Rituxan (rituximab) - 5 indications

Scroll down for information on each indication:

• for the treatment of Non-Hodgkin's lymphoma; approved November 1997
• for the treatment of moderately-to severely-active rheumatoid arthritis; approved February 2006
• for the treatment of chronic lymphocytic leukemia; approved February 2010
• for the treatment of Wegener’s Granulomatosis and Microscopic Polyangiitis; approved April 2011
• for the treatment of Pemphigus Vulgaris; approved June 2018

General Information

Rituxan (rituximab) is a CD20-directed cytolytic antibody. 

Rituxan is specifically indicated for the following:

• Adult patients with Non-Hodgkin’s Lymphoma (NHL)
  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent;
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. 
• for the treatment of rheumatoid arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies.
• for use in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL). 
• for use in combination with glucocorticoids for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA).
• for the treatment of adult patients with moderate to severe pemphigus vulgaris. 

Rituxan is supplied as an injection for intravenous administration. Scroll down to see the recommended dosing/administration for each indication.

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.

Side Effects

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

• infusion-related reactions
• fever
• lymphopenia
• chills
• infection
• asthenia

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

• infusion-related reactions
• neutropenia

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

• upper respiratory tract infection
• nasopharyngitis
• urinary tract infection
• bronchitis
• infusion-related reactions
• serious infections
• cardiovascular events

Adverse effects associated with the use of Rituxan for the treatment of GPA and MPA may include, but are not limited to, the following:

• infections
• nausea
• diarrhea
• headache
• muscle spasms
• anemia
• peripheral edema
• infusion-related reactions

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

• infusion-related reactions
• depression
• upper respiratory tract infection/ nasopharyngitis
• headache
• infections

Indication 1 - Non-Hodgkin's lymphoma

approved November 1997

Dosing/Administration

The recommended dose of Rituxan for NHL is 375 mg/m2 as an intravenous infusion according to the following schedules:

• Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 or 8 doses.
• Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses.
• Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses.
• Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy Following completion of 68 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses.
• Diffuse Large B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions.

Clinical Trial Results

Indication 2 - moderately-to severely-active rheumatoid arthritis

approved February 2006

Dosing/Administration

The recommended dose is Rituxan administered as two-1000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituxan is given in combination with methotrexate.

Clinical Trial Results

The FDA approval of Rituxan for rheumatoid arthritis was based largely on results from the phase III 24-week pivotal REFLEX Study. The study enrolled 520 patients (499 evaluable) with active rheumatoid arthritis (RA) who had an inadequate response to at least one TNFi therapy and active disease (≥8 swollen and ≥8 tender joints). Patients were randomized to receive 2 x 1000-mg Rituxan infusion + methotrexate (MTX) or placebo + MTX. The primary end point was ACR20 at 6 months (24 weeks). At 24 weeks, patients receiving Rituxan displayed clinically and statistically significant improvements in RA signs and symptoms, including pain and disability. In patients receiving Rituxan: 51 percent achieved ACR 20, the primary endpoint of the study, versus 18 percent of placebo patients; 27 percent achieved ACR 50, versus 5 percent of placebo patients and 12 percent achieved ACR 70, versus 1 percent of placebo patients. Rituxan was also shown to reduce biologic markers of inflammation.

Indication 3 - chronic lymphocytic leukemia

approved February 2010

Dosing/Administration

The recommended dose of Rituxan for CLL is 375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2-6 (every 28 days). 

Clinical Trial Results

The FDA approval of Rituxan for CLL was based on two phase III studies. In the CLL8 study of 817 previously untreated patients, the addition of rituximab to FC yielded a 79% improvement in progression-free survival. The duration of progression-free survival was extended by more than 8 months compared with FC alone (39.8 months vs 31.5 months). In the REACH study of 552 rituximab-naive patients with relapsed CLL, the use of rituximab plus FC yielded a 32% improvement in progression-free survival. Progression-free survival was 5 months longer for the combination therapy compared with FC alone (26.7 months vs 21.7 months).

Indication 4 - Wegener’s Granulomatosis and Microscopic Polyangiitis

approved April 2011

Dosing/Administration

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 Trial Results

The FDA approval for granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitiswas 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 older was 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.

Indication 5 - Pemphigus Vulgaris

approved June 2018

Dosing/Administration

Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids.

• Maintenance treatment: Administer Rituxan as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. 
• Treatment of relapse: Administer Rituxan as a 1000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation.

Subsequent infusions of Rituxan may be administered no sooner than 16 weeks following the previous infusion.

Clinical Trial Results

The FDA approval of Rituxan for PV was based on the Ritux 3 trial, a Roche-supported, randomized, controlled trial conducted in France that used Roche-manufactured, European Union (EU)-approved rituximab product as the clinical trial material. The study compared the Ritux 3 regimen (EU-approved rituximab product plus short-term corticosteroids [CS]) to CS alone as a first-line treatment in patients with newly diagnosed, moderate to severe pemphigus. The primary endpoint of the study was complete remission at month 24 without the use of steroids for two or more months. (Complete remission defined as complete epithelialization and absence of new and/or established lesions.) Results of the study showed that 90 percent of PV patients treated with the Ritux 3 regimen met the endpoint, compared to 28 percent of PV patients treated with CS alone.