ADCETRIS SIDE EFFECTS

SIDE EFFECTS

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

• Peripheral Neuropathy.
• Anaphylaxis and Infusion Reactions.
• Hematologic Toxicities.
• Serious Infections and Opportunistic Infections.
• Tumor Lysis Syndrome.
• Increased Toxicity in the Presence of Severe Renal Impairment.
• Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment.
• Hepatotoxicity.
• Progressive Multifocal Leukoencephalopathy.
• Pulmonary Toxicity.
• Serious Dermatologic Reactions.
• Gastrointestinal Complications.
• Hyperglycemia.

Clinical Trial 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 patients with cHL including 662 patients who received ADCETRIS in combination with chemotherapy in a randomized controlled trial, and 269 who received ADCETRIS as monotherapy (167 in a randomized controlled trial and 102 in a single arm trial). 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 CHP, or 1.8 mg/kg every 3 weeks as monotherapy.

The most common adverse reactions (≥20%) with monotherapy were peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia.

The most common adverse reactions (≥20%) in combination with AVD were peripheral neuropathy, neutropenia, nausea, constipation, vomiting, fatigue, diarrhea, pyrexia, alopecia, decreased weight, abdominal pain, anemia, and stomatitis.

The most common adverse reactions (≥20%) in combination with CHP were anemia, neutropenia, peripheral neuropathy, lymphopenia, nausea, diarrhea, fatigue or asthenia, mucositis, constipation, alopecia, pyrexia, and vomiting.

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.

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. 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, regardless of causality, 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%). 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 1: Adverse Reactions Reported in ≥10% of ADCETRIS + AVD-Treated Patients in Previously Untreated Stage III or IV Classical Hodgkin Lymphoma (Study 5: ECHELON-1)

Body System Adverse Reaction	ADCETRIS + AVD Total N = 662 % of patients			ABVD Total N = 659 % of patients
	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 exanthemsa	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	–
* Derived from laboratory values and adverse reaction data; data are included for clinical relevance irrespective of rate between arms a Grouped term includes rash maculo-papular, rash macular, rash, rash papular, rash generalized, and rash vesicular. 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

 

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.

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%). 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 2: Adverse Reactions Reported in ≥10% in ADCETRIS-Treated Patients with Classical Hodgkin Lymphoma Post-Auto-HSCT Consolidation (Study 3: AETHERA)

Body System Adverse Reaction	ADCETRIS Total N = 167 % of patients			Placebo Total N = 160 % of patients
	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	–	–
*Derived from laboratory values and adverse reaction data Events were graded using the NCI CTCAE Version 4

 

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).

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (16%) and peripheral sensory neuropathy (13%). 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 2: Adverse Reactions Reported in ≥10% of Patients with Relapsed Classical Hodgkin Lymphoma (Study 1)

Body System Adverse Reaction	cHL Total N = 102 % of patients
	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	–	–
*Derived from laboratory values and adverse reaction data Events were graded using the NCI CTCAE Version 3.0

 

Previously Untreated Systemic Anaplastic Large Cell Lymphoma Or Other CD30Expressing Peripheral T-Cell Lymphomas (Study 6, ECHELON-2)

ADCETRIS in combination with CHP was evaluated in patients with previously untreated, CD30expressing 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. 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 3: Adverse Reactions Reported in ≥10% of ADCETRIS + CHP-treated Patients with Previously Untreated, CD30-Expressing PTCL (Study 6: ECHELON-2)

Body System Adverse Reaction	ADCETRIS + CHP Total N = 223 % of patients			CHOP Total N = 226 % of patients
	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	–	–
* Derived from laboratory values and adverse reaction data. Laboratory values were obtained at the start of each cycle and end of treatment. 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

 

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).

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were neutropenia (12%) and peripheral sensory neuropathy (7%). 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 4: Adverse Reactions Reported in ≥10% of Patients with Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2)

Body System Adverse Reaction	sALCL Total N = 58 % of patients
	Any Grade	Grade 3	Grade 4
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	–
*Derived from laboratory values and adverse reaction data Events were graded using the NCI CTCAE Version 3.0

 

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.

Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients were peripheral sensory neuropathy (15%) and neutropenia (6%). 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 5: Adverse Reactions Reported in ≥10% ADCETRIS-Treated Patients with pcALCL or CD30-Expressing MF (Study 4: ALCANZA)

Body System Adverse Reaction	ADCETRIS Total N = 66 % of patients			Physician’s Choicea Total N = 62 % of patients
	Any Grade	Grade 3	Grade 4	Any Grade	Grade 3	Grade 4
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	–	–	–	–	–
*Derived from laboratory values and adverse reaction data a Physician’s choice of either methotrexate or bexarotene Events were graded using the NCI CTCAE Version 4.03

 

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.

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.

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.

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.

Gastrointestinal disorders: acute pancreatitis and gastrointestinal complications (including fatal outcomes).

Hepatobiliary disorders: hepatotoxicity.

Infections: PML, serious infections and opportunistic infections.

Metabolism and nutrition disorders: hyperglycemia.

Respiratory, thoracic and mediastinal disorders: noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and ARDS (some with fatal outcomes).

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADCETRIS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Patients with cHL and sALCL in Studies 1 and 2 were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescence immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 time points) and 30% developed transiently positive antibodies (positive at 1 or 2 post-baseline time points). The antibrentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies.

A total of 58 patient samples that were either transiently or persistently positive for antibrentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent (62%) of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.