Side Effects Overview
6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Infusion-related reactions [ see Warnings and Precautions (5.1) ] Severe mucocutaneous reactions [ see Warnings and Precautions (5.2) ] Hepatitis B reactivation with fulminant hepatitis [ see Warnings and Precautions (5.3) ] Progressive multifocal leukoencephalopathy [ see Warnings and Precautions (5.4) ] Tumor lysis syndrome [ see Warnings and Precautions (5.5) ] Infections [ see Warnings and Precautions (5.6) ] Cardiovascular adverse reactions [ see Warnings and Precautions (5.7) ] Renal toxicity [ see Warnings and Precautions (5.8) ] Bowel obstruction and perforation [ see Warnings and Precautions (5.9) ] Most common adverse reactions in clinical trials were: NHL (greater than or equal to 25%): infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia ( 6.1 ). CLL (greater than or equal to 25%): infusion-related reactions and neutropenia ( 6.1 ). RA (greater than or equal to 10%): upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events) ( 6.1 ). GPA and MPA (greater than or equal to 15 %): infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions ( 6.1 ). PV (greater than or equal to 15%): infusion-related reactions, depression, upper respiratory tract infection/nasopharyngitis, headache (other important adverse reactions include infections) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact TEVA Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Lymphoid Malignancies 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 1180 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 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received rituximab 375 mg/m 2 as an initial infusion followed by 500 mg/m 2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-based therapy. The most common adverse reactions of rituximab (incidence ≥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 ≥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) ]. In patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of rituximab at Cycle 2, the incidence of Grade 3-4 infusion-related reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]) [ 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, 1-588 days) and of neutropenia was 13 days (range, 2-116 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 R-FC compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 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) ]. Most patients received rituximab 375 mg/m 2 weekly for 4 doses. Table 1 Incidence of Adverse Reactions in ≥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 products. , 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 ( ≥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 ≥ 2 infections, and Grade ≥ 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. 22%). Grade 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in the rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. <1%). In NHL Study 6, the following adverse reactions were reported more frequently (≥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. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the rituximab arm compared with those who received no further therapy (4% vs. 1%) [see Clinical Studies (14.3) ]. DLBCL In NHL Studies 7 ( NCT00003150 ) and 8, [ see Clinical Studies (14.3) ], the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. 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. 1.0% 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. 3%). 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 ) [) or CLL Study 2 (NCT00090051) [ see Clinical Studies (14.5) ]. The age range was 30-83 years and 71% were men. Detailed safety data collection in CLL Study 1 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. 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. 1%). 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. <1%). Fifty-nine percent of R-FC-treated patients experienced an infusion-related reaction of any severity. 6.2 Clinical Trials Experience in Rheumatoid Arthritis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice. The data presented below reflect the experience in 2578 RA patients treated with rituximab in controlled and long-term studies Pooled studies: NCT00074438, NCT00422383, NCT00468546, NCT00299130, NCT00282308, NCT00266227, NCT02693210, NCT02093026 and NCT02097745 with a total exposure of 5014 patient-years. 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 x 500 mg or 2 x 1000 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 x 1000 mg) or placebo have been pooled ( see Table 2 ). Adverse reactions reported in ≥5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus ( see Table 2 ). The rates and types of adverse reactions in patients who received rituximab 2 x 500 mg were similar to those observed in patients who received rituximab 2 x 1000 mg. Table 2 These data are based on 938 patients treated in Phase 2 and 3 studies of rituximab (2 x 1000 mg) or placebo administered in combination with methotrexate. Incidence of All Adverse Reactions Coded using MedDRA. Occurring in ≥2% and at Least 1% Greater than Placebo Among Rheumatoid Arthritis Patients in Clinical Studies Up to Week 24 (Pooled) Adverse Reactions Placebo + MTX N=398 n (%) Rituximab + MTX N=540 n (%) 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 <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 2578 RA patients, the rate of serious infections was 4.31 per 100 patient years. The most common serious infections (≥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 1.7% and 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 2578 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 TRUXIMA 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 (<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 (>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, 2578 patients have been exposed to rituximab and have received up to 10 courses of rituximab in RA clinical trials, with 1890, 1043, 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), and Dosage and Administration (2.5) ]. 