BRENTUXIMAB VEDOTIN: 9,724 Adverse Event Reports & Safety Profile

ADCETRIS (brentuximab vedotin) is a CD30-directed antibody and microtubule inhibitor conjugate consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10. Brentuximab vedotin has an approximate molecular weight of 153 kDa.

Approximately

4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis. ADCETRIS (brentuximab vedotin) for injection is supplied as a sterile, white to off-white, preservative-free lyophilized cake or powder in single-dose vials. Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6.

Structural

Formula

AND USAGE ADCETRIS is a CD30-directed antibody and microtubule inhibitor conjugate indicated for treatment of:

• Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine ( 1.1 ).
• Pediatric patients 2 years and older with previously untreated high risk classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide ( 1.2 ).
• Adult patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation ( 1.3 ).
• Adult patients with classical Hodgkin lymphoma (cHL) after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates ( 1.4 ).
• Adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified (NOS), in combination with cyclophosphamide, doxorubicin, and prednisone ( 1.5 ).
• Adult patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen ( 1.6 ).
• Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy ( 1.7 ).
• Adult patients with relapsed or refractory large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) NOS, DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy who are not eligible for auto-HSCT or CAR T-cell therapy, in combination with lenalidomide and a rituximab product ( 1.8 ).

1.1 Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (cHL), in Combination with Chemotherapy ADCETRIS is indicated for the treatment of adult patients with previously untreated Stage III or IV cHL, in combination with doxorubicin, vinblastine, and dacarbazine.

1.2 Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL), in Combination with Chemotherapy ADCETRIS is indicated for the treatment of pediatric patients 2 years and older with previously untreated high risk cHL, in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

1.3 Classical Hodgkin Lymphoma (cHL) Consolidation ADCETRIS is indicated for the treatment of adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.

1.4 Relapsed Classical Hodgkin Lymphoma (cHL) ADCETRIS is indicated for the treatment of adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.

1.5 Previously Untreated Systemic Anaplastic Large Cell Lymphoma (sALCL) or Other CD30-Expressing Peripheral T-cell Lymphomas (PTCL), in Combination with Chemotherapy ADCETRIS is indicated for the treatment of adult patients with previously untreated sALCL or other CD30-expressing PTCL, including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified (NOS), in combination with cyclophosphamide, doxorubicin, and prednisone.

1.6 Relapsed Systemic Anaplastic Large Cell Lymphoma (sALCL) ADCETRIS is indicated for the treatment of adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

1.7 Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL) or CD30-Expressing Mycosis Fungoides (MF) ADCETRIS is indicated for the treatment of adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy.

1.8 Relapsed or Refractory Large B-Cell Lymphoma (LBCL) ADCETRIS in combination with lenalidomide and a rituximab product is indicated for the treatment of adult patients with relapsed or refractory LBCL, including diffuse large B-cell lymphoma (DLBCL) NOS, DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), after two or more lines of systemic therapy who are not eligible for auto-HSCT or chimeric antigen receptor (CAR) T-cell therapy.

AND ADMINISTRATION

• Administer only as an intravenous infusion over 30 minutes ( 2.1 ).
• The recommended dosage as monotherapy for adult patients is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks ( 2.1 ).
• The recommended dosage in combination with chemotherapy for adult patients with previously untreated Stage III or IV cHL is 1.2 mg/kg up to a maximum of 120 mg every 2 weeks for a maximum of 12 doses ( 2.1 ).
• The recommended dosage in combination with chemotherapy for pediatric patients 2 years and older with previously untreated high risk cHL is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks for a maximum of 5 doses ( 2.1 ).
• The recommended dosage in combination with chemotherapy for adult patients with previously untreated PTCL is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks for 6 to 8 doses ( 2.1 ).
• The recommended dosage in combination with lenalidomide and a rituximab product for adult patients with relapsed or refractory LBCL is 1.2 mg/kg up to a maximum of 120 mg every 3 weeks ( 2.1 ).
• Avoid use in patients with severe renal impairment ( 2.2 )
• Reduce dose in patients with mild hepatic impairment; avoid use in patients with moderate or severe hepatic impairment ( 2.3 ).

2.1 Recommended Dosage The recommended ADCETRIS dosage is provided in Table 1 . Administer ADCETRIS as a 30-minute intravenous infusion. For recommended dosage for patients with renal or hepatic impairment, see Dosage and Administration (2.2 and 2.3 ) . For dosing instructions of combination agents administered with ADCETRIS, see Clinical Studies (14.1 , 14.2, and 14.5 ) and the manufacturer’s prescribing information.

Table

1: Recommended ADCETRIS Dosage Indication Recommended Dose The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Frequency and Duration Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma 1.2 mg/kg up to a maximum of 120 mg in combination with chemotherapy Administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity Pediatric patients with previously untreated high risk classical Hodgkin lymphoma 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy Administer every 3 weeks with each cycle of chemotherapy for a maximum of 5 doses Adult patients with classical Hodgkin lymphoma consolidation 1.8 mg/kg up to a maximum of 180 mg Initiate ADCETRIS treatment within 4‑6 weeks post-auto-HSCT or upon recovery from auto-HSCT Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Adult patients with relapsed classical Hodgkin lymphoma 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until disease progression or unacceptable toxicity Adult patients with previously untreated systemic ALCL or other CD30-expressing peripheral T-cell lymphomas 1.8 mg/kg up to a maximum of 180 mg in combination with chemotherapy Administer every 3 weeks with each cycle of chemotherapy for 6 to 8 doses Adult patients with relapsed Systemic ALCL 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until disease progression or unacceptable toxicity Adult patients with relapsed primary cutaneous ALCL or CD30-expressing mycosis fungoides 1.8 mg/kg up to a maximum of 180 mg Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Adult patients with relapsed or refractory LBCL 1.2 mg/kg up to a maximum of 120 mg in combination with lenalidomide and rituximab Starting with cycle 2, rituximab intravenous treatment could be substituted with rituximab and hyaluronidase human via subcutaneous injection every 3 weeks. Administer every 3 weeks until disease progression, or unacceptable toxicity

2.2 Recommended Dosage in Patients with Renal Impairment No dosage adjustment is required for mild renal impairment (CrCL greater than 50‑80 mL/min) and moderate renal impairment (CrCL 30-50 mL/min). Avoid use in patients with severe (CrCL less than 30 mL/min) renal impairment <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> .

