Columvi

WARNING: CYTOKINE RELEASE SYNDROME Cytokine Release Syndrome (CRS), including serious or fatal reactions, can occur in patients receiving COLUMVI. Premedicate before each dose, and initiate treatment with the COLUMVI step-up dosing schedule to reduce the risk of CRS. Withhold COLUMVI until CRS resolves or permanently discontinue based on severity [see Dosage and Administration (2.1 , 2.2 , 2.3 , and 2.4) and Warnings and Precautions (5.1) ] . WARNING: CYTOKINE RELEASE SYNDROME See full prescribing information for complete boxed warning Cytokine Release Syndrome (CRS), including serious or fatal reactions, can occur in patients receiving COLUMVI. Premedicate before each dose, and initiate treatment with the COLUMVI step-up dosing schedule to reduce the risk of CRS. Withhold COLUMVI until CRS resolves or permanently discontinue based on severity. ( 2.1 , 2.2 , 2.3 , 2.4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Neurologic Toxicity : Can cause serious neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Monitor for neurologic toxicity; withhold or permanently discontinue based on severity. ( 5.2 ) Serious Infections : Can cause serious or fatal infections. Monitor patients for signs and symptoms of infection and treat appropriately. ( 5.3 ) Tumor Flare : Can cause serious tumor flare reactions. Monitor patients at risk for complications of tumor flare. ( 5.4 ) Embryo-Fetal Toxicity : May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Cytokine Release Syndrome COLUMVI can cause serious and fatal cytokine release syndrome (CRS) [see Adverse Reactions (6.1) ] . Among 145 patients who received COLUMVI, CRS occurred in 70%, with Grade 1 CRS developing in 52% of all patients, Grade 2 in 14%, Grade 3 in 2.8%, and Grade 4 in 1.4%. The most common manifestations of CRS included fever, tachycardia, hypotension, chills, and hypoxia. CRS occurred in 56% of patients after the 2.5 mg dose of COLUMVI, 35% after the 10 mg dose, 29% after the initial 30 mg target dose, and 2.8% after subsequent doses. With the first step-up dose of COLUMVI, the median time to onset of CRS (from the start of infusion) was 14 hours (range: 5 to 74 hours). CRS after any dose resolved in 98% of cases, with a median duration of CRS of 2 days (range: 1 to 14 days). Recurrent CRS occurred in 34% of all patients. CRS can first occur with the 10 mg dose; of 135 patients treated with the 10 mg dose of COLUMVI, 15 patients (11%) experienced their first CRS event with the 10 mg dose, of which 13 events were Grade 1, 1 event was Grade 2, and 1 event was Grade 3. Administer COLUMVI in a facility equipped to monitor and manage CRS. Initiate therapy according to the COLUMVI step-up dosing schedule to reduce the risk of CRS, administer pretreatment medications, and ensure adequate hydration [see Dosage and Administration (2.3) ] . Patients should be hospitalized during and for 24 hours after completing infusion of the 2.5 mg step-up dose. Patients who experienced any grade CRS during the 2.5 mg step-up dose should be hospitalized during and for 24 hours after completion of the 10 mg step-up dose. For subsequent doses, patients who experienced Grade ≥ 2 CRS with the previous infusion should be hospitalized during and for 24 hours after the next COLUMVI infusion [see Dosage and Administration (2.1 and 2.2) ] . At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold or permanently discontinue COLUMVI based on severity [see Dosage and Administration (2.4) ] . If CRS is refractory to management, consider other causes including hemophagocytic lymphohistiocytosis. 5.2 Neurologic Toxicity COLUMVI can cause serious and fatal neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity (ICANS) [see Adverse Reactions (6.1) ] . Among 145 patients who received COLUMVI, the most frequent neurologic toxicities of any grade were headache (10%), peripheral neuropathy (8%), dizziness or vertigo (7%), and mental status changes (4.8%, including confusional state, cognitive disorder, disorientation, somnolence, and delirium). Grade 3 or higher neurologic adverse reactions occurred in 2.1% of patients and included somnolence, delirium, and myelitis. Cases of ICANS of any grade occurred in 4.8% of patients. Coadministration of COLUMVI with other products that cause dizziness or mental status changes may