ADCETRIS

1 INDICATIONS 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 i…

2 DOSAGE 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 patie…

5 WARNINGS 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, <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, <1–50), and the median time to complete resolution was 6.6 months (range, <1–67). Of the patients with ongoing neuropathy (28%), 57% had Grade 1, 30% had Grade 2, 12% had Grade 3, and <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, <1% Grade 4). The peripheral neuropathy was predominantly sensory (94% sensory, 16% motor) and had a median onset time of 2 months (range, <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, <1% Grade 4). Peripheral neuropathy was predominantly sensory. Of the patients who exper…

4 CONTRAINDICATIONS 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) .

7 DRUG 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 [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reaction. Closely monitor adverse reactions when ADCETRIS is given concomitantly with strong CYP3A4 inhibitors.

8.1 Pregnancy Risk Summary ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology (12.1) ] . In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations (see Data ). The available data from case reports on ADCETRIS use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Advise a pregnant woman of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with cHL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

6 ADVERSE 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 neutrop…