RUXIENCE- rituximab-pvvr_injection, solution
Function and Efficacy
Rituximab-pvvr is a monoclonal antibody. Rituximab products target the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab products mediate 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. Non-Hodgkin's Lymphoma (NHL) In NHL patients, administration of rituximab 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 rituximab-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 rituximab. 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 rituximab 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 rituximab in RA patients during repeated rituximab treatment, 23. 5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab 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/muL following the first two infusions of rituximab, 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 greater than 10 cells/muL. By Month 18, most patients (87%) had counts greater than 10 cells/muL. In GPA/MPA Study 2 where patients received non-U. -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/m 2 The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m 2 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 rituximab in patients with RA, the mean (+/-S. ; % CV) concentrations after the first infusion (C max max Based on a population pharmacokinetic analysis of data from 2,005 RA patients who received rituximab, 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. 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 pharmacokinetic parameters in adult patients with GPA/MPA receiving 375 mg/m 2 Table 4 Population PK in Adult Patients with GPA/MPA Parameter Statistic GPA/MPA Study 1 N Number of Patients 97 Terminal Half-life Median 25 (days) (Range) (11 to 52) AUC 0en dash180d Median 10302 (µg/mL*day) (Range) (3653 to 21874) Clearance Median 0. 279 (L/day) (Range) (0. 653) Volume of Distribution Median 3. 12 (L) (Range) (2. 91) 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-drug antibody status is not necessary. Specific Populations The clearance and volume of distribution of rituximab increased with increasing body surface area (BSA). No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab products. Drug Interaction Studies Formal drug interaction studies have not been performed with rituximab products.
Indication
RUXIENCE is a CD20-directed cytolytic antibody indicated for the treatment of: 1. 1 o o o o 1. 2 o 1. 4 RUXIENCE is indicated for the treatment of adult patients with: RUXIENCE, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL. RUXIENCE, 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 Tumor Necrosis Factor (TNF) antagonist therapies. RUXIENCE, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).
Usage and Dosage
1 2 2. 2 2 2 2. 3 registered 2 2. 5 2 2. 6 Administer only as an intravenous infusion [see Dosage and Administration (2. 8) RUXIENCE should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions (5. 1) Premedicate before each infusion [see Dosage and Administration (2. 7) Prior to First Infusion Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE [see Warnings and Precautions (5. 3) During RUXIENCE Therapy In patients with lymphoid malignancies, during treatment with RUXIENCE monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RUXIENCE course. During treatment with RUXIENCE and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias [see Adverse Reactions (6. 1) First Infusion Standard Infusion: Subsequent Infusions Standard Infusion: For Previously Untreated Follicular NHL and DLBCL Adult Patients: 3 [see Clinical Studies (14. 4) [see Boxed Warning Warnings and Precautions (5. 1) The recommended dose is 375 mg/m 2 Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy Diffuse Large B-Cell NHL The recommended dose is 375 mg/m 2 2 When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m 2 Induction Treatment of Adult Patients with Active GPA/MPA 2 Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment Premedicate with acetaminophen and an antihistamine before each infusion of RUXIENCE. For adult patients administered RUXIENCE according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion [see Clinical Studies (14. 4) For RA, GPA and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Provide prophylaxis treatment for Pneumocystis jirovecii [see Warnings and Precautions (5. 6) PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RUXIENCE infusion. Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. RUXIENCE should be a clear to slightly opalescent, colorless to pale brownish-yellow liquid. Do not use vial if particulates or discoloration is present. Administration Use a sterile needle and syringe to prepare RUXIENCE. Withdraw the necessary amount of RUXIENCE and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0. 9% Sodium Chloride Injection or 5% Dextrose Injection. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial. Storage If not used immediately, store diluted RUXIENCE solutions as shown in the table below. Diluted RUXIENCE Solution Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted RUXIENCE Solution Storage Conditions 0. 9% Sodium Chloride Injection, USP Store RUXIENCE solution diluted in 0. 9% Sodium Chloride Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 16 days after preparation. 5% Dextrose Injection, USP Store RUXIENCE solution diluted in 5% Dextrose Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours after preparation. No incompatibilities between RUXIENCE and polyvinylchloride bags have been observed.