increase the risk of neurologic toxicity. Optimize concomitant medications and hydration to avoid dizziness or mental status changes. Institute fall precautions as appropriate. Monitor patients for signs and symptoms of neurologic toxicity, evaluate, and provide supportive therapy; withhold or permanently discontinue COLUMVI based on severity [see Dosage and Administration (2.4) ] . Evaluate patients who experience neurologic toxicity such as tremors, dizziness, or adverse reactions that may impair cognition or consciousness promptly, including potential neurology evaluation. Advise affected patients to refrain from driving and/or engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurologic toxicity fully resolves. 5.3 Serious Infections COLUMVI can cause serious or fatal infections [see Adverse Reactions (6.1) ] . Serious infections were reported in 16% of patients, including Grade 3 or 4 infections in 10%, and fatal infections in 4.8% of patients. Grade 3 or higher infections reported in ≥ 2% of patients were COVID-19 infection (6%), including COVID-19 pneumonia, and sepsis (4.1%). Febrile neutropenia occurred in 3.4% of patients. COLUMVI can cause progressive multifocal leukoencephalopathy (PML), including fatal cases [see Adverse Reactions (6.1) ] . COLUMVI should not be administered to patients with an active infection. Administer antimicrobial prophylaxis according to guidelines. Monitor patients before and during COLUMVI treatment for infection, including for neurologic signs and symptoms of PML, and treat appropriately. Withhold or consider permanent discontinuation of COLUMVI based on severity [see Dosage and Administration (2.4) ] . 5.4 Tumor Flare COLUMVI can cause serious tumor flare [see Adverse Reactions (6.1) ] . Manifestations include localized pain and swelling at the sites of the lymphoma lesions and/or dyspnea from new pleural effusions. Tumor flare was reported in 12% of patients who received COLUMVI, including Grade 2 tumor flare in 4.8% of patients and Grade 3 tumor flare in 2.8%. Recurrent tumor flare occurred in two (12%) of the affected patients. Most tumor flare events occurred during Cycle 1, with a median time to first onset of 2 days (range: 1 to 16 days) after the first dose of COLUMVI. The median duration was 3.5 days (range: 1 to 35 days). Patients with bulky tumors or disease located in close proximity to airways or a vital organ should be monitored closely during initial therapy. Monitor for signs and symptoms of compression or obstruction due to mass effect secondary to tumor flare, and institute appropriate treatment. Withhold COLUMVI until tumor flare resolves [see Dosage and Administration (2.4) ] . 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, COLUMVI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COLUMVI and for 1 month after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurologic Toxicity [see Warnings and Precautions (5.2) ] Serious Infections [see Warnings and Precautions (5.3) ] Tumor Flare [see Warnings and Precautions (5.4) ] The most common (≥ 20%) adverse reactions, excluding laboratory abnormalities, are cytokine release syndrome, musculoskeletal pain, rash, and fatigue. The most common (≥ 20%) Grade 3 to 4 laboratory abnormalities are lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased. ( 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 practice. Relapsed or Refractory DLBCL, NOS or LBCL Arising from Follicular Lymphoma Study NP30179 The safety of COLUMVI was evaluated in Study NP30179, a multi-cohort, multicenter, single-arm clinical trial that included 154 adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy [see Clinical Studies (14.1) ] . The trial required an ECOG performance status of 0 or 1, absolute neutrophil count ≥ 1,500/µL, platelet count ≥ 75,000/µL independent of transfusion, serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CLcr) ≥ 50 mL/min, and hepatic transaminases ≤ 3 × ULN. The trial excluded patients with active or previous central nervous system (CNS) lymphoma or CNS disease, acute infection, recent infection requiring intravenous antibiotics, or prior allogeneic hematopoietic stem cell transplantation (HSCT). Patients received pretreatment with a single dose of obinutuzumab on Day 1 of Cycle 1 (seven days prior to start of COLUMVI). Following