Data from FDA - Curated by Marshall Pearce - Last updated 06 December 2017

Indication(s)

1 INDICATIONS AND USAGE ADCETRIS is a CD30-directed antibody-drug conjugate indicated for treatment of patients with: Classical Hodgkin lymphoma (HL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates (1.1). Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation (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. 1.1 Classical Hodgkin Lymphoma (HL) ADCETRIS is indicated for treatment of patients with classical HL after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates. 1.2 Classical Hodgkin Lymphoma (HL) Post-auto-HSCT Consolidation ADCETRIS is indicated for the treatment of patients with classical HL at high risk of relapse or progression as post-auto-HSCT consolidation [see Clinical Studies (14.1)]. 1.3 Systemic Anaplastic Large Cell Lymphoma (sALCL) ADCETRIS is indicated for treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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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 discussed in greater detail in other sections of the prescribing information: 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: Relapsed classical HL and relapsed sALCL: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting (6.1). Classical HL post-auto-HSCT consolidation: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea (6.1). 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 327 patients with classical Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), including 160 patients in two uncontrolled single-arm trials (Studies 1 and 2) and 167 patients in one placebo-controlled randomized trial (Study 3). In Studies 1 and 2, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting. The most common adverse reactions occurring in at least 10% of patients in either Study 1 or 2, regardless of causality, using the NCI Common Toxicity Criteria (CTC) Version 3.0, are shown in Table 2. In Study 3, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm, regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 3. Experience in Classical Hodgkin Lymphoma Summary of Clinical Trial Experience in Relapsed Classical HL (Study 1) ADCETRIS was studied in 102 patients with classical HL 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 )]. The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3) ADCETRIS was studied in 329 patients with classical HL 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 brentuximab vedotin, 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 (PCP) 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 PCP prophylaxis with a median duration of 6.5 months (range, 0–20). Experience in Systemic Anaplastic Large Cell Lymphoma Summary of Clinical Trial Experience in Relapsed sALCL (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 )]. The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. Table 2: Most Commonly Reported (≥10%) Adverse Reactions in Studies 1 and 2 Classical HL sALCL Total N = 102 % of patients Total N = 58 % of patients 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 54 15 6 55 12 9 Anemia 33 8 2 52 2 - Thrombocytopenia 28 7 2 16 5 5 Lymphadenopathy 11 - - 10 - - Nervous system disorders Peripheral sensory neuropathy 52 8 - 53 10 - Peripheral motor neuropathy 16 4 - 7 3 - Headache 19 - - 16 2 - Dizziness 11 - - 16 - - General disorders and administration site conditions Fatigue 49 3 - 41 2 2 Pyrexia 29 2 - 38 2 - Chills 13 - - 12 - - Pain 7 - - 28 - 5 Edema peripheral 4 - - 16 - - Infections and infestations Upper respiratory tract infection 47 - - 12 - - Gastrointestinal disorders Nausea 42 - - 38 2 - Diarrhea 36 1 - 29 3 - Abdominal pain 25 2 1 9 2 - Vomiting 22 - - 17 3 - Constipation 16 - - 19 2 - Skin and subcutaneous tissue disorders Rash 27 - - 31 - - Pruritus 17 - - 19 - - Alopecia 13 - - 14 - - Night sweats 12 - - 9 - - Dry skin 4 - - 10 - - Respiratory, thoracic and mediastinal disorders Cough 25 - - 17 - - Dyspnea 13 1 - 19 2 - Oropharyngeal pain 11 - - 9 - - Musculoskeletal and connective tissue disorders Arthralgia 19 - - 9 - - Myalgia 17 - - 16 2 - Back pain 14 - - 10 2 - Pain in extremity 10 - - 10 2 2 Muscle spasms 9 - - 10 2 - Psychiatric disorders Insomnia 14 - - 16 - - Anxiety 11 2 - 7 - - Metabolism and nutrition disorders Decreased appetite 11 - - 16 2 - Investigations Weight decreased 6 - - 12 3 - Table 3: Most Commonly Reported (≥10% in the ADCETRIS arm) Adverse Reactions in Study 3 ADCETRIS Placebo Total N = 167 % of patients Total N = 160 % of patients 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 - - Additional Important Adverse Reactions Peripheral neuropathy In Studies 1 and 2, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time to first onset of any grade was 14 weeks (range, 0.1–47), of Grade 2 was 27 weeks (range, 0.4–52) and of Grade 3 was 34 weeks (range, 7–106). The median time from onset to resolution or improvement of any grade was 23 weeks (range, 0.1–138), of Grade 2 was 24 weeks (range, 1–108), and of Grade 3 was 25 weeks (range, 2–98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation. Infusion reactions Two cases of anaphylaxis were reported in the dose-finding trials. There were no Grade 3 or 4 infusion-related reactions reported in Studies 1 and 2; however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). In Studies 1 and 2, the most common adverse reactions (≥2%) associated with infusion-related reactions were chills (4%), nausea (3%), dyspnea (3%), pruritus (3%), pyrexia (2%), and cough (2%). In Study 3, infusion-related reactions were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm. Grade 3 events were reported in 3 of the 25 patients treated with ADCETRIS who experienced infusion-related reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions (≥2%) associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%), pruritus (2%), rash (2%), back pain (2%), and vomiting (2%). Pulmonary Toxicity In a trial in patients with classical HLthat 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, pulmonary toxicity was reported in 8 patients (5%) in the ADCETRIS-treated arm and 5 patients (3%) in the placebo arm. A causal association with single-agent ADCETRIS has not been established. Serious adverse reactions In Studies 1 and 2, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with classical HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%). Other important serious adverse reactions reported include PML, Stevens-Johnson syndrome, and tumor lysis syndrome. In Study 3, serious adverse reactions, regardless of causality, 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%). Dose modifications Adverse reactions that led to dose delays in more than 5% of patients in Studies 1 and 2 were neutropenia (14%) and peripheral sensory neuropathy (11%) [see Dosage and Administration ( 2.2 )]. Adverse reactions that led to dose delays in more than 5% of ADCETRIS-treated patients in Study 3 were neutropenia (22%), peripheral sensory neuropathy (16%), upper respiratory tract infection (6%), and peripheral motor neuropathy (6%) [see Dosage and Administration ( 2.2 )]. Discontinuations Adverse reactions led to treatment discontinuation in 21% of patients in Studies 1 and 2. Adverse reactions that led to treatment discontinuation in 2 or more patients with classical HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%). Adverse reactions led to treatment discontinuation in 32% of ADCETRIS-treated patients in Study 3. 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%). 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: Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain. 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 Patients with classical HL 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 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. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer only as an intravenous infusion over 30 minutes every 3 weeks. The recommended dose is 1.8 mg/kg (2). Reduce dose in patients with mild hepatic impairment (2). 2.1 Dosage Recommendations Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. See Table 1 for the recommended starting dosage. For classical HL post-auto-HSCT consolidation treatment, initiate ADCETRIS treatment within 4–6 weeks post-auto-HSCT or upon recovery from auto-HSCT. These patients should continue treatment until a maximum of 16 cycles, disease progression, or unacceptable toxicity. Table 1: Recommended ADCETRIS Dosage Recommended Starting Dosage Normal renal and hepatic function 1.8 mg/kg up to 180 mg Renal impairment Mild (creatinine clearance >50–80 mL/min) or moderate (creatinine clearance 30–50 mL/min) 1.8 mg/kg up to 180 mg Severe (creatinine clearance less than 30 mL/min) Avoid use [see Warnings and Precautions ( 5.6 )] Hepatic impairment Mild (Child-Pugh A) 1.2 mg/kg up to 120 mg Moderate (Child-Pugh B) or severe (Child-Pugh C) Avoid use [see Warnings and Precautions ( 5.7 )] 2.2 Dose Modification Peripheral Neuropathy: For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles in patients who experience Grade 3 or 4 neutropenia in the previous cycle. In patients with recurrent Grade 4 neutropenia despite the use of G-CSF prophylaxis, consider discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg. 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: Breastfeeding not recommended (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. 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 classical HL 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 infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant 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 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Renal Impairment Avoid the use of ADCETRIS in patients with severe renal impairment (CLcr <30 mL/min) [See Warnings and Precautions (5.6) ]. The kidney is a route of excretion for monomethyl auristatin E (MMAE). The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (CLcr >50–80 mL/min; n=4), moderate (CLcr 30–50 mL/min; n=3) and severe (CLcr <30 mL/min; n=3) renal impairment. In patients with severe renal impairment, the rate of Grade 3 or worse adverse reactions was 3/3 (100%) compared to 3/8 (38%) in patients with normal renal function. Additionally, the AUC of MMAE (component of ADCETRIS) was approximately 2-fold higher 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. 8.7 Hepatic Impairment Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment [See Warnings and Precautions ( 5.7 )]. The liver is a route of clearance for MMAE. The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function. Additionally, the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.

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/Inducers: In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate of CYP3A4/5. MMAE is primarily metabolized by CYP3A [see Clinical Pharmacology (12.3) ] . Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%. P-gp Inhibitors: In vitro data indicate that MMAE is a substrate of the efflux transporter P‑glycoprotein (P-gp). Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE. Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. 7.2 Effect of ADCETRIS on Other Drugs In vitro data indicate that MMAE is an inhibitor of CYP3A4/5. Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations [see Clinical Pharmacology (12.3) ]. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

More information

Category Value
Authorisation number BLA125388
Agency product number 7XL5ISS668
Orphan designation No
Product NDC 51144-050
Date Last Revised 28-09-2016
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).