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ADCETRIS (Seattle Genetics, Inc.)

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INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION 1 VIAL, SINGLE-DOSE in 1 BOX (51144-050-01) > 10.5 mL in 1 VIAL, SINGLE-DOSE Label Information

Complete ADCETRIS Information

  • BOXED WARNING(What is this?)

    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)].


  • 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, primary cutaneous anaplastic large cell lymphoma and CD30-expressing mycosis fungoides (1) 11/2017
    Dosage and Administration, Dosage (2.1) 11/2017
    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:

    • 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).

    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).

    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 (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 peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia. (6)

    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)

    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: 11/2017


  • FULL PRESCRIBING INFORMATION: CONTENTS*

    WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

    1 INDICATIONS AND USAGE

    1.1 Classical Hodgkin lymphoma (cHL) Consolidation 1.2 Relapsed cHL 1.3 Relapsed sALCL 1.4 Relapsed pcALCL or CD30-expressing MF

    2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage 2.2 Dose Modification 2.3 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.

  • 1 INDICATIONS AND USAGE

    ADCETRIS is indicated for the treatment of:

    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)]. 


  • 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.

    Table 1: Recommended ADCETRIS Dosage
    *
    • The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
    Indication Recommended
    Dose
    *
    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 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
    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
    *
    • The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
    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 mg*
    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
    *
    • The  dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
    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 mg*
    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.

  • 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-use 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%)].

    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 (2.2) 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

    Prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. 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)].

    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

    Serious cases of hepatotoxicity, including fatal outcomes, 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

    JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

    5.10 Pulmonary Toxicity

    Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), some with fatal outcomes, 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.

    5.11 Serious Dermatologic Reactions

    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

    5.12 Gastrointestinal Complications

    Acute pancreatitis, including fatal outcomes,has 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.

    5.13 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 well-controlled 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. If ADCETRIS is used during pregnancy or if the patient becomes pregnant during ADCETRIS treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1,8.3)].


  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described elsewhere in the labeling:

    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
    *
    • Derived from laboratory values and adverse reaction data
    Blood and lymphatic system disorders          
        Neutropenia* 78 30 9 34 6 4
        Thrombocytopenia* 41 2 4 20 3 2
        Anemia* 27 4 - 19 2 -
    Nervous system disorders          
        Peripheral sensory neuropathy 56 10 - 16 1 -
        Peripheral motor neuropathy 23 6 - 2 1 -
        Headache 11 2 - 8 1 -
    Infections and infestations          
        Upper respiratory tract infection 26 - - 23 1 -
    General disorders and administration site conditions            
        Fatigue 24 2 - 18 3 -
        Pyrexia 19 2 - 16 - -
        Chills 10 - - 5 - -
    Gastrointestinal disorders            
        Nausea 22 3 - 8 - -
        Diarrhea 20 2 - 10 1 -
        Vomiting 16 2 - 7 - -
        Abdominal pain 14 2 - 3 - -
        Constipation 13 2 - 3 - -
    Respiratory, thoracic and mediastinal disorders            
        Cough 21 - - 16 - -
        Dyspnea 13 - - 6 - 1
    Investigations            
        Weight decreased 19 1 - 6 - -
    Musculoskeletal and connective tissue disorders            
        Arthralgia 18 1 - 9 - -
        Muscle spasms 11 - - 6 - -
        Myalgia 11 1 - 4 - -
    Skin and subcutaneous tissue disorders            
        Pruritus 12 1 - 8 - -
    Metabolism and nutrition disorders          
        Decreased appetite 12 1 - 6 - -

    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       
    *
    • Derived from laboratory values and adverse reaction data
    Blood and lymphatic system disorders        
      Neutropenia*  54 15 6
      Anemia* 33 8 2
      Thrombocytopenia* 28 7 2
      Lymphadenopathy 11 - -
    Nervous system disorders       
      Peripheral sensory neuropathy 52 8 -
      Peripheral motor neuropathy 16 4 -
      Headache 19 - -
      Dizziness 11 - -
    General disorders and administration site conditions      
       Fatigue 49 3 -
       Pyrexia 29 2 -
       Chills 13 - -
    Infections and infestations      
       Upper respiratory tract infection 47 - -
    Gastrointestinal disorders      
       Nausea 42 - -
       Diarrhea 36 1 -
       Abdominal pain 25 2 1
       Vomiting 22 - -
       Constipation 16 - -
    Skin and subcutaneous tissue disorders    
      Rash 27 - -
      Pruritus 17 - -
      Alopecia 13 - -
      Night sweats 12 - -
    Respiratory, thoracic and mediastinal disorders    
      Cough 25 - -
      Dyspnea 13 1 -
      Oropharyngeal pain 11 - -
    Musculoskeletal and connective tissue disorders     
      Arthralgia 19 - -
      Myalgia 17 - -
      Back pain 14 - -
      Pain in extremity 10 - -
    Psychiatric disorders        
      Insomnia 14 - -
      Anxiety 11 2 -
    Metabolism and nutrition disorders        
      Decreased appetite 11 - -

