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  • CLASSES

    Monoclonal Antibodies that Target the CD20 Receptor

    BOXED WARNING

    Serious rash

    Mucocutaneous reactions including serious rash such as paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported with rituximab use; some cases were fatal. The time to onset of mucocutaneous reactions has varied; however, there have been reports of reactions occurring with the first rituximab dose. Discontinue rituximab in patients who develop a severe mucocutaneous reaction; the safety of restarting rituximab in these patients has not been evaluated.[29025] [63786]

    Angina, cardiac arrhythmias, cardiac disease, cytokine release syndrome, infusion-related reactions, pulmonary disease

    Infusion-related reactions have been reported with rituximab use; some cases were fatal. Premedicate with acetaminophen and an antihistamine before each rituximab infusion; follow recommendations for premedication or use of corticosteroids for the particular indication for use and regimen given. Interrupt or permanently discontinue the rituximab infusion in patients who develop severe infusion reactions; an infusion rate reduction is recommended if the infusion is resumed in patients with less severe reactions. Signs and symptoms or sequelae of infusion reactions have included: anaphylaxis, angioedema, bronchospasm, cardiogenic shock, flushing, hypotension, hypoxia, myocardial infarction, pulmonary infiltrates, throat irritation, tremor, urticaria, and ventricular fibrillation. Acute respiratory distress syndrome and cytokine release syndrome have also been reported. Closely monitor patients with preexisting cardiac disease or pulmonary disease, patients with a prior history of cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (i.e., 25,000 cells/mm3 or more). Perform cardiac monitoring (e.g., electrocardiogram) during and following each rituximab infusion in patients with a history of cardiac arrhythmias or angina and in patients who develop clinically significant arrhythmias.[29025] [63786]

    Hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, including rituximab products. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting rituximab therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with current or prior HBV for signs of hepatitis or HBV reactivation during and for several months after therapy. In patients who develop HBV reactivation, discontinue rituximab and any concomitant chemotherapy and initiate appropriate treatment. The safety of restarting rituximab in these patients has not been evaluated.[29025] [63786]

    Immunosuppression, progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML), caused by the JC virus, has been reported in patients with hematologic malignancies and autoimmune diseases who received rituximab products; some cases were fatal. Evaluate patients who develop new neurologic symptoms; consider consulting a neurologist and obtaining a brain MRI and lumbar puncture. Discontinue rituximab in patients who develop PML; additionally, consider discontinuing or reducing concomitant chemotherapy or immunosuppressive therapy. Most patients with hematologic malignancies who developed PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem-cell transplant; patients with autoimmune diseases who developed PML had received prior or concurrent immunosuppression therapy. Most PML cases occurred within 12 months of the final rituximab infusion.[29025] [63786]

    DEA CLASS

    Rx

    DESCRIPTION

    Chimeric monoclonal anti-CD20 antibody that depletes B-cells; given by intravenous infusion
    Used for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and adults with rheumatoid arthritis, Wegener's granulomatosis, microscopic polyangiitis, or pemphigus vulgaris
    Premedication required; boxed warnings for severe infusion-related and mucocutaneous reactions, as well as a risk for hepatitis B virus reactivation or progressive multifocal leukoencephalopathy (PML)

    COMMON BRAND NAMES

    Rituxan

    HOW SUPPLIED

    Rituxan Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of non-Hodgkin's lymphoma (NHL).
    For patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell NHL.
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 or 8 doses. Patients who progress after the initial treatment may be retreated with 4 additional doses of 375 mg/m2 IV once weekly.[29025] [63786] DATA: A dose of 375 mg/m2 IV once weekly for 4 doses produced an overall response rate (ORR) of 48%.[24973] [34663] Response rates are higher in patients with International Working Formulation (IWF) B, C, and D histologic subtypes as compared to IWF A subtypes (58% vs. 12%). Patients with smaller lesions (i.e., less than 5 cm) and those previously treated with autologous bone marrow transplant have response rates of 55% and 78%, respectively. In patients who progressed after the initial treatment, the retreatment schedule produced an ORR of 57% with a median duration of response of 13.4 months.[24974] There is limited data regarding more than 2 courses. In patients with bulky disease (single lesion greater than 10 cm), who were excluded from the previous study, rituximab 375 mg/m2 IV once weekly for 4 doses resulted in an ORR of 36% (3% complete response, 33% partial response) with a median response duration of 6.9 months.[34647]

    For first-line treatment of follicular, CD20-positive, B-cell NHL, in combination with chemotherapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 of each cycle of chemotherapy for up to 8 infusions.[29025] [63786] Rituximab has been studied in combination with first-line therapy consisting of cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 (Max of 2 mg) IV on day 1, and prednisone 40 mg/m2/day PO on days 1, 2, 3, 4, and 5 (R-CVP); cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon alfa-2a (R-CHVP+I); and mitoxantrone, chlorambucil, and prednisolone (R-MCP) in randomized, clinical trials. R-CVP was compared with CVP (repeated every 21 days for up to 8 cycles) in 361 previously untreated patients with stage III or IV follicular lymphoma in a randomized, phase III study. In a preplanned interim analysis (after 189 events), time to progression (TTP) was significantly improved in patients who received R-CVP compared with CVP alone and this study was terminated. At a median follow-up time of 53 months, the median TTP was 34 months in the R-CVP arm compared with 15 months in the CVP arm (p less than 0.0001). Additionally, the 4-year overall survival rates were significantly improved with R-CVP (83% vs. 77%; p = 0.029). Grade 3 or 4 neutropenia occurred more often with R-CVP compared with CVP (24% vs. 14%).

    For the treatment of follicular, CD20-positive NHL, in combination with ibritumomab tiuxetan.
    Intravenous dosage
    Adults

    According to the manufacturer, rituximab 250 mg/m2 IV should be administered within 4 hours prior to the administration of indium (In)-111-ibritumomab followed 7 to 9 days later by rituximab 250 mg/m2 IV given within 4 hours prior to the administration of yttrium (Y)-90-ibritumomab. However, in November 2011, the US Food and Drug Administration removed the requirement for imaging with In-111-ibritumomab. The Y-90-ibritumomab therapeutic regimen consists of 2 rituximab infusions given on day 1 and on day 7, 8, or 9 plus one Y-90-ibritumomab dose given within 4 hours after the second rituximab infusion. The dose for each rituximab infusion is 250 mg/m2 IV (initial rate of 50 mg/hour, increased in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour). Premedicate patients with diphenhydramine 50 mg PO and acetaminophen 650 mg PO 30 minutes prior to each rituximab dose. Decrease the rate of rituximab infusion by 50% for mild to moderate infusion reactions; the infusion may be restarted at 50% of the previous infusion rate when the reaction completely resolves. Immediately stop the rituximab infusion for serious infusion reactions and discontinue the Y-90-ibritumomab therapeutic regimen. In patients with previously untreated follicular NHL who achieved a partial or complete response to first-line chemotherapy, the dose of Y-90-ibritumomab is 0.4 millicuries (mCi)/kg (14.8 megabecquerels (MBq)/kg) IV over 10 minutes. In patients with relapsed or refractory low-grade or follicular NHL who have a normal platelet count (150,000 cells/mm3 or greater), the dose of Y-90-ibritumomab is 0.4 mCi/kg IV over 10 minutes. In patients with relapsed or refractory low-grade or follicular NHL who have a platelet count of 100,000 to 149,000 cells/mm3, the dose of Y-90-ibritumomab is 0.3 mCi/kg (11.1 MBq/kg) IV over 10 minutes. Y-90-ibritumomab should not be administered in patients with relapsed or refractory low-grade or follicular NHL who have a platelet count less than 100,000 cells/mm3. Use the patient's actual body weight to calculate the Y-90-ibritumomab dose; do not exceed 32 mCi (1,184 MBq). Immediately stop the infusion and restart in another limb if signs or symptoms of extravasation occur.

    For first-line treatment of diffuse large B-cell, CD20-positive non-Hodgkin's lymphoma (NHL), in combination with CHOP or other anthracycline-based chemotherapy regimen.
    Intravenous dosage
    Adults 18 to 59 years

    375 mg/m2 IV on day 1 of each cycle of chemotherapy for up to 8 infusions. Rituximab has been studied in combination with 6 cycles of cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 2 mg IV on day 1, and prednisone 100 mg/day PO on days 1, 2, 3, 4, and 5 repeated every 21 days (CHOP-21) or CHOP-like chemotherapy in 824 adult patients less than 60 years of age with previously untreated, good prognosis, diffuse large B-cell lymphoma in a large, multinational, randomized, clinical trial. CHOP-like chemotherapy consisted of CHOP-21 plus etoposide (CHOEP-21); methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B); or prednisone, mitoxantrone, cyclophosphamide, etoposide, bleomycin, and vincristine (PMitCEBO). In a preplanned interim analysis (after 100 events), event-free survival (EFS) was significantly improved with rituximab plus CHOP-like chemotherapy compared with CHOP-like chemotherapy alone and this study was terminated. At a median follow-up of 72 months, the 6-year EFS (74.3% vs. 55.8%; hazard ratio = 0.4; 95% CI, 0.32 to 0.62; p less than 0.0001), progression-free survival (80.2% vs. 63.9%; p less than 0.0001), and overall survival (90.1% vs. 80%; p = 0.0004) rates were significantly higher with rituximab plus CHOP-like chemotherapy compared with CHOP-like chemotherapy alone.

