RITUXAN

Rituximab is a genetically engineered chimeric murine/human monoclonal IgG 1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium that may contain the antibiotic gentamicin. Gentamicin is not detectable in the final product. RITUXAN (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion. RITUXAN is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-dose vials. Each mL of solution contains 10 mg rituximab, polysorbate 80 (0.7 mg), sodium chloride (9 mg), sodium citrate dihydrate (7.35 mg), and Water for Injection, USP. The pH is 6.5.

RITUXAN is a CD20-directed cytolytic antibody indicated for the treatment of: Adult patients with Non-Hodgkin's Lymphoma (NHL) ( 1.1 ). Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens. Pediatric patients aged 6 months and older with mature B-cell NHL and mature B-cell acute leukemia (B-AL) ( 1.1 ) Previously untreated, advanced stage, CD20-positive, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy. Adult patients with Chronic Lymphocytic Leukemia (CLL) ( 1.2 ). Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC). Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies ( 1.3 ). Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) in adult and pediatric patients 2 years of age and older in combination with glucocorticoids ( 1.4 ). Moderate to severe Pemphigus Vulgaris (PV) in adult patients ( 1.5 ). 1.1 Non–Hodgkin's Lymphoma (NHL) RITUXAN is indicated for the treatment of adult patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. RITUXAN is indicated for the treatment of pediatric patients aged 6 months and older with: Previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy. 1.2 Chronic Lymphocytic Leukemia (CLL) RITUXAN, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL. 1.3 Rheumatoid Arthritis (RA) RITUXAN, 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 TNF antagonist therapies. 1.4 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) RITUXAN, in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA). 1.5 Pemphigus Vulgaris (PV) RITUXAN is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.

Administer only as an intravenous infusion ( 2.1 ). Do not administer as an intravenous push or bolus ( 2.1 ). RITUXAN 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. ( 2.1 ). The dose for adult and pediatric B-cell NHL is 375 mg/m 2 ( 2.2 ). The dose for CLL is 375 mg/m 2 in the first cycle and 500 mg/m 2 in cycles 2–6, in combination with FC, administered every 28 days ( 2.3 ). The dose as a component of Zevalin ® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m 2 ( 2.4 ). The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion ( 2.5 ). The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m 2 once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation ( 2.6 ). The induction dose for pediatric patients with GPA and MPA in combination with glucocorticoids is 375 mg/m 2 once weekly for 4 weeks. The follow up dose for pediatric patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 250 mg/m 2 intravenous infusions separated by two weeks, followed by a 250 mg/m 2 intravenous infusion every 6 months thereafter based on clinical evaluation ( 2.6 ). The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion ( 2.7 ). Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion ( 2.8 ). 2.1 Important Dosing Information Administer only as an Intravenous Infusion [see Dosage and Administration (2.8) ] . Do not administer as an intravenous push or bolus. RITUXAN 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 (2.8) ] . Prior to First Infusion: Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN [see Warnings and Precautions (5.3) ] . Obtain complete blood counts (CBC) including platelets prior to the first dose. During RITUXAN Therapy: In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RITUXAN course. During treatment with RITUXAN 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) ]. In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RITUXAN therapy. Continue to monitor for cytopenias after final dose and until resolution. First Infusion : Standard Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. For Pediatric Patients with mature B-cell NHL/B-AL : Initiate infusion at a rate of 0.5 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase infusion rate by 0.5 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr. Subsequent Infusions : Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. For Previously Untreated Follicular NHL and DLBCL adult patients: If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. Initiate at a rate of 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. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8). Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm 3 before Cycle 2 should not be administered the 90-minute infusion [see Clinical Studies (14.4) ] . For Pediatric Patients with mature B-cell NHL/B-AL: Initiate infusion rate of 1 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase rate by 1 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr. Interrupt the infusion or slow the infusion rate for infusion-related reactions [see Boxed Warning , Warnings and Precautions (5.1) ]. Continue the infusion at one-half the previous rate upon improvement of symptoms. 2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL) The recommended dose is 375 mg/m 2 as an intravenous infusion according to the following schedules: Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 or 8 doses. Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses. Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate RITUXAN maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer RITUXAN as a single-agent every 8 weeks for 12 doses. Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. Diffuse Large B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions. Pediatric patients aged 6 months and older with previously untreated mature B-cell NHL/B-AL RITUXAN is given in combination with systemic Lymphome Malin B (LMB) chemotherapy. In total, six infusions of RITUXAN are given, two doses during each of the induction courses, COPDAM1 and COPDAM2, and one dose during each of the two consolidation courses of CYM/CYVE (for details see Table 1 ). Table 1: Posology of RITUXAN Administration for Pediatric Mature B-cell NHL/B-AL Cycle Day of treatment Administration details COP = Cyclophosphamide, Oncovin (vincristine), Prednisone; COPDAM = Cyclophosphamide, Oncovin (vincristine), Prednisolone, Adriamycin (doxorubicin), Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE = CYtarabine (Aracytine, Ara-C), VEposide (VP16) Prephase (COP) No RITUXAN given - Induction courses 1 and 2 (COPDAM1 and COPDAM2) Day -2 1 st and 3 rd RITUXAN infusions During the 1 st induction course, prednisone is given as part of the chemotherapy course, and should be administered prior to RITUXAN. Day 1 2 nd and 4 th RITUXAN infusions RITUXAN will be given 48 hours after the first infusion of RITUXAN. Consolidation courses 1 and 2 (CYM/CYVE) Day 1 5 th and 6 th RITUXAN infusions - 2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL) The recommended dose is 375 mg/m 2 the day prior to the initiation of FC chemotherapy, then 500 mg/m 2 on Day 1 of cycles 2–6 (every 28 days). 2.4 Recommended Dose as a Component of Zevalin ® for treatment of NHL When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m 2 in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen. 2.5 Recommended Dose for Rheumatoid Arthritis (RA) Administer RITUXAN as two-1,000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. RITUXAN is given in combination with methotrexate. 2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Induction Treatment of Adult Patients with Active GPA/MPA Administer RITUXAN as a 375 mg/m 2 intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA. Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RITUXAN and may continue during and after the 4 week induction course of RITUXAN treatment. Follow up Treatment of Adult Patients with GPA/MPA who have achieved disease control with induction treatment Administer RITUXAN as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation. If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RITUXAN within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product. If induction treatment of active disease was with other standard of care immunosuppressants, initiate RITUXAN follow up treatment within the 4 week period that follows achievement of disease control. Induction treatment of Pediatric Patients with Active GPA/MPA Administer RITUXAN as a 375 mg/m 2 intravenous infusion once weekly for 4 weeks. Prior to the first RITUXAN infusion, administer intravenous methylprednisolone 30 mg/kg (not to exceed 1g/day) once daily for 3 days. Following intravenous methylprednisolone administration, oral steroids should be continued per clinical practice. Follow up Treatment of Pediatric Patients with GPA/MPA who have achieved disease control with induction treatment Administer RITUXAN as two 250 mg/m 2 intravenous infusions separated by two weeks, followed by a 250 mg/m 2 intravenous infusion every 6 months thereafter based on clinical evaluation. If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RITUXAN within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product. If induction treatment of active disease was with other standard of care immunosuppressants, initiate RITUXAN follow up treatment within the 4 week period following achievement of disease control. 2.7 Recommended Dose for Pemphigus Vulgaris (PV) Administer RITUXAN as two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids. Maintenance treatment Administer RITUXAN as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Treatment of relapse Administer RITUXAN as a 1,000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation. Subsequent infusions of RITUXAN may be administered no sooner than 16 weeks following the previous infusion. 2.8 Recommended Dose for Premedication and Prophylactic Medications Premedicate with acetaminophen and an antihistamine before each infusion of RITUXAN. For adult patients administered RITUXAN 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 pediatric patients with mature B-cell NHL/B-AL, premedication with acetaminophen and H1 antihistamine (diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of each RITUXAN intravenous infusion. For RA, GPA and MPA, and PV patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Provide prophylaxis treatment for Pneumocystis jirovecii pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate [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 RITUXAN infusion. PCP prophylaxis should be considered for patients with PV during and following RITUXAN treatment. 2.9 Administration and Storage Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. RITUXAN should be a clear, colorless liquid. Do not use vial if particulates or discoloration is present. Administration Use a sterile needle and syringe to prepare RITUXAN. Withdraw the necessary amount of RITUXAN and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. 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 Diluted RITUXAN solutions for infusion may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours. Diluted RITUXAN solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since RITUXAN solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C to 8°C). No incompatibilities between RITUXAN and polyvinylchloride or polyethylene bags have been observed.

