GAZYVA

Obinutuzumab is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is approximately 150 kDa. GAZYVA (obinutuzumab) injection is produced by mammalian cell (CHO) suspension culture. GAZYVA was engineered to have reduced fucose content as compared to a typical IgG1 produced in CHO cells. GAZYVA is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous use. GAZYVA is supplied at a concentration of 25 mg/mL in 1,000 mg single-dose vials. Each vial contains in 40 mL: 1,000 mg obinutuzumab, L-histidine (57.6 mg), L-histidine hydrochloride monohydrate (89.6 mg), trehalose dihydrate (3632 mg), and poloxamer 188 (8 mg). The pH is 6.0.

GAZYVA is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). ( 1.1 , 14 ) in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL)who relapsed after, or are refractory to, a rituximab-containing regimen. ( 1.2 , 14 ) in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma. ( 1.2 , 14 ) for the treatment of adult patients with active lupus nephritis (LN) who are receiving standard therapy ( 1.3 , 14 ) 1.1 Chronic Lymphocytic Leukemia (CLL) GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia. 1.2 Follicular Lymphoma (FL) GAZYVA, in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen . GAZYVA, in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma . 1.3 Lupus Nephritis (LN) GAZYVA is indicated for the treatment of adult patients with active lupus nephritis who are receiving standard therapy.

Premedicate for infusion-related reactions and tumor lysis syndrome. ( 2.1 , 5.3 , 5.4 ) Administer only as intravenous infusion. Do not administer as an intravenous push or bolus. ( 2.1 ) The recommended dosage for chronic lymphocytic leukemia is 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1,000 mg on day 8 and 15 of Cycle 1, and 1,000 mg on day 1 of Cycles 2–6. ( 2.2 ) The recommended dosage for follicular lymphoma is 1,000 mg on day 1, 8 and 15 of Cycle 1, 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8, and then 1,000 mg every 2 months for up to 2 years. ( 2.3 ) The recommended dosage for active lupus nephritis is 1,000 mg at the initial infusion, on Week 2, 24, 26, and every 6 months thereafter. ( 2.4 ) 2.1 Important Dosing Information Premedicate before each infusion [see Dosage and Administration (2.4) ] . Provide prophylactic hydration and anti-hyperuricemics to patients at high risk of tumor lysis syndrome [see Dosage and Administration (2.4) and Warnings and Precautions (5.4) ]. Administer only as an intravenous infusion through a dedicated line [see Dosage and Administration (2.6) ] . Do not administer as an intravenous push or bolus. Monitor blood counts at regular intervals. GAZYVA 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 (5.3) ]. 2.2 Recommended Dosage for Chronic Lymphocytic Leukemia Each dose of GAZYVA is 1,000 mg administered intravenously with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg) according to Table 1 . Table 1 Dose of GAZYVA to be Administered During Six 28-Day Treatment Cycles for Patients with CLL Day of treatment cycle Dose of GAZYVA Rate of infusion Cycle 1 (loading doses) Day 1 100 mg Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate. Day 2 900 mg If no infusion-related reaction (IRR) occurred during the previous infusion, administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. If an IRR occurred during the previous infusion, administer at 25 mg/hr. The rate of infusion can be escalated in increments of up to 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 8 1,000 mg If no IRR occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 15 1,000 mg Cycles 2 – 6 Day 1 1,000 mg If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible and adjust dosing schedule to maintain the time interval between doses. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the Day 2 Cycle 1 dose. 2.3 Recommended Dosage for Follicular Lymphoma Each dose of GAZYVA is 1,000 mg administered intravenously according to Table 2 . For patients with relapsed or refractory FL, administer GAZYVA in combination with bendamustine in six 28-day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years. For patients with previously untreated FL, administer GAZYVA with one of the following chemotherapy regimens: Six 28-day cycles in combination with bendamustine Six 21-day cycles in combination with CHOP, followed by 2 additional 21-day cycles of GAZYVA alone Eight 21-day cycles in combination with CVP Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue on GAZYVA 1,000 mg as monotherapy for up to two years. GAZYVA should be administered at the standard infusion rate in Cycle 1 (see Table 2 ). In patients with FL who do not experience a Grade 3 or higher IRR during Cycle 1, GAZYVA may be administered as a shorter, approximately 90-minute infusion from Cycle 2 onwards (see Table 3 ) with continued premedication. Table 2 Dose and Standard Infusion Rate of GAZYVA to be Administered During 6–8 Treatment Cycles, Followed by GAZYVA Monotherapy for Patients with FL Day of treatment cycle Dose of GAZYVA Rate of infusion Cycle 1 (loading doses) Day 1 1,000 mg Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Day 8 1,000 mg If no infusion-related reaction or an infusion-related reaction of Grade 1 occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. If an infusion-related reaction of Grade 2 or higher occurred during the previous infusion, administer at 50 mg/hr. The rate of infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr. Day 15 1,000 mg Cycles 2 – 6 or 2–8 Day 1 1,000 mg Monotherapy Every two months for up to two years 1,000 mg Table 3 Dose and Infusion Rate of a GAZYVA 90-Minute Infusion for Patients with FL Day of treatment cycle Dose of GAZYVA Rate of infusion Cycle 1 Days 1, 8, 15 1,000 mg See Table 2 Cycles 