RITUXAN Solution for injection Ref.[11139] Active ingredients: Rituximab

Non-Hodgkin’s Lymphoma (NHL)

In NHL patients, administration of RITUXAN resulted in depletion of circulating and tissue-based B cells. Among 166 patients in NHL Study 1 (NCT000168740), circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment.

There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range.

Rheumatoid Arthritis

In RA patients, treatment with RITUXAN induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/µl) within 2 weeks after receiving the first dose of RITUXAN. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment.

Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of RITUXAN treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with RITUXAN in RA patients during repeated RITUXAN treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving RITUXAN, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with RITUXAN are unclear.

Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis

In GPA and MPA patients in GPA/MPA Study 1, peripheral blood CD19 B-cells depleted to less than 10 cells/µl following the first two infusions of RITUXAN, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts >10 cells/µL. By Month 18, most patients (87%) had counts >10 cells/µL.

In GPA/MPA Study 2 where patients received non-U.S.-licensed rituximab as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion at Month 6, 12, and 18, 70% (30 out of 43) of the rituximab-treated patients with CD19+ peripheral B cells evaluated post-baseline had undetectable CD19+ peripheral B cells at Month 24. At Month 24, all 37 patients with evaluable baseline CD19+ peripheral B cells and Month 24 measurements had lower CD19+ B cells relative to baseline.

Non-Hodgkin’s Lymphoma (NHL)

Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m² RITUXAN weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m² in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab.

Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days).

Rheumatoid Arthritis

Following administration of 2 doses of RITUXAN in patients with RA, the mean (± S.D.; % CV) concentrations after the first infusion (C_max first) and second infusion (C_max second) were 157 (± 46; 29%) and 183 (± 55; 30%) mcg/mL, and 318 (± 86; 27%) and 381 (± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively.

Based on a population pharmacokinetic analysis of data from 2005 RA patients who received RITUXAN, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients.

Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis

The PK parameters in adult and pediatric patients 6 years to 17 years of age with GPA/MPA receiving 375 mg/m² intravenous RITUXAN or non-U.S.-licensed rituximab once weekly for four doses are summarized in Table 6.

Table 6. Population PK in pediatric patients (GPA/MPA Study 4) and adult patients (GPA/MPA Study 1) with GPA/MPA:

Based on a population PK analysis in pediatric patients with GPA and MPA, the PK parameters of rituximab were similar to those in adults with GPA and MPA, once taking into account the BSA effect on clearance and volume of distribution parameters. The population PK analysis in adults with GPA and MPA showed that male patients and patients with higher BSA or positive anti-rituximab antibody levels have higher clearance. However, further dose adjustment based on gender or anti-rituximab antibody status is not necessary.

Pemphigus Vulgaris

The PK parameters in adult PV patients receiving 1000 mg IV infusion of RITUXAN at Days 1, 15, 168, and 182 are summarized in Table 7.

Table 7. Population PK in adult PV patients from PV Study 2:

Following the first cycle of rituximab administration, the PK parameters of rituximab in patients with PV were similar to those in patients with RA and in patients with GPA/MPA. Following the 2^nd cycle of rituximab administration, rituximab clearance decreased by 22% assuming Pemphigus Disease Area Index (PDAI) activity score of 0 at the start of both cycles, while the central volume of distribution remained unchanged. The presence of anti-rituximab antibodies was associated with a higher clearance resulting in lower rituximab concentrations.

Specific Populations

The pharmacokinetics of rituximab have been studied in pediatric patients 6 years of age and older with active GPA and MPA (GPA/MPA Study 4). The effect of body surface area on the pharmacokinetics of rituximab was assessed in a population pharmacokinetic analysis which included 6 patients 6 years to less than 12 years of age and 19 patients 12 years to 17 years of age with GPA and MPA. BSA was a significant covariate on rituximab pharmacokinetics. The median AUC_0-180d in patients 2 years to 5 years of age (BSA of 0.5 m²) was estimated to be 10100 (µg/mL*day) and is comparable to that in adults. For follow up treatment of pediatric patients with GPA/MPA, the 250 mg/m² dose is estimated to provide pediatric GPA and MPA patients with exposure comparable to that observed in adults [see Use in Special Populations (8.4) and Clinical Studies (14.7)].

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab.

Drug Interaction Studies

Formal drug interaction studies have not been performed with RITUXAN.

No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN or to determine potential effects on fertility in males or females.

14.1 Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of RITUXAN in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients.

NHL Study 1

A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m² of RITUXAN given as an intravenous infusion weekly for 4 doses. Patients with tumor masses >10 cm or with >5000 lymphocytes/µL in the peripheral blood were excluded from the study.