Label
Adverse Reactions
WARNING: FATAL INFUSION-RELATED REACTIONS,SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete boxed warning. Fatal infusion-related reactions within 24 hours of rituximab infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue RUXIENCE infusion for severe reactions ( 5. 1 Severe mucocutaneous reactions, some with fatal outcomes ( 5. 2 Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death ( 5. 3 Progressive multifocal leukoencephalopathy (PML) resulting in death ( 5. 3 Infusion-Related Reactions Administration of rituximab products can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue RUXIENCE infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5. 1) Adverse Reactions (6. 1) Severe Mucocutaneous Reactions Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products [see Warnings and Precautions (5. 2) Hepatitis B Virus (HBV) Reactivation HBV reactivation can occur in patients treated with rituximab products, 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 RUXIENCE. Discontinue RUXIENCE and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5. 3) Progressive Multifocal Leukoencephalopathy (PML) Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products [see Warnings and Precautions (5. 4) Adverse Reactions (6.
ADVERSE REACTIONS
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 8) [see Warnings and Precautions (5. 9) Most common adverse reactions in clinical trials were: 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. B-Cell Malignancies The data described below reflect exposure to rituximab in 3,092 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2,427). The population included 1,180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 patients with another indication. Most NHL patients received rituximab as an infusion of 375 mg/m 2 2 2 The most common adverse reactions of rituximab (incidence greater than or equal to 25%) observed in clinical trials of patients with NHL were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of rituximab (incidence greater than or equal to 25%) observed in clinical trials of patients with CLL were: infusion-related reactions and neutropenia. Infusion-Related Reactions In the majority of patients with NHL, infusion-related reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first rituximab infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest during the first infusion (77%) and decreased with each subsequent infusion [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 1) Clinical Studies (14. 4) Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%) [see Warnings and Precautions (5. 6) In randomized, controlled studies where rituximab was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received rituximab. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received rituximab. Cytopenias and Hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1en dash588 days) and of neutropenia was 13 days (range, 2en dash116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following rituximab therapy occurred during the single-arm studies. In studies of monotherapy, rituximab-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with rituximab in combination with fludarabine and cyclophosphamide (R-FC) compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3en dash4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3en dash4 neutropenia starting at least 42 days after the last treatment dose. In patients with previously untreated CLL, the frequency of prolonged neutropenia was 8. 5% for patients who received R-FC (n=402) and 5. 8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14. 8% of 209 patients who received R-FC and 4. 3% of 230 patients who received FC. For patients with previously treated CLL, the frequency of prolonged neutropenia was 24. 8% for patients who received R-FC (n=274) and 19. 1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38. 7% in 160 patients who received R-FC and 13. 6% of 147 patients who received FC. Relapsed or Refractory, Low-Grade NHL Adverse reactions presented in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of rituximab administered as a single agent [see Clinical Studies (14. 