DOSING AND ADMINISTRATION GUIDE

Transcription

1 DOSING AND ADMINISTRATION GUIDE for ADCETRIS in classical Hodgkin lymphoma (chl) ADCETRIS is indicated for the treatment of: Previously untreated Stage III/IV chl Adult patients with previously untreated Stage III/IV chl in combination with chemotherapy chl post-auto-hsct consolidation Adult patients with chl at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-hsct) consolidation Relapsed chl 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 IMPORTANT SAFETY INFORMATION BOXED WARNING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients. Please see additional Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com

2 IMPORTANT SAFETY INFORMATION BOXED WARNING PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients. Contraindication ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation). Warnings and Precautions Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly. Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid. Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged ( 1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Administer G-CSF primary prophylaxis starting with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III/IV chl. Monitor complete blood counts prior to each ADCETRIS dose. 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 doses. Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections. Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden. Increased toxicity in the presence of severe renal impairment: The frequency of Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment. Please see full Prescribing Information, including BOXED WARNING, attached or at adcetrispro.com 02 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment. Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS. PML: 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, 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 PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement. Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy. Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious 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. Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. Important Safety Information continued on page 4.

3 IMPORTANT SAFETY INFORMATION (cont d) ABOUT ADCETRIS (brentuximab vedotin) Most Common ( 20%) Adverse Reactions ADCETRIS is a CD30-directed antibody-drug conjugate (ADC) consisting of three components: Neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia. The antibody, brentuximab, specific for CD301 Drug Interactions Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE). Use in Specific Populations Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use. Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS. The synthetic microtubule-disrupting agent, monomethyl auristatin E (MMAE), that induces target cell death1 A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1 INDICATIONS AND USAGE ADCETRIS is indicated for the treatment of: Previously untreated Stage III/IV chl Adult patients with previously untreated Stage III/IV chl in combination with chemotherapy1 chl post-auto-hsct consolidation Adult patients with chl at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-hsct) consolidation1 Relapsed chl 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 candidates1 CONTRAINDICATION ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (eg, interstitial infiltration and/or inflammation).1 Please see full Prescribing Information, including BOXED WARNING, attached or at adcetrispro.com 04 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S

4 DOSAGE AND ADMINISTRATION DOSAGE AND ADMINISTRATION Recommended ADCETRIS (brentuximab vedotin) Dosage1 Recommended Dose for Patients With Renal or Hepatic Impairment1 Indication Previously untreated Stage III/IV chl Recommended Dose Administration 1.2 mg/kg up to a maximum of 120 mg* in combination with chemotherapy Intravenous infusion over 30 minutes Frequency and Duration Administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity Administer G-CSF primary prophylaxis to ADCETRIS+AVD patients starting with Cycle 1 chl postauto-hsct consolidation 1.8 mg/kg up to a maximum of 180 mg* Relapsed chl 1.8 mg/kg up to a maximum of 180 mg* Intravenous infusion over 30 minutes 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 Recommended Dose From Page 6 Degree of Impairment Recommended Dose Renal Impairment Previously untreated Stage III/IV chl Normal Mild (CrCL >50-80 ml/min) Moderate (CrCL ml/min) 1.2 mg/kg up to a maximum of 120 mg every 2 weeks 1.2 mg/kg up to a maximum of 120 mg every 2 weeks Severe (CrCL <30 ml/min) Avoid use chl post-auto-hsct consolidation and relapsed chl Normal Mild (CrCL >50-80 ml/min) Moderate (CrCL ml/min) 1.8 mg/kg up to a maximum of 180 mg every 3 weeks 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Severe (CrCL <30 ml/min) Avoid use Hepatic Impairment Intravenous infusion over 30 minutes Administer every 3 weeks until disease progression or unacceptable toxicity AVD = doxorubicin, vinblastine, dacarbazine. *The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Previously untreated Stage III/IV chl 1.2 mg/kg up to a maximum of 120 mg every 2 weeks chl post-auto-hsct consolidation and relapsed chl 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Normal 1.2 mg/kg up to a maximum of 120 mg every 2 weeks Mild (Child-Pugh A) 0.9 mg/kg up to a maximum of 90 mg every 2 weeks Moderate (Child-Pugh B) Severe (Child-Pugh C) Avoid use Normal 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Mild (Child-Pugh A) 1.2 mg/kg up to a maximum of 120 mg every 3 weeks Moderate (Child-Pugh B) Severe (Child-Pugh C) Avoid use The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. CrCL = creatinine clearance. Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com 06 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S