    Adults and Elderly patients 60 years or older

    375 mg/m2 IV on day 1 of each cycle of chemotherapy for up to 8 infusions. Rituximab has been studied in combination with cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin mg/m2 IV on day 1, vincristine 1.4 mg/m2 (Max of 2 mg) IV on day 1, and prednisone 40 or 100 mg/m2/day PO on days 1, 2, 3, 4, and 5 (R-CHOP) repeated every 21 days for up to 8 cycles in patients 60 years of age or older with previously untreated diffuse large B-cell lymphoma in randomized, clinical trials. In a randomized, phase 3 study in 632 patients aged 60 years or older (range, 60 to 92 years), the 3-year failure-free survival rate was significantly higher with R-CHOP compared with CHOP (53% vs. 46%; hazard ratio (HR) = 0.78; 95% CI, 0.61 to 0.99; p = 0.04) at a median follow-up of 3.5 years. However, overall survival (OS) was not significantly improved in the R-CHOP arm (HR = 0.83; 95% CI, 0.63 to 1.09). In another randomized trial, the median progression-free survival (PFS) (4.8 vs. 1.2 years; p less than 0.0001) and OS (8.4 vs. 3.5 years; p less than 0.0001) times were significantly improved with R-CHOP compared with CHOP in 399 patients aged 60 to 75 years. The 10-year PFS rates were 36.5% and 20.1% in the R-CHOP and CHOP arms, respectively, and the 10-year OS rates were 43.5% and 27.6%, respectively.

    As single-agent maintenance therapy in patients with low-grade, CD20-positive, B-cell non-Hodgkin's lymphoma (NHL) with nonprogressing disease (stable disease or better) following first-line treatment with cyclophosphamide, vincristine, and prednisone (CVP).
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 doses at 6-month intervals for up to 16 doses after completion of 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (CVP).[29025] [63786] This regimen was evaluated in previously untreated patients with advanced indolent lymphoma (including follicular lymphoma [FL]) in a randomized, phase III study. Patients who responded or had stable disease to CVP induction therapy received either rituximab maintenance (n = 158; FL, n=115) or observation (n = 153; FL, n = 113). At a median follow-up time of 3.7 years, the median progression-free survival (PFS) time (primary endpoint) was 4.3 years in the rituximab arm compared with 1.3 years in the observation arm (hazard ratio [HR] = 0.4; 95% CI, 0.3 to 0.5; p = 4.4 x 10-10). The 3-year PFS rate (68% vs. 33%; p less than 0.001) but not the 3-year overall survival rate (92% vs. 86%; HR = 0.6; 95% CI, 0.4 to 1.1) was significantly improved with rituximab maintenance.[40428]

    For the treatment of follicular NHL, in combination with CHOP chemotherapy†.
    Intravenous dosage
    Adults

    375 mg/m2 IV given on day 1 (or day 0) in combination with cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV (Max of 2 mg), and prednisone 100 mg/m2 PO on days 1, 2, 3, 4, and 5 (R-CHOP regimen) repeated every 3 weeks for 6 to 8 cycles has been studied in previously untreated and previously treated patients with follicular lymphoma in randomized, phase 3 trials.

    For the treatment of previously untreated follicular NHL, in combination with fludarabine and mitoxantrone†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with fludarabine 25 mg/m2 IV daily on days 1, 2, and 3 and mitoxantrone 10 mg/m2 IV on day 1 repeated every 21 days for 6 cycles followed by 2 additional rituximab 375 mg/m2 IV doses given at 21-day intervals has been evaluated in patients with previously untreated follicular lymphoma in a randomized, phase 3 trial.

    For the treatment of previously untreated indolent NHL (including follicular lymphoma), in combination with bendamustine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with bendamustine (90 mg/m2 IV on days 1 and 2) repeated every 28 days (B-R regimen) for up to 6 cycles has been evaluated in a phase 3 trial that compared B-R to standard cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) in 514 patients with indolent or mantle cell lymphomas.

    For the treatment of previously treated indolent NHL (including follicular lymphoma), in combination with bendamustine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with bendamustine (90 mg/m2 IV on days 2 and 3) every 28 days for 4 to 6 cycles. In a phase II trial of 67 patients with relapsed indolent B-cell NHL or mantle-cell lymphoma, patients received B-R. An additional dose of rituximab was administered 1 week prior to the first cycle of B-R and 4 weeks after the last cycle. Patients receiving B-R had an overall response rate of 92% with a median progression-free survival of 23 months. Grade 3 or 4 neutropenia (36%) and thrombocytopenia (9%) occurred. Several dose adjustment criteria were used in the study. For example, in the event of grade 3 nonhematologic or grade 4 hematologic toxicity, the bendamustine dose was reduced to 60 mg/m2 in the subsequent cycle. If a similar severity toxicity occurred at the reduced dose, bendamustine was discontinued. In another phase 2 trial, 57 of 63 patients (ORR 90%) with relapsed or refractory mantle-cell or low-grade lymphomas responded to B-R and median PFS was 24 months.

    For the treatment of previously untreated follicular lymphoma, in combination with lenalidomide†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and 375 mg/m2 IV on day 1 only of cycles 2 to 6 in combination with lenalidomide (20 mg/day PO on days 2 to 22 every 28 days for 6 cycles) was evaluated in a multinational, randomized, open-label, phase 3 trial (the RELEVANCE trial; n = 1,030). In responding patients, lenalidomide was continued for a total of 18 cycles and rituximab 375 mg/m2 IV was given every 8 weeks for 12 cycles.[63644]

    As single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response following first-line treatment with rituximab in combination with chemotherapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV every 8 weeks for 12 doses as maintenance therapy starting 8 weeks after the completion of induction chemotherapy.[29025] [63786] This regimen with 8 doses of rituximab plus 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone (R-CVP); 4 to 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); or 4 to 6 cycles of fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) was evaluated in previously untreated patients with follicular lymphoma in a multinational, randomized study. Following a complete or partial response to induction therapy, patients (age range, 22 to 84 years) received either rituximab maintenance (n = 505) or observation (n = 514). In a preplanned interim analysis (after 267 events), progression-free survival (PFS) was significantly improved with rituximab maintenance compared with observation only and this study was terminated. At a median follow-up time of 36 months, the 3-year PFS rate was 74.9% in the rituximab arm and 57.6% in the observation arm (p less than 0.0001), and the risk of progression was significantly reduced with rituximab maintenance (hazard ratio = 0.55; 95% CI, 0.44 to 0.68). Overall survival was not significantly different between the 2 study arms with few deaths reported in either arm.[47205]

    For the treatment of relapsed or refractory, aggressive, CD20-positive NHL in transplant eligible patients, in combination with gemcitabine, dexamethasone, and cisplatin†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with gemcitabine 1,000 mg/m2 IV on days 1 and 8; dexamethasone 40 mg orally daily on days 1, 2, 3, and 4; and cisplatin 75 mg/m2 IV on day 1 (R-GDP regimen) repeated every 21 days for 2 cycles was evaluated in a randomized, phase 3 trial (NCIC-CTG LY.12 trial). Patients in the trial could receive a third cycle of therapy if they did not achieve a complete or partial response after the second cycle. Patients with CD20-positive lymphoma who received an autologous stem-cell transplant (ASCT) were randomized to receive either rituximab 375 mg/m2 IV every 2 months for 6 cycles or observation starting 28 days post ASCT.

    For the treatment of chronic lymphocytic leukemia (CLL).
    NOTE: Pneumocystis jirovecii pneumonia and antiviral prophylaxis is recommended for patients with chronic lymphocytic leukemia during treatment and for up to 12 months after treatment as appropriate.
    For the treatment of CD20-positive CLL, in combination with cyclophosphamide and fludarabine.
    Intravenous dosage
    Adults

    375 mg/m2 IV on cycle 1; give the day prior to (day 0) fludarabine and cyclophosphamide administration. On cycles 2 to 6, give rituximab 500 mg/m2 IV on day 1 in combination with fludarabine and cyclophosphamide; treatment cycles are repeated every 28 days. Rituximab plus fludarabine 25 mg/m2/day on days 1, 2, and 3 and cyclophosphamide 250 mg/m2/day on days 1, 2, and 3 repeated every 28 days (FCR) for 6 cycles has been studied in randomized, phase III trials. The progression-free survival (PFS) time (primary endpoint) was significantly improved with FCR (mean of 5.2 cycles) compared with fludarabine and cyclophosphamide (FC) alone (51.8 months vs. 32.8 months; p < 0.0001) in previously untreated CLL patients in a multinational, randomized, phase III trial (CLL8 trial; n = 817). At a median follow-up time of 3.1 years, the 3-year PFS (65% vs. 45%; hazard ratio (HR) = 0.56; 95% CI, 0.46 to 0.69) and overall survival (OS) (87% vs. 83%; HR = 0.67; 95% CI, 0.48 to 0.92) rates were also significantly improved with FCR. At a median follow-up of 5.9 years, the median PFS times were 56.8 months and 32.9 months in the FCR and FC arms, respectively (HR = 0.59; 95% CI, 0.5 to 0.69); the 5-year PFS rates were 46.8% and 25.5%, respectively. Additionally, the median OS times were not yet reached and 86 months in the FCR and FC arms, respectively (HR = 0.68; 95% CI, 0.54 to 0.89); the 5-year OS rates were 78.7% and 66.9%, respectively. The median PFS time (primary endpoint) was 30.6 months with FCR compared with 20.6 months with FC (HR = 0.65; 95% CI, 0.51 to 0.82; p < 0.001) in CLL patients who had relapsed or refractory disease following 1 prior line of therapy in another multinational, randomized, phase III trial (n = 552). All patients in this study received tumor lysis and antibiotic/antiviral prophylaxis. At a median follow-up time of 25 months, the median OS was not significantly different between treatment arms (FCR, median time not reached; FC, 52 months). There were more treatment-related deaths reported with R-FC therapy (19 vs. 14 deaths).