1) 2 Table 1. Incidence of Adverse Reactions in Greater than or Equal to 5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituximab (N=356) Adverse reactions observed up to 12 months following rituximab. , Adverse reactions graded for severity by NCI-CTC criteria. All Grades (%) Grade 3 and 4 (%) Any Adverse Reactions 99 57 Body as a Whole 86 10 Fever 53 1 Chills 33 3 Infection 31 4 Asthenia 26 1 Headache 19 1 Abdominal Pain 14 1 Pain 12 1 Back Pain 10 1 Throat Irritation 9 0 Flushing 5 0 Heme and Lymphatic System 67 48 Lymphopenia 48 40 Leukopenia 14 4 Neutropenia 14 6 Thrombocytopenia 12 2 Anemia 8 3 Skin and Appendages 44 2 Night Sweats 15 1 Rash 15 1 Pruritus 14 1 Urticaria 8 1 Respiratory System 38 4 Increased Cough 13 1 Rhinitis 12 1 Bronchospasm 8 1 Dyspnea 7 1 Sinusitis 6 0 Metabolic and Nutritional Disorders 38 3 Angioedema 11 1 Hyperglycemia 9 1 Peripheral Edema 8 0 LDH Increase 7 0 Digestive System 37 2 Nausea 23 1 Diarrhea 10 1 Vomiting 10 1 Nervous System 32 1 Dizziness 10 1 Anxiety 5 1 Musculoskeletal System 26 3 Myalgia 10 1 Arthralgia 10 1 Cardiovascular System 25 3 Hypotension 10 1 Hypertension 6 1 In these single-arm rituximab studies, bronchiolitis obliterans occurred during and up to 6 months after rituximab infusion. Previously Untreated, Low-Grade or Follicular, NHL In NHL Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (greater than or equal to 5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%) [see Clinical Studies (14. 2) In NHL Study 5, detailed safety data collection was limited to serious adverse reactions, Grade greater than or equal to 2 infections, and Grade greater than or equal to 3 adverse reactions. In patients receiving rituximab as single-agent maintenance therapy following rituximab plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. Grade 3-4 adverse reactions occurring at a higher incidence (greater than or equal to 2%) in the rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. less than 1%). In NHL Study 6, the following adverse reactions were reported more frequently (greater than or equal to 5%) in patients receiving rituximab following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (greater than or equal to 2%) in the rituximab arm compared with those who received no further therapy (4% vs. 3) DLBCL In NHL Studies 7 (NCT00003150) and 8, [see Clinical Studies (14. 3) In NHL Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4. 5% for R-CHOP vs. 0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (NHL Study 8), neutropenia (NHL Studies 8 and 9 (NCT00064116)), and anemia (NHL Study 9). CLL The data below reflect exposure to rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in CLL Study 1 (NCT00281918) or CLL Study 2 (NCT00090051) [see Clinical Studies (14. 5) Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In CLL Study 1, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion-related reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. In CLL Study 2, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion-related reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity. Rheumatoid Arthritis The data presented below reflect the experience in 2,578 RA patients treated with rituximab in controlled and long-term studies 1 Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion-related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis. In placebo-controlled studies, patients received 2 × 500 mg or 2 × 1,000 mg intravenous infusions of rituximab or placebo, in combination with methotrexate, during a 24-week period. From these studies, 938 patients treated with rituximab (2 × 1,000 mg) or placebo have been pooled (see Table 2 Table 2 Table 2 These data are based on 938 patients treated in Phase 2 and 3 studies of rituximab (2 × 1,000 mg) or placebo administered in combination with methotrexate. Coded using MedDRA. Adverse Reaction Placebo + MTX Rituximab + MTX Hypertension 21 (5) 43 (8) Nausea 19 (5) 41 (8) Upper Respiratory Tract Infection 23 (6) 37 (7) Arthralgia 14 (4) 31 (6) Pyrexia 8 (2) 27 (5) Pruritus 5 (1) 26 (5) Chills 9 (2) 16 (3) Dyspepsia 3 (<1) 16 (3) Rhinitis 6 (2) 14 (3) Paresthesia 3 (<1) 12 (2) Urticaria 3 (<1) 12 (2) Abdominal Pain Upper 4 (1) 11 (2) Throat Irritation 0 (0) 11 (2) Anxiety 5 (1) 9 (2) Migraine 2 (<1) 9 (2) Asthenia 1 (<1) 9 (2) Infusion-Related Reactions In the rituximab RA pooled placebo-controlled studies, 32% of rituximab-treated patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo-treated patients receiving their first infusion. The incidence of adverse reactions during the 24-hour period following the second infusion, rituximab or placebo, decreased to 11% and 13%, respectively. Acute infusion-related reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of rituximab-treated patients following their first infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. The incidence of these acute infusion-related reactions following the second infusion of rituximab or placebo decreased to 9% and 11%, respectively. Serious acute infusion-related reactions were experienced by less than 1% of patients in either treatment group. Acute infusion-related reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion-related reactions decreased with subsequent courses of rituximab. The administration of intravenous glucocorticoids prior to rituximab infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion-related reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to rituximab infusions. Infections In the pooled, placebo-controlled studies, 39% of patients in the rituximab group experienced an infection of any type compared to 34% of patients in the placebo group. