INDICATION
Rituxan (rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Rituxan is not recommended for treatment of patients with severe active infections.

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS
RITUXAN administration can result in serious, including fatal, adverse reactions. These include: infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML).

Warnings and Precautions
Rituxan administration can also result in additional serious, including fatal, adverse reactions including:
• hepatitis B reactivation
• other infections including bacterial, fungal, new or reactivated viral infections
• cardiovascular events

Patients should be closely observed for signs of infection if biologic agents and/or DMARDs other than methotrexate are used concomitantly. Common adverse reactions include infusion reactions and infections.

For additional safety information, please see the full prescribing information, including BOXED WARNINGS and Medication Guide.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

For additional safety information please see the Rituxan prescribing information. CLICK HERE

Rheumatoid arthritis (RA), which affects roughly 1.3 million Americans, can lead to long-term joint damage, resulting in chronic pain as well as loss of function and disability.¹ Several classes of drugs are used to treat RA, including disease-modifying antirheumatic drugs (DMARDs), biologic response modifiers, and other therapies.¹ Rituximab, a monoclonal antibody that selectively targets CD20-positive B-cells, is indicated in combination with methotrexate (MTX) to reduce signs and symptoms and to slow the progression of structural damage in adult patients with moderately-to severely- active RA who have had an inadequate response to 1 or more tumor necrosis factor (TNF) antagonist therapies.² “Some physicians have expressed concerns about serious infections and infusion safety when using rituximab,” explains James W. Levine, DO. While the efficacy of rituximab was supported in four controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs, and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not been established in these populations. The use of rituximab in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended.²

Serious Infections Data

A study presented by van Vollenhoven et al at the 2008 ACR Annual Scientific Meeting pooled safety data from RA patients treated with rituximab in combination with MTX based on 5013 patient-years of rituximab exposure with up to 6 years of follow-up.³ A total of 170 patients (7%) experienced a serious infection event (SIE), yielding a rate of 4.31 events per 100 patient-years.³ Rates of overall adverse events (AEs), serious AEs (SAEs), and infections remained stable over time and by treatment course.

An analysis of infections during consecutive 12-month intervals showed no evidence of increased risk of infection over time, irrespective of multiple courses (Figure 1).³ When analyzed by exposure time from first dosing of rituximab, the number of SIEs per 100 patient-years was low, remained stable between periods (4 to 6 events per 100 patient-years), and was relatively unchanged for each subsequent 6-month period. The overall serious infection rate in this analysis was 4.31 per 100 patient-years.

The overall rate of SIEs for rituximab-treated patients appears similar to epidemiologic data reported in registries of other biologic and non-biologic DMARDs. Registry data include all-comers and do not utilize study-specific inclusions/exclusion criteria. Rituximab has been well tolerated over multiple courses. The most frequent AE was infusion-related reactions, which occurred in 35% of patients, but less than 1% of infusion reactions were considered serious. Most infusion reactions occurred during the first course of treatment.³

Care should be exercised in interpreting open-label results due to the inability to minimize bias.

Infusion Safety

At the 2009 European League Against Rheumatism Annual Congress, van Vollenhoven et al conducted a follow-up analysis based on 5964 patient-years of rituximab exposure.⁴ This is from a later data cut of the all-exposure analysis data presented at ACR 2008. The proportion of patients with infusion reactions was stable over multiple treatment courses (Figure 2). There were 15 events in 14 patients (0.5%) that were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring during courses 1 through 5, respectively.⁴ The rates of AEs and SAEs remained stable following each course.

Care should be exercised in interpreting open-label results due to the inability to minimize bias.

“Less than 1% of RA patients who receive rituximab experience serious acute infusion reactions,” says Dr. Levine. “The patients who do experience a reaction typically do so during their first infusion. In the second infusion, the rate of infusion reactions has been comparable with placebo [Figure 3].” In the pivotal RA clinical trials in 938 patients, 27% of patients receiving rituximab experienced acute infusion reactions in their first infusion, compared with 19% in the placebo group. By the second infusion, the rate of infusion reactions for rituximab was comparable to placebo (9% vs 11%, respectively). Acute infusion reactions that required stopping, slowing, or interruption of infusions occurred in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. “Most acute infusion reaction AEs can be managed by decreasing the rate of infusion or temporarily stopping it, and/or by giving an antihistamine and/or corticosteroid,” adds Dr. Levine.² “To date, no fatal infusion reactions have been reported in RA patients treated with rituximab. However, fatal infusion reactions must be considered a risk for RA patients receiving rituximab therapy. These data and the data on SIEs drive home the message that rituximab for RA has a favorable risk/benefit profile in patients with an inadequate response to TNF inhibitors.”

