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FDA Approval for Rituximab

 Brand name(s): Rituxan®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Approved New Dosing and Administration for Certain Non-Hodgkin Lymphoma Patients

On October 19, 2012, the Food and Drug Administration (FDA) approved a 90-minute infusion for rituximab (Rituxan® Injection, made by Genentech, Inc.) starting at cycle 2 for patients with non-Hodgkin lymphoma (NHL) who did not experience a grade 3 or 4 infusion-related adverse reaction during cycle 1. Patients with clinically significant cardiovascular disease and high circulating lymphocyte counts (greater than 5000/mcL) are not recommended to receive the faster infusion.

The approval was based on an open-label single-arm multicenter phase III trial (RATE). The evaluable patient population was comprised of 363 previously untreated patients with follicular NHL or diffuse large B-cell lymphoma (DLBCL) who had not experienced a grade 3 or 4 infusion-related reaction (IRR) to rituximab in combination with CHOP or CVP chemotherapy during cycle 1. Patients received the faster infusion in cycle 2 and, if tolerated, in all subsequent cycles. The faster infusion regimen consisted of rituximab administered over 90 minutes with 20 percent of the total dose given in the first 30 minutes, and remaining 80 percent of the total dose administered over the subsequent 60 minutes.

The trial’s primary endpoint was the incidence of grade 3 and 4 IRRs in patients who received rituximab by faster infusion at cycle 2. The incidence of grade 3 IRRs at cycle 2 was 1.1 percent (95 percent CI: 0.3, 2.8)], with no grade 4 or 5 IRRs reported. The RATE trial results are comparable to the results of IRRs during cycle 2 reported from trials using the standard infusion regimen.

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Approved for Maintenance Therapy for Untreated Follicular CD-20 Positive B-cell Non-Hodgkin Lymphoma

On January 28, 2011, the FDA approved rituximab (Rituxan®, made by Genentech, Inc.) for maintenance therapy for patients with previously untreated follicular CD-20 positive B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.

The approval was based on the Primary Rituximab and Maintenance (PRIMA) study, an open-label multinational randomized Phase III study evaluating the benefit of rituximab maintenance therapy.  Patients with previously untreated follicular lymphoma with high tumor burden were randomly assigned to receive either rituximab maintenance therapy or no maintenance therapy after achieving a response to a chemotherapy regimen including rituximab.

After achieving a complete or partial response to a rituximab plus chemotherapy induction regimen, 1018 patients were randomly assigned (1:1) to receive either rituximab 375 mg/m2, intravenously, every 8 weeks (maximum 12 doses) or observation.  Forty percent of patients were over 60 years of age, 70 percent had stage IV disease, 96 percent had Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and 42 percent had FLIPI (follicular lymphoma international prognostic index) scores of 3-5.  Induction therapy consisted of R-CHOP (rituximab, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], and prednisone) in 75 percent of patients, R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) in 22 percent of patients, and R-FCM (rituximab, fludarabine, cyclophosphamide, and mitoxantrone) in 3 percent of patients

Progression-free survival (PFS), evaluated by an independent review committee, was the trial's primary endpoint. Maintenance rituximab reduced the risk of a PFS event by 46 percent (stratified hazard ratio: 0.54, 95 percent confidence interval: 0.42-0.70; stratified log-rank test p <0.0001).  Results for overall survival remain immature at this time.

Safety data collection was limited to grade ≥2 infections and grade ≥3 adverse reactions. Among 501 patients who received at least one dose of rituximab maintenance therapy, infections were reported in 37 percent.  In contrast, infections were reported in 22 percent of patients in the observation group.  Grade 3-4 adverse reactions occurred more frequently in rituximab-treated patients, with serious or life-threatening infections occurring in four percent of patients treated with rituximab compared with one percent of patients in the observation group, and moderate to severe neutropenia occurring in four percent of patients treated with rituximab, compared with less than 1 percent of patients in the observation group.