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis. The incidence of serious infections was 2% in the rituximab-treated patients and 1% in the placebo group. In the experience with rituximab in 2,578 RA patients, the rate of serious infections was 4. 31 per 100 patient years. The most common serious infections (greater than or equal to 0. 5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis and colitis. Rates of serious infection remained stable in patients receiving subsequent courses. In 185 rituximab-treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. Thirteen serious infections were observed in 186. 1 patient years (6. 99 per 100 patient years) prior to exposure and 10 were observed in 182. 3 patient years (5. 49 per 100 patient years) after exposure. Cardiovascular Adverse Reactions In the pooled, placebo-controlled studies, the proportion of patients with serious cardiovascular reactions was 1. 3% in the rituximab and placebo treatment groups, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all rituximab regimens (3/769=0. 4%) as compared to none in the placebo treatment group (0/389). In the experience with rituximab in 2,578 RA patients, the rate of serious cardiac reactions was 1. 93 per 100 patient years. The rate of myocardial infarction (MI) was 0. 56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population. These rates did not increase over three courses of rituximab. Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and RUXIENCE should be discontinued in the event of a serious or life-threatening cardiac event. Hypophosphatemia and Hyperuricemia In the pooled, placebo-controlled studies, newly-occurring hypophosphatemia (less than 2. 0 mg/dL) was observed in 12% (67/540) of patients on rituximab versus 10% (39/398) of patients on placebo. Hypophosphatemia was more common in patients who received corticosteroids. Newly-occurring hyperuricemia (greater than 10 mg/dL) was observed in 1. 5% (8/540) of patients on rituximab versus 0. 3% (1/398) of patients on placebo. In the experience with rituximab in RA patients, newly-occurring hypophosphatemia was observed in 21% (528/2570) of patients and newly-occurring hyperuricemia was observed in 2% (56/2570) of patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient. Retreatment in Patients with RA In the experience with rituximab in RA patients, 2,578 patients have been exposed to rituximab and have received up to 10 courses of rituximab in RA clinical trials, with 1,890, 1,043, and 425 patients having received at least two, three, and four courses, respectively. Most of the patients who received additional courses did so 24 weeks or more after the previous course and none were retreated sooner than 16 weeks. The rates and types of adverse reactions reported for subsequent courses of rituximab were similar to rates and types seen for a single course of rituximab. In RA Study 2, where all patients initially received rituximab, the safety profile of patients who were retreated with rituximab was similar to those who were retreated with placebo [see Clinical Studies (14. 6) Dosage and Administration (2. 5) Granulomatosis with Polyangiitis (GPA) (Wegener''s Granulomatosis) and Microscopic Polyangiitis (MPA) Induction Treatment of Adult Patients with Active GPA/MPA (GPA/MPA Study 1) The data presented below from GPA/MPA Study 1 (NCT00104299) reflect the experience in 197 adult patients with active GPA and MPA treated with rituximab or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase [see Clinical Studies (14. 7) 2 Adverse reactions presented below in Table 3 were adverse events which occurred at a rate of greater than or equal to 10% in the rituximab group. This table reflects experience in 99 GPA and MPA patients treated with rituximab, with a total of 47. 6 patient years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47. 