    For the first-line treatment of CLL, in combination with fludarabine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV for 4 weekly doses in patients with stable disease or better after 2 months of observation following six 28-day cycles of fludarabine 25 mg/m2 per day IV on days 1 to 5 (sequential therapy) OR rituximab 375 mg/m2 IV on day 1 and 4 on cycle 1 then 375 mg/m2 IV on day 1 only on cycles 2 to 6 concurrently with six 28-day cycles of fludarabine 25 mg/m2 per day IV on days 1 to 5 followed by rituximab 375 mg/m2 IV for 4 weekly doses in patients who had stable disease or better 2 months after therapy (concurrent therapy) was studied in 104 patients in a randomized, noncomparative, phase II trial. Because the first 44 patients treated with concurrent therapy experienced infusion-related adverse effects, the last 7 patients received stepped up therapy on cycle 1 with rituximab 50 mg/m2 IV over 4 hours on day 1, 325 mg/m2 IV starting at 50 mg/hr titrated to a maximum rate of 400 mg/hr on day 3, and 375 mg/m2 IV at 100 mg/hr for the first 15 minutes with rate increases to complete the infusion in the next 45 minutes on day 5. All patients received allopurinol 300 mg/day for the first 14 days of treatment. At 2 months following the completion of therapy, the overall response rates (ORR) were 77% (complete response (CR) rate, 28%) and 90% (CR rate, 47%) with sequential and concurrent therapy, respectively. The 2-year progression-free survival (PFS) rate was 70% with both sequential and concurrent therapy at a median follow-up of 23 months. In the overall study population, the median PFS and overall survival (OS) times were 42 and 85 months, respectively, and the estimated 5-year PFS and OS rates were 28% and 71%, respectively, at a median follow-up of 117 months. Grade 3 and 4 hematologic toxicity was more common with concurrent therapy; however, infection rates were similar with both therapies and no therapy-related myeloid neoplasms were reported at long-term follow-up. In a retrospective, comparative analysis of the 104 patients from this study (CALGB 9712) and the fludarabine only arm (n=178) from another randomized study (CALGB 9011) in previously untreated CLL patients, combination therapy with rituximab plus fludarabine was associated with a significantly improved CR rate (38% vs. 20%; p = 0.002), ORR (84% vs 63%; p = 0.0003), PFS (p < 0.0001), and OS (p = 0.003) compared with fludarabine alone.

    For the first-line treatment of CLL in elderly patients, in combination with chlorambucil†.
    Intravenous dosage
    Adults and Elderly patients > 60 years

    375 mg/m2 IV on day 1 of cycle 1, then 500 mg/m2 IV on day 1 on cycles 2 to 6 plus chlorambucil 10 mg/m2 per day PO on days 1 to 7 repeated every 28 days for 6 cycles or rituximab 375 mg/m2 IV on day 1 of cycle 3, then 500 mg/m2 IV on day 1 on cycles 4 to 8 plus chlorambucil 8 mg/m2 per day PO on days 1 to 7 repeated every 28 days for 8 cycles has been studied as first-line therapy in elderly patients with chronic lymphocytic leukemia in nonrandomized phase II trials. Treatment with 6 cycles of rituximab plus chlorambucil resulted in an overall response rate (ORR) of 80% (complete response (CR) rate, 12%) and a median progression-free survival time of 23.9 months in 100 patients with previously untreated CLL (median age, 70 years; age range, 43 to 86 years) in a multicenter, phase II study. This study also reported an ORR of 66% (CR rate, 6%) in 200 case-matched control patients who received chlorambucil alone. In another phase II study in 97 elderly patients with CLL (median age, 70 years; range, 61 to 84 years), first-line therapy with 8 cycles of rituximab plus chlorambucil (median of 6 cycles in patients > 80 years) resulted in an ORR (primary endpoint) of 81.2% (CR rate, 16.5%) in 85 evaluable patients. Grade 3 or 4 neutropenia was reported in 13.5% of patients.

    For the treatment of CLL, in combination with cyclophosphamide and pentostatin†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with cyclophosphamide (600 mg/m2 IV on day 1) and pentostatin (2 mg/m2 or 4 mg/m2 IV on day 1) repeated every 21 days for 6 or 8 cycles has been studied in clinical trials. The first cycle rituximab administration varied in these studies with one study giving rituximab 100 mg/m2 on day 1 and 375 mg/m2 on days 3 and 5 on cycle 1 and another study administering rituximab 100 mg/m2 on day 8 and 275 mg/m2 on day 9 on cycle 1. Patients received prophylactic antibiotic and/or antiviral therapy in these studies.

    For the treatment of relapsed or refractory CLL, in combination with idelalisib and bendamustine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in cycle 1 and then rituximab 500 mg/m2 IV on day 1 thereafter in combination with bendamustine 70 mg/m2 IV on days 1 and 2 repeated every 28 days for 6 cycles and idelalisib 150 mg orally twice daily until disease progression was evaluated in a randomized, double-blind, placebo-controlled, phase III trial (n = 416).

    For the treatment of CLL in patients who have received at least 1 prior therapy, in combination with venetoclax†.
    NOTE: Venetoclax is FDA approved in combination with rituximab for the treatment of CLL or SLL in patients with or without a 17p deletion who have received at least 1 prior therapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 of cycle 1 followed by 500 mg/m2 IV on day 1 of cycles 2 to 6 repeated every 28 days starting after dosage titration with venetoclax (20 mg/day PO for 7 days, 50 mg/day PO for 7 days, 100 mg/day PO for 7 days, 200 mg/day PO for 7 days, and then 400 mg/day PO; continue therapy for 24 months from the start of rituximab) was evaluated in a multinational, randomized, open-label, phase 3 trial (n = 389; the MURANO trial).

    For reducing signs and symptoms of moderately- to severely-active rheumatoid arthritis in combination with methotrexate in patients who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies.
    NOTE: In patients with rheumatoid arthritis, obtain a CBC at 2—4 month intervals during rituximab therapy.
    Intravenous dosage
    Adults

    1000 mg IV on days 1 and 15. Administer subsequent courses every 24 weeks or based on clinical evaluation but not sooner than every 16 weeks. Methylprednisolone (100 mg IV, or its equivalent) 30 minutes prior to each infusion is recommended to reduce the incidence and severity of infusion reactions. In a phase II trial, 161 patients with active rheumatoid arthritis (RA) despite methotrexate therapy were randomized to one of 4 groups: methotrexate weekly (control); rituximab; rituximab plus cyclophosphamide (750 mg IV on days 3 and 17); or rituximab plus methotrexate weekly. All patients randomized to rituximab received 1000 mg IV on days 1 and 15. In all groups treated with rituximab, a significantly higher proportion of patients had a 20% improvement in disease symptoms according to the ACR criteria at week 24 (65% to 76% vs. 38%; p <= 0.025). The proportion of patients with 50% improvement in disease symptoms according to ACR criteria at 24 weeks, the primary end point, was significantly greater in the rituximab-methotrexate arm (43%) and the rituximab-cyclophosphamide arm (41%) as compared with methotrexate alone (13%). These responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events were associated with the first rituximab infusion. Guidelines suggest adding or switching to an anti-TNF biologic, abatacept, or rituximab for patients with established disease and moderate or high disease activity after 3 months of methotrexate monotherapy or DMARD combination therapy. Switching to a non-TNF biologic such as rituximab for patients with established disease who have a serious adverse event with a TNF blocker is recommended. Further, a switch to a non-TNF biologic is an option for patients with moderate or high disease activity after >= 3 months of a TNF blocker or with a non-serious adverse event. Also, a switch to another non-TNF biologic is an option for patients with moderate or high disease activity after >= 6 months of abatacept or with a non-serious adverse event to the drug. Lastly, a switch to another type or category of non-TNF biologic is an option for patients with moderate or high disease activity after >= 6 months of the new drug. The goal is low disease activity or remission.

    For the treatment of pemphigus.
    For the treatment of pemphigus vulgaris.
    Intravenous dosage
    Adults

    1,000 mg IV every 2 weeks for 2 doses in combination with a tapering course of corticosteroids, initially. Then, 500 mg IV at month 12 and every 6 months thereafter may be used based on clinical evaluation. For relapsed disease, 1,000 mg IV once with consideration of resuming or increasing the corticosteroid dose based on clinical evaluation. Consider Pneumocystis jirovecii pneumonia prophylaxis during and after rituximab treatment.

    For the treatment of pemphigus foliaceus†.
    Intravenous dosage
    Adults

    1,000 mg IV every 2 weeks for 2 doses in combination with a tapering course of corticosteroids, initially. Then, 500 mg IV at months 12 and 18.

