Rituxan (rituximab)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Approval Status:

Approved April 2011

Specific Treatments:

Wegener’s Granulomatosis and Microscopic Polyangiitis

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General Information

Rituxan is a CD20-directed cytolytic antibody.

Rituxan is specifically indicated for use in combination with glucocorticoids for the treatment of two forms of ANCA-associated vasculitis: granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis. The FDA approval was expanded in September of 2019 to include the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in pediatric patients 2 years of age and older.

Rituxan is supplied as an injection for intravenous administration.  The recommended dose is as follows:

Induction Treatment of Patients with Active GPA/MPA:

Administer Rituxan as a 375 mg/m2 intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA. Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituxan and may continue during and after the 4 week induction course of Rituxan treatment.

Follow up Treatment of Patients with GPA/MPA who have achieved disease control with induction treatment:

Administer Rituxan as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation. Patients should receive 100 mg intravenous methylprednisolone to be completed 30 minutes prior to each Rituxan infusion. If induction treatment of active disease was with Rituxan, follow up treatment with Rituxan should be initiated within 24 weeks after the last Rituxan induction infusion or based on clinical evaluation, but no sooner than 16 weeks after the last Rituxan induction infusion. If induction treatment of active disease was with other standard of care immunosuppressants, Rituxan follow up treatment should be initiated within the 4 week period that follows achievement of disease control.

Clinical Results

FDA Approval

The FDA approval was based on the following studies:

Induction Treatment of Patients with Active Disease (GPA/MPA Study 1) A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculitides) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients in both arms received 1000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either Rituxan 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to Rituxan infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituxan group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. The study demonstrated non-inferiority of Rituxan to cyclophosphamide for complete remission at 6 months.  

Follow up Treatment of Patients with GPA/MPA who have achieved disease control with other Immunosuppressant (GPA/MPA Study 2) A total of 115 patients (86 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated vasculitis) in disease remission were randomized to receive azathioprine (58 patients) or non-U.S.licensed rituximab (57 patients) in this open-label, prospective, multi-center, randomized, active controlled study. Remission of active disease was achieved using a combination of glucocorticoids and cyclophosphamide. Within a maximum of 1 month after the last cyclophosphamide dose, eligible patients (based on BVAS of 0), were randomized in a 1:1 ratio to receive either non-U.S.-licensed rituximab or azathioprine. The non-U.S.-licensed rituximab was administered as two 500 mg intravenous infusions separated by two weeks (on Day 1 and Day 15) followed by a 500 mg intravenous infusion every 6 months for 18 months. Azathioprine was administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months; treatment was discontinued after 22 months. Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatment after month 18 were left at the investigator’s discretion. Planned follow-up was until month 28 (10 or 6 months, respectively, after the last non-U.S. licensed rituximab infusion or azathioprine dose). The primary endpoint was the occurrence of major relapse (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity that could lead to organ failure or damage, or could be life threatening) through month 28. By month 28, major relapse occurred in 3 patients (5%) in the non-U.S.-licensed rituximab group and 17 patients (29%) in the azathioprine group. The observed cumulative incidence rate of first major relapse during the 28 months was lower in patients on non-U.S.-licensed rituximab relative to azathioprine.

The FDA approval of Rituxan (rituximab) in combination with glucocorticoids for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in pediatric patients 2 years of age and olderwas based on data from the PePRS study. The Phase IIa, global, open-label, multi-center, single-arm study investigated the safety, pharmacokinetics, exploratory efficacy and pharmacodynamic outcomes of intravenous Rituxan in 25 patients with active GPA or MPA between 6 and 17 years of age. Treatment with four weekly infusions of Rituxan or non-U.S.-licensed rituximab in combination with a tapering course of oral glucocorticoids was assessed in newly diagnosed or relapsing active GPA or MPA pediatric patients. Of the 25 patients in the study, 19 had GPA and 6 had MPA at baseline. Efficacy was an exploratory endpoint and primarily assessed using the Pediatric Vasculitis Activity Score (PVAS). Efficacy assessment showed that 56% of patients achieved PVAS remission by month 6, 92% by month 12, and 100% of patients achieved remission by month 18.

 

Side Effects

Adverse effects associated with the use of Rituxan may include, but are not limited to, the following:

infections

nausea

diarrhea

headache

muscle spasms

anemia

peripheral edema

infusion-related reactions

The Rituxan drug label comes with the following Black Box Warning:

Infusion-Related Reactions: Rituxan administration can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions. Severe Mucocutaneous Reactions Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan. Discontinue Rituxan and concomitant medications in the event of HBV reactivation. Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving Rituxan.

Mechanism of Action

Rituxan (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). B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, 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.

Additional Information

For additional information regarding Rituxan or Wegener’s Granulomatosis and Microscopic Polyangiitis, please visit https://www.rituxan.com/