6.3 Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 practice 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) ]. In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either rituximab 375 mg/m 2 once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6 month remission induction period and the safety results for this period are described below. 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 (47-62%) and is discussed below. Table 3 Incidence of All Adverse Reactions Occurring in 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 N=99 n (%) Cyclophosphamide N=98 n (%) 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)], evaluating the efficacy and safety of non-U.S.-licensed rituximab versus azathioprine as follow up treatment in adult patients with GPA, MPA or renal-limited ANCA-associated vasculitis who had achieved disease control after induction treatment with cyclophosphamide, a total of 57 GPA and MPA patients in disease remission received follow up treatment with two 500 mg intravenous infusions of non-U.S.-licensed rituximab, separated by two weeks on Day 1 and Day 15, followed by a 500 mg intravenous infusion every 6 months for 18 months. The safety profile was consistent with the safety profile for rituximab in RA and GPA and MPA. Infusion-Related Reactions In GPA/MPA Study 2, 7/57 (12%) patients in the non-U.S.-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 (<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.S.-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 1-28]) for up to 4 years, according to physician standard practice and discretion. Majority of patients received doses ranging from 500 mg to 1000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for rituximab in RA and GPA and MPA. 6.4 Clinical Trials Experience in Pemphigus Vulgaris (PV) PV Study 1 PV Study 1 ( NCT00784589 ), a randomized, controlled, multicenter open-label study, evaluated the efficacy and safety of non-U.S.-licensed rituximab in combination with short-term prednisone compared to prednisone monotherapy in 90 patients (74 Pemphigus Vulgaris [PV] patients and 16 Pemphigus Foliaceus [PF] patients) [see Clinical Studies (14.8) ] . Safety results for the PV patient population during the 24-month treatment period are described below. The safety profile of the non-U.S.-licensed rituximab in patients with PV was consistent with that observed in patients with rituximab-treated RA and GPA and MPA [see Adverse Reactions (6.1) ] . Adverse reactions from PV Study 1 are presented below in Table 4 and were adverse events which occurred at a rate greater than or equal to 5% among PV patients treated with non-U.S.-licensed rituximab and with at least 2% absolute difference in incidence between the group treated with non-U.S.-licensed rituximab and the prednisone monotherapy group up to Month 24. No patients in the group treated with non-U.S.-licensed rituximab withdrew due to adverse reactions. The clinical study did not include sufficient number of patients to allow for direct comparison of adverse reaction rates between treatment groups. Table 4 Incidence of All Adverse Reactions Occurring in greater than or equal to 5% Among PV Patients Treated with Non-U.S.-licensed rituximab and with at Least 2% Absolute Difference in Incidence Between the Group Treated with Non-U.S.-licensed rituximab with Short-term Prednisone and the Group Treated with Prednisone Monotherapy in PV Study 1 (Up to Month 24) Adverse Reaction Non-U.S.-licensed rituximab + short-term prednisone N=38 n (%) Prednisone N = 36 n (%) Infusion-related reactions * 22 (58%) N/A Depression 7 (18%) 4 (11%) Herpes simplex 5 (13%) 1 (3%) Alopecia 5 (13%) 0 (0%) Fatigue 3 (8%) 2 (6%) Abdominal pain upper 2 (5%) 1 (3%) Conjunctivitis 2 (5%) 0 (0%) Dizziness 2 (5%) 0 (0%) Headache 2 (5%) 1 (3%) Herpes zoster 2 (5%) 1 (3%) Irritability 2 (5%) 0 (0%) Musculoskeletal pain 2 (5%) 0 (0%) Pruritus 2 (5%) 0 (0%) Pyrexia 2 (5%) 0 (0%) Skin disorder 2 (5%) 0 (0%) Skin papilloma 2 (5%) 0 (0%) Tachycardia 2 (5%) 0 (0%) Urticaria 2 (5%) 0 (0%) N/A = not applicable * Infusion-related reactions included symptoms collected on the next scheduled visit after each infusion, and adverse reactions occurring on the day of or one day after the infusion. The most common infusion-related reactions included headaches, chills, high blood pressure, nausea, asthenia, and pain. Infusion-Related Reactions Infusion-related reactions were the most commonly reported adverse drug reactions (58%, 22 patients). All infusion-related reactions were mild to moderate (Grade 1 or 2) except one Grade 3 serious infusion-related reaction (arthralgia) associated with the Month 12 maintenance infusion. The proportion of patients experiencing an infusion-related reaction was 29% (11 patients), 40% (15 patients), 13% (5 patients), and 10% (4 patients) following the first, second, third, and fourth infusions, respectively. No patients were withdrawn from treatment due to infusion-related reactions. Symptoms of infusion-related reactions were similar in type and severity to those seen in RA and GPA and MPA patients [see Adverse Reactions (6.1) ] . Infections Fourteen patients (37%) in the group treated with non-U.S.