    For the treatment of Wegener's granulomatosis and microscopic polyangiitis (2 forms of ANCA-associated vasculitis), along with glucocorticoids.
    Intravenous dosage
    Adults

    INDUCTION COURSE FOR ACTIVE DISEASE: Rituximab 375 mg/m2 IV infusion once weekly for 4 weeks. Give methylprednisolone 1,000 mg/day IV for 1 to 3 days, then give prednisone 1 mg/kg/day PO (not to exceed 80 mg/day PO and tapered per clinical need). Begin the glucocorticoid regimen within 14 days prior to or with the initiation of rituximab; steroids may continue during and after the 4-week induction course. MAINTENANCE: Rituximab 500 mg IV infusion every 2 weeks for 2 doses, followed by 500 mg IV every 6 months thereafter based on clinical evaluation. Premedicate each maintenance infusion with methylprednisolone 100 mg IV (to be completed 30 minutes prior to rituximab). Begin maintenance treatment within 24 weeks of, and no sooner than 16 weeks after, the last rituximab induction infusion based on clinical evaluation. If induction treatment of active disease was achieved with other standard-of-care immunosuppressants, initiate rituximab maintenance dosing within 4 weeks of achievement of disease control. Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended during treatment and for at least 6 months after the last rituximab infusion.[29025]

    For the treatment of mantle cell lymphoma (MCL)†.
    For the treatment of previously untreated advanced mantle cell lymphoma (MCL), in combination with CHOP chemotherapy†.
    Intravenous dosage
    Adults

    375 mg/m2 IV followed 1 day later by the CHOP regimen (cyclophosphamide 750 mg/m2 IV on day 1, doxorubicin 50 mg/m2 IV on day 1, vincristine 1.4 mg/m2 (Max of 2 mg) IV on day 1, and prednisone 100 mg/m2 PO days 1—5) repeated every 3 weeks for 6 cycles (R-CHOP) led to a significantly improved overall response rate (ORR) (94% vs 75%; p = 0.0054), complete response (CR) rate (34% vs 7%; p = 0.00024), and time to treatment failure (TTF) (21 vs 14 months; p = 0.0131) compared with CHOP alone in 122 patients in a multicenter, randomized, phase III trial. Responding patients 65 years of age or less were randomized to receive myeloablative radiochemotherapy followed by autologous stem-cell transplant (ASCT) or interferon alfa maintenance therapy; patients greater than 65 years of age received interferon alfa maintenance therapy. Progression-free survival (PFS) was not significantly different between R-CHOP compared with CHOP therapy in 23 patients who received an ASCT (median PFS not reached) or in 62 patients who received maintenance interferon (median PFS, 19 vs 13 months, respectively). No significant difference in overall survival (OS) was observed between the 2 study arms at a median follow-up time of 18 months or in a long-term analysis at a median follow-up time of 65 months; the 5-year OS rate was 59% in the R-CHOP arm and 46% in the CHOP arm. Adverse effects reported significantly more often with R-CHOP compared with CHOP included first-dose infusion reactions (7% vs 0%; p < 0.0001) and grade 3 or 4 granulocytopenia (63% vs 53%; p = 0.01). Induction therapy with 8 cycles of R-CHOP or 6 cycles of rituximab 375 mg/m2 IV on day 1 plus fludarabine 50 mg/m2 IV on days 1 to 3 and cyclophosphamide 250 mg/m2 IV on days 1 to 3 repeated 4 weeks (R-FC) resulted in ORRs of 87% and 78% (p = 0.0581), respectively, and CR rates of 38% and 34%, respectively, in 395 evaluable MCL patients greater than 60 years of age not eligible for high-dose therapy in another randomized study presented in abstract form. Responding patients were randomized to receive maintenance therapy with either rituximab or interferon alfa until disease progression. Fewer patients died from lymphoma during induction (3% vs 12%) or in first remission (3% vs 9%) with R-CHOP compared with R-FC, and the median OS time was significantly improved with R-CHOP (64 vs 38 months; p = 0.0117). In patients who received rituximab as maintenance therapy, the 3-year OS rate was higher with R-CHOP compared with R-FC (83% vs 67%; p = 0.0494).

    For the treatment of previously untreated advanced mantle cell lymphoma (MCL), in combination with hyper-CVAD chemotherapy†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 plus hyper-CVAD alternating with rituximab 375 mg/m2 IV on day 1 plus high-dose methotrexate and cytarabine for a total of 6 to 8 cycles was studied in 97 patients with newly diagnosed aggressive variants of mantle cell lymphoma (MCL) (median age, 61 years; range, 40 to 80 years) in a nonrandomized, phase II trial. Hyper-CVAD consisted of cyclophosphamide 300 mg/m2 IV over 3 hours every 12 hours on days 2 to 4 (with mesna 600 mg/m2/day via continuous IV infusion over 24 hours (CIV) on days 2 to 4), vincristine 2 mg IV on days 5 and 12, doxorubicin 16.6 mg/m2 CIV on days 5 to 7, and dexamethasone 40 mg PO on days 2 to 5 and 12 to 15 on cycles 1, 3, 5, and 7. Methotrexate 200 mg/m2 IV over 2 hours on day 2 then methotrexate 800 mg/m2 IV over 22 hours (followed by leucovorin rescue) and cytarabine 3 grams/m2 (1 gram/m2 IV in patients >= 60 years old or creatinine > 1.5 mg/dL) IV over 2 hours every 12 hours on days 2 and 3 for 4 doses were given on cycles 2, 4, 6, and 8. Cycles were administered every 21 days for 6 total cycles in patients who had a complete response (CR) after cycles 1 and 2 and for 8 total cycles in patients who had a partial response (PR) after 2 cycles and a CR after 6 cycles. All patients received prophylactic filgrastim, antibiotic, antifungal, and antiviral support. IV alkalinization was administered with all methotrexate courses and prednisolone 1% ophthalmic solution (2 drops each eye 4 times daily X 7 days) was given with cytarabine. Rituximab could be omitted or delayed with the first course of treatment if there was risk of tumor lysis or cytokine release syndrome. In this study, treatment led to an overall response rate (ORR) of 97%, a CR rate of 87%, and 3-year failure-free survival (FFS) and overall survival (OS) rates of 64% and 82%, respectively. Although the CR rates did not differ significantly in 65 patients <= 65 years compared with 32 patients > 65 years (89% vs 84%), the estimated 3-year FFS (73% vs 50%; p = 0.02) and OS (86% vs 74%; p = 0.047) rates (median follow-up of 40 months) and 8-year time to treatment failure (46% vs 16%; p = 0.003) and OS (68% vs 33%; p = 0.0007) rates were significantly improved in patients <= 65 years (median follow-up of 8.3 years). Serious toxicity included grade 3 and 4 neutropenia, thrombocytopenia, febrile neutropenia, and infection. There were 5 toxic deaths during therapy; 4 patients developed myelodysplasia and 1 patient developed acute myelogenous leukemia. Induction therapy with a modified R-hyper-CVAD regimen (rituximab 375 mg/m2 IV on day 1 starting on cycle 2 plus cyclophosphamide 300 mg/m2 IV every 12 hours on days 1 to 3, vincristine 2 mg IV on day 3, doxorubicin 25 mg/m2/day CIV on days 1 and 2, and dexamethasone 40 mg PO on days 1 to 4 repeated every 28 days for 4 to 6 cycles) followed 6 months later by maintenance therapy with rituximab (375 mg/m2 IV weekly X 4 weeks repeated every 6 months for a total of 4 cycles) in responding patients resulted in an ORR of 77% and a CR rate of 64% in 22 patients with previously untreated MCL (median age, 63 years; range, 40 to 81 years) in a phase II pilot study. The 2-year progression-free survival (PFS) and OS rates were 59% and 77%, respectively, at a median follow-up time of 37 months. Additionally, the median PFS and OS times were 38 and 70 months, respectively, and the 5-year OS rate was 62% at a median follow-up time of 62 months.Grade 3 and 4 neutropenia was common during induction therapy and there were 2 toxic deaths in the first 5 patients resulting in the omission of day 11 vincristine and day 11 to 14 dexamethasone in the last 17 patients treated.

    For the treatment of previously untreated mantle cell lymphoma (MCL), in combination with bendamustine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with bendamustine (90 mg/m2 IV on days 1 and 2) repeated every 28 days (B-R regimen) for up to 6 cycles has been evaluated in a phase III trial that compared B-R to standard cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) in 514 patients with indolent or mantle cell lymphomas.

    For the treatment of previously treated mantle cell lymphoma (MCL), in combination with bendamustine†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with bendamustine (90 mg/m2 IV on days 2 and 3) every 28 days for 4—6 cycles. In a phase II trial of 67 patients with relapsed indolent B-cell NHL or mantle-cell lymphoma, patients received B-R. An additional dose of rituximab was administered 1 week prior to the first cycle of B-R and 4 weeks after the last cycle. Patients receiving B-R had an overall response rate of 92% with a median progression-free survival of 23 months. Grade 3 or 4 neutropenia (36%) and thrombocytopenia (9%) occurred. Several dose adjustment criteria were used in the study. For example, in the event of grade 3 nonhematologic or grade 4 hematologic toxicity, the bendamustine dose was reduced to 60 mg/m2 in the subsequent cycle. If a similar severity toxicity occurred at the reduced dose, bendamustine was discontinued. In another phase II trial, 57 of 63 patients (ORR 90%) with relapsed or refractory mantle-cell or low-grade lymphomas responded to B-R and median PFS was 24 months.

    For the treatment of mantle cell lymphoma (MCL), in combination with lenalidomide†.
    Intravenous dosage
    Adults

    375 mg/m2 IV given once weekly for 4 weeks in combination with lenalidomide was evaluated in phase II trials. In patients with relapsed or refractory mantle-cell lymphoma (MCL), rituximab was administered for a total of 4 doses in cycle 1 only and lenalidomide was given as 20 mg orally daily on days 1 to 21 repeated every 28 days until disease progression (median of 2 cycles; range, 1 to 26 cycles). In patients with newly diagnosed MCL, induction therapy (weeks 1 to 48) consisted of rituximab 375 mg/m2 IV once on weeks 1, 2, 3, 4, 13, 21, 29, 37, and 45 for a total of 9 doses and lenalidomide 20 mg orally daily on days 1 to 21 repeated every 28 days for 12 cycles. The lenalidomide dose could be escalated to 25 mg after the first cycle if no dose-limiting adverse events occurred. Maintenance therapy consisted of rituximab 375 mg/m2 IV once every 8 weeks (starting week 52) plus lenalidomide 15 mg orally daily on days 1 to 21 repeated every 28 days (starting week 49); treatment was continued for up to 36 cycles or until disease progression.