2.3 Recommended Dosage in Patients with Hepatic Impairment Adult patients with previously untreated Stage III or IV classical Hodgkin lymphoma Reduce the dosage of ADCETRIS to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks for patients with mild hepatic impairment (Child-Pugh A). Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> . Adult patients with relapsed or refractory LBCL Reduce the dosage of ADCETRIS to 0.9 mg/kg up to a maximum of 90 mg every 3 weeks for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate transaminase [AST] &gt; ULN, or total bilirubin &gt;1 to 1.5 × ULN and any AST). Avoid use in patients with moderate and severe hepatic impairment (total bilirubin &gt;1.5 × ULN) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> . Hepatic impairment is defined per the National Cancer Institute Organ Dysfunction Working Group. All other indications Reduce the dosage of ADCETRIS to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks for patients with mild hepatic impairment (Child-Pugh A). Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

2.4 Recommended Prophylactic Medications In adult patients with previously untreated Stage III or IV cHL who are treated with ADCETRIS + doxorubicin, vinblastine, and dacarbazine (AVD), administer G‑CSF beginning with Cycle 1. In pediatric patients with previously untreated high risk cHL who are treated with ADCETRIS + doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (AVEPC), administer G-CSF beginning with Cycle 1. In adult patients with previously untreated PTCL who are treated with ADCETRIS + cyclophosphamide, doxorubicin, and prednisone (CHP), administer G-CSF beginning with Cycle 1. In adult patients with relapsed or refractory LBCL who are treated with ADCETRIS + lenalidomide + rituximab, administer G-CSF beginning with Cycle 1.

2.5 Dosage Modifications for Adverse Reactions Table 2: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Adult Patients <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1, 5.3)]</span> Recommended ADCETRIS Dosage from Table 1 The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Monotherapy or Combination Therapy Severity Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)

Version

5.

Dosage Modification Peripheral Neuropathy

1.2 mg/kg up to a maximum of 120 mg every 2 weeks In combination with chemotherapy Grade 2 Reduce dose to 0.9 mg/kg up to a maximum of 90 mg every 2 weeks.

Grade

3 Hold ADCETRIS dosing until improvement to Grade 2 or lower. Restart at 0.9 mg/kg up to a maximum of 90 mg every 2 weeks. Consider modifying the dose of other neurotoxic chemotherapy agents.

Grade

4 Discontinue dosing. 1.2 mg/kg up to a maximum of 120 mg every 3 weeks In combination with lenalidomide and rituximab Grade 2 Sensory neuropathy: If resolves to Grade 1 or lower before the next scheduled dose, resume at the same dose level.

If Grade

2 persists at the next scheduled dose, reduce one dose level. Motor neuropathy: Reduce dosage to 0.9 mg/kg up to a maximum of 90 mg every 3 weeks.

Grade

3 Sensory neuropathy: Hold ADCETRIS dosing until improvement to Grade 2 or lower, then restart treatment at a reduced dosage of 0.9 mg/kg up to a maximum of 90 mg every 3 weeks. Motor neuropathy: Discontinue dosing.

Grade

4 Discontinue dosing. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks As monotherapy New or worsening Grade 2 or 3 Hold dosing until improvement to baseline or Grade 1. Restart at 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade

4 Discontinue dosing. In combination with chemotherapy Grade 2 Sensory neuropathy: Continue treatment at same dose. Motor neuropathy: Reduce dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Grade

3 Sensory neuropathy: Reduce dose to 1.2 mg/kg, up to a maximum of 120 mg every 3 weeks. Motor neuropathy: Discontinue dosing.

Grade

4 Discontinue dosing.

Neutropenia

1.2 mg/kg up to a maximum of 120 mg every 2 weeks In combination with chemotherapy Grade 3 or 4 Administer G‑CSF prophylaxis for subsequent cycles for patients not receiving primary G‑CSF prophylaxis. 1.2 mg/kg up to a maximum of 120 mg every 3 weeks In combination with lenalidomide and rituximab Grade 3 or 4 Hold dosing until improvement to baseline or Grade 2 or lower. Reduce/discontinue lenalidomide dose per prescribing information. Administer G-CSF prophylaxis for subsequent cycles for patients not receiving primary G-CSF prophylaxis. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks In combination with chemotherapy Grade 3 or 4 Administer G-CSF prophylaxis in subsequent cycles for patients not receiving primary G-CSF prophylaxis. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks As monotherapy Grade 3 or 4 Hold dosing until improvement to baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles.

Recurrent Grade

4 despite G‑CSF prophylaxis Consider discontinuation or dose reduction to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Table

3: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Pediatric Patients Recommended ADCETRIS Dosage from Table 1 The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg.

Severity Dosage Modification Peripheral Neuropathy

Peripheral neuropathy was assessed using the Balis scale. 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Grade 2 Reduce dose of vincristine per prescribing information. Continue dosing with ADCETRIS. If neuropathy improves to Grade ≤1 by day 8 of next cycle, then resume vincristine at full dose.

Grade

3 Discontinue vincristine.

First

Occurrence: Hold ADCETRIS dosing until improvement to ≤ Grade 2 then restart at 1.2 mg/kg up to a maximum of 120 mg.

Second

Occurrence: Hold until improvement to ≤ Grade 2 then restart at 0.8 mg/kg up to a maximum of 80 mg.

Third

Occurrence: Discontinue ADCETRIS.

Grade

4 Discontinue ADCETRIS and vincristine.

Neutropenia

1.8 mg/kg up to a maximum of 180 mg every 3 weeks Grade 3 or 4 Reduce dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks in patients who are unable to start a cycle >5 weeks after the start of the previous cycle (>2-week delay) due to neutropenia.

2.6 Instructions for Preparation and Administration Administration

• Administer ADCETRIS as an intravenous infusion only.
• Do not mix ADCETRIS with, or administer as an infusion with, other medicinal products. Reconstitution
• Follow procedures for proper handling and disposal of hazardous drugs 1 .
• Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
• Determine the number of 50 mg vials needed based on the patient’s weight and the prescribed dose [see Dosage and Administration (2.1) ].
• Reconstitute each 50 mg vial of ADCETRIS with 10.5 mL of Sterile Water for Injection to yield a single-dose solution containing 5 mg/mL brentuximab vedotin.
• Direct the stream toward the wall of vial and not directly at the cake or powder.
• Gently swirl the vial to aid dissolution. DO NOT SHAKE .
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates.
• Following reconstitution, dilute immediately into an infusion bag. If not diluted immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) and use within 24 hours of reconstitution. DO NOT FREEZE.
• Discard any unused portion left in the vial. Dilution
• Calculate the required volume of 5 mg/mL reconstituted ADCETRIS solution needed.
• Withdraw this amount from the vial and immediately add it to an infusion bag containing 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection or Lactated Ringer's Injection to achieve a final concentration of 0.4 mg/mL to 1.8 mg/mL brentuximab vedotin.
• Gently invert the bag to mix the solution.
• Following dilution, infuse the ADCETRIS solution immediately. If not used immediately, store the solution refrigerated at 2°C to 8°C (36°F to 46°F) and use within 24 hours of reconstitution. DO NOT FREEZE.

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions (6.1) ] . Concomitant use with bleomycin due to pulmonary toxicity (4) .

