Obinutuzumab

12.1 Mechanism of Action Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis. As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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

6 ADVERSE REACTIONS 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 %