    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
    *
    • Derived from laboratory values and adverse reaction data
    Blood and lymphatic system disorders      
      Neutropenia*  55 12 9
      Anemia* 52 2 -
      Thrombocytopenia* 16 5 5
      Lymphadenopathy 10 - -
    Nervous system disorders      
      Peripheral sensory neuropathy 53 10 -
      Headache 16 2 -
      Dizziness 16 - -
    General disorders and administration site conditions      
       Fatigue 41 2 2
       Pyrexia 38 2 -
       Chills 12 - -
       Pain 28 - 5
       Edema peripheral 16 - -
    Infections and infestations      
       Upper respiratory tract infection 12 - -
    Gastrointestinal disorders      
       Nausea 38 2 -
       Diarrhea 29 3 -
       Vomiting 17 3 -
       Constipation 19 2 -
    Skin and subcutaneous tissue disorders      
      Rash 31 - -
      Pruritus 19 - -
      Alopecia 14 - -
      Dry skin 10 - -
    Respiratory, thoracic and mediastinal disorders      
      Cough 17 - -
      Dyspnea 19 2 -
    Musculoskeletal and connective tissue disorders      
      Myalgia 16 2 -
      Back pain 10 2 -
      Pain in extremity 10 2 2
      Muscle spasms 10 2 -
    Psychiatric disorders      
      Insomnia 16 - -
    Metabolism and nutrition disorders      
      Decreased appetite 16 2 -
    Investigations      
      Weight decreased 12 3 -

    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     
    *
    • Derived from laboratory values and adverse reaction data
    Blood and lymphatic system disorders            
    Anemia* 62 - - 65 5 -
    Neutropenia* 21 3 2 24 5 -
    Thrombocytopenia* 15 2 2 2 - -
    Nervous system disorders  
    Peripheral sensory neuropathy 45 5 - 2 - -
    Gastrointestinal disorders
    Nausea 36 2 - 13 - -
    Diarrhea 29 3 - 6 - -
    Vomiting 17 2 - 5 - -
    General disorders and administration site conditions
    Fatigue 29 5 - 27 2 -
    Pyrexia 17 - - 18 2 -
    Edema peripheral 11 - - 10 - -
    Asthenia 11 2 - 8 - 2
    Skin and subcutaneous tissue disorders
    Pruritus 17 2 - 13 3 -
    Alopecia 15 - - 3 - -
    Rash maculo-papular 11 2 - 5 - -
    Pruritus generalized 11 2 - 2 - -
    Metabolism and nutrition disorders
    Decreased appetite 15 - - 5 - -
    Musculoskeletal and connective tissue disorders
    Arthralgia 12 - - 6 - -
    Myalgia 12 - - 3 - -
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 11 - - - - -

    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.


  • 7 DRUG INTERACTIONS

    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.


  • 8 USE IN SPECIFIC POPULATIONS

    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)].


  • 10 OVERDOSAGE

    There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.


  • 11 DESCRIPTION

    ADCETRIS (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components: 1) the chimeric IgG1 antibody cAC10, specific for human CD30, 2) the microtubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to cAC10.

    Structural Formula

    Brentuximab vedotin has an approximate molecular weight of 153 kDa. Approximately 4 molecules of MMAE are attached to each antibody molecule. Brentuximab vedotin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

    ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white, preservative-free lyophilized cake or powder in single-dose vials. Following reconstitution with 10.5 mL Sterile Water for Injection, USP, a solution containing 5 mg/mL brentuximab vedotin is produced. The reconstituted product contains 70 mg/mL trehalose dihydrate, 5.6 mg/mL sodium citrate dihydrate, 0.21 mg/mL citric acid monohydrate, and 0.20 mg/mL polysorbate 80 and water for injection. The pH is approximately 6.6.