premedication, COLUMVI was administered by intravenous infusion according to the step-up dosing schedule with 2.5 mg on Day 8 of Cycle 1, and 10 mg on Day 15 of Cycle 1. Patients received the 30 mg COLUMVI dose by intravenous infusion on Day 1 of subsequent cycles for a maximum of 12 cycles (including step-up dosing). Each cycle was 21 days. Patients were hospitalized during and for 24 hours following completion of at least the first step-up dose. Of the 154 patients who initiated study treatment, 145 received COLUMVI; nine patients (6%) did not receive COLUMVI due to infection, progressive disease, or patient decision. Patients received a median of 5 cycles of COLUMVI with 30% receiving all 12 cycles of COLUMVI. Of patients who received COLUMVI, the median age was 66 years (range: 21 to 90 years); 66% were male; 77% were White, 4.8% were Asian, 1.4% were Black or African American, 6% were Hispanic or Latino. The main diagnoses were DLBCL, NOS and LBCL arising from follicular lymphoma. Serious adverse reactions occurred in 48% of patients who received COLUMVI. Serious adverse reactions in ≥ 2% of patients included CRS, COVID-19 infection, sepsis, and tumor flare. Fatal adverse reactions occurred in 5% of patients from COVID-19 infection (3.4%), sepsis (1.4%), and delirium (0.6%). Adverse reactions led to permanent discontinuation of COLUMVI in 7% of patients, including from infection, delirium, neutropenia, and CRS. Adverse reactions led to dose interruptions of COLUMVI in 19% of patients, most frequently (≥ 2%) from neutropenia and thrombocytopenia. The most common (≥ 20%) adverse reactions, excluding laboratory terms, were CRS, musculoskeletal pain, rash, and fatigue. The most common Grade 3 to 4 laboratory abnormalities (≥ 20%) were lymphocyte count decreased, phosphate decreased, neutrophil count decreased, uric acid increased, and fibrinogen decreased. Table 9 summarizes adverse reactions observed in Study NP30179. Table 9: Select Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179 Adverse Reactions COLUMVI N=145 All grades (%) Grade 3 or 4 (%) The table includes a combination of grouped and ungrouped terms. Adverse reactions were graded using NCI CTCAE version 4.03, with the exception of CRS, which was graded per ASTCT consensus criteria in most cases. Immune system disorders Cytokine release syndrome 70 4.1 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes musculoskeletal pain, back pain, bone pain, flank pain, myalgia, neck pain, and pain in extremity. 21 2.1 General disorders Fatigue Includes fatigue and asthenia. 20 1.4 Pyrexia 16 0 Edema Includes edema, edema peripheral, swelling face, and face edema. 10 0 Skin and subcutaneous tissue disorders Rash Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative, erythema, palmar erythema, pruritus, and rash erythematous. 20 1.4 Gastrointestinal disorders Constipation 14 0 Diarrhea 14 0 Nausea 10 0 Abdominal pain Includes abdominal pain, abdominal discomfort, and abdominal pain upper. 10 0 Neoplasms Tumor flare 12 2.8 Neurologic Disorders Headache 10 0 Clinically relevant adverse reactions occurring in < 10% of patients who received COLUMVI included infusion-related reaction, peripheral neuropathy, pneumonia, mental status changes, vomiting, tumor lysis syndrome, febrile neutropenia, upper respiratory tract infection, sepsis, herpes zoster infection, gastrointestinal hemorrhage, tremor, myelitis, and colitis. Table 10 summarizes laboratory abnormalities in Study NP30179. Table 10: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179 Laboratory Abnormality COLUMVI The denominator used to calculate the rate varied from 137 to 145 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grade 3 or 4 (%) Hematology Lymphocytes decreased 90 83 Hemoglobin decreased 72 8 Neutrophils decreased 56 26 Grade 4 neutrophil decrease occurred in 9% of patients. Platelets decreased 56 8 Chemistry Fibrinogen decreased 84 21 Phosphate decreased 69 28 Sodium decreased 49 7 Calcium decreased 48 2.1 Gamma-glutamyl transferase increased 33 9 Potassium decreased 32 6 Uric acid increased 23 23 Clinically relevant adverse reactions occurring in other clinical trials Immune system disorders : Hemophagocytic Lymphohistiocytosis Infections: Progressive Multifocal Leukoencephalopathy