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:

• Peripheral Neuropathy [see Warnings and Precautions (5.1) ]
• Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.2) ]
• Hematologic Toxicities [see Warnings and Precautions (5.3) ]
• Serious Infections and Opportunistic Infections [see Warnings and Precautions (5.4) ]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.5) ] o Increased Toxicity in the Presence of Severe Renal Impairment [see Warnings and Precautions (5.6) ]
• Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see Warnings and Precautions (5.7) ]
• Hepatotoxicity [see Warnings and Precautions (5.8) ]
• Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.9) ]
• Pulmonary Toxicity [see Warnings and Precautions (5.10) ]
• Serious Dermatologic Reactions [see Warnings and Precautions (5.11) ]
• Gastrointestinal Complications [see Warnings and Precautions (5.12) ]
• Hyperglycemia [see Warnings and Precautions (5.13) ] The most common adverse reactions (≥20%) are peripheral neuropathy, nausea, fatigue, musculoskeletal pain, constipation, diarrhea, vomiting, pyrexia, upper respiratory tract infection, mucositis, abdominal pain, and rash. The most common laboratory abnormalities (≥20%) are decreased neutrophils, increased creatinine, decreased hemoglobin, decreased lymphocytes, increased glucose, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Seagen Inc. at 1-855-473-2436 or FDA at 1-800-FDA-1088 or www.fda.gov/Safety/MedWatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to ADCETRIS in 931 adult patients with cHL including 662 patients who received ADCETRIS in combination with chemotherapy in a randomized controlled trial, 269 who received ADCETRIS as monotherapy (167 in a randomized controlled trial and 102 in a single arm trial), and 296 pediatric patients with high risk cHL who received ADCETRIS in combination with chemotherapy. Data summarizing ADCETRIS exposure are also provided for 347 patients with T-cell lymphoma, including 223 patients with PTCL who received ADCETRIS in combination with chemotherapy in a randomized, double-blind, controlled trial; 58 patients with sALCL who received ADCETRIS monotherapy in a single-arm trial; and 66 patients with pcALCL or CD30-expressing MF who received ADCETRIS monotherapy in a randomized, controlled trial. ADCETRIS was administered intravenously at a dose of either 1.2 mg/kg every 2 weeks in combination with AVD, 1.8 mg/kg every 3 weeks in combination with AVEPC in pediatric patients, 1.8 mg/kg every 3 weeks in combination with CHP, or 1.8 mg/kg every 3 weeks as monotherapy. The most common adverse reactions (≥20%) with monotherapy in adult patients were peripheral neuropathy, fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, diarrhea, pyrexia, rash, and cough. The most common laboratory abnormalities (≥20%) with monotherapy in adult patients were decreased neutrophils, increased creatinine, increased glucose, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased lymphocytes, decreased hemoglobin, and decreased platelets. The most common adverse reactions (≥20%) with combination therapy in adult patients were peripheral neuropathy, nausea, fatigue, musculoskeletal pain, constipation, diarrhea, mucositis, vomiting, abdominal pain, pyrexia, alopecia, upper respiratory tract infection, and rash. The most common laboratory abnormalities (≥20%) with combination therapy in adult patients were decreased neutrophils, increased creatinine, decreased hemoglobin, decreased lymphocytes, increased ALT, increased AST, increased glucose, and increased uric acid. The most common Grade ≥3 adverse reactions (≥5%) in combination with AVEPC in pediatric patients were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.

Previously Untreated

Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON-1) ADCETRIS in combination with AVD was evaluated for the treatment of previously untreated patients with Stage III or IV cHL in a randomized, open-label, multicenter clinical trial of 1334 patients. Patients were randomized to receive up to 6 cycles of ADCETRIS + AVD or ABVD on Days 1 and 15 of each 28‑day cycle. The recommended starting dose of ADCETRIS was 1.2 mg/kg intravenously over 30 minutes, administered approximately 1 hour after completion of AVD therapy. A total of 1321 patients received at least one dose of study treatment (662 ADCETRIS + AVD, 659 ABVD). The median number of treatment cycles in each study arm was 6 (range, 1–6); 76% of patients on the ADCETRIS + AVD arm received 12 doses of ADCETRIS [see Clinical Studies (14.1) ] .

After

75% of patients had started study treatment, the use of prophylactic G‑CSF was recommended with the initiation of treatment for all ADCETRIS + AVD treated patients, based on the observed rates of neutropenia and febrile neutropenia [see Dosage and Administration (2.2) ] .

Among

579 patients on the ADCETRIS + AVD arm who did not receive G‑CSF primary prophylaxis beginning with Cycle 1, 96% experienced neutropenia (21% with Grade 3; 67% with Grade 4), and 21% had febrile neutropenia (14% with Grade 3; 6% with Grade 4).

Among

83 patients on the ADCETRIS + AVD arm who received G-CSF primary prophylaxis beginning with Cycle 1, 61% experienced neutropenia (13% with Grade 3; 27% with Grade 4), and 11% experienced febrile neutropenia (8% with Grade 3; 2% with Grade 4). Serious adverse reactions were reported in 43% of ADCETRIS + AVD-treated patients and 27% of ABVD-treated patients. The most common serious adverse reactions in ADCETRIS + AVD-treated patients were febrile neutropenia (17%), pyrexia (7%), neutropenia and pneumonia (3% each). Adverse reactions that led to dose delays of one or more drugs in more than 5% of ADCETRIS + AVD-treated patients were neutropenia (21%) and febrile neutropenia (8%) [see Dosage and Administration (2.2) ] . Adverse reactions led to treatment discontinuation of one or more drugs in 13% of ADCETRIS + AVD-treated patients. Seven percent of patients treated with ADCETRIS + AVD discontinued due to peripheral neuropathy. There were 9 on-study deaths among ADCETRIS + AVD-treated patients; 7 were associated with neutropenia, and none of these patients had received G-CSF prior to developing neutropenia.