    As maintenance therapy†.
    Intravenous dosage
    Adults

    Multiple regimens have been studied. Maintenance therapy with rituximab 375 mg/m2 IV weekly for 4 weeks at 3 and 9 months after the completion of 4 cycles of salvage chemotherapy with fludarabine, cyclophosphamide, and mitoxantrone (FCM) or rituximab plus FCM was evaluated in a randomized, phase III study. Following a complete or partial response to 4 cycles of FCM or R-FCM, 176 patients received either rituximab maintenance or observation, and 57 of these patients had advanced MCL (median age, 63 years; range, 39-78 years). In the 47 patients who achieved a response with R-FCM induction therapy, the median response duration times were not significantly different in the rituximab maintenance arm compared with observation (14 vs 12 months); however, the response duration was improved with longer than 2-year remission rates of 49% and 9%, respectively (p = 0.049). At a median follow-up time of 26 months, the median overall survival (OS) time had not been reached for patients in either study arm and the estimated 3-year OS rate for all patients was nonsignificantly higher in the rituximab maintenance arm compared with the observation arm (77% vs 57%). The role of rituximab maintenance therapy was also studied in a multicenter, randomized trial in 104 MCL patients. In the 61 randomized patients who achieved stable disease or better following initial therapy with 4 weekly cycles of rituximab, the median event-free survival time was nonsignificantly higher in 34 patients who received maintenance therapy with a single rituximab 375 mg/m2 IV dose given at week 12 and at months 5, 7, and 9 after the completion of initial therapy compared with the 27 patients who received observation only (12 vs 6 months) at a median follow-up time of 29 months. Serious toxicities during rituximab maintenance included 3 episodes of pneumonia and 1 case each of hepatitis and acute renal failure.

    For the treatment of acute lymphocytic leukemia (ALL)†.
    For the treatment of CD20-positive acute lymphocytic leukemia (ALL)† in combination with hyper-CVAD chemotherapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV over 2 to 6 hours on days 1 and 11 of cycles 1 and 3 (with hyper-CVAD chemotherapy) and on days 2 and 8 of cycles 2 and 4 (with methotrexate/cytarabine) was studied in 31 patients with Burkitt-type acute lymphoblastic leukemia (ALL) or lymphoma in a nonrandomized, phase II study. Hyper-CVAD consisted of cyclophosphamide 300 mg/m2 IV every 12 hours on days 1, 2, and 3 (with mesna 600 mg/m2 daily via continuous IV infusion over 24 hours (CIV) on days 1, 2, and 3), vincristine 2 mg IV on days 4 and 11, doxorubicin 50 mg/m2 continuous IV on day 4, and dexamethasone 40 mg PO on days 1, 2, 3, and 4 and 11, 12, 13, and 14, given approximately every 21 days (at least 14 days apart) in cycles 1, 3, 5, and 7. Methotrexate 1 gram/m2 over 24 hours on day 1 (followed by leucovorin rescue) and cytarabine 3 grams/m2 IV (1 gram/m2 IV in patients >= 60 years old) every 12 hours on days 2 and 3 for 4 doses, given approximately every 21 days (at least 14 days apart) in cycles 2, 4, 6, and 8. Methotrexate 12 mg intrathecally (6 mg if given via an Ommaya reservoir) on day 2 and cytarabine 100 mg intrathecally on day 7 are administered in each course (8 total intrathecal doses of each agent). Prophylactic filgrastim, antibiotic, antifungal, and antiviral support were also given. IV alkalinization (with all methotrexate courses), IV hydration, and allopurinol or rasburicase were given to all patients with the first course of treatment to prevent tumor-lysis syndrome. In this study, treatment with rituximab plus hyper-CVAD (median of 8 cycles) led to a 3-year overall survival (OS) rate of 77% in 14 patients with ALL and efficacy with rituximab plus hyper-CVAD was similar between patients >= 60 years old and younger patients. In data presented from 3 sequential, nonrandomized, phase II trials in 282 patients with precursor B-lineage ALL (age range, 13 to 83 years) who received standard hyper-CVAD therapy with no rituximab or one of 2 modified hyper-CVAD regimens that included rituximab (375 mg/m2 on day 1 and 11 of cycles 1 and 3 and on days 1 and 8 of cycles 2 and 4) for CD20+ disease (defined as 20% or greater expression), patients with CD20+ disease who were treated on a modified hyper-CVAD regimen with rituximab had a significantly improved 3-year complete response (CR) duration rate (67% vs. 40%; p = 0.002) but not OS rate (61% vs. 45%) compared with standard hyper-CVAD therapy. However, rituximab-containing therapy was associated with a significant improvement in 3-year CR duration (70% vs. 38%; p < 0.001) and OS (75% vs. 47%; p = 0.003) rates in younger patients (age less than 60 years) with CD20+ disease and nonsignificantly worse 3-year CR duration (45% vs. 50%) and OS (28% vs. 32%) rates in patients 60 years of age or older with CD20+ disease. 

    For the treatment of relapsed or refractory acute lymphocytic leukemia (ALL) in combination with ifosfamide, etoposide, and carboplatin†.
    Intravenous dosage
    Adults <= 21 years, Adolescents, and Children

    Rituximab 375 mg/m2 IV on days 1 and 3 of cycles 1 and 2, and on day 3 only of cycle 3. Carboplatin 635 mg/m2 IV was given on day 3 in combination with ifosfamide 3000 mg/m2/day IV on days 3—5 (each dose mixed with mesna 600 mg/m2 IV, followed by mesna 600 mg/m2 IV over 15 minutes at 3, 6, 9, and 12 hours after the start of ifosfamide) and etoposide 100 mg/m2/day IV on days 3—5, of each cycle. Treatment was given up to a maximum of 3 cycles. Colony-stimulating factors were initiated on day 6 of each cycle and IT chemotherapy was also given as appropriate. Overall response rate was 60% and overall survival at 2 to 3 years was 37.5%

    For the treatment of refractory autoimmune hemolytic anemia†.
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 weeks. In a systematic review, rituximab with or without other agents produced a 71 % response rate. Responses have also been reported in patients with hemolytic anemia and chronic lymphocytic leukemia.

    For the treatment of immune thrombocytopenic purpura (ITP)†.
    For steroid-refractory ITP†.
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 doses, or alternately, 1,000 mg IV on days 1 and 15 has been used.

    For previously untreated ITP† in combination with dexamethasone.
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 doses in combination with dexamethasone (days 1 to 4). In a trial of 101 patients with previously untreated ITP, rituximab plus dexamethasone produced a sustained platelet response (50,000/mm3 or more at 6 months) in significantly more patients than dexamethasone alone (63% vs. 36%; p = 0.004). No substantial differences were observed in toxicity between the 2 treatment arms.

    For the treatment of relapsing or refractory thrombotic thrombocytopenia purpura† (TTP).
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 doses.

    For the treatment of acquired blood factor deficiency† in hemophilia A†.
    Intravenous dosage
    Adults

    375 mg/m2 IV once weekly for 4 doses.

    Children and Adolescents

    375 mg/m2 IV once weekly for 4 doses.

    For the treatment of multicentric Castleman disease (MCD)† associated with human herpesvirus 8 (HHV-8) infection† in HIV-infected patients.
    Intravenous dosage
    Adults and Adolescents

    375 mg/m2/dose IV once weekly for 4 to 8 weeks as an alternative to antiviral therapy is recommended by the HIV guidelines. Antiretroviral therapy should be initiated or optimized in all patients with MCD. A prospective, open-label trial of 21 consecutive patients with HIV-associated plasmablastic MCD receiving rituximab 375 mg/m2/dose IV once weekly for 4 weeks showed an overall survival of 95% and disease-free survival of 79% at 2 years. There were no grade 3 or 4 toxicities. The main adverse event was a reactivation of Kaposi's sarcoma. Another prospective, open-label study evaluated rituximab 375 mg/m2/dose IV once weekly for 4 weeks in 24 patients with HIV-associated MCD after the discontinuation of chemotherapy. Ninety-two percent of patients had a sustained remission off treatment at day 60. At day 365, 71% of patients were alive and in sustained remission. Eight of 12 patients with previous KS showed mild exacerbations of Kaposi's sarcoma as a result of therapy.

    For the treatment of relapsing-remitting multiple sclerosis† (RRMS†).
    Intravenous dosage
    Adults

    Dosage is not established. A phase 2 trial used a rituximab dose of 1,000 mg IV infusion on days 1 and 15; the duration of the trial did not allow for maintenance dosing. A common off-label regimen is: 500 mg or 1,000 mg IV single infusion every 6 to 12 months, in some cases initiated 6 to 12 months after an initial higher-dose treatment course (1,000 to 2,000 mg subdivided into 2 infusions given within 1 month on days 1 and 15 for initial course). Optimal dosing frequency and duration for maintenance treatment are not clear. In addition to monotherapy trials, lower-dose, weekly add-on therapy has been studied in refractory RRMS patients. Guidelines do not include rituximab specifically as a treatment option; however, the drug reduces the incidence of relapses clinically, and radiologically reduces new and/or active lesions. It is not clear if rituximab impacts progression to disability. Rituximab is not considered a first-line treatment as ocrelizumab, another B cell-depleting treatment, is already FDA-approved for RRMS and also for progressive MS.