None. None ( 4 )

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 ). Pediatric B-NHL/B-AL with chemotherapy (Grade 3 or higher greater than 15%): febrile neutropenia, stomatitis, enteritis, sepsis, alanine aminotransferase increased and hypokalemia ( 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 Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 RITUXAN in 3092 patients, with exposures ranging from a single infusion up to 2 years. RITUXAN was studied in both single-arm and controlled trials (n=356 and n=2427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 pediatric patients with mature B-cell NHL/B-AL. Most NHL patients received RITUXAN 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. Pediatric patients received 6 total doses of RITUXAN or a non-U.S. licensed rituximab in combination with chemotherapy. CLL patients received RITUXAN 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 RITUXAN-based therapy. The most common adverse reactions of RITUXAN (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 RITUXAN (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 RITUXAN infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the RITUXAN 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 adult 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 RITUXAN at Cycle 2, the incidence of Grade 3-4 infusion 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%]). In pediatric patients, the incidence of grade 3 infusion reactions was 3.4% with the first infusion and 1% for subsequent infusions. One patient experienced a grade 4 infusion reaction with the fifth infusion. [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 RITUXAN was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received RITUXAN. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received RITUXAN. In pediatric patients with mature B-cell NHL/B-AL, the rate of serious infections was higher, with an incidence of 32%, in those receiving RITUXAN or a non-U.S. licensed rituximab with chemotherapy. 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 RITUXAN therapy occurred during the single-arm studies. In studies of monotherapy, RITUXAN-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 2 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of RITUXAN administered as a single agent [see Clinical Studies (14.1) ] . Most patients received RITUXAN 375 mg/m 2 weekly for 4 doses. Table 2 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 RITUXAN (N=356) Adverse reactions observed up to 12 months following RITUXAN. , 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 RITUXAN studies, bronchiolitis obliterans occurred during and up to 6 months after RITUXAN 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 RITUXAN as single-agent maintenance therapy following RITUXAN 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 (greater than or equal to 2%) in the RITUXAN 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 RITUXAN 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 ( greater than or equal to 2%) in the RITUXAN 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 ( greater than or equal to 5%) in patients age greater than or equal to 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). Pediatric Patients with DLBCL/BL/BLL/B-AL The safety of RITUXAN administered in combination with LMB chemotherapy in pediatric patients was evaluated in NHL Study 11 [see Clinical Studies (14.2) ] , which included 309 patients treated with RITUXAN or non-U.S. licensed rituximab with chemotherapy and 164 patients treated with chemotherapy alone. Pediatric patients randomized to the LMB chemotherapy arm with RITUXAN or non-U.S.-licensed rituximab, or enrolled in the single arm part of the study, were administered RITUXAN or non-U.S. licensed rituximab intravenous at a dose of 375 mg/m 2 BSA and received a total of six infusions of RITUXAN (two during each of the two induction courses and one during each of the two consolidation courses of the LMB scheme). In NHL Study 11, serious adverse reactions occurred in 55% of patients who received RITUXAN or non-US licensed rituximab with LMB chemotherapy. Serious adverse reactions in more than or equal to 5% included febrile neutropenia (15%), stomatitis (11%), sepsis (8%), and device-related infections (5%). Fatal adverse reactions occurred in 3% of patients, most often due to sepsis (2%), and included one case of second primary malignancy. Permanent discontinuation of RITUXAN or non- U.S. licensed rituximab occurred in 2% of patients. Adverse reactions which resulted in permanent discontinuation of RITUXAN or non-U.S. licensed rituximab included infection, anaphylaxis, hypotension, and leukoencephalopathy. Detailed safety data collection in this study was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Table 3 shows Grade 3 and higher adverse reactions (greater than or equal to 10%) in the RITUXAN or non-U.S.