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 Approved for Chronic Lymphocytic Leukemia (CLL)

On February 18, 2010, the FDA granted approval to rituximab (Rituxan®, made by Genentech), in combination with fludarabine and cyclophosphamide (FC), for the treatment of both previously untreated and previously treated patients with chronic lymphocytic leukemia (CLL). The approval was based on clinically meaningful and statistically significant increases in progression-free survival (PFS) observed in two randomized multicenter open-label trials in patients randomly assigned to receive either FC or the combination of FC with rituximab (R-FC).

In both studies, patients received intravenous (i.v.) fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day, daily for 3 days, repeated every 28 days for a total of 6 cycles. Rituximab 375 mg/m2 by i.v. infusion was administered on day 1 of the first cycle (the day before chemotherapy) and 500 mg/m2 i.v. on day 1 of subsequent cycles (on the same day as chemotherapy). The primary efficacy outcome was PFS, defined as the time from randomization to disease progression, relapse, or death. Secondary endpoints included overall survival (OS) and overall response rates, as determined by the 1996 National Cancer Institute-sponsored Working Group Guidelines.

Study ML17102, also known as CLL8, was conducted by the German CLL Study Group and enrolled patients who were previously untreated. A total of 408 patients were randomly assigned to the R-FC arm and 409 patients to the FC arm. The median age was 61 years (30 percent were 65 years or older), 74 percent were male, 31 percent were Binet stage C, 45 percent had B symptoms, and more than 99 percent had ECOG performance status (PS) 0-1.

The primary efficacy endpoint was PFS, as determined by the investigators. The median PFS were 39.8 months in the R-FC arm and 31.5 months in FC arm [HR 0.56 (95 percent CI: 0.43, 0.71), p <0.01]. Overall response rates were 86 percent (95 percent CI 82, 89) in the R-FC arm and 73 percent (95 percent CI 68, 77) in the FC arm.

Study BO17072, also known as REACH, conducted by Roche and Biogen Idec, enrolled 552 patients with relapsed or refractory CLL following prior systemic therapy. Patients were randomly selected to receive either R-FC (n=276) or FC (n=276). The median age was 62 years (44 percent were 65 years or older), and 67 percent were male. Eighty-two percent had received a prior alkylator-containing regimen and 18 percent had received a fludarabine-containing regimen. “B” symptoms were present in 28 percent, and all patients had ECOG PS 0-1.

The median PFS was 26.7 months for the R-FC arm and 21.7 months for the FC arm, as determined by an independent review committee [HR 0.76 (95 percent CI: 0.60, 0.96), p= 0.022,]. Overall response rates were 54 percent (95 percent CI: 48, 60) in the R-FC arm and 45 percent (95 percent CI: 37, 51) in the FC arm.

Too few events had occurred by the time of regulatory submission to conduct a meaningful analysis of OS in either study. Follow-up of patients for OS is ongoing.

Across both studies, 100 patients who received R-FC and 89 patients who received FC were at least 70 years old. The results of exploratory analyses in this elderly population did not suggest a treatment benefit for the addition of Rituxan to FC in either the previously untreated [HR 1.17 (95 percent CI: 0.51, 2.66)] or previously treated [HR 1.22 (95 percent CI: 0.73, 2.04)] settings.

The safety of rituximab when combined with FC was assessed in 676 patients who received the R-FC regimen. In both studies, 71 percent received 6 cycles and 90 percent received at least 3 cycles of Rituxan-based therapy. Grade 3-4 infusion reactions occurred in 7-9 percent of R-FC treated patients. The following Grade 3-4 adverse events were more frequently observed in the R-FC arm compared to the FC arm: neutropenia, febrile neutropenia, leucopenia, thrombocytopenia, hypotension, hepatitis B, and pancytopenia.

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 Low-grade or follicular B-cell, CD20-positive NHL

On September 29, 2006, the FDA granted approval to rituximab (Rituxan®, made by Genentech, Inc.) for use in the first-line treatment of patients with low grade or follicular B-cell, CD20-positive non-Hodgkin’s lymphoma. One approval was for the use of rituximab combined with CVP chemotherapy (cyclophosphamide, vincristine, and prednisone); the second is for use of rituximab following CVP chemotherapy.