0 patient years of observation. Infection was the most common category of adverse events reported (47en dash62%) and is discussed below. Table 3 Incidence of All Adverse Reactions Occurring in Greater than or Equal to 10% of Rituximab-treated Patients with active GPA and MPA in the GPA/MPA Study 1 Up to Month 6 The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6 month study period. Adverse Reaction Rituximab Cyclophosphamide Nausea 18 (18%) 20 (20%) Diarrhea 17 (17%) 12 (12%) Headache 17 (17%) 19 (19%) Muscle Spasms 17 (17%) 15 (15%) Anemia 16 (16%) 20 (20%) Peripheral Edema 16 (16%) 6 (6%) Insomnia 14 (14%) 12 (12%) Arthralgia 13 (13%) 9 (9%) Cough 13 (13%) 11 (11%) Fatigue 13 (13%) 21 (21%) Increased ALT 13 (13%) 15 (15%) Hypertension 12 (12%) 5 (5%) Epistaxis 11 (11%) 6 (6%) Dyspnea 10 (10%) 11 (11%) Leukopenia 10 (10%) 26 (27%) Rash 10 (10%) 17 (17%) Infusion-Related Reactions Infusion-related reactions in GPA/MPA Study 1 were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with rituximab, 12% experienced at least one infusion-related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the rituximab group, the proportion of patients experiencing an infusion-related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each rituximab infusion and were on background oral corticosteroids which may have mitigated or masked an infusion-related reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion-related reactions. Infections In GPA/MPA Study 1, 62% (61/99) of patients in the rituximab group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% in the rituximab-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient years, respectively. The most common serious infection was pneumonia. Hypogammaglobulinemia Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with rituximab in GPA/MPA Study 1. At 6 months, in the rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50%, and 46% in the cyclophosphamide group. Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment (GPA/MPA Study 2) In GPA/MPA Study 2 (NCT00748644), an open-label, controlled, clinical study [see Clinical Studies (14. 7) The safety profile was consistent with the safety profile for rituximab in RA, GPA, and MPA. Infusion-Related Reactions In GPA/MPA Study 2, 7/57 (12%) patients in the non-U. -licensed rituximab arm reported infusion-related reactions. The incidence of IRR symptoms was highest during or after the first infusion (9%) and decreased with subsequent infusions (less than 4%). One patient had two serious IRRs, two IRRs led to a dose modification, and no IRRs were severe, fatal, or led to withdrawal from the study. Infections In GPA/MPA Study 2, 30/57 (53%) patients in the non-U. -licensed rituximab arm and 33/58 (57%) in the azathioprine arm reported infections. The incidence of all grade infections was similar between the arms. The incidence of serious infections was similar in both arms (12%). The most commonly reported serious infection in the group was mild or moderate bronchitis. Long-term, Observational Study with Rituximab in Patients with GPA/MPA (GPA/MPA Study 3) In a long-term observational safety study (NCT01613599), 97 patients with GPA or MPA received treatment with rituximab (mean of 8 infusions [range 1en dash28]) for up to 4 years, according to physician standard practice and discretion. Majority of patients received doses ranging from 500 mg to 1,000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for rituximab in RA, GPA and MPA. As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other rituximab products may be misleading. Using an ELISA assay, anti-rituximab antibody was detected in 4 of 356 (1. 1%) patients with low-grade or follicular NHL receiving single-agent rituximab. Three of the four patients had an objective clinical response. A total of 273/2578 (11%) patients with RA tested positive for anti-rituximab antibodies at any time after receiving rituximab. Anti-rituximab antibody positivity was not associated with increased rates of infusion-related reactions or other adverse events. Upon further treatment, the proportions of patients with infusion-related reactions were similar between anti-rituximab antibody positive and negative patients, and most reactions were mild to moderate. Four anti-rituximab antibody positive patients had serious infusion-related reactions, and the temporal relationship between anti-rituximab antibody positivity and infusion-related reaction was variable. A total of 23/99 (23%) rituximab-treated adult patients with GPA and MPA developed anti-rituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximab-treated adult patients is unclear. The following adverse reactions have been identified during post-approval use of rituximab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 6) .