5 MANAGEMENT RECOMMENDATIONS TO MAINTAIN DOSING SCHEDULE MANAGEMENT RECOMMENDATIONS TO MAINTAIN DOSING SCHEDULE Monitoring for peripheral neuropathy Monitoring for neutropenia ADCETRIS (brentuximab vedotin) treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative.1 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.1 Throughout treatment, monitor patients for peripheral neuropathy symptoms, which include1: G-CSF primary prophylaxis is recommended starting with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III/IV chl.1 Hypoesthesia Hyperesthesia Paresthesia Discomfort A burning sensation Neuropathic pain Weakness Monitor complete blood counts (CBC ) prior to each dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever.1 NCI CTCAE Version 4.03: Peripheral Neuropathy2 Grade 1 Grade 2 M Asymptomatic; clinical or diagnostic observations only; intervention not indicated Criteria S Asymptomatic; loss of deep tendon reflexes or paresthesia Grade 3 Grade 4 Moderate symptoms; limiting instrumental activities of daily living (ADL) Severe symptoms; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Moderate symptoms; limiting instrumental ADL Severe symptoms; limiting self-care ADL; assistive device indicated Life-threatening consequences; urgent intervention indicated S = sensory; M = motor; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. Dose Modifications for Peripheral Neuropathy1 Recommended Dose Previously untreated Stage III/IV chl 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks chl post-auto-hsct consolidation and relapsed chl 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks Severity Dose Modification Grade 2 Reduce to 0.9 mg/kg up to a maximum of 90 mg* every 2 weeks Grade 3 Hold until improvement to Grade 2. Restart at 0.9 mg/kg up to a maximum of 90 mg* every 2 weeks. Consider modifying dose of other neurotoxic chemotherapy agents Grade 4 Discontinue dosing New or worsening Grade 2 or 3 Hold 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 See back cover for NCI CTCAE version used to grade events in respective trials. *The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Refer to pages for more information on peripheral neuropathy in clinical trials. Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com 08 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S NCI CTCAE Version 4.03: Neutropenia and Febrile Neutropenia2 Neutropenia Grade 1 Grade 2 Grade 3 Grade 4 <LLN-1,500/mm3; <LLN /L <1,500-1,000/mm3; < /L <1, /mm3; < /L <500/mm3; < /L - ANC <1000/mm3 with a single temperature of >38.3 C (101 F) or a sustained temperature of 38 C (100.4 F) for more than one hour Life-threatening consequences; urgent intervention indicated Febrile Neutropenia - ANC = absolute neutrophil count; LLN = lower limit of normal; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. Dose Modifications for Neutropenia1 Recommended Dose Previously untreated Stage III/IV chl 1.2 mg/kg up to a maximum of 120 mg every 2 weeks chl post-auto-hsct consolidation and relapsed chl 1.8 mg/kg up to a maximum of 180 mg every 3 weeks Severity Dose Modification Grade 3 or 4 Administer G-CSF prophylaxis for subsequent cycles for patients not receiving primary G-CSF prophylaxis 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 See back cover for NCI CTCAE version used to grade events in respective trials. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Refer to page 12 for more information on neutropenia in clinical trials.