    For the treatment of Burkitt's lymphoma† in combination with Hyper-CVAD chemotherapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV over 2 to 6 hours on days 1 and 11 of cycles 1 and 3 (with hyper-CVAD chemotherapy) and on days 2 and 8 of cycles 2 and 4 (with methotrexate/cytarabine) was studied in 31 patients with Burkitt-type acute lymphoblastic leukemia (ALL) or lymphoma in a nonrandomized, phase II trial. Hyper-CVAD consisted of cyclophosphamide 300 mg/m2 IV every 12 hours on days 1—3 (with mesna 600 mg/m2/day via continuous IV infusion over 24 hours (CIV) on days 1—3), vincristine 2 mg IV on days 4 and 11, doxorubicin 50 mg/m2 CIV on day 4, and dexamethasone 40 mg on days 1—4 and 11—14, given approximately every 21 days (at least 14 days apart) in cycles 1, 3, 5, and 7. Methotrexate 1 gram/m2 over 24 hours on day 1 (followed by leucovorin rescue) and cytarabine 3 grams/m2 IV (1 gram/m2 IV in patients >= 60 years old) every 12 hours on days 2 and 3 for 4 doses, given approximately every 21 days (at least 14 days apart) in cycles 2, 4, 6, and 8. Methotrexate 12 mg intrathecally (IT) (6 mg if given via an Ommaya reservoir) on day 2 and cytarabine 100 mg IT on day 7 are administered in each cycle (8 total IT doses of each agent). Prophylactic filgrastim, antibiotic, antifungal, and antiviral support were also given. IV alkalinization (with all methotrexate courses), IV hydration, and allopurinol or rasburicase were given to all patients with the first course of treatment to prevent tumor-lysis syndrome. In this study, treatment with rituximab plus hyper-CVAD (median of 8 cycles) led to a 3-year OS of 100% in 17 patients with Burkitt lymphoma. Additionally, efficacy with rituximab plus hyper-CVAD was similar between patients >= 60 years old and younger patients. All patients experienced grade 3 or 4 myelosuppression and infection and febrile neutropenia were commonly reported.

    For the treatment of steroid-refractory chronic graft-versus-host disease (GVHD)†.
    Intravenous dosage
    Adolescents > 15 years and Adults

    The optimal duration of rituximab therapy has not been established. In a phase II study, adult patients (age range, 39—66 years) received rituximab 375 mg/m2 IV weekly for 4 weeks. In another phase II study, patients (n = 38; age range, 8—57 years) received rituximab 375 mg/m2 IV weekly for 4 weeks followed by maintenance therapy with rituximab 375 mg/m2 IV monthly for 4 months; infection-related deaths were reported in this study.

    Children > 8 years and Adolescents <= 15 years

    375 mg/m2 IV weekly for 4 weeks followed by maintenance therapy with rituximab 375 mg/m2 IV monthly for 4 months resulted in an objective response at day 365 in 7 of 8 patients (87.5%) aged 8 to 15 years. Infection-related deaths were reported in this multicenter, phase II study (n = 38; age range, 8—57 years).

    For the treatment of lupus nephritis† in patients with systemic lupus erythematosus (SLE) unresponsive to conventional therapy.
    Intravenous dosage
    Adults

    375 mg/m2 IV every week for 4 weeks as induction for severe class IV, IV and V, or V disease largely refractory or relapsing led to complete remission in 7 patients and a partial remission in 5 of the 20 patients. The remissions occurred in < 6 months in 6 patients, at month 12 in 5 patients, and at month 26 in 1 patient. Absence of renal remission was significantly associated with black ethnicity and with the absence of B cell depletion one month after rituximab initiation. None of the 3 patients with rapidly progressive glomerulonephritis responded. Guidelines recommend rituximab for some patients whose nephritis fails to improve or worsens after 6 months of induction with cyclophosphamide, mycophenolate mofetil, or both. Further, rituximab may be a consideration if nephritis is worsening in patients treated for 3 months with glucocorticoids plus either cyclophosphamide or mycophenolate mofetil.

    For the treatment of Waldenstrom macroglobulinemia†.
    For the treatment of newly diagnosed Waldenstrom macroglobulinemia, in combination with dexamethasone and cyclophosphamide†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on day 1 in combination with dexamethasone 20 mg IV on day 1 and cyclophosphamide 100 mg/m2 orally twice daily on days 1 to 5 (total dose of 1,000 mg/m2/cycle) repeated every 21 days for 6 cycles was evaluated in a single-arm, phase II trial.

    For the treatment of newly diagnosed Waldenstrom macroglobulinemia, in combination with bortezomib and dexamethasone†.
    Intravenous dosage
    Adults

    375 mg/m2 IV on days 1, 8, 15, and 22 in cycles 2 and 5 (for 8 total doses) in combination with bortezomib and dexamethasone was evaluated in a nonrandomized phase II trial. Bortezomib was given as follows: 1.3 mg/m2 IV on days 1, 4, 8, and 11 for the first 21-day cycle (cycle 1) then 1.6 mg/m2 IV on days 1, 8, 15, and 22 repeated every 35 days for 4 additional cycles (cycles 2, 3, 4, and 5). Dexamethasone was given as 40 mg IV on days 1, 8, 15, and 22 in cycles 2 and 5. All patients received premedication with acetaminophen 1,000 mg PO and diphenhydramine 50 mg IV prior to rituximab and herpes zoster prophylaxis with valacyclovir or acyclovir.

    For the treatment of Waldenstrom macroglobulinemia, in combination with ibrutinib†.
    NOTE: Ibrutinib is FDA approved in combination with rituximab for the treatment of Waldenstrom macroglobulinemia.[56410]
    Intravenous dosage
    Adults

    375 mg/m2 IV weekly on weeks 1, 2, 3, and 4 and 17, 18, 19, and 20 (for a total of 8 doses) in combination with ibrutinib 420 mg orally daily until disease progression was evaluated in a randomized, placebo-controlled, phase 3 trial (n = 150; iNNOVATE trial).

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for rituximab products is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    Adults

    The maximum dosage is dependent on indication for therapy.

    Geriatric

    The maximum dosage is dependent on indication for therapy.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    For intravenous infusion only; follow directions for proper dilution and administration rates. Do NOT administer as an IV push or bolus.
    Administration needs to be by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur.
    Premedicate prior to each infusion as recommended for the patient's disease/condition and rituximab treatment regimen.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.[29025] [63786] Rituxan is a clear, colorless liquid.[29025] Truxima is a clear to opalescent, colorless to pale yellow solution.[63786] Do not use vial if particulates or discoloration is present.[29025] [63786]

    Intravenous Administration

    Premedication with acetaminophen and an antihistamine should be given before each infusion of rituximab to attenuate infusion-related events.
    Premedication with corticosteroids is given according to the disease/condition and specific regimen.
    For oncology patients administered rituximab according to the 90-minute infusion rate, the glucocorticoid component of the chemotherapy regimen should be administered prior to infusion.[29025] [63786]
    For patients with rheumatoid arthritis and pemphigus vulgaris, methylprednisolone 100 mg IV or its equivalent is recommended 30 minutes before each infusion.
    Corticosteroids are also given as part of the regimen for patients with Wegener's granulomatosis or microscopic polyangiitis; follow the dosing regimen recommended.[29025]
    Patients require close monitoring during rituximab infusion due to the potential for serious infusion-related reactions.[29025] [63786]
     
    Preparation of intravenous infusion:
    Rituximab must be diluted as an infusion prior to administration.
    Withdraw the necessary amount of rituximab and dilute with Sodium Chloride 0.9% Injection or Dextrose 5% Injection to a final concentration of 1 to 4 mg/mL. Gently invert the bag to mix the solution. Do not shake.
    Do not mix or dilute with other drugs.
    Discard any unused portion left in the vial.
    Storage: The prepared infusion solution is stable at 2 to 8 degrees C (36 to 46 degrees F) for 24 hours and at room temperature for an additional 24 hours. Since rituximab solutions do not contain a preservative, prepared infusions are recommended to be stored under refrigeration, 2 to 8 degrees C (36 to 46 degrees F). Do not freeze.[29025] [63786]
     
    Intravenous infusion administration:
    Do not mix the rituximab infusion with other drugs.
    First infusion: Administer intravenously at an initial rate of 50 mg/hour. If no hypersensitivity or infusion-related events occur, increase infusion rate in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.
    Subsequent infusions:
    Standard infusion: Administer at an initial rate of 100 mg/hour. Increase by 100 mg/hour at 30 minute intervals to a maximum of 400 mg/hour, as tolerated.
    For previously untreated follicular NHL and DLBCL patients: In patients who did not experience a grade 3 or 4 infusion-related adverse event during cycle 1 and do not have clinically significant cardiovascular disease or a circulating lymphocyte count of 5,000 cells/mm3 or more, rituximab may be infused over 90 minutes in cycle 2 with a glucocorticoid-containing chemotherapy regimen. The glucocorticoid should be administered prior to the 90-minute infusion. Initiate rituximab at a rate of 20% of the total dose over the first 30 minutes and the remaining 80% of the total dose over 60 minutes. If tolerated, this infusion schedule may be given in subsequent cycles.[29025] [63786] In a safety analysis of 150 patients who received this rapid infusion schedule beginning in cycle 2 with corticosteroid-containing chemotherapy, no grade 3 or 4 infusion-related reactions were observed.[34664]
    Monitor patients closely during each infusion. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue the drug. For less severe reactions, resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (i.e., 25,000/mm3 or more). Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of rituximab for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.[29025] [63786]

    STORAGE

    Rituxan:
    - Diluted product is stable and sterile for 24 hours when stored refrigerated or at room temperature
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from direct sunlight
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Serious rash

    Mucocutaneous reactions including serious rash such as paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported with rituximab use; some cases were fatal. The time to onset of mucocutaneous reactions has varied; however, there have been reports of reactions occurring with the first rituximab dose. Discontinue rituximab in patients who develop a severe mucocutaneous reaction; the safety of restarting rituximab in these patients has not been evaluated.[29025] [63786]

    Angina, cardiac arrhythmias, cardiac disease, cytokine release syndrome, infusion-related reactions, pulmonary disease