Special Population Medication
5 Risk Summary Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero (see Clinical Considerations Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The estimated background risk in the U. general population of major birth defects is 2%en dash4% and of miscarriage is 15%en dash20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions Observe newborns and infants for signs of infection and manage accordingly. Data Human Data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Animal Data An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum Days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21, and 22, at 15, 37. 5, or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43, and 50, at 20, 50, or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells. A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in-utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum. There are limited data on the presence of rituximab in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab is detected in the milk of lactating cynomolgus monkeys, and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RUXIENCE and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children. Rituximab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8. 1) Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RUXIENCE. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with RUXIENCE and for 12 months after the last dose. The safety and effectiveness of RUXIENCE have not been established in pediatric patients with NHL, CLL or RA. Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system. Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin's Lymphoma Patients with previously untreated follicular NHL evaluated in NHL Study 5 were randomized to rituximab as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older; of these, 100 rituximab-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2 [see Clinical Studies (14. 5) The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (CLL Study 1); 56% vs. 39% (CLL Study 2)], febrile neutropenia [16% vs. 6% (NHL Study 10 (NCT00719472))], anemia [5% vs. 2% (CLL Study 1); 21% vs. 10% (CLL Study 2)], thrombocytopenia [19% vs. 8% (CLL Study 2)], pancytopenia [7% vs. 2% (CLL Study 1); 7% vs. 2% (CLL Study 2)], and infections [30% vs. 14% (CLL Study 2)]. Rheumatoid Arthritis Among the 2,578 patients in global RA studies completed to date, 12% were 65en dash75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Of the 99 rituximab-treated GPA and MPA patients in GPA/MPA Study 1, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In GPA/MPA Study 2, 30 (26%) of the enrolled patients were at least 65 years old, of which 12 patients were exposed to non-U. -licensed rituximab and 18 were exposed to azathioprine.
Drug Interactions
Formal drug interaction studies have not been performed with rituximab products. In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. Renal toxicity when used in combination with cisplatin ( 5.
Other Information
NONCLINICAL TOXICOLOGY
No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab products or to determine potential effects on fertility in males or females.
CLINICAL STUDIES
The safety and effectiveness of rituximab 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/m 2 Results are summarized in Table 5. 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/m 2 NHL Study 3 In a multicenter, single-arm study, 60 patients received 375 mg/m 2 Bulky Disease In pooled data from studies 1 and 3, 39 patients with bulky (single lesion greater than 10 cm in diameter) and relapsed or refractory, low-grade NHL received rituximab 375 mg/m 2 Table 5 Summary of Rituximab NHL Efficacy Data by Schedule and Clinical Setting NHL Study 1 NHL Study 2 NHL Study 1 and NHL Study 3 Six of these patients are included in the first column. Thus, data from 296 intent-to-treat patients are provided in this table. NHL Study 3 Overall Response Rate 48% 57% 36% 38% Complete Response Rate 6% 14% 3% 10% Median Duration of Response Kaplan-Meier projected with observed range. , "+" indicates an ongoing response. , Duration of response: interval from the onset of response to disease progression. 0 The safety and effectiveness of rituximab 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 rituximab 375 mg/m 2 Twenty-six percent of the study population was greater than 60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score greater than or equal to 2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 6. 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 6 Efficacy Results in NHL Study 4 Study Arm R-CVP CVP Median PFS (years) p <0. 0001, two-sided stratified log-rank test. 4 Hazard ratio (95% CI) Estimates of Cox regression stratified by center. 65) 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 rituximab in combination with chemotherapy. Patients were randomized to rituximab as single-agent maintenance therapy, 375 mg/m 2 Of the randomized patients, 40% were greater than or equal to 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0en dash1, and 42% had FLIPI scores of 3en dash5. 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 rituximab as single-agent maintenance therapy (HR: 0. 