  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    CD30 is a member of the tumor necrosis factor receptor family. CD30 is expressed on the surface of sALCL cells and on Hodgkin Reed-Sternberg (HRS) cells in cHL, and has limited expression on healthy tissue and cells. In vitro data suggest that signaling through CD30-CD30L binding may affect cell survival and proliferation.

    Brentuximab vedotin is an ADC. The antibody is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting agent. MMAE is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of ADCETRIS is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC‑CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells. Additionally, in vitro data provide evidence for antibody-dependent cellular phagocytosis (ADCP).

    12.2 Pharmacodynamics

    Cardiac Electrophysiology

    The effect of brentuximab vedotin (1.8 mg/kg) on the QTc interval was evaluated in an open-label, single-arm study in 46 evaluable patients with CD30-expressing hematologic malignancies. Administration of brentuximab vedotin did not prolong the mean QTc interval >10 ms from baseline. Small increases in the mean QTc interval (<10 ms) cannot be excluded because this study did not include a placebo arm and a positive control arm.

    12.3 Pharmacokinetics

    The pharmacokinetics of brentuximab vedotin were evaluated in early development trials, including dose-finding trials, and in a population pharmacokinetic analysis of data from 314 patients. The pharmacokinetics of three analytes were determined: the ADC, MMAE, and total antibody. Total antibody had the greatest exposure and had a similar PK profile as the ADC. Hence, data on the PK of the ADC and MMAE have been summarized.

    Maximum concentrations of ADC were typically observed close to the end of infusion. Exposures were approximately dose proportional from 1.2 to 2.7 mg/kg. Steady-state of the ADC was achieved within 21 days with every 3-week dosing of ADCETRIS, consistent with the terminal half-life estimate. Minimal to no accumulation of ADC was observed with multiple doses at the every 3-week schedule.

    The time to maximum concentration for MMAE ranged from approximately 1 to 3 days. Similar to the ADC, steady‑state of MMAE was achieved within 21 days with every 3 week dosing of ADCETRIS. MMAE exposures decreased with continued administration of ADCETRIS with approximately 50% to 80% of the exposure of the first dose being observed at subsequent doses.

    Distribution

    In humans, the mean steady state volume of distribution was approximately 6–10 L for ADC.

    In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs. In vitro, MMAE was a substrate of P-gp and was not a potent inhibitor of P-gp.

    Elimination

    MMAE appeared to follow metabolite kinetics, with the elimination of MMAE appearing to be limited by its rate of release from ADC.

    In pharmacokinetic analyses, a multiexponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 6 days.

           Metabolism
           In vivo data in animals and humans suggest that only a small fraction of MMAE released
           from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism
           that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver
           microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did
           not induce any major CYP450 enzymes in primary cultures of human hepatocytes.

           Excretion
           An excretion study was undertaken in patients who received a dose of 1.8 mg/kg of
           ADCETRIS. Approximately 24% of the total MMAE administered as part of the ADC during
           an ADCETRIS infusion was recovered in both urine and feces over a 1-week period. Of the
           recovered MMAE, approximately 72% was recovered in the feces and the majority of the
           excreted MMAE was unchanged.

    Specific Populations

           Renal Impairment:  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
           (CrCL >50–80 mL/min; n=4), moderate (CrCL 30–50 mL/min; n=3) and severe (CrCL
           <30 mL/min; n=3) renal impairment. In patients with severe renal impairment, the rate of
           â‰¥Grade 3 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.

           Hepatic Impairment: 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.

           Effects of Gender, Age, and Race: Based on the population pharmacokinetic analysis,
           gender, age, and race do not have a meaningful effect on the pharmacokinetics of
           brentuximab vedotin.

    Drug Interaction Studies

           CYP3A4 Inhibitors/Inducers: In vitro data indicate that monomethyl auristatin E (MMAE) is a
           substrate of CYP3A4/5. MMAE is primarily metabolized by CYP3A. Co-administration of
           ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by
           approximately 34%.

           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.

           Effects 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.


  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.

    MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

    Fertility studies with brentuximab vedotin or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility. In a 4-week repeat-dose toxicity study in rats with weekly dosing at 0.5, 5, or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed. Effects in animals were seen mainly at 5 and 10 mg/kg of brentuximab vedotin. These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on body weight.