Results are summarized in Table 8. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry.

NHL Study 2

In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m² of RITUXAN weekly for 8 doses. Results are summarized in Table 8.

NHL Study 3

In a multicenter, single-arm study, 60 patients received 375 mg/m² of RITUXAN weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to RITUXAN administered 3.8–35.6 months (median 14.5 months) prior to retreatment with RITUXAN. Of these 60 patients, 5 received more than one additional course of RITUXAN. Results are summarized in Table 8.

Bulky Disease

In pooled data from studies 1 and 3, 39 patients with bulky (single lesion >10 cm in diameter) and relapsed or refractory, low-grade NHL received RITUXAN 375 mg/m² weekly for 4 doses. Results are summarized in Table 8.

Table 8. Summary of RITUXAN Efficacy Data in NHL by Schedule and Clinical Setting:

^* Six of these patients are included in the first column. Thus, data from 296 intent-to-treat patients are provided in this table.
^† Kaplan-Meier projected with observed range.
^‡ “+” indicates an ongoing response.
^§ Duration of response: interval from the onset of response to disease progression.

14.2 Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

The safety and effectiveness of RITUXAN in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients.

NHL Study 4

A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with RITUXAN 375 mg/m² on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death.

Twenty-six percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score ≥2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 9. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Table 9. Efficacy Results in NHL Study 4:

^* p<0.0001, two-sided stratified log-rank test.
^† Estimates of Cox regression stratified by center.

NHL Study 5

An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to RITUXAN in combination with chemotherapy. Patients were randomized to RITUXAN as single-agent maintenance therapy, 375 mg/m² every 8 weeks for up to 12 doses or to observation. RITUXAN was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review.

Of the randomized patients, 40% were ≥60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response.

PFS was longer in patients randomized to RITUXAN as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment.

Figure 1. Kaplan-Meier Plot of IRC Assessed PFS in NHL Study 5:

NHL Study 6

A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive RITUXAN, 375 mg/m² intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score ≥2.

There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to RITUXAN as compared to those who received no additional treatment.

14.3 Diffuse Large B-Cell NHL (DLBCL)

The safety and effectiveness of RITUXAN were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received RITUXAN in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

NHL Study 7

A total of 632 patients age ≥60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of RITUXAN 375 mg/m² on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received RITUXAN prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive RITUXAN or no further therapy.

Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores ≥2, 86% had ECOG performance status of <2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 10. These results reflect a statistical approach which allows for an evaluation of RITUXAN administered in the induction setting that excludes any potential impact of RITUXAN given after the second randomization.

Analysis of results after the second randomization in NHL Study 7 demonstrates that for patients randomized to R-CHOP, additional RITUXAN exposure beyond induction was not associated with further improvements in progression-free survival or overall survival.

NHL Study 8

A total of 399 patients with DLBCL, age ≥60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received RITUXAN 375 mg/m² on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI ≥2, 80% had ECOG performance status scores <2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 10.

NHL Study 9

A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with RITUXAN. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of ≤1, 99% had ECOG performance status of <2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 10.

Table 10. Efficacy Results in NHL Studies 7, 8, and 9*:

^* NE = Not reliably estimable.
^† R-CHOP vs. CHOP.
^‡ Significant at p<0.05, 2-sided.
^§ Kaplan-Meier estimates.

In NHL Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively.

14.4 Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL

In NHL Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m² plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m² plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count ≤5000/mm³ before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to RITUXAN infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2 [see Adverse Reactions (6.1)].

Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes [see Dosage and Administration (2.1)]. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8).

The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion-related reactions were observed.

14.5 Chronic Lymphocytic Leukemia (CLL)

The safety and effectiveness of RITUXAN were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with RITUXAN for up to 6 cycles in patients with previously untreated CLL [CLL Study 1 (n=817)] or previously treated CLL [CLL Study 2 (n=552)]. Patients received fludarabine 25 mg/m²/day and cyclophosphamide 250 mg/m²/day on days 1, 2 and 3 of each cycle, with or without RITUXAN. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of RITUXAN-based therapy.

In CLL Study 1, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In CLL Study 2, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White.

The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (CLL Study 1) or an independent review committee (CLL Study 2). The investigator assessed results in CLL Study 2 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 11.

Table 11. Efficacy Results in CLL Studies 1 and 2:

^* As defined in 1996 National Cancer Institute Working Group guidelines.

Across both studies, 243 of 676 RITUXAN-treated patients (36%) were 65 years of age or older and 100 RITUXAN-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 12.

