Data from FDA - Curated by Marshall Pearce - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE ADCETRIS is indicated for the treatment of: ADCETRIS is a CD30-directed antibody-drug conjugate indicated for treatment of adult patients with: Classical Hodgkin lymphoma (cHL) at high risk of relapse or progression as post autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (1.1). 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 (1.2). Systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen (1.3). Accelerated approval was granted for the sALCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials Primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy (1.4). 1.1 Classical Hodgkin lymphoma (cHL) Consolidation Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation [see Clinical Studies (14.1)] . 1.2 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 [see Clinical Studies (14.1)]. ADCETRIS is also indicated for the treatment of: 1.3 Relapsed sALCL Adult patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen [see Clinical Studies ( 14.2 )] The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.4 Relapsed pcALCL or CD30-expressing MF Adult patients with pcALCL or CD30-expressing MF who have received prior systemic therapy [see Clinical Studies (14.2)].

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Advisory information

contraindications
4 CONTRAINDICATIONS ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation) [see Adverse Reactions ( 6.1 )]. Concomitant use with bleomycin due to pulmonary toxicity (4).
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Peripheral Neuropathy [see Warnings and Precautions ( 5.1 )] Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.2 )] Hematologic Toxicities [see Warnings and Precautions ( 5.3 )] Serious Infections and Opportunistic Infections [see Warnings and Precautions ( 5.4 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.5 )] Increased Toxicity in the Presence of Severe Renal Impairment [see Warnings and Precautions ( 5.6 )] Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see Warnings and Precautions ( 5.7 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions ( 5.9 )] Pulmonary Toxicity [see Warnings and Precautions (5.10)] Serious Dermatologic Reactions [see Warnings and Precautions (5.11) ] Gastrointestinal Complications [see Warnings and Precautions (5.12)] The most common adverse reactions (≥20%) were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia. To report SUSPECTED ADVERSE REACTIONS, contact Seattle Genetics, Inc. at 1-855-473-2436 or FDA at 1-800-FDA-1088 or www.fda.gov/Safety/MedWatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to ADCETRIS as monotherapy in 393 patients, including 160 patients in two uncontrolled single-arm trials in cHL and systemic ALCL (Studies 1 and 2) and 233 patients in two controlled randomized trials in cHL, and pcALCL and CD30-expressing MF (Study 3: AETHERA and Study 4: ALCANZA). In these trials, ADCETRIS was administered at 1.8 mg/kg every 3 weeks. Across the clinical trials of ADCETRIS as monotherapy (Studies 1-4), the most common adverse reactions (≥20%) in ADCETRIS-treated patients were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia. 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 (2.2)]. 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%), paraesthesia (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 4: Adverse Reactions Reported in ≥10% in ADCETRIS-treated Patients with Classical Hodgkin Lymphoma Post-auto-HSCT Consolidation (Study 3: AETHERA) ADCETRIS Total N = 167 % of patients Placebo Total N = 160 % of patients Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Events were graded using the NCI CTCAE Version 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 (2.2)]. 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 5: Adverse Reactions Reported in ≥10% of Patients with Relapsed Classical Hodgkin Lymphoma (Study 1) cHL Total N = 102 % of patients 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 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 - - 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 (2.2)]. 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 6: Adverse Reactions Reported in ≥10% of Patients with Relapsed Systemic Anaplastic Large Cell Lymphoma (Study 2) sALCL Total N = 58 % of patients 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)]. 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 (2.2)]. 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 7: 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 Choicea Total N = 62 % of patients Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 a Physician’s choice of either methotrexate or bexarotene 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. 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 (adriamycin, 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)]. Cases of pulmonary toxicity have also been reported in patients receiving ADCETRIS. 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. 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of ADCETRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: febrile neutropenia [see Warnings and Precautions ( 5.3 )]. Gastrointestinal disorders: acute pancreatitis and gastrointestinal complications (including fatal outcomes) [see Warnings and Precautions (5.12)]. Hepatobiliary disorders: hepatotoxicity [see Warnings and Precautions ( 5.8 )]. Infections: PML [see Boxed Warning, Warnings and Precautions (5.9)], serious infections and opportunistic infections [see Warnings and Precautions ( 5.4 )]. Metabolism and nutrition disorders: hyperglycemia. 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)]. 6.3 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ADCETRIS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Patients with cHL and sALCL in Studies 1 and 2 [see Clinical Studies ( 14) ] were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 timepoints) and 30% developed transiently positive antibodies (positive in 1 or 2 post-baseline timepoints). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies. Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies. A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies. Sixty-two percent (62%) of these patients had at least one sample that was positive for the presence of neutralizing antibodies. The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer only as an intravenous infusion over 30 minutes every 3 weeks (2.1). The recommended dose is 1.8 mg/kg up to a maximum of 180 mg (2.1). Reduce dose in patients with mild hepatic impairment (2.2). 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. 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 Administration Frequency and Duration Classical Hodgkin Lymphoma Consolidation 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 Relapsed Classical Hodgkin L ymphoma 1.8 mg/kg up to a maximum of 180 mg Intravenous infusion over 30 minutes Administer every 3 weeks until disease progression or unacceptable toxicity Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or CD30-expressing Mycosis Fungoides 1.8 mg/kg up to a maximum of 180 mg Intravenous infusion over 30 minutes Administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity Relapsed Systemic Anaplastic Large Cell Lymphoma 1.8 mg/kg up to a maximum of 180 mg Intravenous infusion over 30 minutes Administer every 3 weeks until disease progression or unacceptable toxicity Table 2: Recommended Dose for Patients with Renal or Hepatic Impairment CrCL: creatinine clearance Impairment Degree of Impairment Recommended Dose Renal Normal Mild (CrCL greater than 50–80 mL/min) Moderate (CrCL 30–50 mL/min) 1.8 mg/kg up to a maximum of 180 mgThe dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg Severe (CrCL less than 30 mL/min) Avoid use [see Warnings and Precautions (5.6)] Hepatic Normal 1.8 mg/kg up to a maximum of 180 mg Mild (Child-Pugh A) 1.2 mg/kg up to a maximum of 120 mg Moderate (Child-Pugh B) Severe (Child-Pugh C) Avoid use [see Warnings and Precautions (5.7)] 2.2 Dose Modification Table 3: Dose Modifications for Peripheral Neuropathy or Neutropenia Toxicity Severity Dose Modification Events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 Peripheral Neuropathy 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 mgThe dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg Grade 4 Dosing should be discontinued Neutropenia 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 2.3 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-use 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.
Use in special populations
8 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). 8.1 Pregnancy Risk Summary ADCETRIS can cause fetal harm based on the findings from animal studies and the drug’s mechanism of action [see Clinical Pharmacology ( 12.1 )]. In animal reproduction studies, administration of brentuximab vedotin to pregnant rats during organogenesis at doses similar to the clinical dose of 1.8 mg/kg every three weeks caused embryo-fetal toxicities, including congenital malformations (see Data). Consider the benefits and risks of ADCETRIS and possible risks to the fetus when prescribing ADCETRIS to a pregnant woman. 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. 8.2 Lactation 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. 8.3 Females and Males of Reproductive Potential 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), Clinical Pharmacology (12.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating ADCETRIS therapy. Contraception Females Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final 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 at least 6 months after the final dose of ADCETRIS [see Nonclinical Toxicology ( 13.1 )]. Infertility Males Based on findings in rats, male fertility may be compromised by treatment with ADCETRIS [see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness of ADCETRIS have not been established in pediatric patients. 8.5 Geriatric Use Clinical trials of ADCETRIS in cHL (Studies 1 and 3: AETHERA) and sALCL (Study 2) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In the clinical trial of ADCETRIS in pcALCL or CD30-expressingMF (Study 4: ALCANZA), 42% of ADCETRIS-treated patients were aged 65 or older. No meaningful differences in safety or efficacy were observed between these patients and younger patients. 8.6 Renal Impairment Avoid the use of ADCETRIS in patients with severe renal impairment (CrCL <30 mL/min) [See Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. No dosage adjustment is required for mild (CLcr >50–80 mL/min) or moderate (CrCL 30–50 mL/min) renal impairment. 8.7 Hepatic Impairment Avoid the use of ADCETRIS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [See Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. Dosage reduction is required in patients with mild (Child-Pugh A) hepatic impairment [See Dosage and Administration (2.1)].

Interactions

7 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). 7.1 Effect of Other Drugs on ADCETRIS CYP3A4 Inhibitors: Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE [see Clinical Pharmacology (12.3) ] which may increase the risk of adverse reaction. Closely monitor adverse reactions when ADCETRIS is given concomitantly with strong CYP3A4 inhibitors. P-gp Inhibitors: Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE. Closely monitor adverse reactions when ADCETRIS is given concomitantly with P-gp inhibitors.

More information

Category Value
Authorisation number BLA125388
Agency product number 7XL5ISS668
Orphan designation No
Product NDC 51144-050
Date Last Revised 01-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1147323
Marketing authorisation holder Seattle Genetics, Inc.
Warnings 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 ) ]. 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).