects in patients receiving single-agent rituximab for NHL included asthenia1, 7, 16, 17 in 26%, pain1, 7 in 12%,1 angioedema in 11%,1 and flushing1 in 5% of patients.1
Among patients receiving rituximab and methotrexate for RA, pyrexia occurred in 5%, chills in 3%, and asthenia in 2% of patients.1
The incidences and types of adverse effects reported in patients with RA were similar following a single course versus repeated courses of rituximab.1 In a clinical study in which patients received an initial course of methotrexate in combination with rituximab, followed by a second course of methotrexate in combination with either rituximab or placebo, the safety profile reported in patients receiving methotrexate plus rituximab was similar to that reported in patients receiving methotrexate plus placebo.1
Precautions and Contraindications
The use of rituximab is not recommended in patients with severe, active infections.1
Serious adverse effects, including infusion-related reactions, tumor lysis syndrome, mucocutaneous reactions, progressive multifocal leukoencephalopathy, hepatitis B reactivation with fulminant hepatitis, bacterial/fungal/viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation, have occurred in patients receiving rituximab and have sometimes been fatal.1 (See Cautions for further discussion of adverse effects.)
Interruption or discontinuance of rituximab therapy is required in patients experiencing severe or life-threatening adverse reactions.1 Reinitiation at a slower infusion rate (minimum of 50% reduction in rate) is required if rituximab therapy is resumed following complete resolution of symptoms.1 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy under Dosage and Administration: Dosage.)
Rituximab may be administered in an outpatient setting; however, appropriate diagnostic and treatment facilities, including medications for the treatment of severe adverse reactions, such as infusion-related reactions, hypersensitivity reactions, and cardiac arrhythmias, must be readily available.54, 56
To minimize the risk of infusion-related effects associated with rituximab, premedication is recommended before each infusion of the drug.1 (See Dosage and Administration.) Patients (particularly those with preexisting cardiac or pulmonary conditions, those with a high number of circulating malignant B-cells [i.e., 25,000/mm3 or greater], and patients with a history of a cardiopulmonary reaction to rituximab) should be carefully monitored during rituximab infusions.1 If an infusion reaction occurs, the rituximab infusion should be interrupted and appropriate medications and supportive care provided as clinically indicated.1 (See Infusion-related Effects under Dosage and Administration: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Because infusion reactions may occur during or within 24 hours after rituximab infusion, patients should be instructed to notify a clinician if they experience any of the following symptoms during or following rituximab infusion: hives (red itchy welts) or rash; itching; swelling of the lips, tongue, throat, or face; sudden cough; shortness of breath, difficulty breathing, or wheezing; weakness; dizziness or feeling faint; palpitations; or chest pain.1
Patients receiving rituximab should be closely monitored for development of tumor lysis syndrome, including manifestations of renal failure.1 The manufacturer states that patients at high risk of tumor lysis syndrome (i.e., patients with a high number of circulating malignant cells [25,000/mm3 or greater] or a high tumor burden) should receive aggressive IV hydration and anti-hyperuricemic therapy.1 If tumor lysis syndrome develops, patients should receive appropriate medical treatment, including correction of electrolyte abnormalities, monitoring of renal function and fluid balance, and any necessary supportive care (e.g., dialysis) as clinically indicated.1
Mucocutaneous and Dermatologic Effects
Severe mucocutaneous reactions, sometimes fatal, have been reported in patients receiving rituximab.1, 15 Patients should be instructed to notify a clinician or to immediately seek medical attention if they experience any of the following symptoms at any time during rituximab therapy: painful sores or ulcers on the skin, lips, or in the mouth; blisters; peeling skin; rash; or pustules.1 (See Mucocutaneous Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration and also see Cautions: Mucocutaneous and Dermatologic Effects.)