Table

4: Adverse Reactions Reported in ≥10% of ADCETRIS + AVD-Treated Patients in Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON‑1) AVD = doxorubicin, vinblastine, and dacarbazine ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine Events were graded using the NCI CTCAE Version

4.03 Events listed are those having a ≥5% difference in rate between treatment arms ADCETRIS + AVD Total N = 662 % of patients ABVD Total N = 659 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Blood and lymphatic system disorders Anemia Derived from laboratory values and adverse reaction data; data are included for clinical relevance irrespective of rate between arms 98 11 &lt;1 92 6 &lt;1 Neutropenia 91 20 62 89 31 42 Febrile neutropenia 19 13 6 8 6 2 Gastrointestinal disorders Constipation 42 2 - 37 &lt;1 &lt;1 Vomiting 33 3 - 28 1 - Diarrhea 27 3 &lt;1 18 &lt;1 - Stomatitis 21 2 - 16 &lt;1 - Abdominal pain 21 3 - 10 &lt;1 - Nervous system disorders Peripheral sensory neuropathy 65 10 &lt;1 41 2 - Peripheral motor neuropathy 11 2 - 4 &lt;1 - General disorders and administration site conditions Pyrexia 27 3 &lt;1 22 2 - Musculoskeletal and connective tissue disorders Bone pain 19 &lt;1 - 10 &lt;1 - Back pain 13 &lt;1 - 7 - - Skin and subcutaneous tissue disorders Rashes, eruptions and exanthems Grouped term includes rash maculo-papular, rash macular, rash, rash papular, rash generalized, and rash vesicular. 13 &lt;1 &lt;1 8 &lt;1 - Respiratory, thoracic and mediastinal disorders Dyspnea 12 1 - 19 2 - Investigations Decreased weight 22 &lt;1 - 6 &lt;1 - Increased alanine aminotransferase 10 3 - 4 &lt;1 - Metabolism and nutrition disorders Decreased appetite 18 &lt;1 - 12 &lt;1 - Psychiatric disorders Insomnia 19 &lt;1 - 12 &lt;1 - Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL)

Study

7: AHOD1331 The safety of ADCETRIS was evaluated in Study 7: AHOD1331 [see Clinical Studies (14.1) ] . The study included pediatric patients with previously untreated high risk cHL. Patients received ADCETRIS plus AVEPC chemotherapy at 1.8 mg/kg intravenously over 30 minutes prior to other chemotherapy in 21-day cycles (n = 296) or ABVE-PC in 21-day cycles (n = 297). Among patients who received ADCETRIS in combination with AVEPC chemotherapy, the median number of treatment cycles was 5 (range, 1-5). Serious adverse reactions occurred in 22% of patients who received ADCETRIS plus AVEPC chemotherapy. Serious adverse reactions in >2% of patients included hypotension (3%) and febrile neutropenia (3%).

Table

5: Grade 3 or 4 Adverse Reactions Reported in ≥2% of ADCETRIS + AVEPC Treated Pediatric Patients with Previously Untreated High Risk Classical Hodgkin Lymphoma in Study 7: AHOD1331 ADCETRIS + AVEPC Total N = 296 % of patients ABVE-PC Total N = 297 % of patients System Organ Class Preferred Term Grade 3 Grade 4 Grade 3 Grade 4 Blood and lymphatic system disorders Anemia 35 1.7 28 2 Febrile neutropenia 28 3.4 31

1.7 Lymphopenia 13 11 8 18 Thrombocytopenia Includes thrombocytopenia and platelet count decreased 10 22 11 16 Neutropenia 8 43 4.4 36 Gastrointestinal disorders Stomatitis 10 - 7 - Nausea 3.7 - 2 - Vomiting 3.7 - 1.3 - Diarrhea 2.4 - 0.3 - Colitis 2 0.3 1 - Infections and infestations Infections Includes sepsis, device related infection, skin infection, enterocolitis infectious, pneumonia, appendicitis, cellulitis, urinary tract infection, candida infection, mucosal infection, vaginal infection, wound infection, anorectal infection, arteritis infective, bacteremia, catheter site infection, clostridium difficile colitis, gastroenteritis norovirus, gingivitis, H1N1 influenza, herpes simplex reactivation, infective myositis, klebsiella bacteremia, klebsiella sepsis, meningitis, esophageal infection, oral candidiasis, osteomyelitis, otitis media, septic shock, serratia infection, sinusitis, soft tissue infection, staphylococcal infection, vulvitis 9 2.7 7

3.4 Nervous system disorders Peripheral sensory neuropathy 6 - 4.4 - Metabolism and nutrition disorders Hypokalemia 5 0.7 6 1 Hyponatremia 3.4 - 3 - Decreased appetite 2.7 - 1.7 - Dehydration 2.7 - 1 - Hepatobiliary disorders Alanine aminotransferase increased 3.7 0.3 2.7

0.3 General disorders and administration site conditions Infusion-related reactions Includes anaphylactic reaction, hypersensitivity, drug hypersensitivity, infusion-related reaction, and bronchospasm 3 1 5 1 Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA) ADCETRIS was studied in 329 patients with cHL at high risk of relapse or progression post-auto-HSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 ADCETRIS, 160 placebo) received at least one dose of study treatment. The median number of treatment cycles in each study arm was 15 (range, 1–16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV), varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PJP) post-auto-HSCT. Overall, 312 patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0–20) and 319 patients (98%) received PJP prophylaxis with a median duration of 6.5 months (range, 0–20). Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (14%), peripheral motor neuropathy (7%), acute respiratory distress syndrome (1%), paresthesia (1%), and vomiting (1%). Serious adverse reactions were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were pneumonia (4%), pyrexia (4%), vomiting (3%), nausea (2%), hepatotoxicity (2%), and peripheral sensory neuropathy (2%).

Table

6: Adverse Reactions Reported in ≥10% in ADCETRIS-Treated Patients with Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA) Events were graded using the NCI CTCAE Version 4 ADCETRIS Total N = 167 % of patients Placebo Total N = 160 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Blood and lymphatic system disorders Neutropenia Derived from laboratory values and adverse reaction data 78 30 9 34 6 4 Thrombocytopenia 41 2 4 20 3 2 Anemia 27 4 - 19 2 - Nervous system disorders Peripheral sensory neuropathy 56 10 - 16 1 - Peripheral motor neuropathy 23 6 - 2 1 - Headache 11 2 - 8 1 - Infections and infestations Upper respiratory tract infection 26 - - 23 1 - General disorders and administration site conditions Fatigue 24 2 - 18 3 - Pyrexia 19 2 - 16 - - Chills 10 - - 5 - - Gastrointestinal disorders Nausea 22 3 - 8 - - Diarrhea 20 2 - 10 1 - Vomiting 16 2 - 7 - - Abdominal pain 14 2 - 3 - - Constipation 13 2 - 3 - - Respiratory, thoracic and mediastinal disorders Cough 21 - - 16 - - Dyspnea 13 - - 6 - 1 Investigations Weight decreased 19 1 - 6 - - Musculoskeletal and connective tissue disorders Arthralgia 18 1 - 9 - - Muscle spasms 11 - - 6 - - Myalgia 11 1 - 4 - - Skin and subcutaneous tissue disorders Pruritus 12 1 - 8 - - Metabolism and nutrition disorders Decreased appetite 12 1 - 6 - - Relapsed Classical Hodgkin Lymphoma (Study 1) ADCETRIS was studied in 102 patients with cHL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 9 cycles (range, 1–16) [see Clinical Studies (14.1) ] . Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (16%) and peripheral sensory neuropathy (13%) [see Dosage and Administration (2.3) ] . Adverse reactions led to treatment discontinuation in 20% of ADCETRIS-treated patients. Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy (6%) and peripheral motor neuropathy (3%). Serious adverse reactions were reported in 25% of ADCETRIS-treated patients. The most common serious adverse reactions were peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Table

