On October 19, 2012, FDA approved a 90-minute infusion for rituximab (Rituxan) starting at cycle 2 for patients with previously untreated follicular non-Hodgkin or diffuse large B-cell lymphoma who do not experience a grade 3 or 4 infusion-related reaction during cycle 1.1 Patients with clinically significant cardiovascular disease and those with high circulating lymphocyte counts (≥ 5,000/µL) before cycle 2 should not receive the faster infusion.
The non-Hodgkin lymphoma indications affected by the approval are previously untreated follicular, CD20-positive, B-cell non-Hodgkin lymphoma in combination with first-line chemotherapy and previously untreated diffuse large B-cell lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy regimens.
The recommended dose of rituximab in non-Hodgkin lymphoma is 375 mg/m2 via IV infusion given on day 1 of each cycle of chemotherapy for up to eight doses in both follicular non-Hodgkin and diffuse large B-cell lymphoma patients. For the initial dose in cycle 1, rituximab infusion is initiated at a rate of 50 mg/h; in the absence of infusion toxicity, the rate is increased by 50 mg/h increments every 30 minutes to a maximum of 400 mg/h.
New Infusion Recommendations
Under the new approval, a 90-minute infusion can be administered in cycle 2 with a glucocorticoid-containing regimen in patients who do not experience a grade 3 or 4 infusion-related adverse reaction in cycle 1. The 90-minute infusion is started at a rate of 20% of the total dose given in the first 30 minutes, with the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through cycle 6 or 8).
RATE Trial Details
Approval of the faster infusion rate is based on findings in an open-label, single-arm, multicenter phase III trial (RATE trial) in which 363 patients with previously untreated follicular non-Hodgkin lymphoma (n = 113) or diffuse large B-cell lymphoma (n = 250) received rituximab 375 mg/m2 plus CVP (cyclophosphamide, vincristine, prednisone) in follicular non-Hodgkin lymphoma patients and CHOP in diffuse large B-cell lymphoma patients.2 Patients with clinically significant cardiovascular disease were excluded from the study.
Patients were eligible for a 90-minute rituximab infusion in cycle 2 if they did not experience a grade 3 or 4 infusion-related adverse event in cycle 1 and had a circulating lymphocyte count < 5,000/µL before cycle 2. All patients were premedicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to rituximab infusion. Patients who tolerated the 90-minute infusion in cycle 2 continued to receive subsequent rituximab infusions at this rate for the remainder of the treatment regimen (through cycle 6 or 8).
Infusion-related Reactions
The main outcome measure of the trial was the development of grade 3 or 4 infusion-related reactions on the day of or the day after the 90-minute infusion in cycle 2. The incidence of grade 3 infusion-related reactions in cycle 2 was 1.1% (95% confidence interval [CI] = 0.3%–2.8%) among all patients, including an incidence of 3.5% (95% CI = 1.0%–8.8%) in follicular non-Hodgkin lymphoma patients (who received CVP) and 0.0% (95% CI = 0.0%–1.5%) in diffuse large B-cell lymphoma patients (who received CHOP). No grade 4 or 5 infusion-related reactions were reported in cycle 2. These results are comparable to those reported for cycle 2 in rituximab trials using the standard infusion regimen.
For cycles 2 through 8, the incidence of grade 3 or 4 infusion-related reactions was 2.8% (95% CI = 1.3%–5.0%). No acute fatal infusion-related reactions were observed. ■
References
1. US Food and Drug Administration: Rituximab infusion. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm324890.htm. Accessed November 9, 2012.
2. RITUXAN® (rituximab) injection for intravenous use prescribing information, Biogen Idec Inc and Genentech, Inc, October 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103705s5367s5388lbl.pdf. Accessed November 9, 2012.