The first indication was based on a 322 patient study. Patients had an advanced-stage, follicular, CD20+ NHL and were previously untreated with chemotherapy. Patients were randomized (1:1) to receive either a maximum of eight three-week cycles of CVP chemotherapy alone or CVP chemotherapy in combination with rituximab (375 mg/m2 on day 1 of each 21-day cycle).

Patients receiving rituximab plus CVP showed a statistically significant improvement in progression-free survival (PFS) compared to those receiving CVP alone (median PFS 2.4 vs. 1.4 years; hazard ratio 0.44, p<0.0001 two-sided stratified log rank test).

The second indication was based on a 322 patient trial enrolling previously untreated low-grade, B-cell NHL (IWF Grades A, B or C) patients with stable disease or partial or complete responses following six to eight CVP chemotherapy cycles. Patients were randomized (1:1) to receive either no additional therapy or rituximab (375 mg/m2 once weekly for four doses) every six months for up to 16 doses.

A statistically significant reduction in PFS was observed; the hazard ratio for reduction in the risk of progression, relapse, or death ranged from 0.36 to 0.49 for rituximab versus those who received no additional treatment.

The safety profile observed in these trials was consistent with the previously described safety profile provided in the product label.

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 Diffuse large B-cell, CD20-positive NHL

On February 10, 2006, the FDA granted approval to rituximab for use in the first-line treatment of patients with diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

Safety and efficacy were demonstrated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1,854 patients. These trials enrolled primarily patients with diffuse large B-cell lymphoma who had not received prior therapy.

Two of the three studies (E4494 and LNH 98-5/GELA) were restricted to patients 60 years of age or greater, while the third (M39045/MiNT) enrolled patients between ages 18 and 60 years. In E4494 and LNH98-5, the majority of patients had stage III-IV disease, while the majority had stage I-II disease in M39045. Patients received rituximab 375 mg/m2 by differing schedules in combination with CHOP or other anthracycline-based chemotherapy regimens (R-CHEMO).

Each study utilized composite time-to-event endpoints, incorporating disease progression events as the main outcome measure and included overall survival among secondary analyses. Determination of the primary endpoint was based upon investigator-assessment.

In each study, hazard ratios for the main outcome measures favored the rituximab-containing arms. In addition, each study showed an overall survival benefit among patients receiving rituximab. With two years of follow-up, more patients were alive by Kaplan-Meier estimates in the rituximab-containing versus control arms for each study as follows: 74 percent vs. 63 percent, 69 percent vs. 58 percent, and 95 percent vs. 86 percent.

In one of the studies, five-year data were available and demonstrated that the survival advantage persisted with estimated five-year survival rates of 58 percent vs. 46 percent for R-CHOP and CHOP, respectively. Results were generally consistent across subgroups, including age, gender and disease prognostic variables.

There was neither additional improvement in progression-free survival nor overall survival for patients in E4494 receiving R-CHOP who were subsequently randomized to additional rituximab after achieving a complete or partial response as compared to those who received R-CHOP alone.

In all three studies, the dose intensity for rituximab in the R-CHOP and R-CHEMO induction arms was high and rituximab treatment was not associated with a reduction in the dose intensities of individual chemotherapy components.

Adverse events associated with rituximab were generally consistent with the labeled adverse reactions described for single-agent rituximab. Grade 3/ 4 adverse events occurring with ≥ 2 percent excess in the rituximab arm in at least one study included infection, thrombocytopenia, and lung toxicity/dyspnea.

The following serious adverse reactions, some with fatal outcomes, have been reported in patients receiving rituximab: severe or fatal infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, hepatitis B reactivation with fulminant hepatitis, other viral infections, hypersensitivity reactions, cardiac arrhythmias, renal (kidney) toxicity, and bowel obstruction and perforation.

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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 3, 2013