7: Adverse Reactions Reported in ≥10% of Patients with Relapsed Classical Hodgkin Lymphoma (Study 1) Events were graded using the NCI CTCAE Version 3.0 cHL Total N = 102 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Blood and lymphatic system disorders Neutropenia Derived from laboratory values and adverse reaction data 54 15 6 Anemia 33 8 2 Thrombocytopenia 28 7 2 Lymphadenopathy 11 - - Nervous system disorders Peripheral sensory neuropathy 52 8 - Peripheral motor neuropathy 16 4 - Headache 19 - - Dizziness 11 - - General disorders and administration site conditions Fatigue 49 3 - Pyrexia 29 2 - Chills 13 - - Infections and infestations Upper respiratory tract infection 47 - - Gastrointestinal disorders Nausea 42 - - Diarrhea 36 1 - Abdominal pain 25 2 1 Vomiting 22 - - Constipation 16 - - Skin and subcutaneous tissue disorders Rash 27 - - Pruritus 17 - - Alopecia 13 - - Night sweats 12 - - Respiratory, thoracic and mediastinal disorders Cough 25 - - Dyspnea 13 1 - Oropharyngeal pain 11 - - Musculoskeletal and connective tissue disorders Arthralgia 19 - - Myalgia 17 - - Back pain 14 - - Pain in extremity 10 - - Psychiatric disorders Insomnia 14 - - Anxiety 11 2 - Metabolism and nutrition disorders Decreased appetite 11 - - Previously Untreated Systemic Anaplastic Large Cell Lymphoma or Other CD30-Expressing Peripheral T-Cell Lymphomas (Study 6, ECHELON-2) ADCETRIS in combination with CHP was evaluated in patients with previously untreated, CD30-expressing PTCL in a multicenter randomized, double-blind, double dummy, actively controlled trial. Patients were randomized to receive ADCETRIS + CHP or CHOP for 6 to 8, 21-day cycles. ADCETRIS was administered on Day 1 of each cycle, with a starting dose of 1.8 mg/kg intravenously over 30 minutes, approximately 1 hour after completion of CHP [see Clinical Studies (14.2) ] . The trial required hepatic transaminases ≤3 times upper limit of normal (ULN), total bilirubin ≤1.5 times ULN, and serum creatinine ≤2 times ULN and excluded patients with Grade 2 or higher peripheral neuropathy. A total of 449 patients were treated (223 with ADCETRIS + CHP, 226 with CHOP), with 6 cycles planned in 81%. In the ADCETRIS + CHP arm, 70% of patients received 6 cycles, and 18% received 8 cycles. Primary prophylaxis with G-CSF was administered to 34% of ADCETRIS + CHP-treated patients and 27% of CHOP-treated patients. Fatal adverse reactions occurred in 3% of patients in the A+CHP arm and in 4% of patients in the CHOP arms, most often from infection. Serious adverse reactions were reported in 38% of ADCETRIS + CHP- treated patients and 35% of CHOP-treated patients. Serious adverse reactions occurring in >2% of ADCETRIS + CHP-treated patients included febrile neutropenia (14%), pneumonia (5%), pyrexia (4%), and sepsis (3%). The most common adverse reactions observed ≥2% more in recipients of ADCETRIS + CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Other common (≥10%) adverse reactions observed ≥2% more with ADCETRIS + CHP were febrile neutropenia, abdominal pain, decreased appetite, dyspnea, edema, cough, dizziness, hypokalemia, decreased weight, and myalgia. In recipients of ADCETRIS + CHP, adverse reactions led to dose delays of ADCETRIS in 25% of patients, dose reduction in 9% (most often for peripheral neuropathy), and discontinuation of ADCETRIS with or without the other components in 7% (most often from peripheral neuropathy and infection).

Table

8: Adverse Reactions Reported in ≥10% of ADCETRIS + CHP-Treated Patients with Previously Untreated, CD30-Expressing PTCL (Study 6: ECHELON-2) The table includes a combination of grouped and ungrouped terms. CHP = cyclophosphamide, doxorubicin, and prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone Events were graded using the NCI CTCAE Version

4.03 ADCETRIS + CHP Total N = 223 % of patients CHOP Total N = 226 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Blood and lymphatic system disorders Anemia Derived from laboratory values and adverse reaction data. Laboratory values were obtained at the start of each cycle and end of treatment. 66 13 &lt;1 59 12 &lt;1 Neutropenia 59 17 22 58 14 22 Lymphopenia 51 18 1 57 19 2 Febrile neutropenia 19 17 2 16 12 4 Thrombocytopenia 17 3 3 13 3 2 Gastrointestinal disorders Nausea 46 2 - 39 2 - Diarrhea 38 6 - 20 &lt;1 - Mucositis 30 2 &lt;1 27 3 - Constipation 29 &lt;1 &lt;1 30 1 - Vomiting 26 &lt;1 - 17 2 - Abdominal pain 17 1 - 13 &lt;1 - Nervous system disorders Peripheral neuropathy 52 3 &lt;1 55 4 - Headache 15 &lt;1 - 15 &lt;1 - Dizziness 13 - - 9 &lt;1 - General disorders and administration site conditions Fatigue or asthenia 35 2 - 29 2 - Pyrexia 26 1 &lt;1 19 - - Edema 15 &lt;1 - 12 &lt;1 - Infections and infestations Upper respiratory tract infection 14 &lt;1 - 15 &lt;1 - Skin and subcutaneous disorders Alopecia 26 - - 25 1 - Rash 16 1 &lt;1 14 1 - Musculoskeletal and connective tissue disorders Myalgia 11 - - 8 - - Respiratory, thoracic and mediastinal disorders Dyspnea 15 2 - 11 2 - Cough 13 &lt;1 - 10 - - Metabolism and nutrition disorders Decreased appetite 17 1 - 12 1 - Hypokalemia 12 4 - 8 &lt;1 &lt;1 Investigations Weight decreased 12 &lt;1 - 8 &lt;1 - Psychiatric disorders Insomnia 11 - - 14 - - Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2) ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 7 cycles (range, 1–16) <span class="opacity-50 text-xs">[see Clinical Studies (14.2 )]</span> . Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (12%) and peripheral sensory neuropathy (7%) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Adverse reactions led to treatment discontinuation in 19% of ADCETRIS-treated patients. The adverse reaction that led to treatment discontinuation in 2 or more patients was peripheral sensory neuropathy (5%). Serious adverse reactions were reported in 41% of ADCETRIS-treated patients. The most common serious adverse reactions were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Table

9: Adverse Reactions Reported in ≥10% of Patients with Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2) sALCL Total N = 58 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Events were graded using the NCI CTCAE Version