2–6 Consider an approximately 90-minute infusion in patients with FL who do not experience a Grade 3 or higher infusion-related reaction to GAZYVA in Cycle 1 and subsequent cycles. or 2-8 Day 1 1,000 mg If no Grade 3 or higher IRR occurred during Cycle 1: 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurred during the previous approximately 90-minute infusion, administer all subsequent GAZYVA infusions at the standard infusion rate (see Table 2 ). Monotherapy Every two months for up to two years 1,000 mg If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible. During GAZYVA and chemotherapy treatment, adjust the dosing schedule accordingly to maintain the time interval between chemotherapy cycles. During monotherapy, maintain the original dosing schedule for subsequent doses. Initiate monotherapy approximately two months after the last dose of GAZYVA administered during the induction phase. 2.4 Recommended Dosage for Active Lupus Nephritis Each recommended dose of GAZYVA is 1,000 mg administered intravenously according to Table 4 . Table 4 Dose and Infusion Rate for Standard Infusion of GAZYVA in Adults with Active Lupus Nephritis Dose number Timing of treatment Dose of GAZYVA Rate of infusion 1 Initial infusion 1,000 mg Administer at a rate of 50 mg/hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. For management of IRRs that occur during infusion, see Dosage Modifications for Adverse Reactions (2.6) . 2 Week 2 (two weeks after Dose 1) 1,000 mg Administer at a rate of 100 mg/hr. The rate of infusion can be escalated at a rate of 100 mg/hr every 30 minutes to a maximum of 400 mg/hr. 3 Week 24 1,000 mg 4 Week 26 (two weeks after Dose 3) 1,000 mg 5 Dose 5 should be administered six months after Dose 4 and thereafter Every 6 months 1,000 mg Patients who do not experience Grade ≥ 3 infusion related reactions during the previous infusion may receive GAZYVA over approximately 90 minutes from Dose 2 onwards (see Table 5 ), with continued premedication. Table 5 Dose and Infusion Rate for a 90-Minute Infusion of GAZYVA in Adults with Active Lupus Nephritis Dose number Rate of infusion 1 See Table 4 2 and thereafter (if no Grade 3 or higher IRR during previous infusion) 100 mg/hr for 30 minutes, then 900 mg/hr for approximately 60 minutes. If an IRR of Grade 1-2 with ongoing symptoms or a Grade 3 or higher IRR occurs during the previous approximately 90-minute infusion, administer GAZYVA at the standard infusion rate (see Table 4 ). If a planned dose of GAZYVA is missed, it should be administered as soon as possible – do not wait until the next planned dose. The schedule of administration should be adjusted to maintain the appropriate interval between doses. 2.5 Recommended Premedication and Prophylactic Medications Infusion-Related Reactions Premedication to reduce the risk of IRRs is outlined in Table 6 [see Warnings and Precautions (5.3) ] . Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration [see Warnings and Precautions (5.3) ] . Table 6 Premedication for GAZYVA Infusion to Reduce Infusion-Related Reactions Indication/Cycle/Day of Treatment Patients requiring premedication Premedication Administration Premedication applies to both standard and approximately 90-minute infusions. CLL Cycle 1 Days 1 and 2 FL Cycle 1 Day 1 All patients Intravenous glucocorticoid: 20 mg dexamethasone or 80 mg methylprednisolone Hydrocortisone is not recommended as it has not been effective in reducing the rate of IRRs. , If a glucocorticoid-containing chemotherapy regimen is administered on the same day as GAZYVA, the glucocorticoid can be administered as an oral medication if given at least 1 hour prior to GAZYVA, in which case additional intravenous glucocorticoid as premedication is not required. Completed at least 1 hour prior to GAZYVA infusion. 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) CLL or FL All subsequent infusions All patients 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. Patients with an IRR (Grade 1-2) with the previous infusion 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) Patients with a Grade 3 IRR with the previous infusion OR with a lymphocyte count > 25 × 10 9 /L prior to next treatment Intravenous glucocorticoid: 20 mg dexamethasone or 80 mg methylprednisolone Completed at least 1 hour prior to GAZYVA infusion. 650–1,000 mg acetaminophen At least 30 minutes before GAZYVA infusion. anti-histamine (e.g., 50 mg diphenhydramine) LN All patients Intravenous glucocorticoid (80 mg methylprednisolone) Completed between 30 and 60 minutes prior to GAZYVA infusion Starting from Dose 6, intravenous corticosteroid should only be administered to patients who have experienced an IRR in the prior infusion 650–1,000 mg acetaminophen anti-histamine (e.g., 50 mg diphenhydramine) Tumor Lysis Syndrome Prophylaxis Patients with high tumor burden, high circulating absolute lymphocyte counts (greater than 25 × 10 9 /L) or renal impairment are considered at risk of tumor lysis syndrome and should receive prophylaxis. Premedicate with anti-hyperuricemics (e.g., allopurinol or rasburicase) and ensure adequate hydration prior to start of GAZYVA therapy. Continue prophylaxis prior to each subsequent GAZYVA infusion, as needed [see Warnings and Precautions (5.4) ] . Antimicrobial Prophylaxis Patients with Grade 3 to 4 neutropenia lasting more than one week are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis for patients with severe and long lasting (> 1 week) neutropenia. 