6 RATES OF PERIPHERAL NEUROPATHY RATES OF PERIPHERAL NEUROPATHY In a study of ADCETRIS (brentuximab vedotin) as combination therapy: Peripheral Neuropathy Rates From Select Studies1,3 67% of patients treated with ADCETRIS+AVD experienced any grade of neuropathy1 Peripheral sensory neuropathy was reported in 65% of patients; peripheral motor neuropathy, 11% of patients1 Median time to onset of any grade was 8 weeks (range, 0-29), of Grade 2 was 14 weeks (range, 0-28), and of Grade 3 was 16 weeks (range, 1-29)1 Median time from onset to resolution or improvement of any grade was 10 weeks (range, 0-139), of Grade 2 was 12 weeks (range, 0-123), and of Grade 3 was 17 weeks (range, 0-139)1 Grades 1-2 Of the patients with residual neuropathy at the time of their last evaluation (57%), patients reported Grade 1 (36%), Grade 2 (16%), Grade 3 (4%), Grade 4 (1 patient) neuropathy. Median time of overall study follow-up was 84.3 weeks (range, 0-194)1 In studies of ADCETRIS as monotherapy: Grade 4 S 55% 10% <1% (N = 662) M 9% 2% S 46% 10% M 17% 6% S 44% 8% M 12% 4% chl postauto-hsct consolidation (N = 167) Of the patients who experienced neuropathy, 43% had complete resolution, 24% had improvement (a decrease in severity by 1 grade from worst grade), and 33% had no improvement at the time of their last evaluation1 Grade 3 Previously untreated Stage III/IV chl Relapsed chl (N = 102) See back cover for NCI CTCAE version used to grade events in respective trials. S = sensory; M = motor. Dose Delay and Discontinuation Rates Due to Peripheral Neuropathy1 62% of patients experienced any grade of neuropathy 1 Previously untreated chl post-auto-hsct Stage III/IV chl consolidation Median time to onset of any grade was 13 weeks (range, 0-52)1 Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at the time of their last evaluation1 The median time from onset to resolution or improvement of any grade was 21 weeks (range, 0-195)1 Of the patients who reported neuropathy, 38% had residual neuropathy at the time of their last evaluation [Grade 1 (27%), Grade 2 (9%), Grade 3 (2%)]1 Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com 10 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S Dose delays Discontinuation Relapsed chl 16% (sensory) 6% (motor) 13% (sensory) 7% (any PN) 14% (sensory) 7% (motor) 6% (sensory) 3% (motor) Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.1 See dose modification information on page 8.

7 RATES OF NEUTROPENIA DRUG INTERACTIONS Among ADCETRIS+AVD patients in the phase 3 clinical trial in frontline Stage III/IV chl, 91% experienced neutropenia. In 579 patients who did not receive G-CSF primary prophylaxis, 96% experienced neutropenia. In 83 patients who received G-CSF primary prophylaxis, 61% experienced neutropenia.1 In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5. In vitro data indicate that MMAE is also a substrate of the efflux transporter P-glycoprotein (P-gp).1 Neutropenia led to dose delays of 1 drug in 21% of patients.1 Effect of other drugs on ADCETRIS (brentuximab vedotin) Neutropenia and Febrile Neutropenia Rates: Previously Untreated Stage III/IV chl1,3 CYP3A4 inhibitors/inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Closely monitor patients for adverse reactions when ADCETRIS is given concomitantly with strong CYP3A4 inhibitors. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%1 All Grades Grades 1-2 Grade 3 Grade 4 Neutropenia Without G-CSF (N = 579) 96% 8% 21% 67% With G-CSF (N = 83) 61% 22% 13% 27% P-gp inhibitors: Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE. Closely monitor patients for adverse reactions when ADCETRIS is given concomitantly with P-gp inhibitors1 Febrile Neutropenia Without G-CSF (N = 579) 21% - 14% 6% With G-CSF (N = 83) 11% - 8% 2% See back cover for NCI CTCAE version used to grade events in respective trials. In the phase 3 chl post-auto-hsct consolidation trial, 78% of patients experienced neutropenia. Neutropenia led to dose delays in 22% of patients1 In the phase 2 clinical trial in relapsed chl, 54% of patients experienced neutropenia. Neutropenia led to dose delays in 16% of patients1 Neutropenia Rates: chl Post-Auto-HSCT Consolidation and Relapsed chl1 chl post-autohsct consolidation Grades 1-2 Grade 3 Grade 4 39% 30% 9% 33% 15% 6% (N = 167) Relapsed chl (N = 102) See back cover for NCI CTCAE version used to grade events in respective trials. 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 neutropenia1 If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.1 See dose modification information on page 9 Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com 12 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S Effect of ADCETRIS on other drugs Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.1 OVERDOSAGE There is no known antidote to overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.1