-licensed rituximab with chemotherapy or chemotherapy alone arms in patients with untreated mature B-cell NHL/B-AL. The most common (greater than or equal to 15%) Grade 3 and higher adverse reactions were febrile neutropenia, stomatitis, enteritis, sepsis, alanine aminotransferase increased, and hypokalemia. Table 3 Grade 3 or Higher Adverse Reactions Occurring (greater than or equal to 10%) in Pediatric Patients treated with RITUXAN with Chemotherapy or Chemotherapy Alone Adverse Reaction RITUXAN + Chemotherapy N=162 (%) Chemotherapy N=153 (%) Blood and lymphatic system disorders Febrile Neutropenia 93 91 Gastrointestinal disorders Stomatitis 80 75 Enteritis 24 16 Investigations Alanine aminotransferase increased 19 14 Aspartate aminotransferase increased 11 7 Infections and infestations Sepsis 18 Includes fatal adverse reaction 13 Device Related infection 13 12 Lung Infection 12 9 Enterocolitis infections 9 12 Metabolism and nutrition disorders Hypokalemia 16 13 Decreased appetite 11 5 CLL The data below reflect exposure to RITUXAN 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) ] . 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. Rheumatoid Arthritis The data presented below reflect the experience in 2578 RA patients treated with RITUXAN 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 × 500 mg or 2 × 1,000 mg intravenous infusions of RITUXAN or placebo, in combination with methotrexate, during a 24-week period. From these studies, 938 patients treated with RITUXAN (2 × 1,000 mg) or placebo have been pooled (see Table 4 ). Adverse reactions reported in greater than or equal to 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus (see Table 4 ). The rates and types of adverse reactions in patients who received RITUXAN 2 × 500 mg were similar to those observed in patients who received RITUXAN 2 × 1,000 mg. Table 4 These data are based on 938 patients treated in Phase 2 and 3 studies of RITUXAN (2 × 1,000 mg) or placebo administered in combination with methotrexate. Incidence of All Adverse Reactions Coded using MedDRA. Occurring in greater than or equal to 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 (%) RITUXAN + 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 RITUXAN RA pooled placebo-controlled studies, 32% of RITUXAN-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, RITUXAN 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 RITUXAN-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 RITUXAN 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 RITUXAN. The administration of intravenous glucocorticoids prior to RITUXAN 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 RITUXAN infusions. Infections In the pooled, placebo-controlled studies, 39% of patients in the RITUXAN 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 RITUXAN-treated patients and 1% in the placebo group. In the experience with RITUXAN in 2578 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 RITUXAN-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 RITUXAN 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 RITUXAN 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 RITUXAN. 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 RITUXAN 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 RITUXAN 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 RITUXAN versus 0.3% (1/398) of patients on placebo. In the experience with RITUXAN 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 RITUXAN in RA patients, 2578 patients have been exposed to RITUXAN and have received up to 10 courses of RITUXAN 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 RITUXAN were similar to rates and types seen for a single course of RITUXAN. In RA Study 2, where all patients initially received RITUXAN, the safety profile of patients who were retreated with RITUXAN was similar to those who were retreated with placebo [see Clinical Studies (14.6) , and 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 RITUXAN 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 RITUXAN 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 RITUXAN 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 5 were adverse events which occurred at a rate of greater than or equal to 10% in the RITUXAN group. This table reflects experience in 99 GPA and MPA patients treated with RITUXAN, 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 5 Incidence of All Adverse Reactions Occurring in greater than or equal to 10% of RITUXAN-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 RITUXAN 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 RITUXAN, 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 RITUXAN 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 RITUXAN 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 RITUXAN 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 RITUXAN group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% in the RITUXAN-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 RITUXAN in GPA/MPA Study 1. At 6 months, in the RITUXAN 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 RITUXAN 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 (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.