2.6 Dosage Modifications for Adverse Reactions Infusion-Related Reactions If a patient experiences an IRR, adjust the infusion as follows [see Warnings and Precautions (5.3) ] : Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue GAZYVA. Grade 3 (severe): Interrupt infusion and manage symptoms. For patients who experience Grade 3 IRRs during standard infusion, upon resolution of symptoms, consider restarting GAZYVA infusion at no more than half the previous rate (the rate being used at the time that the IRR reaction occurred), and if patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge. For patients with FL who experience Grade 3 IRRs during the approximately 90-minute infusion, upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and not greater than 400 mg/hr. Administer subsequent infusions at the standard rate. Permanently discontinue treatment if patients experience a Grade 3 or higher IRR at rechallenge. For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and manage symptoms. Upon resolution of symptoms, continue or resume GAZYVA infusion, and if patient does not experience any further IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. For patients with CLL only, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. For patients with LN, reduce infusion rate to half the rate that was used at the time of the reaction and treat symptoms. Upon resolution of symptoms, the infusion should be kept at the reduced rate for an additional 30 minutes. If no further symptoms of IRR, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose. Other Adverse Reactions Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or Grade 2 or higher non-hematologic toxicity. 2.7 Preparation and Administration Preparation Prepare the solution for infusion, using aseptic technique, as follows: Inspect visually for any particulate matter and discoloration prior to administration. Use a sterile needle and syringe to prepare GAZYVA. Dilute into a 0.9% Sodium Chloride Injection, USP PVC or non-PVC polyolefin infusion bag. Chronic Lymphocytic Leukemia Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1: Prepare day 1 (100 mg) and day 2 (900 mg) infusion bags at the same time using one vial (1,000 mg/40 mL) on day 1. Withdraw 40 mL of GAZYVA solution from the vial. Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% Sodium Chloride Injection, USP infusion bag for immediate administration. Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag at the same time for use on day 2 and store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately. Clearly label each infusion bag. Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 of Cycles 2–6: Withdraw 40 mL of GAZYVA solution from the vial. Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag. Follicular Lymphoma and Active Lupus Nephritis Preparation of solution for infusion: Withdraw 40 mL of GAZYVA solution from the vial. Dilute 40 mL (1,000 mg) into a 250 mL 0.9% Sodium Chloride Injection, USP infusion bag. Mix diluted solution by gentle inversion. Do not shake or freeze. For microbiological stability, immediately use diluted GAZYVA infusion solution. If not used immediately, store in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use. The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL. Storage Use the diluted solution immediately. If not used immediately, store for up to 24 hours at 2°C to 8°C. Discard after 24 hours. Administration Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix GAZYVA with other drugs. No incompatibilities between GAZYVA and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed.

GAZYVA is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use [see Warnings and Precautions (5.4) ]. GAZYVA is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use. ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatitis B virus reactivation [see Warnings and Precautions (5.1) ] Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2) ] Infusion-related reactions [see Warnings and Precautions (5.3) ] Hypersensitivity reactions including serum sickness [see Warnings and Precautions (5.4) ] Tumor lysis syndrome [see Warnings and Precautions (5.5) ] Infections [see Warnings and Precautions (5.6) ] Neutropenia [see Warnings and Precautions (5.7) ] Thrombocytopenia [see Warnings and Precautions (5.8) ] Disseminated intravascular coagulation [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence ≥ 20% and ≥ 2% greater in the GAZYVA treated arm in CLL and NHL, and incidence ≥ 5% in the GAZYVA treated arm in LN) were: Previously untreated CLL : infusion-related reactions and neutropenia. ( 6 ) Relapsed or refractory non-Hodgkin lymphoma (NHL) : infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain. ( 6 ) Previously untreated NHL : infusion-related reactions, neutropenia, upper respiratory tract infections, cough, constipation, and diarrhea. ( 6 ) Lupus Nephritis : upper respiratory tract infection, COVID-19, urinary tract infection, bronchitis, pneumonia, infusion-related reactions, and neutropenia. ( 6 ) 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 practice. Chronic Lymphocytic Leukemia The data below are based on a safety population of 773 previously untreated patients with CLL in the CLL11 study. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab product in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab product in combination with chlorambucil. Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are presented below and are consistent with the rates in Stage 1. In addition to the adverse reactions observed in Stage 2, in Stage 1, back pain (5% vs. 2%), anemia (12% vs. 10%) and cough (10% vs. 7%) were observed at a higher incidence in the GAZYVA treated patients. The incidence of Grade 3 to 4 back pain (< 1% vs. 0%), cough (0% vs. < 1%) and anemia (5% vs. 4%) was similar in both treatment arms. With regard to laboratory abnormalities, in Stage 1 hyperkalemia (33% vs. 18%), creatinine increased (30% vs. 20%) and alkaline phosphatase increased (18% vs. 11%) were observed at a higher incidence in patients treated with GAZYVA with similar incidences of Grade 3 to 4 abnormalities between the two arms. Patients received three 1,000 mg doses of GAZYVA on the first cycle and a single dose of 1,000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.2) ] . In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy. Adverse reactions in ≥ 10% of patients in the GAZYVA containing arm were infusion-related reactions, neutropenia, thrombocytopenia, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥ 10%) in the GAZYVA containing arm were neutropenia, infusion-related reactions, and thrombocytopenia. Table 7 Adverse Reactions (Incidence ≥ 5% and ≥ 2% Greater in the GAZYVA Arm) in Patients with CLL (Stage 2) Body System Adverse Reactions GAZYVA + Chlorambucil n = 336 Rituximab product + Chlorambucil n = 321 All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Injury, Poisoning and Procedural Complications Infusion-Related Reaction 66 20 38 4 Blood and Lymphatic System Disorders Adverse reactions reported under "Blood and lymphatic system disorders" reflect those reported by investigator as clinically significant. Neutropenia 38 33 32 28 Thrombocytopenia 14 10 7 3 Gastrointestinal Disorders Diarrhea 10 2 8 < 1 Constipation 8 0 5 0 General Disorders and Administration Site Conditions Pyrexia 9 < 1 7 < 1 Infections and Infestations Nasopharyngitis 6 < 1 3 0 Urinary Tract Infection 5 1 2 < 1 Table 8 Post-Baseline Laboratory Abnormalities (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with CLL (Stage 2) Laboratory Abnormalities GAZYVA + Chlorambucil n = 336 Rituximab product + Chlorambucil n = 321 All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Hematology Leukopenia 84 35 62 16 Lymphopenia 80 39 50 16 Neutropenia 76 46 69 41 Thrombocytopenia 48 13 40 8 Anemia 39 10 37 10 Chemistry Hypocalcemia 37 3 32 < 1 ALT increased 28 2 21 1 AST increased 27 2 21 < 1 Hyponatremia 26 7 18 2 Hypoalbuminemia 23 < 1 16 < 1 Hypokalemia 14 1 10 < 1 Non-Hodgkin Lymphoma GADOLIN Study The GADOLIN study evaluated safety in 407 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma and marginal zone lymphoma (a disease for which GAZYVA is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In the population of patients with FL, the profile of adverse reactions was consistent with the overall NHL population. Patients received either GAZYVA in combination with bendamustine (204 patients), followed by GAZYVA monotherapy in patients that had not progressed, or bendamustine alone (203 patients). Patients randomized to the GAZYVA + bendamustine arm received three weekly 1,000 mg doses of GAZYVA in the first cycle and a single dose of 1,000 mg once every 28 days for 5 additional cycles, in combination with bendamustine 90 mg/m 2 intravenously on Days 1 and 2 in all 6 cycles. Patients who did not progress on the combination received a single 1,000 mg dose of GAZYVA monotherapy every two months until progression or for a maximum of two years. The control arm received bendamustine 120 mg/m 2 on Days 1 and 2 of each cycle for 6 cycles, with a cycle length of 28 days. In the GAZYVA arm, 78% of patients received 6 cycles of bendamustine and 82% received their full 6 cycles of GAZYVA; 72 (46%) of the 158 patients who began GAZYVA monotherapy received all planned doses. In the control arm, 72% of patients received 6 cycles of bendamustine. Serious adverse reactions occurred in 45% of the GAZYVA arm and 37% of the bendamustine-only arm. Fatal adverse reactions within 90 days of treatment occurred in 3.4% and 2.5%, respectively. During treatment and follow-up combined, fatal adverse reactions occurred in 10% of GAZYVA recipients and in 7.4% of recipients of bendamustine alone, with infection and second primary malignancies being the leading causes. Dose modification due to adverse reactions occurred in 50% of the GAZYVA arm and 42% of the control arm, and discontinuation of any study drug due to adverse reactions occurred in 20% and 17%, respectively. Table 9 presents selected adverse reactions in GADOLIN. The most common adverse reactions (incidence ≥ 20%) in GAZYVA recipients included infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain. Table 9 Adverse Reactions (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with Relapsed or Refractory NHL (GADOLIN) Body System Adverse Reactions Includes adverse reactions reported throughout study treatment and follow-up. , Includes grouped terms. GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 204 Bendamustine n = 203 All Grades % Grades 3 to 5 % All Grades % Grades 3 to 5 % Procedural Complications Infusion-Related Reaction Except where noted, individual events that meet the definition of "infusion-related reaction" are excluded from Table 9 above, as they are included in the grouped term "Infusion-Related Reaction". 67 11 63 5 General Disorders Fatigue 40 3 36 3 Pyrexia 19 1 15 1 Blood and Lymphatic System Disorders Neutropenia 37 35 Includes 1 fatal event. 29 27 Infections and Infestations Upper Respiratory Tract Infection 36 3 23 1 Respiratory Tract Infection, Unspecified 14 1 8 0 Urinary Tract Infection 13 3 7 0 Respiratory, Thoracic and Mediastinal Disorders Cough 31 <1 21 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain 28 1 20 0 Arthralgia 12 <1 5 0 Skin and Subcutaneous Tissue Disorders Rash 17 <1 14 <1 Pruritus 11 0 6 0 Infusion-related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion. Fatigue includes fatigue, lethargy, asthenia. Pyrexia includes pyrexia, hyperthermia, body temperature increased. Cough includes cough, productive cough, upper-airway cough syndrome. Neutropenia includes neutropenia, agranulocytosis, granulocytopenia, neutrophil count decreased. Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, upper respiratory fungal infection, rhinovirus infection, and all terms containing: upper respiratory tract infection, laryngitis, nasopharyngitis, pharyngitis, rhinitis, tonsillitis, and sinusitis with the exception of sinobronchitis. Respiratory tract infection unspecified includes respiratory tract infection, respiratory tract infection viral, influenza, influenza-like illness, sinobronchitis, respiratory syncytial virus infection. Urinary tract infection includes all terms containing: urinary tract infection, cystitis, pyelonephritis. Musculoskeletal pain includes non-cardiac chest pain, bone pain, spinal pain, myalgia, back pain, neck pain, musculoskeletal discomfort, pain in extremity, and all terms containing "musculoskeletal pain". Rash includes drug eruption, skin reaction, all terms containing "rash", urticaria, and selected terms containing "dermatitis". Pruritus includes pruritus, pruritus generalized. Other clinically relevant adverse reactions (incidence < 10% and ≥ 2% greater in the GAZYVA arm) included: Blood and lymphatic system disorders : febrile neutropenia (6%) Infection: sepsis (7%) During GAZYVA monotherapy (158 patients), adverse reactions in ≥ 10% of patients included upper and lower respiratory tract infections, cough, neutropenia, musculoskeletal pain, fatigue, diarrhea, rash, and urinary tract infection. Table 10 presents selected new or worsening laboratory abnormalities in the GADOLIN trial. Table 10 New or Worsening Laboratory Abnormalities (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm Two percent difference in either any-grade or Grade 3 to 4 laboratory abnormalities. ) in Patients with Relapsed or Refractory NHL (GADOLIN) Laboratory Abnormalities GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 204 Bendamustine n = 203 All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Hematology Lymphopenia 97 92 96 84 Leukopenia 84 47 87 34 Neutropenia 76 53 75 42 Chemistry Hypophosphatemia 41 8 38 7 Hypocalcemia 39 3 24 1 ALT/SGPT increased 36 2 31 3 Alkaline phosphatase increased 27 0 23 0 Hyperbilirubinemia 21 2 17 2 Hyperkalemia 20 3 18 0 In the GAZYVA monotherapy phase, new or worsening grade 3 or 4 abnormalities included neutropenia in 25% of patients (Grade 4, 10%) and lymphopenia in 23% (Grade 4, 5%). GALLIUM Study A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). Patients received chemotherapy (bendamustine, CHOP, or CVP) combined with either GAZYVA (691 patients) or rituximab product (694 patients), followed in responding patients by GAZYVA or rituximab product monotherapy every two months until disease progression or for a maximum of two years. The study excluded patients having an absolute neutrophil count (ANC) < 1500 / µL, platelets < 75,000 / µL, CLcr < 40 mL/min and, unless attributable to lymphoma, hepatic transaminases > 2.5 × upper limit of normal. The median age was 60 (range: 23-88), 47% were male, 82% were white, and 97% had an ECOG performance status of 0 or 1. The chemotherapy was bendamustine in 59%, CHOP in 31% and CVP in 10% of patients. Following combination therapy, 624 patients (90%) in the GAZYVA arm and 612 patients (88%) in the rituximab product arm received monotherapy. Serious adverse reactions occurred in 50% of patients on the GAZYVA arm and 43% of patients on the rituximab product arm. Fatal adverse reactions were reported during treatment in 3% in the GAZYVA arm and 2% in the rituximab product arm, most often from infections in the GAZYVA arm. During treatment and follow-up combined, fatal adverse reactions were reported in 5% of the GAZYVA arm and 4% of the rituximab product arm, with infections and second malignancies being leading causes. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to < 1% in the rituximab product arm. During combination therapy, 93% of patients received all treatment cycles in the GAZYVA arm, and 92% received all treatment cycles in the rituximab product arm. Of the responding patients who began monotherapy with GAZYVA or rituximab product, 76% and 73%, respectively, completed the full course. Dose modification due to adverse reactions occurred in 74% of the GAZYVA arm and 63% of the rituximab product arm throughout study treatment, and discontinuation of any study drug due to adverse reactions occurred in 18% and 15%, respectively. Throughout treatment and follow-up, the most common adverse reactions (incidence ≥ 20%) observed at least 2% more in the GAZYVA arm included infusion-related reactions, neutropenia, upper respiratory tract infections, constipation and diarrhea ( Table 11 ). Neutropenia, infusion-related reactions, febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions (incidence ≥ 5%) observed more frequently in the GAZYVA arm. Table 11 Adverse Reactions (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM) Body System Adverse Reactions Includes adverse reactions reported throughout study treatment and follow-up. , Includes grouped terms. GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 691 Rituximab product + chemotherapy followed by rituximab product monotherapy n = 694 All Grades % Grades 3 to 5 % All Grades % Grades 3 to 5 % Injury, Poisoning and Procedural Complications Infusion-Related Reaction Except where noted, individual events that meet the definition of "infusion-related reaction" are excluded from Table 11 above, as they are already included in the grouped term "Infusion-Related Reaction". The most common individual terms within the grouped term "Infusion-Related Reaction" in decreasing order of frequency are nausea, chills, pyrexia and vomiting. 72 12 60 8 Blood and Lymphatic System Disorders Neutropenia Includes adverse reactions reported as infusion-related reactions. 