8 INSTRUCTIONS FOR PREPARATION AND ADMINISTRATION PATIENT COUNSELING INFORMATION Administration Advise patients to contact their physician if they experience any of the following signs or symptoms: Administer ADCETRIS (brentuximab vedotin) as an intravenous infusion only 1 Do not mix ADCETRIS with, or administer as an infusion with, other medicinal products1 Numbness or tingling of the hands or feet, or any muscle weakness, indicative of peripheral neuropathy1 Reconstitution A fever of F or greater or other evidence of potential infection, such as chills, a cough, or pain upon urination1 Follow procedures for proper handling and disposal of anticancer drugs1,4 Fever, chills, a rash, or breathing problems within 24 hours of infusion, indicative of an infusion reaction1 Use appropriate aseptic technique for reconstitution and preparation of dosing solutions1 Determine the number of 50-mg vials needed based on the patient s weight and the prescribed dose1 Reconstitute each 50-mg vial of ADCETRIS with 10.5 ml of Sterile Water for Injection, USP, to yield a single-use solution containing 5 mg/ml of brentuximab vedotin1 Fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice, indicative of liver injury1 Changes in mood or usual behavior; confusion, thinking problems, or loss of memory; changes in vision, speech, or walking; or decreased strength or weakness on one side of the body, possibly indicative of PML1 New or worsening cough or shortness of breath, possibly indicative of pulmonary toxicity1 Direct the stream toward the wall of vial and not directly at the cake or powder 1 Severe abdominal pain, indicative of acute pancreatitis1 Gently swirl the vial to aid dissolution. DO NOT SHAKE Severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea1 Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to slightly opalescent, colorless, and free of visible particulates1 ADCETRIS (brentuximab vedotin) can cause fetal harm. Advise women receiving ADCETRIS to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS1 1 Following reconstitution, dilute immediately into an infusion bag. If not diluted immediately, store the solution at 2-8 C (36-46 F) and use within 24 hours of reconstitution. DO NOT FREEZE1 Discard any unused portion left in the vial1 Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS1 Advise patients to report pregnancy immediately1 Advise patients to avoid breastfeeding while receiving ADCETRIS1 Dilution Calculate the required volume of 5 mg/ml reconstituted ADCETRIS solution needed1 Withdraw this amount from the vial and immediately add it to an infusion bag containing a minimum volume of 100 ml of 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer s Injection to achieve a final concentration of 0.4 mg/ml to 1.8 mg/ml brentuximab vedotin1 Gently invert the bag to mix the solution1 Following dilution, infuse the ADCETRIS solution immediately. If not used immediately, store the solution at 2-8 C (36-46 F) and use within 24 hours of reconstitution. DO NOT FREEZE1 Encourage patients to engage in their treatment by recognizing and reporting possible adverse reactions early. HOW SUPPLIED/STORAGE AND HANDLING How supplied ADCETRIS for injection is supplied in individually boxed, single-dose vials containing 50 mg of brentuximab vedotin as a sterile, white-to-off-white, preservative-free, lyophilized cake or powder.1 NDC ( ), 50 mg brentuximab vedotin.1 Storage Store vial at 2-8 C (36-46 F) in the original carton to protect from light.1 Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com 14 D O S I N G A N D A D M I N I S T R AT I O N G U I D E F O R A D C E T R I S Special handling ADCETRIS is an antineoplastic product. Follow special handling and disposal procedures.4

9 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) event grading in ADCETRIS (brentuximab vedotin) clinical trials Previously untreated Stage III/IV chl: Events graded using Version 4.03 ( /CTCAE_4.03_ _QuickReference_8.5x11.pdf. Published June 14, Accessed March 13, 2018). chl post-auto-hsct consolidation: Events graded using Version 4.0. ( /CTCAE_4.0_ _QuickReference_8.5x11.pdf. Published May 28, Accessed March 13, 2018). Relapsed chl: Events graded using Version 3.0 ( Published August 9, Accessed March 13, 2018). Please see Important Safety Information, including BOXED WARNING, on pages 2-4 and full Prescribing Information attached or at adcetrispro.com References: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc. March National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version _QuickReference_8.5x11.pdf. Published June 14, Accessed March 13, Data on file. Seattle Genetics, Inc. 4. Hazardous drugs. OSHA Web site. Accessed March 13, ADCETRIS and its logo, and Seattle Genetics and, are US registered trademarks of Seattle Genetics, Inc Seattle Genetics, Inc., Bothell, WA All rights reserved Printed in USA USP-BVP (1)