Table 12. Efficacy Results in CLL Studies 1 and 2 in Subgroups Defined by Age*:

^* From exploratory analyses.

14.6 Rheumatoid Arthritis (RA)

Reducing the Signs and Symptoms: Initial and Re-Treatment Courses

The efficacy and safety of RITUXAN were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints.

In RA Study 1 (NCT00468546), patients were randomized to receive either RITUXAN 2 × 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of RITUXAN 2 × 1000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of RITUXAN. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 13.

In RA Study 2 (NCT00266227), all patients received the first course of RITUXAN 2 × 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either RITUXAN 2 × 1000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 13.

Table 13. ACR Responses in RA Study 1 and RA Study 2 (Percent of Patients) (Modified Intent-to-Treat Population):

^* For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive >20 IU/mL, negative <20 IU/mL) at baseline; For RA Study 2, weighted difference stratified by RF status at baseline and ≥20% improvement from baseline in both SJC and TJC at Week 24 (Yes/No).
^† In RA Study 2, all patients received a first course of RITUXAN 2 × 1000 mg. Patients who experienced ongoing disease activity were randomized to receive a second course of either RITUXAN 2 × 1000 mg + MTX or placebo + MTX at or after Week 24.
^‡ Since all patients received a first course of RITUXAN, no comparison between Placebo + MTX and RITUXAN + MTX is made at Week 24.

Improvement was also noted for all components of ACR response following treatment with RITUXAN, as shown in Table 14.

Table 14. Components of ACR Response at Week 24 in RA Study 1 (Modified Intent-to-Treat Population):

^* Visual Analogue Scale: 0 = best, 100 = worst.
^† Disability Index of the Health Assessment Questionnaire: 0 = best, 3 = worst.

The time course of ACR 20 response for RA Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the RITUXAN group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with RITUXAN. Similar patterns were demonstrated for ACR 50 and 70 responses.

Figure 2. Percent of Patients Achieving ACR 20 Response by Visit*
RA Study 1 (Inadequate Response to TNF Antagonists):

^* The same patients may not have responded at each time point.

Radiographic Response

In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. RITUXAN + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 15.

Table 15. Mean Radiographic Change From Baseline to 104 Weeks in RA Study 1:

^* Patients received up to 2 years of treatment with RITUXAN + MTX.
^† Patients receiving Placebo + MTX. Patients receiving Placebo + MTX could have received retreatment with RITUXAN + MTX from Week 16 onward.
^‡ Based on radiographic scoring following 104 weeks of observation.

In RA Study 1 and its open-label extension, 70% of patients initially randomized to RITUXAN + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 15, progression of structural damage in RITUXAN + MTX patients was further reduced in the second year of treatment.

Following 2 years of treatment with RITUXAN + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of RITUXAN + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with RITUXAN + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the RITUXAN + MTX treated patients who had no progression in the first year also had no progression in the second year.

Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes

RA Study 3 (NCT00299104) is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to RITUXAN 2 × 500 mg + MTX and RITUXAN 2 × 1000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both RITUXAN dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the RITUXAN 1000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction.

Physical Function Response

RA Study 4 (NCT00299130) is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of RITUXAN 500 mg, RITUXAN 1000 mg, or placebo in addition to background MTX.

Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of RITUXAN-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 16. HAQ-DI results for the RITUXAN 500 mg treatment group were similar to the RITUXAN 1000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks.

Table 16. Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in RA Study 4:

^* Adjusted difference stratified by region (US, rest of the world) and rheumatoid factor (RF) status (positive ≥20 IU/mL, negative <20 IU/mL) at baseline.
^† Minimal Clinically Important Difference: MCID for HAQ = 0.22.

14.7 Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA)

Induction Treatment of Adult 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 were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) ≥3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease.

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%. As shown in Table 17, the study demonstrated non-inferiority of RITUXAN to cyclophosphamide for complete remission at 6 months.

Table 17. Percentage of Patients with GPA/MPA Who Achieved Complete Remission at 6 Months (Intent-to-Treat Population):

^* The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.
^† Non-inferiority was demonstrated because the lower bound was higher than the prespecified non-inferiority margin (-3% > -20%).

Complete Remission (CR) at 12 and 18 months

In the RITUXAN group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months.

Retreatment of Flares with RITUXAN

Based upon investigator judgment, 15 patients received a second course of RITUXAN therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the induction treatment course of RITUXAN.

Follow up Treatment of Adult 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. Eligible patients were 21 years and older and had either newly diagnosed (80%) or relapsing disease (20%). A majority of the patients were ANCA-positive. 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 (Figure 3).