Neurologic function should be monitored during rituximab therapy.1 The possible diagnosis of PML should be considered in any patient receiving rituximab who experiences new onset of neurologic manifestations.1, 41, 43 Diagnostic evaluation, including consultation with a neurologist, brain magnetic resonance imaging (MRI) scan, and lumbar puncture, should be considered as clinically indicated.1, 41
Patients receiving rituximab should be advised to immediately inform a clinician if they experience any of the following symptoms: confusion, trouble thinking, loss of balance, change in walking or talking, decreased strength or weakness on one side of the body, or blurred or loss of vision.1
To decrease the risk of HBV reactivation, all patients should be screened for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with rituximab.56, 57, 62, 63 Hepatitis experts should be consulted regarding monitoring and use of antiviral therapy in those with evidence of HBV infection (HBsAg-positive with any antibody status or HBsAg-negative and anti-HBc-positive);56, 57 although data are limited, treatment guidelines from some experts recommend the use of prophylactic antiviral therapy in patients who are chronic carriers of HBV.61, 62, 63 Patients with evidence of current or prior HBV infection should be monitored for clinical and laboratory evidence of hepatitis or HBV reactivation during rituximab therapy and for several months thereafter, since reactivation has occurred more than 12 months following completion of therapy.56, 57, 58 Rituximab and any concomitant chemotherapy should be discontinued immediately if HBV reactivation occurs, and appropriate treatment for HBV infection should be initiated.56, 57 Concomitant chemotherapy should be discontinued until the HBV infection has been controlled or has resolved.56, 57 Clinicians with expertise in managing HBV infection should be consulted regarding resumption of rituximab therapy once control of the reactivated HBV infection has been achieved.56 It has not been established whether rituximab can be safely readministered in patients who develop HBV reactivation.56, 57 (See Hepatitis B Virus Reactivation under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Serious, sometimes fatal, infections, have been reported with rituximab therapy.1 (See Cautions: Infectious Complications.) The manufacturer states that rituximab should not be used in patients with severe, active infections.1
Patients receiving rituximab in combination with fludarabine and cyclophosphamide for treatment of CLL should receive prophylaxis against Pneumocystis jiroveci (formerly Pneumocystis carinii ) pneumonia (PCP) (i.e., co-trimoxazole) and herpes virus infection (e.g., acyclovir or valacyclovir) during treatment and for up to 12 months following discontinuance of therapy.1, 39
Patients should be advised to inform a clinician before initiating rituximab therapy if they have an infection, a weakened immune system, or a history of severe infections (e.g., hepatitis B or C virus, cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus [chickenpox or shingles], West Nile virus).1 Patients also should be advised to immediately inform a clinician if they experience any of the following symptoms: fever; persistent runny nose or sore throat; cough; tiredness; body aches; earache; headache; pain during urination; white patches in the mouth or throat; or cuts, scrapes, or incisions that are red, warm, swollen, or painful.1 (See Infectious Complications under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Cardiac monitoring should be performed during and after all infusions of rituximab in patients who develop clinically important arrhythmias or who have a history of arrhythmia or angina.1 Because patients with RA are at increased risk for cardiovascular toxicity compared with the general population, such patients should be monitored carefully throughout the rituximab infusion.1 (See Cautions: Cardiovascular Effects and also see Cardiovascular Effects under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
Patients receiving rituximab should be advised to inform a clinician if they experience chest pain or irregular heart beats.1
The manufacturer makes no specific recommendations regarding vaccination in patients with NHL receiving rituximab; however, the US Centers for Disease Control and Prevention (CDC) and US Public Health Service Advisory Committee on Immunization Practices (ACIP) have established guidelines on the use of vaccines in individuals with altered immunocompetence.51, 53
Prior to administering rituximab therapy for RA, the manufacturer states that clinicians should follow CDC guidelines and administer non-live (i.e., inactivated) vaccines at least 4 weeks prior to a course of rituximab.1 Some experts state that appropriate vaccination (e.g., to prevent influenza) may be given during rituximab therapy when clinically indicated; however, immune responses have been shown to be submaximal.50