53 49 47 41 Thrombocytopenia 14 7 8 3 Infections and Infestations Upper Respiratory Tract Infection 50 3 43 1 Herpesvirus Infection 18 3 14 1 Pneumonia 14 7 12 6 Respiratory, Thoracic and Mediastinal Disorders Cough 35 < 1 28 < 1 Gastrointestinal Disorders Constipation 32 < 1 29 < 1 Diarrhea 30 3 26 2 Nervous System Disorders Headache 18 < 1 15 < 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 16 0 14 < 1 Psychiatric Disorders Insomnia 15 < 1 12 < 1 Metabolism and Nutrition Disorders Decreased Appetite 14 < 1 12 < 1 Skin and Subcutaneous Tissue Disorders Pruritus 11 < 1 9 0 Infusion-related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion. Neutropenia includes neutropenia, agranulocytosis, granulocytopenia, and neutrophil count decreased. Febrile neutropenia includes febrile neutropenia, neutropenic infection, neutropenic sepsis, and febrile bone marrow aplasia. Thrombocytopenia includes thrombocytopenia and platelet count decreased. Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, upper respiratory tract infection, rhinovirus infection, and all terms containing: laryngitis, nasopharyngitis, pharyngitis, rhinitis, tonsillitis, and sinusitis with the exception of sinobronchitis. Herpesvirus infection includes all terms containing "herpes" or "varicella." Pneumonia includes all terms containing "pneumonia," bacterial, pneumonia haemophilus, pneumonia pneumococcal, pneumonia fungal, pneumocystis jirovecii infection, lung infection, and lung infiltration. Diarrhea includes diarrhea, defecation urgency, frequent bowel movement, and all terms containing "gastroenteritis". Headache includes all terms containing "headache" and migraine. Insomnia includes all terms containing "insomnia" and sleep disorder. Pruritus includes pruritus and pruritus generalized. During the monotherapy period, the common adverse reactions (incidence ≥ 10%) observed at least 2% more with GAZYVA were upper respiratory tract infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%), and herpesvirus infection (13%). Table 12 summarizes treatment-emergent laboratory abnormalities during treatment and follow-up. The Grade 3 to 4 abnormalities reported at least 2% more in the GAZYVA arm were lymphopenia, leukopenia, neutropenia, thrombocytopenia, and hyperuricemia. Patients in the GAZYVA arm, as compared to the rituximab product arm, had higher incidences of Grade 4 neutropenia (38% vs. 30%, respectively), Grade 4 lymphopenia (33% vs. 22%), and Grade 4 leukopenia (17% vs. 12%). Table 12 New or Worsening Laboratory Abnormalities (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM) Laboratory Abnormalities Includes lab abnormalities, reported throughout treatment and follow-up, that were new or worsening, or worsening from baseline unknown. GAZYVA+ chemotherapy followed by GAZYVA monotherapy n = 691 Rituximab product + chemotherapy followed by rituximab product monotherapy n = 694 All Grades % Grades 3 to 4 % All Grades % Grades 3 to 4 % Hematology Lymphopenia 97 83 95 67 Leukopenia 92 49 89 39 Neutropenia 84 59 76 50 Thrombocytopenia 68 11 50 4 Chemistry ALT increased 50 3 43 2 AST increased 44 1 41 1 Hypophosphatemia 36 5 33 5 Hypoalbuminemia 33 1 25 1 Hypoproteinemia 32 0 30 0 Hypocalcemia 32 1 26 1 Hyperuricemia 28 28 22 22 Hyponatremia 26 4 20 3 Hyperkalemia 23 1 17 1 Hypernatremia 16 < 1 13 0 In the monotherapy phase, new-onset Grade 3 or 4 neutropenia was reported in 21% of patients in the GAZYVA arm (Grade 4, 10%) and 17% of patients in the rituximab product arm (Grade 4, 9%). GAZELLE Study GAZELLE (NCT03817853) is a single-arm study designed to characterize the safety of GAZYVA administered as a shortened-duration infusion (approximately 90 minutes) in patients with previously untreated FL. All patients received GAZYVA at the standard infusion rate with premedication during Cycle 1. If no Grade 3 or higher IRR occurred with any infusion during Cycle 1, GAZYVA was administered over approximately 90 minutes in Cycle 2 and subsequent cycles. The primary safety measure was the proportion of patients who experienced Grade 3 or higher IRRs with the 90-minute infusion at Cycle 2. GAZYVA was administered in combination with CHOP, CVP or bendamustine for 6 to 8 cycles (induction), followed by monotherapy for up to 2 years. Of the 113 patients treated with GAZYVA, 99 (88%) received the 90-minute infusion starting in Cycle 2. In total, 97% of patients who received GAZYVA at either a standard or shorter infusion duration received premedication in Cycle 2. IRRs were observed in 63% of patients throughout induction (including IRRs observed after standard-duration infusion). In cycle 1, 58% of patients developed IRRs with the standard infusion rate (Grade ≥3 IRR, 5%). Of the patients who received the 90-minute infusion, 10% had IRRs of any grade in Cycle 2, with 8% and 2% of patients having a Grade 1 IRR or Grade 2 IRR, respectively. Following Cycle 2, one (1%) patient experienced a Grade 3 IRR, which occurred after the 90-minute infusion at Cycle 5. Lupus Nephritis The data below reflects exposure to GAZYVA administered intravenously in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis in the REGENCY and NOBILITY studies, up to week 76. REGENCY (NCT04221477) is a Phase III study which included 136 patients treated with GAZYVA plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids [ see Clinical Studies (14.3) ]. NOBILITY (NCT02550652) is a Phase II study which included 64 patients treated with GAZYVA plus standard therapy consisting of MMF/mycophenolic acid (MPA) and corticosteroids. The most common adverse reactions (incidence ≥ 5% in the GAZYVA arm) were upper respiratory tract infection, COVID-19, urinary tract infection, bronchitis, pneumonia, infusion related reactions and neutropenia. The most common serious adverse reactions in the GAZYVA arm were: COVID-19 (11 patients [5.5%]), pneumonia (9 patients [4.5%]), neutropenia (7 patients [3.5%]), urinary tract