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 RITUXAN 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 RITUXAN (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 1,000 mg, approximately every 6 months. The safety profile was consistent with the safety profile for RITUXAN in RA and GPA and MPA. Treatment of Pediatric Patients with GPA/MPA (GPA/MPA Study 4) An open-label, single arm study (NCT01750697) was conducted in 25 pediatric patients 6 years to 17 years of age with active GPA or MPA. The overall study period consisted of a 6-month remission induction phase and a minimum 12-month follow-up phase, up to 54 months. During the remission induction phase, patients received RITUXAN or non-U.S.-licensed rituximab. During the follow-up phase, RITUXAN or non-U.S.-licensed rituximab were given at the discretion of the investigator (17 out of 25 patients received this additional treatment). Concomitant treatment with other immunosuppressive therapy was permitted [see Clinical Studies (14.7) ]. The safety profile in pediatric GPA and MPA patients was consistent in type, nature and severity with the known safety profile of RITUXAN in adult patients with RA, GPA and MPA, and PV. Infusion-Related Reactions In GPA/MPA Study 4, the proportion of patients experiencing an IRR was 32%, 20%, 12%, and 8% following the first, second, third, and fourth infusions, respectively. The observed symptoms of IRRs were similar to those in adult GPA and MPA patients treated with RITUXAN. [see Warning and Precautions (5.1) ]. Serious Infections Serious infections were reported in 7 patients (28%), and included influenza (2 patients [8%]) and lower respiratory tract infection (2 patients [8%]) as the most frequently reported events. Hypogammaglobulinemia 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 GPA/MPA Study 4. During the overall study period, 18/25 patients (72%) had prolonged low IgG levels, including 15 patients who also had prolonged low IgM. Three patients received treatment with intravenous immunoglobulin. 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 RITUXAN-treated RA and GPA and MPA [see Adverse Reactions (6.1) ] . Adverse reactions from PV Study 1 are presented below in Table 6 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 6 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 (%) N/A = not applicable Infusion-related reactions 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. 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%) 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 RITUXAN compared to mycophenolate mofetil (MMF) in patients with moderate-to-severe PV requiring oral corticosteroids, 67 PV patients received treatment with RITUXAN (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 RITUXAN arms and assessed as related are shown in Table 7 . Table 7 Incidence of All Adverse Reactions occurring in greater than or equal to 5% of RITUXAN-treated Pemphigus Vulgaris Patients (N=67) from PV Study 2 (up to Week 52) Adverse Reactions RITUXAN (N=67) Infusion-related reactions 15 (22%) The most common infusion-related reaction symptoms/Preferred Terms for PV Study 2 in the RITUXAN arm were dyspnoea, erythema, hyperhidrosis, flushing/hot flush, hypotension/low blood pressure and rash/rash pruritic 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%) 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 RITUXAN 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 RITUXAN arm experienced infections. The most common infections in the RITUXAN arm were upper respiratory tract infection, nasopharyngitis, oral candidiasis and urinary tract infection. Six patients (9%) in the RITUXAN arm experienced serious infections. Laboratory Abnormalities In PV Study 2, in the RITUXAN 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 RITUXAN. 6.2 Immunogenicity 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 RITUXAN. 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 RITUXAN. 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%) RITUXAN-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 RITUXAN-treated adult patients is unclear. In GPA/MPA Study 4, a total of 4/21 (19%) RITUXAN-treated pediatric patients with GPA and MPA developed anti-rituximab antibodies during the overall study period (assessed at Month 18). 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%) RITUXAN- 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 RITUXAN-treated PV patients is unclear. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of RITUXAN. 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).

Formal drug interaction studies have not been performed with RITUXAN. In patients with CLL, RITUXAN 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 ( 5.8 ).

Store RITUXAN vials refrigerated at 2°C to 8°C (36°F to 46°F). RITUXAN vials should be protected from direct sunlight. Do not freeze or shake.