The manufacturer states that administration of vaccines containing live virus is not recommended prior to or during rituximab therapy.1 However, some experts state that live, attenuated vaccines may be administered in patients with RA, but only before initiation of rituximab therapy.50
Prior to initiation of rituximab therapy, patients should be advised to inform their clinician if they recently received or are scheduled to receive any vaccines.1 Patients also should be advised to inform their clinician if any household contacts are scheduled to receive vaccines.1
In patients with lymphoid malignancies receiving rituximab as a single agent, CBCs and platelet counts should be obtained prior to each rituximab course.1 In those receiving rituximab in combination with chemotherapy, CBCs and platelet counts should be obtained at weekly to monthly intervals; more frequent monitoring is recommended in patients who develop cytopenias.1
In patients with RA receiving rituximab, CBCs and platelet counts should be obtained every 2-4 months during treatment.1
Cytopenias associated with rituximab may persist for an extended duration (i.e., months) following discontinuance of the drug.1
Patients with preexisting pulmonary conditions should be closely monitored for possible infusion-related toxicity.1
Patients presenting with manifestations of delayed pulmonary toxicity (e.g., dyspnea, fever, cough) that are not associated with an acute infusion-related reaction should undergo prompt medical evaluation (i.e., pulse oximetry or blood gases, chest CT, pulmonary function tests documenting a restrictive pattern and decreased pulmonary diffusion capacity for carbon monoxide [DLCO], other evaluations to rule out an infectious etiology or interstitial fibrosis) for possible interstitial lung disease.45 If interstitial lung disease is suspected, some clinicians recommend that rituximab be discontinued and corticosteroid (i.e., glucocorticoid) therapy, along with other clinically appropriate measures (e.g., antibiotics), initiated.44, 45, 48 (See Cautions: Respiratory Effects.)
Other Precautions and Contraindications
Prior to each treatment session, the patient should be given a copy of the manufacturer's patient information (medication guide) and an opportunity to discuss any questions.1
The manufacturer states there are no known contraindications to the use of rituximab.1
Safety and efficacy of rituximab in children have not been established.1 The pharmacokinetics of rituximab have not been studied in children or adolescents.1
Clinical studies of rituximab in low-grade or follicular, antigen CD20-positive, B-cell NHL did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 Among patients with diffuse large B-cell NHL in 3 randomized trials, 927 patients received rituximab in combination with chemotherapy; of these, 396 (43%) were 65 years of age or older and 123 (13%) were 75 years of age or older.1 Although no overall difference in efficacy was observed between geriatric and younger patients, geriatric patients were more likely to experience certain adverse effects, such as supraventricular arrhythmias and severe respiratory effects, including pneumonia and pneumonitis.1
Among the 676 patients with previously untreated or previously treated chronic lymphocytic leukemia (CLL) receiving rituximab in 2 randomized studies (CLL8 and REACH studies), 243 (36%) were 65 years of age or older and 100 (15%) were 70 years of age or older.1 Based on results of an exploratory analysis (stratified by age), the addition of rituximab to fludarabine and cyclophosphamide (FC) resulted in no additional benefit in previously untreated patients 70 years of age or older or in previously treated patients 65 years of age or older.1, 51 (See Uses: Chronic Lymphocytic Leukemia.) Previously untreated geriatric patients received lower dosages of fludarabine and cyclophosphamide compared with younger patients, while previously treated geriatric patients received lower dosages of fludarabine, cyclophosphamide, and rituximab.1 Compared with younger patients, patients 70 years of age or older experienced higher incidences of grade 3 or 4 adverse effects, including neutropenia, febrile neutropenia, anemia, and pancytopenia (among patients with previously untreated CLL), and neutropenia, anemia, thrombocytopenia, pancytopenia, and infections (among patients with previously treated CLL).1
Among the 2578 patients with RA enrolled in studies worldwide, 12% were 65-75 years of age and 2% were 75 years of age or older.1 In one clinical trial among patients receiving rituximab and methotrexate for RA, ACR 20 response rates were similar (53 versus 51%) in geriatric (65 years of age or older) and younger patients, respectively.54 The incidences of adverse effects were similar in older and younger patients; however, the rates of serious adverse effects, including serious infections, malignancies, and cardiovascular events, were higher in older patients.1
Mutagenicity and Carcinogenicity
Long-term animal studies to determine the mutagenic or carcinogenic potential of rituximab have not been performed to date.1
Pregnancy, Fertility, and Lactation