  • 14 CLINICAL STUDIES

    14.1 Classical Hodgkin Lymphoma

    Randomized Placebo-controlled Clinical Trial in Classical Hodgkin Lymphoma Post-auto-HSCT Consolidation (Study 3: AETHERA)

    The efficacy of ADCETRIS in patients with cHL at high risk of relapse or disease progression post-auto-HSCT was studied in a randomized, double-blind, placebo-controlled clinical trial. Three hundred twenty-nine (329) patients were randomized 1:1 to receive placebo or ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles, beginning 30–45 days post-auto-HSCT. Patients in the placebo arm with progressive disease per investigator could receive ADCETRIS as part of a separate trial. The primary endpoint was progression-free survival (PFS) determined by independent review facility (IRF). Standard international guidelines were followed for infection prophylaxis for HSV, VZV, and PJP post-auto-HSCT [see Clinical Trial Experience (6.1)].

    High risk of post-auto-HSCT relapse or progression was defined according to status following frontline therapy: refractory, relapse within 12 months, or relapse ≥12 months with extranodal disease. Patients were required to have obtained a complete response (CR), partial response (PR), or stable disease (SD) to most recent pre-auto-HSCT salvage therapy.

    A total of 329 patients were enrolled and randomized (165 ADCETRIS, 164 placebo); 327 patients received study treatment. Patient demographics and baseline characteristics were generally balanced between treatment arms. The 329 patients ranged in age from 18–76 years (median, 32 years) and most were male (53%) and white (94%). Patients had received a median of 2 prior systemic therapies (range, 2–8) excluding autologous hematopoietic stem cell transplantation.

    The efficacy results are summarized in Table 8. PFS is calculated from randomization to date of disease progression or death (due to any cause). The median PFS follow-up time from randomization was 22 months (range, 0–49). Study 3 (AETHERA) demonstrated a statistically significant improvement in IRF-assessed PFS and increase in median PFS in the ADCETRIS arm compared with the placebo arm. At the time of the PFS analysis, an interim overall survival analysis demonstrated no difference.

    Table 8: Efficacy Results in Patients with Classical Hodgkin Lymphoma Post-auto-HSCT Consolidation (Study 3: AETHERA)
    + Estimates are unreliable
    *
    • Not estimable
    Progression-free Survival ADCETRIS
    N = 165
    Placebo
    N = 164
    Independent Review Facility
                Number of events (%) 60 (36) 75 (46)
                Median months (95% CI) 42.9+ (30.4, 42.9+) 24.1 (11.5, NE*)
                Stratified Hazard Ratio (95% CI) 0.57 (0.40, 0.81)
                Stratified Log-Rank Test p-value P=0.001
    Figure 1

    Clinical Trial in Relapsed Classical Hodgkin Lymphoma (Study 1)

    The efficacy of ADCETRIS in patients with cHL who relapsed after autologous hematopoietic stem cell transplantation was evaluated in one open-label, single-arm, multicenter trial. One hundred two (102) patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks. An independent review facility (IRF) performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

    The 102 patients ranged in age from 15–77 years (median, 31 years) and most were female (53%) and white (87%). Patients had received a median of 5 prior therapies including autologous hematopoietic stem cell transplantation.

    The efficacy results are summarized in Table 9. Duration of response is calculated from date of first response to date of progression or data cutoff date.

    Table 9:  Efficacy Results in Patients with Classical Hodgkin Lymphoma (Study 1)
    +Follow up was ongoing at the time of data submission
    *
    • Not estimable
      N = 102
    Percent (95% CI) Duration of Response, in months
    Median (95% CI) Range
    CR 32 (23, 42) 20.5 (12.0, NE*) 1.4 to 21.9+
    PR 40 (32, 49) 3.5 (2.2, 4.1) 1.3 to 18.7
    ORR 73 (65, 83) 6.7 (4.0, 14.8) 1.3 to 21.9+

    14.2 Systemic Anaplastic Large Cell Lymphoma

    Clinical Trial in Relapsed sALCL (Study 2)

    The efficacy of ADCETRIS in patients with relapsed sALCL was evaluated in one open-label, single-arm, multicenter trial. This trial included patients who had sALCL that was relapsed after prior therapy. Fifty-eight (58) patients were treated with 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. An IRF performed efficacy evaluations which included overall response rate (ORR = complete remission [CR] + partial remission [PR]) and duration of response as defined by clinical and radiographic measures including computed tomography (CT) and positron-emission tomography (PET) as defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).