54, 95% CI: 0. Figure 1 Figure 1 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 rituximab, 375 mg/m 2 There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0. 49) for patients randomized to rituximab as compared to those who received no additional treatment. The safety and effectiveness of rituximab were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1,854 patients. Patients with previously untreated diffuse large B-cell NHL received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens. NHL Study 7 A total of 632 patients age greater than or equal to 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 rituximab 375 mg/m 2 Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage IIIen dashIV disease, 56% had IPI scores greater than or equal to 2, 86% had ECOG performance status of less than 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 7. These results reflect a statistical approach which allows for an evaluation of rituximab administered in the induction setting that excludes any potential impact of rituximab 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 rituximab 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 greater than or equal to 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 rituximab 375 mg/m 2 NHL Study 9 A total of 823 patients with DLBCL, aged 18en dash60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with rituximab. 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 IIIen dashIV disease, 100% had IPI scores of less than or equal to 1, 99% had ECOG performance status of less than 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Table 7 Efficacy Results in NHL Studies 7, 8, and 9 NHL Study 7 NHL Study 8 NHL Study 9 R-CHOP CHOP R-CHOP CHOP R-Chemo Chemo Main outcome Progression-free survival Event-free survival Time to treatment failure Median of main outcome measure 3. 1 NE NE=Not reliably estimable. NE Hazard ratio R-CHOP vs. 69 Significant at p <0. 05, 2-sided. 45 Overall survival at 2 years Kaplan-Meier estimates. 74% 63% 69% 58% 95% 86% Hazard ratio 0. 40 In NHL Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively. 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, multicenter, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m 2 2 3 [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) The incidence of Grade 3en dash4 infusion-related reactions at Cycle 2 was 1. 1% (95% CI [0. 8%]) among all patients, 3. 5% (95% CI [1. 8%]) for those patients treated with R-CVP, and 0. 0% (95% CI [0. 5%]) for those patients treated with R-CHOP. For Cycles 2en dash8, the incidence of Grade 3en dash4 infusion-related reactions was 2. 8% (95% CI [1. No acute fatal infusion-related reactions were observed. The safety and effectiveness of rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with rituximab 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/m 2 2 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) 0en dash1, 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 0en dash1, 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 8. Table 8 Efficacy Results in CLL Studies 1 and 2 CLL Study 1 As defined in 1996 National Cancer Institute Working Group guidelines. CLL Study 2 R-FC FC R-FC FC Median PFS (months) 39. 7 Hazard ratio (95% CI) 0. 96) P value (Log-Rank test) <0. 02 Response rate 86% 73% 54% 45% (95% CI) (82, 89) (68, 77) (48, 60) (37, 51) Across both studies, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older and 100 rituximab-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 9. Table 9 Efficacy Results in CLL Studies 1 and 2 in Subgroups Defined by Age From exploratory analyses. Age subgroup CLL Study 1 CLL Study 2 Number of Patients Hazard Ratio for PFS (95% CI) Number of Patients Hazard Ratio for PFS (95% CI) Age less than 65 yrs 572 0. 84) Age greater than or equal to 65 yrs 245 0. 40) Age less than 70 yrs 736 0. 87) Age greater than or equal to 70 yrs 81 1. 04) Reducing the Signs and Symptoms: Initial and Retreatment Courses The efficacy and safety of rituximab 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 rituximab 2 × 1,000 mg + MTX or placebo + MTX for 24 weeks. Further courses of rituximab 2 × 1,000 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 rituximab. 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 10. In RA Study 2 (NCT00266227), all patients received the first course of rituximab 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24en dash28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the retreatment course, and at Week 48, after retreatment, are shown in Table 10. Table 10 ACR Responses in RA Study 1 and RA Study 2 (Percent of Patients) (Modified Intent-to-Treat Population) Inadequate Response to TNF Antagonists RA Study 1 RA Study 2 Response Placebo + MTX Rituximab + MTX Treatment Difference Response Placebo + MTX Retreatment Rituximab + MTX Retreatment Treatment Difference In RA Study 2, all patients received a first course of rituximab 2 × 1,000 mg. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or Placebo + MTX at or after Week 24. Since all patients received a first course of rituximab, no comparison between Placebo + MTX and rituximab + MTX is made at Week 24. For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive greater than 20 IU/mL, negative less than 20 IU/mL) at baseline; For RA Study 2, weighted difference stratified by RF status at baseline and greater than or equal to 20% improvement from baseline in both SJC and TJC at Week 24 (Yes/No). ACR20 ACR20 Week 24 18% 51% 33% Week 24 48% 45% NA Week 48 45% 54% 11% ACR50 ACR50 Week 24 5% 27% 21% Week 24 27% 21% NA Week 48 26% 29% 4% ACR70 ACR70 Week 24 1% 12% 11% Week 24 11% 8% NA Week 48 13% 14% 1% Improvement was also noted for all components of ACR response following treatment with rituximab, as shown in Table 11. Table 11 Components of ACR Response at Week 24 in RA Study 1 (Modified Intent-to-Treat Population) Inadequate Response to TNF Antagonists Placebo + MTX Rituximab + MTX Parameter Baseline Wk 24 Baseline Wk 24 Tender Joint Count 31. 0 Swollen Joint Count 20. 5 Physician Global Assessment Visual Analog Scale: 0=best, 100=worst. 0 Patient Global Assessment 73. 5 Disability Index (HAQ) Disability Index of the Health Assessment Questionnaire: 0=best, 3=worst. 5 CRP (mg/dL) 2. 9 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 rituximab group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with rituximab. Similar patterns were demonstrated for ACR 50 and 70 responses. Figure 2 The same patients may not have responded at each time point. Figure 2 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. Rituximab + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 12. Table 12 Mean Radiographic Change from Baseline to 104 Weeks in RA Study 1 Inadequate Response to TNF Antagonists Parameter Rituximab Patients received up to 2 years of treatment with rituximab + MTX. Placebo + MTX Patients receiving Placebo + MTX. Patients receiving Placebo + MTX could have received retreatment with rituximab + MTX from Week 16 onward. Treatment Difference 95% CI Change during First Year TSS 0. 19) JSN Score 0. 62) Change during Second Year Based on radiographic scoring following 104 weeks of observation. 04 em dash em dash ES 0. 62 em dash em dash JSN Score 0. 42 em dash em dash In RA Study 1 and its open-label extension, 70% of patients initially randomized to rituximab + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 12, progression of structural damage in rituximab + MTX patients was further reduced in the second year of treatment. Following 2 years of treatment with rituximab + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of rituximab + 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 rituximab + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the rituximab + MTX treated patients who had no progression in the first year also had no progression in the second year. Lesser Efficacy of 500 vs. 1,000 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 rituximab 2 × 500 mg + MTX and rituximab 2 × 1,000 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 retreatment 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 rituximab dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the rituximab 1,000 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 rituximab 500 mg, rituximab 1,000 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 rituximab-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 13. HAQ-DI results for the rituximab 500 mg treatment group were similar to the rituximab 1,000 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 13 Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in RA Study 4 Placebo + MTX Rituximab Treatment Difference Adjusted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive greater than or equal to 20 IU/mL, negative less than 20 IU/mL) at baseline. Mean Improvement from Baseline 0. 34) Percent of patients with "Improved" score Minimal Clinically Important Difference: MCID for HAQ=0. 48% 58% 11% (0%, 21%) 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 en dash 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) greater than or equal to 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 1,000 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 rituximab 375 mg/m 2 Table 14 Percentage of Patients with GPA/MPA Who Achieved Complete Remission at 6 Months (Intent-to-Treat Population) Rituximab Cyclophosphamide Treatment Difference Rate 64% 53% 11% 95. 1% confidence level reflects an additional 0. 001 alpha to account for an interim efficacy analysis. (54%, 73%) (43%, 63%) (-3%, 24%) Non-inferiority was demonstrated because the lower bound was higher than the prespecified non-inferiority margin (-3% greater than -20%). Complete Remission (CR) at 12 and 18 Months In the rituximab 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 Rituximab Based upon investigator judgment, 15 patients received a second course of rituximab therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the induction treatment course of rituximab. 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. -licensed rituximab (57 patients) in this open-label, prospective, multicenter, 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. -licensed rituximab or azathioprine. -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. -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. -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. -licensed rituximab relative to azathioprine (Figure 3). Patients were censored at the last follow up dates if they had no event. Figure 3 Figure 3.