Although rituximab has been shown to cross the monkey placenta, results of an embryofetal developmental toxicity study in which IV rituximab was administered to pregnant cynomolgus monkeys during early gestation did not indicate teratogenicity.1 However, a decrease in levels of lymphoid tissue B cells was observed in the offspring of treated dams.1 In another developmental toxicity study in cynomolgus monkeys receiving rituximab during prenatal and postnatal periods, decreased levels of B cells and immunosuppression were observed in the offspring; levels of B cells and immune function returned to normal within 6 months of birth.1 There are no adequate and well-controlled studies in pregnant women.1 Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to rituximab in utero.1 Rituximab was detected postnatally in the serum of infants exposed to the drug in utero.1 The manufacturer states that rituximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1 Individuals of childbearing potential should use effective contraception during treatment and for up to 12 months following rituximab therapy.1
Studies have not been conducted to date to determine whether rituximab affects fertility in males or females.1
Rituximab is distributed into milk in lactating cynomolgus monkeys.1 It is not known whether rituximab is distributed into milk in humans.1 IgG is distributed into human milk; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.1 The unknown risks to the infant from oral ingestion of rituximab should be weighed against the known benefits of breastfeeding.1
Formal drug interaction studies of rituximab have not been conducted.1
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
Renal toxicity has been reported in patients receiving cisplatin in combination with rituximab for NHL in clinical studies.1 If rituximab is administered concomitantly with cisplatin (e.g., in the clinical trial setting), extreme caution should be used, and patients should be monitored closely for signs of renal toxicity.1
Concomitant administration of rituximab with cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) did not alter systemic exposure to cyclophosphamide.1
Concomitant administration of rituximab with fludarabine in patients with CLL did not alter systemic exposure to fludarabine.1
The safety of immunization with live viral vaccines following rituximab therapy has not been established.1 The manufacturer states that use of vaccines containing live virus is not recommended prior to or during rituximab therapy.1 (See Cautions: Immunologic Effects and also see Vaccination Status under Cautions: Precautions and Contraindications.)
Limited information is available on the acute toxicity of rituximab.1 Overdosage has not been reported in clinical studies with patients receiving rituximab in single doses of up to 500 mg/m2.1
Rituximab is an antineoplastic agent that binds specifically to antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein located on pre-B and mature B lymphocytes.1, 3, 11 Antigen CD20 also is expressed on greater than 90% of B-cell non-Hodgkin's lymphomas (NHL) but is not found on hematopoietic stem cells, early pre-B cells, normal plasma cells, or other normal tissues.1, 3, 11 Antigen CD20 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 antigen CD20 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 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 rituximab for NHL in a clinical study.1 Antigen CD20 is not shed from the cell surface and does not internalize following antibody binding.1 Circulation of free CD20 antigen does not occur.1 Following completion of rituximab therapy, recovery of B cells begins at approximately 6 months, and median levels of B cells return to normal by 12 months.1
Inhibition of cellular proliferation and induction of apoptosis by rituximab have been demonstrated in some 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 By binding and causing lysis of B cells, rituximab interferes with the autoimmune and inflammatory processes in rheumatoid arthritis.1 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 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
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
The pharmacokinetics of rituximab have not been studied in children or adolescents.1 The effects of renal or hepatic impairment on the pharmacokinetic disposition of rituximab have not been formally studied.1
In a study of 203 patients with non-Hodgkin's 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
In patients with rheumatoid arthritis (RA) receiving rituximab, the peak serum concentration averaged 183 mcg/mL following two 500-mg doses and 381 mcg/mL following two 1-g doses.1
Following IV infusion, binding of rituximab has been observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes.1 Little or no binding has been observed upon examination of non-lymphoid tissues.1
Based on a population pharmacokinetic analysis of data in 2005 patients with RA, the volume of distribution of rituximab was 3.1 L.1
It is not known whether rituximab crosses the placenta or distributes into milk in humans; however, IgG distributes into milk in humans.1 (See Cautions: Pregnancy, Fertility, and Lactation.)