<table ID="Tb9" width="85%"><caption>Table 9: Select Adverse Reactions (&#x2265; 10%) in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179</caption><col width="50%" align="left" valign="middle"/><col width="28%" align="center" valign="middle"/><col width="22%" align="center" valign="middle"/><thead><tr><th rowspan="2" styleCode="Lrule Rrule">Adverse Reactions</th><th colspan="2" styleCode="Rrule Botrule">COLUMVI N=145</th></tr><tr><th align="center" styleCode="Rrule">All grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">The table includes a combination of grouped and ungrouped terms. Adverse reactions were graded using NCI CTCAE version 4.03, with the exception of CRS, which was graded per ASTCT consensus criteria in most cases.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Immune system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cytokine release syndrome</td><td styleCode="Rrule">70</td><td styleCode="Rrule">4.1</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal pain<footnote>Includes musculoskeletal pain, back pain, bone pain, flank pain, myalgia, neck pain, and pain in extremity.</footnote></td><td styleCode="Rrule">21</td><td styleCode="Rrule">2.1</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">General disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Includes fatigue and asthenia.</footnote></td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">16</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Includes edema, edema peripheral, swelling face, and face edema.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote>Includes rash, rash pruritic, rash maculo-papular, dermatitis, dermatitis acneiform, dermatitis exfoliative, erythema, palmar erythema, pruritus, and rash erythematous.</footnote></td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">14</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain<footnote>Includes abdominal pain, abdominal discomfort, and abdominal pain upper.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Neoplasms</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Tumor flare</td><td styleCode="Rrule">12</td><td styleCode="Rrule">2.8</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Neurologic Disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Headache</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table ID="Tb10" width="85%"><caption>Table 10: Select Laboratory Abnormalities (&#x2265; 20%) That Worsened from Baseline in Patients with Relapsed or Refractory LBCL Who Received COLUMVI in Study NP30179</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th rowspan="2" styleCode="Lrule Rrule">Laboratory Abnormality</th><th colspan="2" styleCode="Rrule Botrule">COLUMVI<footnote>The denominator used to calculate the rate varied from 137 to 145 based on the number of patients with a baseline value and at least one post-treatment value.</footnote></th></tr><tr><th align="center" styleCode="Rrule">All Grades (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Lymphocytes decreased </td><td styleCode="Rrule">90</td><td styleCode="Rrule">83</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hemoglobin decreased</td><td styleCode="Rrule">72</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Neutrophils decreased</td><td styleCode="Rrule">56</td><td styleCode="Rrule">26<footnote>Grade 4 neutrophil decrease occurred in 9% of patients.</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Platelets decreased</td><td styleCode="Rrule">56</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fibrinogen decreased</td><td styleCode="Rrule">84</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Phosphate decreased </td><td styleCode="Rrule">69</td><td styleCode="Rrule">28</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Sodium decreased</td><td styleCode="Rrule">49</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Calcium decreased</td><td styleCode="Rrule">48</td><td styleCode="Rrule">2.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Gamma-glutamyl transferase increased </td><td styleCode="Rrule">33</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Potassium decreased</td><td styleCode="Rrule">32</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule Rrule"> Uric acid increased</td><td styleCode="Rrule">23</td><td styleCode="Rrule">23</td></tr></tbody></table>