10 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ADCETRIS safely and effectively. See full prescribing information for ADCETRIS. ADCETRIS (brentuximab vedotin) for injection, for intravenous use Initial U.S. approval: 2011 WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) See full prescribing information for complete boxed warning. JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (5.9, 6.1). RECENT MAJOR CHANGES Indications and Usage (1.1) 03/2018 Indications and Usage (1.5) 11/2017 Dosage and Administration, Dosage (2.1) 03/2018 Dosage and Administration, Recommended Prophylactic Medications (2.2) 03/2018 Warnings and Precautions, Hematologic Toxicities (5.3) 03/2018 Warnings and Precautions, Gastrointestinal Complications (5.12) 11/2017 INDICATIONS AND USAGE ADCETRIS is a CD30-directed antibody-drug conjugate indicated for treatment of adult patients with: Previously untreated Stage III or IV classical Hodgkin lymphoma (chl), in combination with chemotherapy (1.1). Classical Hodgkin lymphoma at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-hsct) consolidation (1.2). Classical Hodgkin lymphoma after failure of auto-hsct or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-hsct candidates (1.3). Systemic anaplastic large cell lymphoma (salcl) after failure of at least one prior multiagent chemotherapy regimen (1.4). Primary cutaneous anaplastic large cell lymphoma (pcalcl) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy (1.5). DOSAGE AND ADMINISTRATION Administer only as an intravenous infusion over 30 minutes (2.1). The recommended dose as monotherapy is 1.8 mg/kg up to a maximum of 180 mg every 3 weeks (2.1). The recommended dose in combination with chemotherapy for previously untreated Stage III or IV chl is 1.2 mg/kg up to a maximum of 120 mg every 2 weeks for a maximum of 12 doses (2.1). Reduce dose in patients with mild hepatic impairment (2.3). DOSAGE FORMS AND STRENGTHS For injection: 50 mg lyophilized powder in a single-dose vial (3). CONTRAINDICATIONS Concomitant use with bleomycin due to pulmonary toxicity (4). WARNINGS AND PRECAUTIONS Peripheral neuropathy: Monitor patients for neuropathy and institute dose modifications accordingly (5.1). Anaphylaxis and infusion reactions: If an infusion reaction occurs, interrupt the infusion. If anaphylaxis occurs, immediately discontinue the infusion (5.2). Hematologic toxicities: Monitor complete blood counts prior to each dose of ADCETRIS. Closely monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses. Administer G-CSF starting with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III & IV chl (5.3). Serious infections and opportunistic infections: Closely monitor patients for the emergence of bacterial, fungal or viral infections (5.4). Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor or high tumor burden (5.5). Hepatotoxicity: Monitor liver enzymes and bilirubin (5.8). Pulmonary toxicity: Monitor patients for new or worsening symptoms (5.10). Serious dermatologic reactions: Discontinue if Stevens-Johnson syndrome or toxic epidermal necrolysis occurs (5.11). Gastrointestinal complications: Monitor patients for new or worsening symptoms (5.12). Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy (5.13). ADVERSE REACTIONS The most common adverse reactions ( 20%) were neutropenia, anemia, peripheral sensory neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and pyrexia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Seattle Genetics, Inc. at or FDA at FDA-1088 or DRUG INTERACTIONS Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE) (7.1). USE IN SPECIFIC POPULATIONS Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use (5.6, 5.7, 8.6, 8.7). Lactation: Advise women not to breastfeed (8.2). See 17 for PATIENT COUNSELING INFORMATION. Revised: 03/2018 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) 1 INDICATIONS AND USAGE 1.1 Previously untreated Stage III or IV classical Hodgkin lymphoma (chl), in combination with chemotherapy. 1.2 chl consolidation 1.3 Relapsed chl 1.4 Relapsed salcl 1.5 Relapsed pcalcl or CD30-expressing MF 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Recommended Prophylactic Medications 2.3 Dose Modification 2.4 Instructions for Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Peripheral Neuropathy 5.2 Anaphylaxis and Infusion Reactions 5.3 Hematologic Toxicities 5.4 Serious Infections and Opportunistic Infections 5.5 Tumor Lysis Syndrome 5.6 Increased Toxicity in the Presence of Severe Renal Impairment 5.7 Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment 5.8 Hepatotoxicity 5.9 Progressive Multifocal Leukoencephalopathy 5.10 Pulmonary Toxicity 5.11 Serious Dermatologic Reactions 5.12 Gastrointestinal Complications 5.13 Embryo-Fetal Toxicity 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Post Marketing Experience 6.3 Immunogenicity 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on ADCETRIS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Classical Hodgkin Lymphoma 14.2 Systemic Anaplastic Large Cell Lymphoma 14.3 Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 16.3 Special Handling 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.