    Infusion-related reactions have been reported with rituximab use; some cases were fatal. Premedicate with acetaminophen and an antihistamine before each rituximab infusion; follow recommendations for premedication or use of corticosteroids for the particular indication for use and regimen given. Interrupt or permanently discontinue the rituximab infusion in patients who develop severe infusion reactions; an infusion rate reduction is recommended if the infusion is resumed in patients with less severe reactions. Signs and symptoms or sequelae of infusion reactions have included: anaphylaxis, angioedema, bronchospasm, cardiogenic shock, flushing, hypotension, hypoxia, myocardial infarction, pulmonary infiltrates, throat irritation, tremor, urticaria, and ventricular fibrillation. Acute respiratory distress syndrome and cytokine release syndrome have also been reported. Closely monitor patients with preexisting cardiac disease or pulmonary disease, patients with a prior history of cardiopulmonary adverse reactions, and patients with high numbers of circulating malignant cells (i.e., 25,000 cells/mm3 or more). Perform cardiac monitoring (e.g., electrocardiogram) during and following each rituximab infusion in patients with a history of cardiac arrhythmias or angina and in patients who develop clinically significant arrhythmias.[29025] [63786]

    Hepatitis, herpes infection, hypogammaglobulinemia, infection, viral infection

    Do not administer rituximab products in patients with an active, severe infection. Serious infections have been reported during and following the completion of rituximab product therapy, including new or reactivated viral infection; some cases were fatal. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia more than 11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue rituximab in patients who develop serious infections; start appropriate anti-infective therapy.[29025] [63786] Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and herpes infection prophylaxis is recommended for certain patients receiving rituximab. PCP and anti-herpetic viral prophylaxis are recommended for patients with chronic lymphocytic leukemia (CLL) during treatment and up to 12 months after treatment as appropriate.[29025] PCP prophylaxis is also recommended for patients with Wegener's granulomatosis and microscopic polyangiitis during treatment and for at least 6 months after the last rituximab infusion. Consider PCP prophylaxis for patients with pemphigus vulgaris during and after rituximab treatment.[29025]

    Hepatitis B exacerbation

    Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, fulminant hepatitis, hepatic failure, and death may occur during or following treatment with an anti-CD20 antibody, including rituximab products. Screen all patients for HBV (e.g., HBsAg and anti-HBc titers) prior to starting rituximab therapy. In patients who have evidence of HBV, consult with an expert in hepatitis management for monitoring and treatment recommendations. Additionally, monitor all patients with current or prior HBV for signs of hepatitis or HBV reactivation during and for several months after therapy. In patients who develop HBV reactivation, discontinue rituximab and any concomitant chemotherapy and initiate appropriate treatment. The safety of restarting rituximab in these patients has not been evaluated.[29025] [63786]

    Immunosuppression, progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML), caused by the JC virus, has been reported in patients with hematologic malignancies and autoimmune diseases who received rituximab products; some cases were fatal. Evaluate patients who develop new neurologic symptoms; consider consulting a neurologist and obtaining a brain MRI and lumbar puncture. Discontinue rituximab in patients who develop PML; additionally, consider discontinuing or reducing concomitant chemotherapy or immunosuppressive therapy. Most patients with hematologic malignancies who developed PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem-cell transplant; patients with autoimmune diseases who developed PML had received prior or concurrent immunosuppression therapy. Most PML cases occurred within 12 months of the final rituximab infusion.[29025] [63786]

    Vaccination

    The safety of immunization with live viral vaccines following rituximab product therapy has not been studied. Vaccination with live virus vaccines is not recommended before or during treatment.[29025] [63786] For patients with rheumatoid arthritis, follow current immunization guidelines and administer any required non-live vaccines at least 4 weeks prior to a course of rituximab.[29025]

    Anemia, neutropenia, thrombocytopenia

    Hematologic toxicity (e.g., anemia, neutropenia, and thrombocytopenia) has been reported with rituximab therapy; cytopenias may last months after treatment. In patients with lymphoid malignancies, who are receiving rituximab monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each course of rituximab treatment. During treatment with rituximab along with chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias.[29025] [63786] In patients with rheumatoid arthritis, granulomatosis with polyangiitis, or microscopic polyangiitis, obtain CBC with differential and platelet counts at 2 to 4 month intervals during rituximab therapy. Continue to monitor for cytopenias after the final dose and until resolution.[29025]

    Hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, renal failure, tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) resulting in acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia has been reported in patients with non-Hodgkin lymphoma who received rituximab product therapy; some cases were fatal. Administer aggressive hydration and anti-hyperuricemic therapy as prophylaxis in patients at high-risk for developing TLS; correct electrolyte abnormalities prior to starting therapy. Monitor renal function and fluid balance during therapy in all patients and administer supportive care including dialysis if necessary if TLS occurs. Patients with a high number of circulating malignant cells (i.e., 25,000 cells/mm3 or higher) or high tumor burden are at increased risk for developing TLS. The time to onset of TLS is typically within 12 to 24 hours of rituximab administration.

    Nephrotoxicity

    Severe and life-threatening nephrotoxicity may occur following treatment with rituximab products. Monitor closely for renal dysfunction or renal failure; discontinue rituximab in patients with rising serum creatinine or oliguria. Renal toxicity has been reported in patients experiencing tumor lysis syndrome and in patients who received concomitant cisplatin therapy. The combination of cisplatin and rituximab is not an approved treatment regimen.[29025] [63786]

    GI obstruction, GI perforation

    Be alert for serious gastrointestinal (GI) events in patients receiving rituximab. GI perforation and GI obstruction have occurred in patients who received rituximab products in combination with chemotherapy; some cases were fatal. Promptly evaluate patients who develop symptoms of obstruction such as abdominal pain or repeated vomiting. The mean time to GI perforation was 6 days (range, 1 to 77 days).[29025] [63786]

    Geriatric

    No overall differences in safety or effectiveness were observed between geriatric patients and younger patients receiving rituximab for previously untreated follicular NHL.  However, some serious adverse reactions were more common in geriatric patients with diffuse large B-cell non-Hodgkin lymphoma (e.g., cardiac toxicity including supraventricular arrhythmias; pulmonary toxicity including pneumonia and pneumonitis), chronic lymphocytic leukemia (e.g., neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections), rheumatoid arthritis (e.g., infections, malignancies, and cardiovascular events), Wegener's granulomatosis, and microscopic polyangiitis in clinical studies when compared to younger adults.

    Infants, neonates, pregnancy

    Rituximab products may cause fetal harm if used in pregnant women; therefore, females of reproductive potential should avoid pregnancy during rituximab therapy and for 12 months following the last dose of the drug. Based on human data, rituximab products can cause adverse developmental outcomes, including lymphoid B-cell depletion. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than 6 months can occur in infants exposed to rituximab in utero. Rituximab was detected postnatally in the serum of neonates exposed in-utero. If rituximab is used during pregnancy, advise pregnant women of the risk to the fetus; monitor neonates and infants for signs of infection and manage as indicated.[29025] [63786]

    Contraception requirements, reproductive risk

    Counsel female patients about the reproductive risk and contraception requirements during rituximab treatment. Rituximab can cause fetal harm. Females of reproductive potential should avoid pregnancy and use effective contraception during and for 12 months after the last dose of treatment with rituximab.[29025] [63786]

    Breast-feeding

    There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. However, rituximab is detected in the milk of lactating cynomolgus monkeys, and IgG is present in human milk. Since many drugs including antibodies are present in human milk (e.g., human IgG), women should discontinue breast-feeding during rituximab therapy and for at least 6 months after the last dose due to the potential for serious adverse reactions in breast-fed infants.[29025] [63786]

    Children

    The safety and effectiveness of rituximab have not been established in infants, children, or adolescents.[29025] [63786] Concerns exist regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system. The FDA has not required pediatric studies in polyarticular juvenile idiopathic arthritis patients ages 0 to 16 years because of these concerns.[29025] Hypogammaglobulinemia has been observed in pediatric patients who received rituximab.[29025] [63786]

    ADVERSE REACTIONS

    Severe

    lymphopenia / Delayed / 40.0-40.0
    angioedema / Rapid / 11.0-11.0
    bronchospasm / Rapid / 8.0-8.0
    neutropenia / Delayed / 6.0-6.0
    leukopenia / Delayed / 4.0-4.0
    anemia / Delayed / 3.0-3.0
    pancytopenia / Delayed / 3.0-3.0
    thrombocytopenia / Delayed / 2.0-2.0
    cytokine release syndrome / Rapid / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    hyperkalemia / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    uveitis / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    GI perforation / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 1.0-56.0
    peripheral neuropathy / Delayed / 30.0-30.0
    depression / Delayed / 18.0-18.0
    peripheral edema / Delayed / 8.0-16.0
    hypertension / Early / 6.0-12.0
    dyspnea / Early / 7.0-10.0
    hypotension / Rapid / 10.0-10.0
    hyperglycemia / Delayed / 9.0-9.0
    conjunctivitis / Delayed / 5.0-5.0
    migraine / Early / 2.0-2.0
    infusion-related reactions / Rapid / 10.0
    hypoxia / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    angina / Early / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    hyperphosphatemia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known

