ADCETRIS is indicated for the treatment of adult patients with previously untreated Stage III or IV cHL, in combination with doxorubicin, vinblastine, and dacarbazine.

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.

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.

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.

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, in combination with cyclophosphamide, doxorubicin, and prednisone.

ADCETRIS is indicated for the treatment of adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

ADCETRIS is indicated for the treatment of adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy.

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 and 14.2) 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

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 [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.7)].

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.

Table 2: Dosage Modifications for Peripheral Neuropathy or Neutropenia in Adult 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	Monotherapy or Combination Therapy	Severity	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
1.8 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
1.8 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
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

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 [see References (15)].
• 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, USP, 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 at 2° to 8°C (36° 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, USP or Lactated Ringer's Injection, USP 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 at 2° to 8°C (36° to 46°F) and use within 24 hours of reconstitution. DO NOT FREEZE.

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 experienced peripheral neuropathy, 81% experienced sensory neuropathy and 29% experienced motor neuropathy.

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 [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

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.

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 with chemotherapy for previously untreated Stage III or IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

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)].

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.

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

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) <30 mL/min] [see Use in Specific Populations (8.6)].

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 [see Use in Specific Populations (8.7)].

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.

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.

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.

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.

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.

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.

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 [see Use in Specific Populations (8.1, 8.3)].

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, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia.

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

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
AnemiaDerived from laboratory values and adverse reaction data; data are included for clinical relevance irrespective of rate between arms	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 exanthemsGrouped term includes rash maculo-papular, rash macular, rash, rash papular, rash generalized, and rash vesicular.	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

	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
ThrombocytopeniaIncludes 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
InfectionsIncludes 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 reactionsIncludes 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 [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
	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
NeutropeniaDerived 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
NeutropeniaDerived 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
AnemiaDerived from laboratory values and adverse reaction data. Laboratory values were obtained at the start of each cycle and end of treatment.	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
Blood and lymphatic system disorders
NeutropeniaDerived 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/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 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
AnemiaDerived 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	-	-	-	-	-

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 [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)].

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)].

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.

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.

Risk Summary

There is no information regarding the presence of brentuximab vedotin in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child from ADCETRIS, including cytopenias and neurologic or gastrointestinal toxicities, advise patients that breastfeeding is not recommended during ADCETRIS treatment.

ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during ADCETRIS treatment and for 2 months after the last dose of ADCETRIS. Advise females to immediately report pregnancy [see Use in Specific Populations (8.1)].

Males

ADCETRIS may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during ADCETRIS treatment and for 4 months after the last dose of ADCETRIS [see Nonclinical Toxicology (13.1)].

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), ADCETRIS may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

Males

Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of ADCETRIS have been established in pediatric patients age 2 years and older with previously untreated high risk classical Hodgkin lymphoma in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide. The safety and effectiveness of ADCETRIS have not been established for all other indications [see Indications and Usage (1)].

Previously Untreated, High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Doxorubicin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide

The safety and effectiveness of ADCETRIS have been established in pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide chemotherapy.

Use of ADCETRIS for this indication is supported by evidence from Study 7: AHOD1331, a randomized study which included pediatric patients with previously untreated high risk cHL, including patients in the following age groups: 9 patients 3 to less than 6 years of age, 81 patients 6 to less than 12 years of age, and 345 patients 12 to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

The safety and efficacy of ADCETRIS have not been established for this indication in patients younger than 2 years.

Previously Untreated High Risk Classical Hodgkin Lymphoma (cHL) in Combination with Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Prednisone, and Dacarbazine

The safety and effectiveness of ADCETRIS in combination with etoposide (E), prednisone (P), and doxorubicin (A)/cyclophosphamide (C), prednisone (P), and dacarbazine (Dac) (AEPA/CAPDac) were assessed but have not been established based on a single arm, open-label trial (NCT01920932) in 77 patients, which included 48 pediatric patients age 6 to less than 17 with previously untreated high risk (IIB, IIIB, IVA, or IVB) cHL. No new safety signals were identified in this study.