11 FULL PRESCRIBING INFORMATION WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS [see Warnings and Precautions (5.9), Adverse Reactions (6.1)]. 1 INDICATIONS AND USAGE 1.1 Previously untreated Stage III or IV classical Hodgkin lymphoma (chl), in combination with chemotherapy. ADCETRIS is indicated for the treatment of adult patients with previously untreated Stage III or IV chl, in combination with chemotherapy. 1.2 chl consolidation ADCETRIS is indicated for the treatment of adult patients with chl at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-hsct) consolidation. 1.3 Relapsed chl ADCETRIS is indicated for the treatment of adult patients with chl after failure of auto-hsct or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-hsct candidates. 1.4 Relapsed salcl ADCETRIS is indicated for the treatment of adult patients with systemic anaplastic large cell lymphoma (salcl) after failure of at least one prior multi-agent chemotherapy regimen. 1.5 Relapsed pcalcl or CD30-expressing MF ADCETRIS is indicated for the treatment of adult patients with pcalcl or CD30- expressing MF who have received prior systemic therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended ADCETRIS dosage is provided in Table 1. The recommended dose for patients with renal or hepatic impairment is provided in Table 2. For dosing instructions of combination agents administered with ADCETRIS, see Clinical Studies (14.1) and the manufacturer s prescribing information. Table 1: Recommended ADCETRIS Dosage Indication Previously Untreated Stage III or IV Classical Hodgkin Lymphoma Classical Hodgkin Lymphoma Consolidation Relapsed Classical Hodgkin Lymphoma Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or CD30-expressing Mycosis Fungoides Relapsed Systemic Anaplastic Large Cell Lymphoma Recommended Dose* 1.2 mg/kg up to a maximum of 120 mg in combination with chemotherapy 1.8 mg/kg up to a maximum of 180 mg 1.8 mg/kg up to a maximum of 180 mg 1.8 mg/kg up to a maximum of 180 mg 1.8 mg/kg up to a maximum of 180 mg Administration Intravenous infusion over 30 minutes Intravenous infusion over 30 minutes Intravenous infusion over 30 minutes Intravenous infusion over 30 minutes Intravenous infusion over 30 minutes Frequency and Duration Administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity 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 Administer every 3 weeks until disease progression or unacceptable toxicity Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Administer every 3 weeks until disease progression or unacceptable toxicity * The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg Table 2: Recommended Dose for Patients with Renal or Hepatic Impairment Recommended Dose from Table 1 Degree of Impairment Recommended Dose Renal Impairment 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks Normal Mild (CrCL greater than ml/min) Moderate (CrCL ml/min) Severe (CrCL less than 30 ml/min) 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks Avoid use [see Warnings and Precautions (5.6)] (continued) Table 2: Recommended Dose for Patients with Renal or Hepatic Impairment Recommended Dose from Table 1 Degree of Impairment Recommended Dose Renal Impairment 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks Normal Mild (CrCL greater than ml/min) Moderate (CrCL ml/min) Severe (CrCL less than 30 ml/min) Normal Mild (Child-Pugh A) Hepatic Impairment Moderate (Child-Pugh B) Severe (Child-Pugh C) Normal Mild (Child-Pugh A) Moderate (Child-Pugh B) Severe (Child-Pugh C) 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks Avoid use [see Warnings and Precautions (5.6)] 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks 0.9 mg/kg up to a maximum of 90 mg* every 2 weeks Avoid use [see Warnings and Precautions (5.7)] 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks 1.2 mg/kg up to a maximum of 120 mg* every 3 weeks Avoid use [see Warnings and Precautions (5.7)] * The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg CrCL: creatinine clearance 2.2 Recommended Prophylactic Medications In patients with previously untreated Stage III or IV chl who are treated with ADCETRIS + AVD, administer G-CSF beginning with Cycle Dose Modification Table 3: Dose Modifications for Peripheral Neuropathy or Neutropenia Recommended dose Severity Dose Modification from Table mg/kg up to a maximum of 120 mg* every 2 weeks 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks 1.2 mg/kg up to a maximum of 120 mg* every 2 weeks 1.8 mg/kg up to a maximum of 180 mg* every 3 weeks Grade 2 Grade 3 Grade 4 Peripheral Neuropathy New or worsening Grade 2 or 3 Grade 4 Reduce dose to 0.9 mg/kg up to a maximum of 90 mg* every 2 weeks 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 Discontinue dosing 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 Discontinue dosing Neutropenia Grade 3 or 4 Administer G-CSF prophylaxis for subsequent cycles for patients not receiving primary G-CSF prophylaxis Grade 3 or 4 Recurrent Grade 4 despite G-CSF prophylaxis Hold dosing until improvement to baseline or Grade 2 or lower Consider G-CSF prophylaxis for subsequent cycles Consider discontinuation or dose reduction to 1.2 mg/kg up to a maximum of 120 mg* every 3 weeks Events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 * The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg

12 2.4 Instructions for Preparation and Administration Administration Administer ADCETRIS as an intravenous infusion only. Do not mix ADCETRIS with, or administer as an infusion with, other medicinal products. Reconstitution Follow procedures for proper handling and disposal of anticancer 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. Inspect the reconstituted solution for particulates and discoloration. 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 8 C (36 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 a minimum volume of 100 ml of 0.9% Sodium Chloride Injection, 5% Dextrose Injection or Lactated Ringer s Injection to achieve a final concentration of 0.4 mg/ml to 1.8 mg/ml brentuximab vedotin. Gently invert the bag to mix the solution. Following dilution, infuse the ADCETRIS solution immediately. If not used immediately, store the solution at 2 8 C (36 46 F) and use within 24 hours of reconstitution. DO NOT FREEZE. 3 DOSAGE FORMS AND STRENGTHS For injection: 50 mg of brentuximab vedotin as a sterile, white to off-white lyophilized, preservative-free cake or powder in a single-dose vial for reconstitution. 4 CONTRAINDICATIONS ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Peripheral Neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In studies of ADCETRIS as monotherapy, 62% of patients experienced any grade of neuropathy. The median time to onset of any grade was 13 weeks (range, 0 52). Of the patients who experienced neuropathy, 62% had complete resolution, 24% had partial improvement, and 14% had no improvement at the time of their last evaluation. The median time from onset to resolution or improvement of any grade was 21 weeks (range, 0 195). Of the patients who reported neuropathy, 38% had residual neuropathy at the time of their last evaluation [Grade 1 (27%), Grade 2 (9%), Grade 3 (2%)]. In a study of ADCETRIS as combination therapy (Study 5, ECHELON-1) 67% of patients treated with ADCETRIS + AVD experienced any grade of neuropathy. The median time to onset of any grade was 8 weeks (range, 0 29), of Grade 2 was 14 weeks (range, 0 28) and of Grade 3 was 16 weeks (range, 1 29). The median time from onset to resolution or improvement of any grade was 10 weeks (range, 0 139), of Grade 2 was 12 weeks (range, 0 123), and of Grade 3 was 17 weeks (range, 0 139). Of these patients, 43% had complete resolution, 24% had partial improvement (a decrease in severity by one or more grade from worst grade) and 33% had no improvement at the time of their last evaluation. Of the patients with residual neuropathy at the time of their last evaluation (57%), patients reported Grade 1 (36%), Grade 2 (16%), Grade 3 (4%), or Grade 4 (1 patient) neuropathy. Median time of overall study follow-up was 84.3 weeks (range, 0 194). 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)]. 5.2 Anaphylaxis and Infusion Reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid. 5.3 Hematologic Toxicities Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged ( 1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Start primary prophylaxis with G-CSF beginning with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III or IV 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)]. 5.4 Serious Infections and Opportunistic Infections Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Monitor patients closely during treatment for the emergence of possible bacterial, fungal, or viral infections. 5.5 Tumor Lysis Syndrome Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures. 5.6 Increased Toxicity in the Presence of Severe Renal Impairment The frequency of Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Due to higher MMAE exposure, Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment [creatinine clearance (CrCL) <30 ml/min] [see Use in Specific Populations (8.6)]. 5.7 Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment The frequency of Grade 3 adverse reactions and deaths was greater in patients with moderate and severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.7)]. 5.8 Hepatotoxicity Fatal and serious cases of hepatotoxicity have occurred in patients receiving ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin. Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS. 5.9 Progressive Multifocal Leukoencephalopathy Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIStreated 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 Pulmonary Toxicity Fatal and serious events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement Serious Dermatologic Reactions Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy Gastrointestinal Complications Fatal and serious events of acute pancreatitis have been reported. Other fatal and serious gastrointestinal (GI) complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. There are no adequate and wellcontrolled studies of ADCETRIS in pregnant women. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to the clinical dose of 1.8 mg/kg every three weeks. Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. Advise a pregnant woman of the potential risk to the fetus [see Use in Specific Populations (8.1, 8.3].