Figure 3. Cumulative Incidence Over Time of First Major Relapse in Patients with GPA/MPA:

Patients were censored at the last follow-up dates if they had no event

Treatment of Pediatric Patients (GPA/MPA Study 4)

The study design consisted of an initial 6-month remission induction phase, and a minimum 12-month follow-up phase up to a maximum of 54 months (4.5 years) in pediatric patients 2 years to 17 years of age with GPA and MPA. Patients were to receive a minimum of 3 doses of intravenous methylprednisolone (30 mg/kg/day, not exceeding 1g/day) prior to the first RITUXAN or non-U.S.-licensed rituximab intravenous infusion. If clinically indicated, additional daily doses (up to three), of intravenous methylprednisolone could be given. The remission induction regimen consisted of four once weekly intravenous infusions of RITUXAN or non-U.S.-licensed rituximab at a dose of 375 mg/m² BSA, on study days 1, 8, 15 and 22 in combination with oral prednisolone or prednisone at 1 mg/kg/day (max 60 mg/day) tapered to 0.2 mg/kg/day minimum (max 10 mg/day) by Month 6. After the remission induction phase, patients could receive subsequent RITUXAN or non-U.S.-licensed rituximab intravenous infusions on or after Month 6 to maintain remission and control disease activity.

The primary objectives of this study were to evaluate safety and PK parameters in pediatric GPA and MPA patients (2 years to 17 years of age). The efficacy objectives of the study were exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS).

A total of 25 pediatric patients 6 years to 17 years of age with active GPA and MPA were treated with RITUXAN or non-U.S.-licensed rituximab in a multicenter, open-label, single-arm, uncontrolled study (NCT01750697). The median age of patients in the study was 14 years and the majority of patients (20/25 [80%]) were female. A total of 19 patients (76%) had GPA and 6 patients (24%) had MPA at baseline. Eighteen patients (72%) had newly diagnosed disease upon study entry (13 patients with GPA and 5 patients with MPA) and 7 patients had relapsing disease (6 patients with GPA and 1 patient with MPA).

All 25 patients completed all four once weekly intravenous infusions for the 6-month remission induction phase. A total of 24 out of 25 patients completed at least 18 months from Day 1 (baseline).

The exploratory efficacy using the PVAS is described in Table 18.

Table 18. Percentage of Patients Who Achieved PVAS Remission by Month 6, 12 and 18 (GPA/MPA Study 4):

PVAS remission is defined by a PVAS of 0 and achieved glucocorticoid taper to 0.2 mg/kg/day (or 10 mg/day, whichever is lower), or a PVAS of 0 on two consecutive readings ≥4 weeks apart irrespective of glucocorticoid dose
^* The efficacy results are exploratory and no formal statistical testing was performed for these endpoints

Follow-Up Treatment

After the 6-month remission induction phase, patients who had not achieved remission or who had progressive disease or flare that could not be controlled by glucocorticoids alone received additional treatment for GPA and MPA, that could include RITUXAN or non-U.S.-licensed rituximab and/or other therapies, at the discretion of the investigator. Planned follow-up was until Month 18 (from Day 1).

Fourteen out of 25 patients (56%) received additional RITUXAN or non-U.S.-licensed rituximab treatment at or post Month 6, up to Month 18. Five of these patients received four once weekly doses (375 mg/m²) of intravenous RITUXAN or non-U.S.-licensed rituximab approximately every 6 months; 5 of these patients received a single dose (375 mg/m²) of RITUXAN or non-U.S.-licensed rituximab every 6 months, and 4 of these patients received various other RITUXAN or non-U.S.-licensed rituximab doses/regimens according to investigator. Of the 14 patients who received follow-up treatment between Month 6 and Month 18, 4 patients first achieved remission between Months 6 and 12 and 1 patient first achieved remission between Months 12 and 18. Nine of these 14 patients achieved PVAS remission by Month 6 but required additional follow-up treatment after Month 6.

14.8 Pemphigus Vulgaris (PV)

PV Study 1 (NCT00784589)

Non-U.S.-licensed rituximab in combination with short-term prednisone was compared to prednisone monotherapy as first-line treatment in 90 newly diagnosed adult patients with moderate to severe pemphigus (74 Pemphigus Vulgaris [PV] and 16 Pemphigus Foliaceus [PF]) in this randomized, open-label, controlled, multicenter study (PV Study 1). Patients were between 19 and 79 years of age and had not received prior therapies for pemphigus. In the PV population, 5 (13%) patients in the group treated with non-U.S.-licensed rituximab and 3 (8%) patients in the prednisone group had moderate disease and 33 (87%) patients in the group treated with non-U.S.-licensed rituximab and 33 (92%) patients in the prednisone group had severe disease according to disease severity defined by Harman’s criteria.