infections (5 patients [2.5%]) and infusion-related reactions (1 patient [0.5%]). No serious adverse reactions were reported for bronchitis, herpes simplex and upper respiratory tract infections. Two fatal adverse reactions of COVID-19 were reported in the GAZYVA arm. Adverse reaction rates are presented in Table 13 . Table 13 Adverse Reactions in Adults with Active Lupus Nephritis Treated with GAZYVA Versus Placebo (≥ 2% Greater in the GAZYVA Arm) in REGENCY and NOBILITY Studies Body System Adverse Reactions GAZYVA + standard therapy n = 200 Placebo + standard therapy n = 193 All Grades (%) Grades 3-5(%) All Grades (%) Grades 3-5 (%) Infections and Infestations Upper Respiratory Tract Infection 29 0 24 0 COVID-19 23 5 Includes 2 fatal events in the GAZYVA arm and 1 fatal event in the placebo arm 16 0.5 Urinary Tract Infection 21 3 18 4 Bronchitis 14 0 8 0.5 Pneumonia 10 2 6 2 Herpes Simplex 3 0 0 0 Injury, Poisoning and Procedural Complications Infusion Related Reaction 14 2 10 0.5 Blood and Lymphatic System Disorders Neutropenia 14 7 6 0.5 Specific Adverse Reactions Infusion-Related Reactions Chronic Lymphocytic Leukemia The incidence of IRRs in the CLL11 study was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 IRRs was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1,000 mg and < 1% thereafter. No Grade 3 or 4 IRRs were reported beyond the first 1,000 mg infused. Of the first 53 patients receiving GAZYVA in CLL11, 47 (89%) experienced an IRR. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1,000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2.2) ] . Non-Hodgkin Lymphoma Overall, 67% of patients in the GADOLIN study experienced an IRR (all grades) during treatment with GAZYVA in combination with bendamustine. The incidence of Grade 3 to 4 IRRs in GADOLIN was 11%. In Cycle 1, the incidence of IRRs (all grades) was 53% in patients receiving GAZYVA in combination with bendamustine of which 34 (9%) were Grade 3 to 4 in severity. In patients receiving GAZYVA in combination with bendamustine, the incidence of IRRs was highest on Day 1 (37%), and gradually decreased on Days 2, 8 and 15 (23%, 6% and 4%, respectively). During Cycle 2, the incidence of IRRs was 24% in patients receiving GAZYVA in combination with bendamustine and decreased with subsequent cycles. During GAZYVA monotherapy in GADOLIN, IRRs (all grades) were observed in 8% of patients. One Grade 3 and no Grade 4 IRRs were reported during GAZYVA monotherapy. Overall, 2% of patients in GADOLIN experienced an IRR leading to discontinuation of GAZYVA. In GALLIUM, 72% of patients in the GAZYVA treated arm experienced an IRR (all grades). The incidence of Grade 3 to 4 IRRs for these patients was 12%. In Cycle 1, the incidence of IRRs (all grades) was 62% in the GAZYVA treated arm with Grade 3 to 4 IRRs reported in 10%. The incidence of IRRs (all grades) was highest on Day 1 (60%) and decreased on Days 8 and 15 (9% and 6%, respectively). During Cycle 2, the incidence of IRRs (all grades) in the GAZYVA treated arm was 13% and decreased with subsequent cycles. During GAZYVA monotherapy treatment in GALLIUM, IRRs (all grades) were observed in 9% of patients. Overall, 1% of patients in GALLIUM experienced an IRR leading to discontinuation of GAZYVA. In GAZELLE, 10% of patients with FL experienced IRRs of any grade at Cycle 2 when GAZYVA was administered over approximately 90 minutes. Lupus Nephritis In the pooled REGENCY and NOBILITY studies, infusion-related reactions (IRRs) were reported in 14% of patients in the GAZYVA arm versus 10% of patients in the placebo arm. IRRs in both arms were predominantly Grade 1-2 and occurred during or after the first infusion. Grade 3-4 IRRs were reported in 1.5% of patients in the GAZYVA arm vs 0.5% of patients in the placebo arm. All Grade 3-4 events occurred during or after either the first or second infusion. The incidence of IRRs in the GAZYVA arm decreased from 11% during the first infusion to 3% during the second infusion, decreasing further with subsequent infusions to 0.5% during the sixth infusion. The severity of IRRs in the GAZYVA arm also decreased with subsequent infusions with 1% patients reporting Grade 3-4 IRRs during the first infusion and 0.5% patients reporting Grade 3-4 IRRs during the second infusion. In subsequent infusions all IRRs were Grade 1-2 in severity. No Grade 5 IRRs were reported [see Warnings and Precautions (5.3) ]. In the REGENCY study, most common IRR signs or symptoms included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia. Neutropenia Chronic Lymphocytic Leukemia The incidence of neutropenia reported as an adverse reaction in CLL11 was 38% in the GAZYVA treated arm and 32% in the rituximab product treated arm, with the incidence of serious adverse reactions being 1% and < 1%, respectively ( Table 7 ). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab product treated arm. Non-Hodgkin Lymphoma The incidence of neutropenia in GADOLIN was higher in the GAZYVA plus bendamustine arm (37%) compared to the arm treated with bendamustine alone (30%). Cases of prolonged neutropenia (3%) and late onset neutropenia (8%) were also reported in the GAZYVA plus bendamustine arm. The incidence of neutropenia was higher during treatment with GAZYVA in combination with bendamustine (30%) compared to the GAZYVA monotherapy treatment phase (13%). The incidence of neutropenia in GALLIUM was higher in the GAZYVA treated arm (53%) compared to the rituximab product treated arm (47%). Cases of prolonged neutropenia (1%) and late onset neutropenia (4%) were also reported in the GAZYVA treated arm. The incidence of neutropenia was higher during treatment with GAZYVA in combination with chemotherapy (45%) compared to the GAZYVA monotherapy treatment phase (20%). Lupus Nephritis In the