3.0 Blood and lymphatic system disorders Neutropenia Derived from laboratory values and adverse reaction data 55 12 9 Anemia 52 2 - Thrombocytopenia 16 5 5 Lymphadenopathy 10 - - Nervous system disorders Peripheral sensory neuropathy 53 10 - Headache 16 2 - Dizziness 16 - - General disorders and administration site conditions Fatigue 41 2 2 Pyrexia 38 2 - Chills 12 - - Pain 28 - 5 Edema peripheral 16 - - Infections and infestations Upper respiratory tract infection 12 - - Gastrointestinal disorders Nausea 38 2 - Diarrhea 29 3 - Vomiting 17 3 - Constipation 19 2 - Skin and subcutaneous tissue disorders Rash 31 - - Pruritus 19 - - Alopecia 14 - - Dry skin 10 - - Respiratory, thoracic and mediastinal disorders Cough 17 - - Dyspnea 19 2 - Musculoskeletal and connective tissue disorders Myalgia 16 2 - Back pain 10 2 - Pain in extremity 10 2 2 Muscle spasms 10 2 - Psychiatric disorders Insomnia 16 - - Metabolism and nutrition disorders Decreased appetite 16 2 - Investigations Weight decreased 12 3 - Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-Expressing Mycosis Fungoides (Study 4: ALCANZA) ADCETRIS was studied in 131 patients with pcALCL or CD30-expressing MF requiring systemic therapy in a randomized, open-label, multicenter clinical trial in which the recommended starting dose and schedule was ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks or physician’s choice of either methotrexate 5 to 50 mg orally weekly or bexarotene 300 mg/m 2 orally daily. Of the 131 enrolled patients, 128 (66 brentuximab vedotin, 62 physician’s choice) received at least one dose of study treatment. The median number of treatment cycles in the ADCETRIS treatment arm was 12 (range, 1–16) compared to 3 (range, 1–16) and 6 (range, 1–16) in the methotrexate and bexarotene arms, respectively. Twenty-four (24) patients (36%) in the ADCETRIS-treatment arm received 16 cycles compared to 5 patients (8%) in the physician’s choice arm <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were peripheral sensory neuropathy (15%) and neutropenia (6%) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Adverse reactions led to treatment discontinuation in 24% of ADCETRIS-treated patients. The most common adverse reaction that led to treatment discontinuation was peripheral neuropathy (12%). Serious adverse reactions were reported in 29% of ADCETRIS-treated patients. The most common serious adverse reactions were cellulitis (3%) and pyrexia (3%).

Table

10: Adverse Reactions Reported in ≥10% ADCETRIS-Treated Patients with pcALCL or CD30-Expressing MF (Study 4: ALCANZA)

Adcetris

Total N = 66 % of patients Physician’s Choice Physician’s choice of either methotrexate or bexarotene Total N = 62 % of patients Body System Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Events were graded using the NCI CTCAE Version

4.03 Blood and lymphatic system disorders Anemia Derived from laboratory values and adverse reaction data 62 - - 65 5 - Neutropenia 21 3 2 24 5 - Thrombocytopenia 15 2 2 2 - - Nervous system disorders Peripheral sensory neuropathy 45 5 - 2 - - Gastrointestinal disorders Nausea 36 2 - 13 - - Diarrhea 29 3 - 6 - - Vomiting 17 2 - 5 - - General disorders and administration site conditions Fatigue 29 5 - 27 2 - Pyrexia 17 - - 18 2 - Edema peripheral 11 - - 10 - - Asthenia 11 2 - 8 - 2 Skin and subcutaneous tissue disorders Pruritus 17 2 - 13 3 - Alopecia 15 - - 3 - - Rash maculo-papular 11 2 - 5 - - Pruritus generalized 11 2 - 2 - - Metabolism and nutrition disorders Decreased appetite 15 - - 5 - - Musculoskeletal and connective tissue disorders Arthralgia 12 - - 6 - - Myalgia 12 - - 3 - - Respiratory, thoracic and mediastinal disorders Dyspnea 11 - - - - - Relapsed or Refractory Large B-Cell Lymphoma (Study 8: ECHELON-3) The safety of ADCETRIS in combination with lenalidomide and a rituximab product was evaluated in ECHELON-3, a randomized, multicenter, double-blind, placebo-controlled trial in patients with relapsed or refractory LBCL who had received at least 2 prior lines of systemic therapy and who were not eligible for HSCT or CAR T-cell therapy <span class="opacity-50 text-xs">[see Clinical Studies (14.5) ]</span> . Patients in the treatment arm (n = 112) received ADCETRIS, 1.2 mg/kg via intravenous infusion every 3 weeks, lenalidomide, and a rituximab product. Placebo replaced ADCETRIS in the placebo plus lenalidomide and rituximab arm (n = 116). The trial required an absolute neutrophil count ≥1,000/µL, platelet count ≥50,000/µL, creatinine clearance (CrCL) ≥45 mL/min, hepatic transaminases ≤3 times the upper limit of normal (ULN), and bilirubin &lt;1.5 times ULN. The trial excluded patients having Eastern Cooperative Oncology Group (ECOG) performance status above 2, active central nervous system (CNS) lymphoma, and Grade 2 or higher peripheral neuropathy. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 98% of patients in the ADCETRIS plus lenalidomide and rituximab arm and 91% of patients in the lenalidomide and rituximab arm. The median age was 71 years (range: 21 to 89 years); 44% of patients were female; 53% were White, 26% were Asian, and 4% were Hispanic or Latino. There were no Black or African American patients enrolled in ECHELON-3. Among patients who received ADCETRIS, the median number of treatment cycles was 5 (range, 1-34). Serious adverse reactions occurred in 60% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product. Serious adverse reactions that occurred in &gt;2% of patients included pneumonia (21%), COVID-19 (13%, includes COVID-19 pneumonia), sepsis (9%), febrile neutropenia (7%), hemorrhage (3.6%), urinary tract infection (3.6%), thrombocytopenia (2.7%) and upper respiratory tract infection (2.7%). Fatal adverse reactions occurred in 12% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product, including COVID-19 (4.5%, includes COVID-19 pneumonia), pneumonia (3.6%), and sepsis (1.8%). Adverse reactions led to dose reduction of ADCETRIS in 6% of patients, all due to peripheral neuropathy. Adverse reactions leading to dose delay of ADCETRIS in more than 5% of patients included neutropenia (23%), COVID-19 (13%), pneumonia (8%), and thrombocytopenia (8%). Adverse reactions led to discontinuation of ADCETRIS in 20% of patients. Adverse reactions that led to treatment discontinuation in 3 or more patients included peripheral neuropathy (4.5%) and pneumonia (2.7%).