Post-Rituximab Biologic Use

An analysis published by Genovese et al in the December 2009 Annals of Rheumatic Diseases described the safety of biologic DMARDs in RA patients following rituximab. Patients from 9 clinical trials who received at least 1 course of rituximab, entered the safety follow-up (SFU) period, and subsequently received another biologic therapy were included in the analysis. The analysis assessed 185 patients who entered SFU and received another DMARD, 153 of whom had received a subsequent TNF inhibitor.⁵ Of the 185 total patients receiving any biological agent after rituximab treatment, 13 SIEs (6.99 events per 100 patient-years) occurred following rituximab but prior to another biologic, and 10 SIEs (5.49 events per 100 patient-years) occurred following another biological DMARD (Table).⁵ The majority of patients (88.6%) had peripheral B-cell depletion at the time of treatment with another biologic DMARD.

The data suggest that patients who receive another biologic after being treated with rituximab do not have an increased risk of infection. Additionally, the SIEs observed in the study from Genovese et al were of typical type and severity for RA patients. There were no fatal or opportunistic infections before or after another biological DMARD was used following rituximab treatment.⁵

Care should be exercised in interpreting open-label results due to the inability to minimize bias.

Efficacy

In the September 2006 issue of Arthritis & Rheumatism, Cohen et al evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multi-center, randomized, double-blind, placebo-controlled, phase III study of rituximab. The study enrolled 520 patients with long-standing disease (mean duration: 12 years), active RA (≥8 swollen and ≥8 tender joints), and an inadequate response to 1 or more anti-TNF agents. Patients were randomized to receive rituximab (1 course consisting of 2 infusions of 1000 mg each) or placebo, both with background MTX.⁶ At Week 24, significantly more rituximab-treated patients than placebo-treated patients demonstrated American College of Rheumatology 20% improvement criteria (ACR20) responses (51% vs 18%). Also, the American College of Rheumatology 50% improvement criteria (ACR50) response was 27% for the rituximab group compared with 5% for the placebo group. American College of Rheumatology 70% improvement criteria (ACR70) responses were 12% and 1% for rituximab and placebo recipients, respectively.⁶ “Rituximab-treated patients had clinically meaningful improvements in fatigue, disability, and health-related quality of life,” says Dr. Levine.⁶ Rituximab was also shown to slow the progression of joint damage in these patients who had an inadequate response to 1 or more anti-TNF agents.⁶

At the 2008 American College of Rheumatology (ACR) Annual Scientific Meeting, Keystone et al updated interim data from an open-label extension of the REFLEX study.⁷ Repeated courses of rituximab showed sustained efficacy (relative to the original baseline) in patients with active RA and an inadequate response to TNF inhibitors. “A completer analysis of 179 patients that examined ACR20, ACR50, and ACR70 scores at 24 weeks following 3 courses of rituximab showed that repeated treatment with the agent was effective over multiple courses,” adds Dr. Levine. ACR50 and ACR70 responses improved throughout the completer analysis, with overall ACR70 responses increasing from 14% following the first course of rituximab to 26% following the third course.⁷

Care should be exercised in interpreting open-label results due to the inability to minimize bias.

Conclusion

Rituximab has a favorable risk/benefit profile in RA patients with an inadequate response to TNF inhibitors. Safety and efficacy are sustained over the course of treat­ment. The rates of SAEs, including serious infections, were stable over multiple courses of rituximab. The incidence of infusion reactions decreased with subsequent courses. Rituximab has an established safety profile. RA patients should be instructed to read the medication guide prior to starting therapy.

James W. Levine, DO, has indicated to Physician’s Weekly that he has worked as a paid speaker for Abbott Laboratories, Eli Lilly, and Genentech.

Genentech and Biogen Idec participated in the review of content for this issue.

Please CLICK HERE for Rituxan prescribing information. 

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Industry Focus represents a special article that is sponsored by and developed
in conjunction with the featured physician and Genentech and Biogen Idec.

Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate
in patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely
for signs of infection if biologic agents and/or DMARDs are used concomitantly.

For additional safety information please see the Rituxan prescribing information. CLICK HERE