Based on a population pharmacokinetic analysis of data in 298 patients with NHL receiving rituximab once weekly or once every 3 weeks, the estimated median terminal elimination half-life was 22 days (range: 6-52 days).1 Patients with higher CD19-positive cell count or larger measurable tumor lesions at pretreatment had a higher rate of clearance.1 Age and gender had no effect on the pharmacokinetics of rituximab in patients with NHL.1
In 21 patients with chronic lymphocytic leukemia (CLL) receiving 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 RA, the estimated clearance of rituximab was 0.335 L/day (approximately 0.014 L/hour), and the mean terminal elimination half-life was 18 days (range: 5-78 days).1 Age, weight, and gender had no effect on the pharmacokinetics of rituximab in patients with RA.1
Rituximab, a chimeric human-murine anti-human antigen CD20 monoclonal antibody, is an antineoplastic agent.1
The rituximab antibody is an IgG1 kappa immunoglobulin containing murine light-chain and heavy-chain variable region sequences and human constant region sequences.1, 2 Because of the presence of human constant region sequences, the chimeric antibody is characterized by lower immunogenicity, longer half-life, and more effective lysis of tumor cells compared with murine monoclonal antibodies.3, 4
Rituximab binds specifically to antigen CD20, a hydrophobic transmembrane protein located on pre-B and mature B lymphocytes.1, 3, 11
Commercially available rituximab concentrate for injection occurs as a sterile, clear, colorless, preservative-free solution.1 The product is formulated for IV administration in 9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and water for injection and has been adjusted to a pH of 6.5.1
Vials of rituximab should be stored at 2-8°C and should not be frozen or shaken; when stored under recommended conditions, commercially available rituximab liquid concentrate for injection should be stable up to the date of expiration marked on the vial.1 Vials of rituximab should be protected from direct sunlight.1
Following dilution of rituximab as recommended, solutions of the drug may be stored for 24 hours at 2-8°C.1 Rituximab solutions for infusion have been shown to be stable for an additional 24 hours at room temperature; however, since rituximab solutions do not contain a preservative, diluted solutions should be stored at 2-8°C.1 No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been observed.1
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. 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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection concentrate, for IV infusion | 10 mg/mL (100 and 500 mg) |
1. Biogen Idec/Genentech. Rituxan® (rituximab) prescribing information. San Diego/South San Francisco, CA; 2010 Feb.
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]
8. Czuczman M, Grillo-López AJ, White CA et al. IDEC-C2B8/CHOP chemoimmunotherapy in patients with low-grade lymphoma: clinical and bcl-2 (PCR) final results. Blood . 1996; 88(Suppl 1):453A.
9. Adult non-Hodgkin's lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Apr 5.
10. US Department of Health and Human Services (HHS). First monoclonal antibody approved to treat cancer. Rockville, MD. 1997 Nov 26. Press release No. P97-39.
11. Genentech, Inc., South San Francisco, CA: Personal communication.
12. Anon. Rituximab for non-Hodgkins lymphoma. Med Lett Drugs Ther . 1998; 40:65-6. [PubMed 9653426]
13. Hellmann SD, Grillo-Lopez AJ. Dear doctor letter regarding important prescribing information on severe infusion-related events and deaths with Rituxan® (rituximab). South San Francisco, CA; 1998 Dec 5.
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