    The 58 patients ranged in age from 14–76 years (median, 52 years) and most were male (57%) and white (83%). Patients had received a median of 2 prior therapies; 26% of patients had received prior autologous hematopoietic stem cell transplantation. Fifty percent (50%) of patients were relapsed and 50% of patients were refractory to their most recent prior therapy. Seventy-two percent (72%) were anaplastic lymphoma kinase (ALK)-negative.

    The efficacy results are summarized in Table 10. Duration of response is calculated from date of first response to date of progression or data cutoff date.

    Table 10: Efficacy Results in Patients with Systemic Anaplastic Large Cell Lymphoma (Study 2)
      N = 58
    Percent (95% CI) Duration of Response, in months
    Median (95% CI) Range
    + Follow up was ongoing at the time of data submission
    *
    • Not estimable
    CR 57 (44, 70) 13.2 (10.8, NE*) 0.7 to 15.9+
    PR 29 (18, 41) 2.1 (1.3, 5.7) 0.1 to 15.8+
    ORR 86 (77, 95) 12.6 (5.7, NE*) 0.1 to 15.9+

    14.3 Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides

    Randomized Clinical Trial in Primary Cutaneous Anaplastic Large Cell Lymphoma and CD30-expressing Mycosis Fungoides (Study 4: ALCANZA)

    The efficacy of ADCETRIS in patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or mycosis fungoides (MF) requiring systemic therapy was studied in ALCANZA, a randomized, open-label, multicenter clinical trial. In ALCANZA, one hundred thirty-one (131) patients were randomized 1:1 to receive ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks or physician’s choice of methotrexate (5 to 50 mg orally weekly) or bexarotene (300 mg/m2 orally daily). The randomization was stratified by baseline disease diagnosis (MF or pcALCL). Patients could receive a maximum of 16 cycles (21-day cycle) of therapy every 3 weeks for those receiving brentuximab vedotin or 48 weeks of therapy for those in the control arm.

    Patients with pcALCL must have received prior radiation or systemic therapy, and must have at least 1 biopsy with CD30-expression of ≥10%. Patients with MF must have received prior systemic therapy and have had skin biopsies from at least 2 separate lesions, with CD30-expression of ≥10% in at least 1 biopsy.

    A total of 131 patients were randomized (66 ADCETRIS, 65 physician’s choice). The efficacy results were based on 128 patients (64 patients in each arm with CD30-expression of ≥10% in at least one biopsy). Among 128 patients, the patients’ age ranged from 22–83 years (median, 60 years) and 55% of them were male and 85% of them were white. Patients had received a median of 4 prior systemic therapies (range, 0–15), including a median of 1 prior skin-directed therapy (range, 0–9) and 2 systemic therapies (range, 0–11). At study entry, patients were diagnosed as Stage 1 (25%), Stage 2 (38%), Stage 3 (5%), or Stage 4 (13%).

    Efficacy was established based on the proportion of patients achieving an objective response (CR +PR) that lasts at least 4 months (ORR4). ORR4 was determined by independent review facility (IRF) using the global response score (GRS), consisting of skin evaluations per modified severity-weighted assessment tool (mSWAT), nodal and visceral radiographic assessment, and detection of circulating Sézary cells (MF patients only). Additional efficacy outcome measures included proportion of patients achieving a complete response (CR) per IRF, and progression-free survival (PFS) per IRF.

    The efficacy results are summarized in Table 11 below and the Kaplan-Meier curves of IRF-Assessed Progression-free Survival are shown in Figure 2.

    Table 11:       Efficacy Results in Patients with Relapsed pcALCL or CD30-expressing MF (Study 4: ALCANZA)
    a physician’s choice of either methotrexate or bexarotene.
    b ORR4 is defined as proportion of patients achieving an objective response (CR +PR) that lasts at least 4 months
    c CI=Confidence Interval ;
    d test of the treatment difference was stratified by baseline disease diagnosis (MF or pcALCL)
    e adjusted for multiplicity
      ADCETRIS
    N = 64
    Physician’s Choicea
    N = 64
    ORR4b
                Percent (95% CIc) 56.3 (44.1, 68.4) 12.5 (4.4, 20.6)
    P-valued  <0.001
    ORR 67.2 (55.7, 78.7) 20.3 (10.5, 30.2)
    CR
    Percent (95% CIc) 15.6 (7.8, 26.9) 1.6 (0, 8.4)
    P-valued,e 0.0066
    PR 51.6 (39.3, 63.8) 18.8 (9.2, 28.3)
    PFS
                Number of events (%) 36 (56.3) 50 (78.1)
                Median months (95% CIc) 16.7 (14.9, 22.8) 3.5 (2.4, 4.6)
                Hazard Ratioc (95% CIc) 0.27 (0.17, 0.43)
                Log-Rank Test p-valued,e p<0.001
    Figure 2

    Supportive trials include 2 single-arm trials which enrolled patients with MF and were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks. Out of 73 patients with MF from the 2 pooled supportive trials, 34% (25/73) achieved ORR4. Among these 73 patients, 35 had 1% to 9% CD30-expression and 31% (11/35) achieved ORR4.