Table

11: Adverse Reactions Reported in ≥10% of ADCETRIS in Combination with Lenalidomide and a Rituximab Product-Treated Patients in Relapsed or Refractory LBCL (Study 8: ECHELON-3) ADCETRIS + Lenalidomide + Rituximab N = 112 Placebo + Lenalidomide + Rituximab N = 116 Body System Adverse Reaction All Grades % Grade 3-4 % All Grades % Grade 3-4 % General disorders and Administration Site Conditions Fatigue Includes other related terms. 46 10 29 5 Pyrexia 15 1.8 15

0.9 Gastrointestinal disorders Diarrhea 31 4.5 23

1.7 Constipation 17 1.8 18 0 Nausea 15 0.9 16

0.9 Abdominal pain 12 1.8 12

1.7 Stomatitis 11 0 7 0 Nervous system disorders Peripheral neuropathy Includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, neuropathy peripheral, hypoesthesia oral, oral dysesthesia, neuralgia, paresthesia oral. 27 5 21 0 Infections and Infestations COVID-19 Includes COVID-19 and COVID-19 pneumonia. 27 13 16 8 Pneumonia Includes pneumonia, COVID-19 pneumonia, atypical pneumonia, bronchopulmonary aspergillosis, lung infiltration, organizing pneumonia, pneumocystis jirovecii pneumonia, pneumonia bacterial, pneumonia fungal, pneumonia streptococcal, pneumonia viral. 27 21 10 9 Upper respiratory tract infection 12 2.7 5 0 Skin and subcutaneous tissue disorders Rash 27 2.7 16

0.9 Pruritus 17 0 6 0 Renal and urinary disorders Renal insufficiency 20 3.6 14

4.3 Respiratory, thoracic and mediastinal disorders Cough 17 0 9 0 Dyspnea 12 0.9 14

2.6 Metabolism and nutrition disorders Decreased appetite 17 0.9 9 0 Investigations Weight decreased 13 0.9 5

0.9 Clinically relevant adverse reactions in &lt;10% of patients who received ADCETRIS in combination with lenalidomide and a rituximab product include febrile neutropenia, edema, hypotension, urinary tract infection, sepsis, respiratory tract infection, vomiting, back pain, dizziness, arthralgia, herpes virus infection, bone pain, atrial fibrillation or flutter, lower respiratory tract infection, and cardiac failure.

Table

12: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients Who Received ADCETRIS + Lenalidomide + Rituximab-Treated Patients in Relapsed or Refractory LBCL (Study 8: ECHELON-3) ADCETRIS + Lenalidomide + Rituximab N = 112 The denominator used to calculate the rate varied from 105 to 107 in the ADCETRIS + lenalidomide + rituximab arm, and from 97 to 103 in the placebo + lenalidomide + rituximab arm based on the number of patients with a baseline value and at least one post-treatment value. Placebo + Lenalidomide + Rituximab N = 116 Laboratory Abnormality All Grades (%)

Grade

3-4 (%)

All

Grades (%)

Grade

3-4 (%)

Hematology

Neutrophils decreased 77 49 63 42 Lymphocytes decreased 65 38 53 30 Platelets decreased 65 29 54 18 Hemoglobin decreased 54 19 49 14 Chemistry Alanine aminotransferase increased 31 0.9 17 0 Potassium decreased 31 7 29

2.9 Albumin decreased 29 0.9 25 1 Creatinine increased 26 2.8 23 0 Calcium decreased 21 0.9 7 0 Additional Important Adverse Reactions Infusion reactions In studies of ADCETRIS as monotherapy (Studies 1–4), 13% of ADCETRIS-treated patients experienced infusion-related reactions. The most common adverse reactions in Studies 1–4 (≥3% in any study) associated with infusion-related reactions were chills (4%), nausea (3–4%), dyspnea (2–3%), pruritus (2–5%), pyrexia (2%), and cough (2%).

Grade

3 events were reported in 5 of the 51 ADCETRIS-treated patients who experienced infusion-related reactions. In a study of ADCETRIS in combination with AVD (Study 5, ECHELON-1), infusion-related reactions were reported in 57 patients (9%) in the ADCETRIS + AVD-treated arm.

Grade

3 events were reported in 3 of the 57 patients treated with ADCETRIS + AVD who experienced infusion-related reactions. The most common adverse reaction (≥2%) associated with infusion-related reactions was nausea (2%). In a study of ADCETRIS in combination with CHP (Study 6, ECHELON-2), infusion-related reactions were reported in 10 patients (4%) in the ADCETRIS + CHP-treated arm: 2 (1%) patients with events that were Grade 3 or higher events, and 8 (4%) patients with events that were less than Grade 3. In a study of ADCETRIS in combination with lenalidomide and rituximab (Study 8, ECHELON-3), Grade 1 or 2 infusion-related reactions were reported in 6 patients (5%) in the ADCETRIS + lenalidomide + rituximab arm. Pulmonary toxicity In a trial in patients with cHL that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. The concomitant use of ADCETRIS with bleomycin is contraindicated [see Contraindications (4) ]. In a study of ADCETRIS in combination with AVD (Study 5, ECHELON-1), non-infectious pulmonary toxicity events were reported in 12 patients (2%) in the ADCETRIS + AVD arm. These events included lung infiltration (6 patients) and pneumonitis (6 patients), or interstitial lung disease (1 patient). In a study of ADCETRIS in combination with CHP (Study 6, ECHELON-2), non-infectious pulmonary toxicity events were reported in 5 patients (2%) in the ADCETRIS + CHP arm; all 5 events were pneumonitis. Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS monotherapy.

In Study

3 (AETHERA), pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions During treatment in patients with relapsed or refractory cHL and relapsed or refractory systemic ALCL in Studies 1 and 2, two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment [see Warnings and Precautions (5.2) ]. Overall, a higher incidence of infusion-related reactions was observed in patients who developed persistently positive antibodies [see Clinical Pharmacology (12.6) ] .

6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of ADCETRIS. 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. Blood and lymphatic system disorders : febrile neutropenia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> . Gastrointestinal disorders : acute pancreatitis and gastrointestinal complications (including fatal outcomes) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.12) ]</span> . Hepatobiliary disorders : hepatotoxicity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.8) ]</span> . Infections : PML <span class="opacity-50 text-xs">[see Boxed Warning , Warnings and Precautions (5.9) ]</span> , serious infections and opportunistic infections <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . Metabolism and nutrition disorders : hyperglycemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.13) ]</span> . Respiratory, thoracic and mediastinal disorders : noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10) and Adverse Reactions (6.1) ]</span> . Skin and subcutaneous tissue disorders : Toxic epidermal necrolysis, including fatal outcomes <span class="opacity-50 text-xs">[see Warnings and Precautions (5.11) ]</span> .