pooled REGENCY and NOBILITY studies, neutropenia and related adverse reactions (i.e., leukopenia, lymphopenia, lymphocyte count decreased, febrile neutropenia, and neutrophil count decreased) were reported in 14% of patients in the GAZYVA arm versus 6% of patients in the placebo arm. Grade 3-4 neutropenia was reported in 7% of patients treated with GAZYVA versus 0.5% of patients in the placebo arm. Neutropenia and related adverse reactions resolved/improved spontaneously or with use of granulocyte colony-stimulating factors in 96% of patients [see Warnings and Precautions (5.7) ]. Infection Chronic Lymphocytic Leukemia The incidence of infections was similar between GAZYVA and rituximab product treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab product treated arm experienced an infection, with Grade 3 to 4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms. Non-Hodgkin Lymphoma The incidence of infection in GADOLIN was 68% in the GAZYVA plus bendamustine arm and 59% in the bendamustine arm, with Grade 3 to 4 events reported in 20% and 16%, respectively. Fatal events were reported in 3% of patients in the GAZYVA plus bendamustine arm and 3% in the bendamustine arm. The incidence of infections in GALLIUM was 82% in the GAZYVA treated arm and 73% in the rituximab product treated arm, with Grade 3 to 4 events reported in 21% and 17%, respectively. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm. The incidence of Grade 3 to 4 infections in the GAZYVA and rituximab product treated arms was lower in patients receiving GCSF prophylaxis (14%; 16%) compared with patients not receiving GCSF prophylaxis (24%; 18%). The incidence of fatal infections in patients receiving GCSF prophylaxis in the GAZYVA and rituximab product treated arms was 2% and 0%, respectively, and was 2% and < 1% in patients not receiving GCSF prophylaxis. Lupus Nephritis In the pooled REGENCY and NOBILITY studies, infections were reported in 72% of patients in the GAZYVA arm versus 62% of patients in the placebo arm. The most frequently reported infections were upper and lower respiratory tract infections. Grade 3-5 infections were reported in 11% of patients in the GAZYVA arm versus 10% of patients in the placebo arm. Fatal infection events were reported in 1% of patients in the GAZYVA arm versus 0.5% of patients in the placebo arm [see Warnings and Precautions (5.6) ]. Thrombocytopenia Chronic Lymphocytic Leukemia The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab product treated arm (7%), with the incidence of Grade 3 to 4 events being 10% and 3%, respectively ( Table 7 ). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle was 11% in the GAZYVA and 3% in the rituximab product treated arms, with Grade 3 to 4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab product and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1. Non-Hodgkin Lymphoma The incidence of thrombocytopenia in GADOLIN was lower in the GAZYVA plus bendamustine arm (15%) compared to the arm treated with bendamustine alone (25%). The incidence of hemorrhagic events in GAZYVA plus bendamustine treated patients compared to bendamustine alone was 12% and 11%, respectively. Grade 3 to 4 hemorrhagic events were similar in both treatment arms (4% in the GAZYVA plus bendamustine arm and 2% in the bendamustine arm). In GALLIUM, thrombocytopenia was reported as an adverse reaction in 14% of the GAZYVA treated arm and 8% of the rituximab product treated arm, with the incidence of Grade 3 to 4 events being 7% and 3%, respectively. The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle was 9% in the GAZYVA and 3% in the rituximab product treated arms, with Grade 3 to 4 rates being 5% and 1%, respectively. In GALLIUM, both treatment arms had a 12% overall incidence of hemorrhagic events and a < 1% incidence of fatal hemorrhagic events. Disseminated Intravascular Coagulation In GALLIUM, DIC was reported as an adverse reaction in 0.3% of the GAZYVA treated patients. All events occurred within 1-2 days after the first infusion. Tumor Lysis Syndrome The incidence of Grade 3 or 4 tumor lysis syndrome in GAZYVA treated patients was 2% in CLL11, 0.5% in GADOLIN and 0.9% in GALLIUM. Musculoskeletal Disorders Chronic Lymphocytic Leukemia Adverse reactions related to musculoskeletal disorders (all events from the body system), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab product treated arm (18% vs. 15%). Non-Hodgkin Lymphoma In GADOLIN, adverse reactions related to musculoskeletal disorders (all events from the body system), including pain, have been reported in the GAZYVA plus bendamustine treated arm with higher incidence than in the bendamustine alone arm (44% vs. 30%). In GALLIUM, musculoskeletal disorders were reported in 54% of patients in the GAZYVA treated arm and 49% of patients in the rituximab product treated arm. Liver Enzyme Elevations Hepatic enzyme elevations have occurred in CLL patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT and ALP). The events occurred most frequently within 24–48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with IRRs or tumor lysis syndrome. In the CLL11 study, there was no clinically meaningful difference in overall hepatotoxicity adverse reactions between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent IRRs (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity. Gastrointestinal Perforation Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA, mainly in NHL. Worsening of Pre-existing Cardiac Conditions Fatal cardiac events have been reported in patients treated with GAZYVA. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of GAZYVA. 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. Immune/Autoimmune Events: Serum sickness

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