-licensed rituximab experienced treatment-related infections compared to 15 patients (42%) in the prednisone group. The most common infections in the group treated with non-U.S.-licensed rituximab were herpes simplex, herpes zoster, bronchitis, urinary tract infection, fungal infection, and conjunctivitis. Three patients (8%) in the group treated with non-U.S.-licensed rituximab experienced a total of 5 serious infections ( Pneumocystis jirovecii pneumonia, infective thrombosis, intervertebral discitis, lung infection, Staphylococcal sepsis) and 1 patient (3%) in the prednisone group experienced 1 serious infection ( Pneumocystis jirovecii pneumonia). PV Study 2 In PV Study 2 ( NCT02383589 ), a randomized, double-blind, double-dummy, active-comparator, multicenter study evaluating the efficacy and safety of rituximab compared to mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with rituximab (initial 1,000 mg IV on Study Day 1 and a second 1,000 mg IV on Study Day 15 repeated at Weeks 24 and 26) for up to 52 weeks [see Clinical Studies (14.8)] . In PV Study 2, ADR defined as adverse events occurring in greater than or equal to 5% of patients in the rituximab arms and assessed as related are shown in Table 5 . Table 5 Incidence of All Adverse Reactions Occurring in greater than or equal to 5% of rituximab-treated Pemphigus Vulgaris Patients (N=67) from PV Study 2 (up to Week 52) Adverse Reactions Rituximab (N=67) Infusion-related reactions * 15 (22%)* Upper respiratory tract infection/Nasopharyngitis 11 (16%) Headache 10 (15%) Asthenia/Fatigue 9 (13%) Oral candidiasis 6 (9%) Arthralgia 6 (9%) Back pain 6 (9%) Urinary tract infection 5 (8%) Dizziness 4 (6%) * The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 in the rituximab arm were dyspnoea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic Infusion-Related Reactions In PV Study 2, IRRs occurred primarily at the first infusion and the frequency of IRRs decreased with subsequent infusions: 17.9%, 4.7%, 3.5% and 3.5% of patients experienced IRRs at the first, second, third, and fourth infusions, respectively. In 11/15 patients who experienced at least one IRR, the IRRs were Grade 1 or 2. In 4/15 patients, Grade greater than or equal to 3 IRRs were reported and led to discontinuation of rituximab treatment; three of the four patients experienced serious [life-threatening] IRRs. Serious IRRs occurred at the first (2 patients) or second (1 patient) infusion and resolved with symptomatic treatment. Infections In PV Study 2, 42/67 patients (62.7%) in the rituximab arm experienced infections. The most common infections in the rituximab arm were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the rituximab arm experienced serious infections. Laboratory Abnormalities In PV Study 2, in the rituximab arm, transient decreases in T-cell lymphocytes and phosphorus level were very commonly observed post-infusion. In some cases, treatment of hypophosphatemia was required. Hypogammaglobulinemia (IgG or IgM below the lower limit of normal), including prolonged hypogammaglobulinemia (defined as Ig levels below lower limit of normal for at least 4 months) was observed in PV Study 2. Based on levels less than LLN measured at Week 16, Week 24, Week 40, and Week 52, 16.4% (11/67) of patients with normal baseline immunoglobulins had prolonged hypogammaglobulinemia (10 patients – IgM, 1 patient – both IgG and IgM) after treatment with rituximab. 6.5 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of rituximab or of other rituximab products. 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 273/2,578 (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 antirituximab antibodies by 18 months in GPA/MPA Study 1. The clinical relevance of anti-rituximab antibody formation in rituximab-treated adult patients is unclear. Using a new ELISA assay, a total of 19/34 (56%) patients with PV, who were treated with non- U.S.-licensed rituximab, tested positive for anti-rituximab antibodies by 18 months in PV Study 1. In PV Study 2, a total of 20/63 (32%) rituximab-treated PV patients tested positive for ADA by week 52 (19 patients had treatment-inducted ADA and 1 patient had treatment-enhanced ADA). The clinical relevance of anti-rituximab antibody formation in rituximab-treated PV patients is unclear. 6.6 Postmarketing Experience 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. Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia, prolonged hypogammaglobulinemia [see Warnings and Precautions (5.6) ] . Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections [see Warnings and Precautions (5.6) ] . Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation). Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease. Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible Posterior Leukoencephalopathy Syndrome (RPLS).