    Mild

    infection / Delayed / 31.0-62.0
    fever / Early / 53.0-53.0
    chills / Rapid / 33.0-33.0
    asthenia / Delayed / 26.0-26.0
    nausea / Early / 18.0-23.0
    headache / Early / 19.0-19.0
    diarrhea / Early / 10.0-17.0
    night sweats / Early / 15.0-15.0
    rash / Early / 10.0-15.0
    pruritus / Rapid / 14.0-14.0
    insomnia / Early / 14.0-14.0
    abdominal pain / Early / 2.0-14.0
    fatigue / Early / 13.0-13.0
    cough / Delayed / 13.0-13.0
    alopecia / Delayed / 13.0-13.0
    arthralgia / Delayed / 10.0-13.0
    rhinitis / Early / 12.0-12.0
    epistaxis / Delayed / 11.0-11.0
    weight gain / Delayed / 11.0-11.0
    dizziness / Early / 10.0-10.0
    vomiting / Early / 10.0-10.0
    myalgia / Early / 10.0-10.0
    throat irritation / Early / 9.0-9.0
    urticaria / Rapid / 8.0-8.0
    sinusitis / Delayed / 6.0-6.0
    flushing / Rapid / 5.0-5.0
    irritability / Delayed / 5.0-5.0
    anxiety / Delayed / 5.0-5.0
    musculoskeletal pain / Early / 5.0-5.0
    dyspepsia / Early / 3.0-3.0
    paresthesias / Delayed / 2.0-2.0
    sneezing / Early / Incidence not known
    lichen planus-like eruption / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Avoid the concomitant use of rituximab and abatacept; coadministration may result in additive immunosuppression and an increased risk of infection. There is insufficient experience to assess the safety and efficacy of abatacept administered concurrently with other biologic therapy, such as rituximab, and therefore such use is not recommended.
    Adalimumab: (Major) Avoid the concomitant use of rituximab with adalimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
    Anakinra: (Major) The concomitant use of rituximab with other biologic agents, such as anakinra, may result in additive immunosuppression and an increased risk of infection. Limited data are available on the safety of the use of biologic agents in rheumatoid arthritis patients exhibiting peripheral B-cell depletion following treatment with rituximab. Monitor patients closely for signs or symptoms of infection.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk for the development of severe infections, malignancies, myelodysplastic syndromes, and lymphoproliferative disorders. Some protocols recommend decreasing the dosage of the standard immunosuppressive agents during treatment with ATG.
    Azathioprine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as azathioprine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Azelastine; Fluticasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Beclomethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including rituximab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Betamethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Budesonide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Budesonide; Formoterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Certolizumab pegol: (Major) Avoid the concomitant use of rituximab with certolizumab pegol, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients who received rituximab in combination with a TNF blocker.
    Ciclesonide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Cisplatin: (Moderate) The concomitant use of rituximab and cisplatin may increase the risk of nephrotoxicity. Monitor patients closely for signs of renal dysfunction; discontinue rituximab in patients who develop oliguria or rising serum creatinine concentrations. Renal toxicity has been reported in patients with non-Hodgkin lymphoma who received rituximab and cisplatin therapy in clinical trials.
    Corticosteroids: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Corticotropin, ACTH: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Cortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Cyclophosphamide: (Moderate) These drugs are commonly used together in various treatment regimens for cancer or other diseases. However, the use of these drugs together may cause additive immunosuppression and increase the risk for infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of cyclophosphamide did not alter the pharmacokinetics of rituximab.
    Deflazacort: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Dexamethasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like rituximab. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Etanercept: (Major) The concomitant use of rituximab with etanercept, a tumor necrosis factor inhibitor, may result in additive immunosuppression and an increased risk of infection. Combination therapy has been reported in published open-label trials for patients refractory to rituximab alone, but further study is needed to establish an increased clinical benefit and impact on side effects, including immunosuppression and infection rates. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor in controlled clinical trials. Monitor patients receiving this combination closely for signs or symptoms of infection.
    Fludrocortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Flunisolide: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Salmeterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Fluticasone; Vilanterol: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Formoterol; Mometasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Gold: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), including gold compounds, may result in additive immunosuppression and an increased risk of infection. According to treatment guidelines, thare no data that adequately address the safety and efficacy of gold compounds in combination with biologic therapies. Monitor patients closely for signs or symptoms of infection.
    Golimumab: (Major) Avoid the concomitant use of rituximab with golimumab, a tumor necrosis factor (TNF) inhibitor; coadministration may result in additive immunosuppression and an increased risk of infection. Higher rates of serious infection were observed in patients with rheumatoid arthritis treated with rituximab who received subsequent treatment with a TNF inhibitor.
    Hydrocortisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Hydroxychloroquine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as hydroxychloroquine, may result in an increased risk of infection. Hydroxychloroquine itself does not increase immunosuppression or infection risk, but, is often used in DMARD regimens where infection risk is increased. Monitor patients closely for signs or symptoms of infection.
    Infliximab: (Major) Avoid the concomitant use of rituximab and infliximab if they are used to treat the same condition due to additive immunosuppression and an increased risk of infection. If coadministration is necessary for separate conditions, monitor patients closely for signs or symptoms of infection.
    Leflunomide: (Moderate) Coadministration may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection.
    Live Vaccines: (Severe) Do not administer live vaccines to rituximab recipients; no data are available regarding the risk of secondary transmission of infection by live vaccines in patients receiving rituximab. At least 4 weeks before initiation of rituximab therapy, consider completion of all age appropriate vaccinations per current immunization guidelines. Rituximab recipients may receive inactivated vaccines, but the immune response to vaccines or toxoids may be decreased.
    Methotrexate: (Moderate) These drugs are commonly used together. However, coadministration of rituximab with immunosuppressive DMARDs, like methotrexate, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs and symptoms of infection. In clinical trials of patients with rheumatoid arthritis, concomitant administration of methotrexate did not alter the pharmacokinetics of rituximab.
    Methylprednisolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Mometasone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Natalizumab: (Major) Natalizumab should not be used in combination with rituximab because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, multiple sclerosis patients receiving chronic immunomodulatory therapy should not be treated with natalizumab.
    Ocrelizumab: (Major) Avoid the use of ocrelizumab and rituximab together. Both drugs are monoclonal antibodies directed against CD20-expressing B-cells. There are no data on the safety and efficacy of using these drugs at the same time. The concomitant use of rituximab and ocrelizumab may result in additive immunosuppression and an increased risk of infection. Additionally, additive immunosuppression may occur if ocrelizumab is administered before or after rituximab therapy. When switching from drugs with prolonged immune effects, such as rituximab, consider the duration and mode of action of rituximab when initiating ocrelizumab. Monitor patients closely for signs or symptoms of infection.
    Penicillamine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as penicillamine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Prednisolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Prednisone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.
    Sarilumab: (Major) Avoid the concomitant use of rituximab and sarilumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    Sipuleucel-T: (Moderate) Use rituximab and sipuleucel-T together with caution. If appropriate, consider reducing or discontinuing immunosuppressive agents prior to treatment with sipuleucel-T. Sipuleucel-T works by stimulating the immune system; therefore, concurrent use with immunosuppressive agents, such as rituximab, may alter its efficacy or safety.
    Sulfasalazine: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as sulfasalazine, may result in an increased risk of infection. Monitor patients closely for signs or symptoms of infection. For a patient who develops a new infection during treatment with sulfasalazine, perform a prompt and complete diagnostic workup for infection and myelosuppression.
    Tocilizumab: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Triamcinolone: (Moderate) Rituximab and corticosteroids are commonly used together; however, monitor the patient for immunosuppression and signs and symptoms of infection during combined chronic therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. However, rituximab is detected in the milk of lactating cynomolgus monkeys, and IgG is present in human milk. Since many drugs including antibodies are present in human milk (e.g., human IgG), women should discontinue breast-feeding during rituximab therapy and for at least 6 months after the last dose due to the potential for serious adverse reactions in breast-fed infants.[29025] [63786]

    MECHANISM OF ACTION

    Rituximab is a monoclonal antibody that binds to the antigen CD20, a hydrophobic transmembrane protein found on the surface of B-cell precursors and mature B-lymphocytes. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. The Fab domain of rituximab binds to the CD20 antigen on B-lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation. Rituximab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC).[29025] [63786] Rituximab is associated with the release of cytokines, specifically tumor necrosis factor-alpha (TNFa) and interleukin-6 (IL-6), which may be responsible for the infusion-related adverse reactions.
     
    In oncology patients with non-Hodgkin's lymphoma (NHL), rituximab causes a rapid and sustained depletion of circulating and tissue-based B-cells. Circulating B-cells (measured as CD19+ cells) are generally depleted within the first 3 doses, with sustained depletion for up to 6 to 9 months after treatment. B-cell recovery begins about 6 months following completion of the treatment course, and median B-cell levels return to normal by 12 months.[29025] [63786] Rituximab has also been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line and to sensitize drug-resistant human B-cell lymphoma cell lines to cytotoxic chemotherapy.
     
    B-cells are believed to play a role in the pathogenesis of rheumatoid arthritis and associated chronic synovitis, as well as other inflammatory and/or autoimmune processes. In these conditions, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production.[29025]

    PHARMACOKINETICS

    Rituximab is given as an intravenous infusion. Based on a population pharmacokinetic analysis of data from 298 non-Hodgkin's lymphoma (NHL) patients who received rituximab once weekly or once every 3 weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m2 rituximab weekly by intravenous infusion for 4 doses; rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.
     
    In patients with NHL, the median time to onset of response is about 50 days, and the median duration of response is projected to be 10 to 12 months. The pharmacokinetic profile of rituximab (375 mg/m2 for 6 cycles) in combination with CHOP chemotherapy was similar to that seen with rituximab alone.
     
    Administration of rituximab 1,000 mg IV on days 1 and 15 to patients with rheumatoid arthritis led to a mean systemic clearance of 0.01 L/hour, and a mean terminal elimination half-life after the second dose of 19 days. Improvement occurred over the first 4 weeks after rituximab administration, and the ACR 20, 50, or 70 responses were maintained through week 24 after a single treatment course (2 doses).
     
    Affected cytochrome P450 isoenzymes and drug transporters: Unknown
    Formal drug-drug interactions studies have not been performed with rituximab.

    Intravenous Route

    Single doses ranging from 10 to 500 mg/m2 given as an IV infusion produce serum concentrations proportional to the dose. Following administration of rituximab 375 mg/m2 IV at weekly intervals for 4 doses to 203 rituximab-naive patients with non-Hodgkin's lymphoma (NHL), the mean Cmax following the fourth infusion was 486 mcg/mL (range: 77.5 to 996.6 mcg/mL). Administration of rituximab 1,000 mg IV on days 1 and 15 to patients with rheumatoid arthritis (RA) led to a mean Cmax of 370 mcg/mL.