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)]

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
* Derived from laboratory values and adverse reaction data; data are included for clinical relevance irrespective of rate between arms † Grouped term includes rash maculo-papular, rash macular, rash, rash papular, rash generalized, and rash vesicular.
	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*	98	11	<1	92	6	<1
Neutropenia*	91	20	62	89	31	42
Febrile neutropenia	19	13	6	8	6	2
Gastrointestinal disorders
Constipation	42	2	-	37	<1	<1
Vomiting	33	3	-	28	1	-
Diarrhea	27	3	<1	18	<1	-
Stomatitis	21	2	-	16	<1	-
Abdominal pain	21	3	-	10	<1	-
Nervous system disorders
Peripheral sensory neuropathy	65	10	<1	41	2	-
Peripheral motor neuropathy	11	2	-	4	<1	-
General disorders and administration site conditions
Pyrexia	27	3	<1	22	2	-
Musculoskeletal and connective tissue disorders
Bone pain	19	<1	-	10	<1	-
Back pain	13	<1	-	7	-	-
Skin and subcutaneous tissue disorders
Rashes, eruptions and exanthems†	13	<1	<1	8	<1	-
Respiratory, thoracic and mediastinal disorders
Dyspnea	12	1	-	19	2	-
Investigations
Decreased weight	22	<1	-	6	<1	-
Increased alanine aminotransferase	10	3	-	4	<1	-
Metabolism and nutrition disorders
Decreased appetite	18	<1	-	12	<1	-
Psychiatric disorders
Insomnia	19	<1	-	12	<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
* Includes thrombocytopenia and platelet count decreased † 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 ‡ Includes anaphylactic reaction, hypersensitivity, drug hypersensitivity, infusion-related reaction, and bronchospasm
	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*	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†	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‡	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 [see Clinical Studies (14.1)].

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%) [see Dosage and Administration (2.3)]. 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
* Derived from laboratory values and adverse reaction data
	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*	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
* Derived from laboratory values and adverse reaction data
	cHL Total N = 102 % of patients
Body System Adverse Reaction	Any Grade	Grade 3	Grade 4
Blood and lymphatic system disorders
Neutropenia*	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
* Derived from laboratory values and adverse reaction data. Laboratory values were obtained at the start of each cycle and end of treatment.
	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*	66	13	<1	59	12	<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	<1	-
Mucositis	30	2	<1	27	3	-
Constipation	29	<1	<1	30	1	-
Vomiting	26	<1	-	17	2	-
Abdominal pain	17	1	-	13	<1	-
Nervous system disorders
Peripheral neuropathy	52	3	<1	55	4	-
Headache	15	<1	-	15	<1	-
Dizziness	13	-	-	9	<1	-
General disorders and administration site conditions
Fatigue or asthenia	35	2	-	29	2	-
Pyrexia	26	1	<1	19	-	-
Edema	15	<1	-	12	<1	-
Infections and infestations
Upper respiratory tract infection	14	<1	-	15	<1	-
Skin and subcutaneous disorders
Alopecia	26	-	-	25	1	-
Rash	16	1	<1	14	1	-
Musculoskeletal and connective tissue disorders
Myalgia	11	-	-	8	-	-
Respiratory, thoracic and mediastinal disorders
Dyspnea	15	2	-	11	2	-
Cough	13	<1	-	10	-	-
Metabolism and nutrition disorders
Decreased appetite	17	1	-	12	1	-
Hypokalemia	12	4	-	8	<1	<1
Investigations
Weight decreased	12	<1	-	8	<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) [see Clinical Studies (14.2)].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (12%) and peripheral sensory neuropathy (7%) [see Dosage and Administration (2.3)]. 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
* Derived from laboratory values and adverse reaction data
Blood and lymphatic system disorders
Neutropenia*	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/m2 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 [see Clinical Studies (14.2)].

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were peripheral sensory neuropathy (15%) and neutropenia (6%) [see Dosage and Administration (2.3)]. 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* 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
* Physician’s choice of either methotrexate or bexarotene † Derived from laboratory values and adverse reaction data
Blood and lymphatic system disorders
Anemia†	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 [see Clinical Studies (14.5)].

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 <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 >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 %
* Includes other related terms. † Includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, hypoesthesia, neuropathy peripheral, hypoesthesia oral, oral dysesthesia, neuralgia, paresthesia oral. ‡ Includes COVID-19 and COVID-19 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.
General disorders and Administration Site Conditions
Fatigue*	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†	27	5	21	0
Infections and Infestations*
COVID-19‡	27	13	16	8
Pneumonia§	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 <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*		Placebo + Lenalidomide + Rituximab N = 116*
Laboratory Abnormality*	All Grades (%)	Grade 3-4 (%)	All Grades (%)	Grade 3-4 (%)
* 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.
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 [see Warnings and Precautions (5.3)].

Gastrointestinal disorders: acute pancreatitis and gastrointestinal complications (including fatal outcomes) [see Warnings and Precautions (5.12)].

Hepatobiliary disorders: hepatotoxicity [see Warnings and Precautions (5.8)].

Infections: PML [see Boxed Warning, Warnings and Precautions (5.9)], serious infections and opportunistic infections [see Warnings and Precautions (5.4)].

Metabolism and nutrition disorders: hyperglycemia [see Warnings and Precautions (5.13)].

Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes) [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)].

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes [see Warnings and Precautions (5.11)].

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