Patients were stratified by baseline disease severity (moderate or severe) and randomized 1:1 to receive either the non-U.S.-licensed rituximab and short-term prednisone or long-term prednisone monotherapy. Patients were pre-medicated with antihistamine, acetaminophen and methylprednisolone prior to infusion of the non-U.S.-licensed rituximab. Patients randomized to the group treated with non-U.S.-licensed rituximab received an initial intravenous infusion of 1000 mg non-U.S.-licensed rituximab on Study Day 1 in combination with a short-term regimen of 0.5 mg/kg/day oral prednisone tapered off over 3 months if they had moderate disease or 1 mg/kg/day oral prednisone tapered off over 6 months if they had severe disease. All patients received a second intravenous infusion of 1000 mg non-U.S.-licensed rituximab on Study Day 15. Maintenance infusions of 500 mg non-U.S.-licensed rituximab were administered at Months 12 and 18. Patients randomized to the prednisone monotherapy group received an initial 1 mg/kg/day oral prednisone tapered off over 12 months if they had moderate disease or 1.5 mg/kg/day oral prednisone tapered off over 18 months if they had severe disease. Patients in the group treated with non-U.S.-licensed rituximab who relapsed could receive an additional infusion of 1000 mg non-U.S.-licensed rituximab in combination with reintroduced or escalated prednisone dose. Maintenance and relapse infusions were administered no sooner than 16 weeks following the previous infusion.

The primary endpoint for the study was complete remission (complete epithelialization and absence of new and/or established lesions) at Month 24 without the use of prednisone therapy for 2 months or more (CRoff for ≥2 months).

The results of the trial are presented in Table 19.

Table 19. Percentage of Pemphigus Patients in Complete Remission Off Corticosteroid Therapy for Two Months or More (CRoff ≥2 months) at Month 24, PV Study 1 (Intent-to-Treat Population):

PV Study 2 (NCT02383589)

In a randomized, double-blind, double-dummy, active-comparator, multicenter study, the efficacy and safety of RITUXAN compared to mycophenolate mofetil (MMF) were evaluated in patients with moderate-to-severe PV receiving 60-120 mg/day oral prednisone or equivalent (1.0-1.5 mg/kg/day) at study entry and tapered to reach a dose of 60 or 80 mg/day by Day 1. Patients had a confirmed diagnosis of PV within the previous 24 months and evidence of moderate-to-severe disease defined as a total Pemphigus Disease Area Index (PDAI) activity score of ≥15. The study consisted of a screening period of up to 28 days, a 52-week double-blind treatment period, and a 48-week safety follow up period.

One hundred and thirty-five patients were randomized to treatment with RITUXAN 1000 mg administered on Day 1, Day 15, Week 24 and Week 26 or oral MMF 2 g/day (starting at 1 g/day on Day 1 and titrated to achieve a goal of 2 g/day by Week 2) for 52 weeks in combination with an initial dose of 60 or 80 mg oral prednisone with the aim of tapering to 0 mg/day by Week 24. Randomization was stratified by duration of PV (within the 1 year prior to screening or greater than 1 year) and geographical region. A dual-assessor approach was used during the study for efficacy and safety evaluations to prevent potential unblinding.

One hundred and twenty-five patients (excluding exploratory data from ten telemedicine patients) were analyzed for efficacy (Modified Intent-to-Treat Population). The primary efficacy endpoint for this study was the proportion of subjects achieving sustained complete remission defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-week treatment period.

Secondary endpoints included cumulative oral corticosteroid dose and the total number of disease flares.

The results of the trial are presented in Table 20.

Table 20. Percentage of PV Patients Who Achieved Sustained Complete Remission Off Corticosteroid Therapy for 16 Weeks or More at Week 52 (Modified Intent-to-Treat Population):

MMF = Mycophenolate mofetil. CI = Confidence Interval.

Glucocorticoid exposure

The median (min, max) cumulative oral prednisone dose at Week 52 was 2775 mg (450, 22180) in the RITUXAN group compared to 4005 mg (900, 19920) in the MMF group. Topical corticosteroid use and pre-infusion IV methylprednisolone were not included in this analysis. Prior to each infusion, the RITUXAN group received IV methylprednisolone 100 mg and the MMF group received IV saline solution.

Disease flare

Disease flare was defined as an appearance of 3 or more new lesions a month that do not heal spontaneously within 1 week or by the extension of established lesions in a patient who has achieved disease control. The total number of disease flares was lower in patients treated with RITUXAN compared to MMF (6 vs. 44).