AND PRECAUTIONS

• Peripheral neuropathy : Monitor patients for neuropathy and institute dose modifications accordingly ( 5.1 ).
• Anaphylaxis and infusion reactions : If an infusion reaction occurs, interrupt the infusion. If anaphylaxis occurs, immediately discontinue the infusion ( 5.2 ).
• Hematologic toxicities : Monitor complete blood counts. Monitor for signs of infection. Manage using dose delays and growth factor support ( 5.3 ).
• Serious infections and opportunistic infections : Closely monitor patients for the emergence of bacterial, fungal or viral infections ( 5.4 ).
• Tumor lysis syndrome : Closely monitor patients with rapidly proliferating tumor or high tumor burden ( 5.5 ).
• Hepatotoxicity : Monitor liver enzymes and bilirubin ( 5.8 ).
• Pulmonary toxicity : Monitor patients for new or worsening symptoms ( 5.10 ).
• Serious dermatologic reactions : Discontinue if Stevens-Johnson syndrome or toxic epidermal necrolysis occurs ( 5.11 ).
• Gastrointestinal complications : Monitor patients for new or worsening symptoms ( 5.12 ).
• Hyperglycemia : Monitor patients for new or worsening hyperglycemia. Manage with anti-hyperglycemic medications as clinically indicated ( 5.13 ).
• Embryo-Fetal toxicity : Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception ( 5.14 , 8.1 , 8.3 ).

5.1 Peripheral Neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In studies of ADCETRIS as monotherapy, 62% of patients experienced any grade of peripheral neuropathy. The median time to onset was 3 months (range, 0–12). Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at their last evaluation. The median time from onset to resolution or improvement was 5 months (range, 0–45). Of the patients with ongoing neuropathy (38%), 71% had Grade 1, 24% had Grade 2, and 4% had Grade 3. In ECHELON-1 (Study 5), 67% of patients treated with ADCETRIS + AVD experienced any grade of peripheral neuropathy. The median time to onset of any grade was 2 months (range, 0–7), of Grade 2 was 3 months (range, 0–6) and of Grade 3 was 4 months (range, &lt;1–7). By the time of the primary analysis, 43% of affected patients had complete resolution, 24% had partial improvement, and 33% had no improvement at their last evaluation. The median time from onset to resolution or improvement of any grade was 2 months (range, 0–32). At the updated analysis of ECHELON-1, 72% of the patients who experienced peripheral neuropathy had complete resolution, 14% had partial improvement, and 14% had no improvement. The median time to partial improvement was 2.9 months (range, &lt;1–50), and the median time to complete resolution was 6.6 months (range, &lt;1–67). Of the patients with ongoing neuropathy (28%), 57% had Grade 1, 30% had Grade 2, 12% had Grade 3, and &lt;1% had Grade 4. In ECHELON-2 (Study 6), 52% of patients treated with ADCETRIS + CHP experienced new or worsening peripheral neuropathy of any grade (by maximum grade, 34% Grade 1, 15% Grade 2, 3% Grade 3, &lt;1% Grade 4). The peripheral neuropathy was predominantly sensory (94% sensory, 16% motor) and had a median onset time of 2 months (range, &lt;1–5). At last evaluation, 50% had complete resolution of neuropathy, 12% had partial improvement, and 38% had no improvement. The median time to resolution or improvement overall was 4 months (range, 0–45). Of patients with ongoing neuropathy (50%), 72% had Grade 1, 25% had Grade 2, and 3% had Grade 3. In AHOD1331 (Study 7), 20% of pediatric patients treated with ADCETRIS + AVEPC experienced peripheral neuropathy of any grade (7% Grade 3, &lt;1% Grade 4). Peripheral neuropathy was predominantly sensory. Of the patients who experienced peripheral neuropathy, 81% experienced sensory neuropathy and 29% experienced motor neuropathy. In ECHELON-3 (Study 8), 27% of patients treated with ADCETRIS + lenalidomide + a rituximab product experienced peripheral neuropathy of any grade (by maximum grade, 14% Grade 1, 7% Grade 2, 5% Grade 3). The peripheral neuropathy was predominantly sensory and had a median onset time of 3 months (range, &lt;1-10). Peripheral neuropathy resulted in ADCETRIS dose reduction in 6% of treated patients, and permanent discontinuation in 4.5%. At last evaluation, 7% of the patients who experienced peripheral neuropathy had complete resolution of neuropathy, 10% had partial improvement, and 83% had no improvement. The median time to resolution was 2 months (range &lt;1-3). The median time to improvement was 4 months (range, 3-4). Of patients who experienced peripheral neuropathy, 93% had ongoing peripheral neuropathy (47% had Grade 1, 33% had Grade 2, and 13% had Grade 3). Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Adverse Reactions (6.1) ]</span> .

5.2 Anaphylaxis and Infusion Reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

5.3 Hematologic Toxicities Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Start primary prophylaxis with G‑CSF beginning with Cycle 1 for adult patients who receive ADCETRIS in combination for previously untreated Stage III or IV cHL or previously untreated PTCL or relapsed or refractory LBCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Adverse Reactions (6.1) ]</span> . Monitor complete blood counts prior to each dose of ADCETRIS. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever.

If Grade

3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses [see Dosage and Administration (2.2 , 2.3) ] .

5.4 Serious Infections and Opportunistic Infections Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Monitor patients closely during treatment for the emergence of possible bacterial, fungal, or viral infections.

5.5 Tumor Lysis Syndrome Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

5.6 Increased Toxicity in the Presence of Severe Renal Impairment The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment [creatinine clearance (CrCL) &lt;30 mL/min] <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) ]</span>.

5.7 Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment The frequency of ≥ Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span> .

5.8 Hepatotoxicity Fatal and serious cases of hepatotoxicity have occurred in patients receiving ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

5.9 Progressive Multifocal Leukoencephalopathy Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

5.10 Pulmonary Toxicity Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

5.11 Serious Dermatologic Reactions Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

5.12 Gastrointestinal Complications Fatal and serious events of acute pancreatitis have been reported. Other fatal and serious gastrointestinal (GI) complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.

5.13 Hyperglycemia Serious events of hyperglycemia, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported in ADCETRIS-treated patients. In studies of ADCETRIS monotherapy, 8% of patients experienced any grade hyperglycemia, with 6% experiencing Grade 3 or 4 hyperglycemia. The median time to onset for any grade or Grade 3 or 4 was 1 month (range, 0-10). Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.

5.14 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. In animal reproduction studies, brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability, and fetal malformations at maternal exposures that were similar to the clinical dose of 1.8 mg/kg every three weeks. Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise male patients with female partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS. Advise a pregnant woman of the potential risk to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .

INTERACTIONS Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE) ( 7.1 ).

7.1 Effect of Other Drugs on ADCETRIS CYP3A4 Inhibitors: Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, which may increase the risk of adverse reaction. Closely monitor adverse reactions when ADCETRIS is given concomitantly with strong CYP3A4 inhibitors.