  • 15 REFERENCES

    1. OSHA Hazardous Drugs. OSHA. [Accessed on 30 July 2013, from
      http://www.osha.gov/SLTC/hazardousdrugs/index.html]

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    ADCETRIS (brentuximab vedotin) for Injection is supplied as a sterile, white to off-white preservative-free lyophilized cake or powder in individually-boxed single-dose vials:

    • NDC (51144-050-01), 50 mg brentuximab vedotin.

    16.2 Storage

    Store vial at 2–8°C (36–46°F) in the original carton to protect from light.

    16.3 Special Handling

    ADCETRIS is an antineoplastic product. Follow special handling and disposal procedures1.


  • 17 PATIENT COUNSELING INFORMATION

    Peripheral Neuropathy

    Advise patients that ADCETRIS can cause a peripheral neuropathy. They should be advised to report to their health care provider any numbness or tingling of the hands or feet or any muscle weakness [see Warnings and Precautions (5.1)].

    Fever/Neutropenia

    Advise patients to contact their health care provider if a fever of 100.5°F or greater or other evidence of potential infection such as chills, cough, or pain on urination develops [see Warnings and Precautions (5.3)].

    Infusion Reactions

    Advise patients to contact their health care provider if they experience signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.2)].

    Hepatotoxicity

    Advise patients to report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.8)].

    Progressive Multifocal Leukoencephalopathy

    Instruct patients receiving ADCETRIS to immediately report if they have any of the following neurological, cognitive, or behavioral signs and symptoms or if anyone close to them notices these signs and symptoms [see Boxed Warning, Warnings and Precautions (5.9)]:

           changes in mood or usual behavior
           confusion, thinking problems, loss of memory
           changes in vision, speech, or walking
           decreased strength or weakness on one side of the body

    Pulmonary Toxicity

    Instruct patients to report symptoms that may indicate pulmonary toxicity, including cough or shortness of breath [see Warnings and Precautions (5.10)].

    Acute Pancreatitis

    Advise patients to contact their health care provider if they develop severe abdominal pain [see Warnings and Precautions (5.12)].

    Gastrointestinal Complications

    Advise patients to contact their health care provider if they develop severe abdominal pain, chills, fever, nausea, vomiting, or diarrhea [see Warnings and Precautions (5.12)].

    Females and Males of Reproductive Potential

    ADCETRIS 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 ADCETRIS.

    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 [see Use in Specific Populations (8.3)].

    Advise patients to report pregnancy immediately [see Warnings and Precautions (5.13)].

    Lactation

    Advise patients to avoid breastfeeding while receiving ADCETRIS [see Use in Specific Populations (8.2)].

    Seattle Genetics

    Manufactured by:
    Seattle Genetics, Inc.
    Bothell, WA 98021
    1-855-473-2436
    U.S. License 1853

    ADCETRIS, Seattle Genetics and Trademark Logo are US registered trademarks of Seattle Genetics, Inc. © 2017 Seattle Genetics, Inc., Bothell, WA 98021.  All rights reserved.


  • PACKAGE LABEL

    NDC 51144-050-01

    ADCETRIS®

    (brentuximab vedotin)
    FOR INJECTION

    50 mg/vial

    Single-use vial.

    Discard unused portion.

    Reconstitution and dilution required

    For intravenous use only

    Rx Only

    SeattleGenetics®

    Carton Label

  • INGREDIENTS AND APPEARANCE
    ADCETRIS  
    brentuximab vedotin injection, powder, lyophilized, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51144-050
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    Brentuximab Vedotin (UNII: 7XL5ISS668) (Brentuximab Vedotin - UNII:7XL5ISS668) Brentuximab Vedotin 50 mg  in 10.5 mL
    Inactive Ingredients
    Ingredient Name Strength
    Trehalose Dihydrate (UNII: 7YIN7J07X4)  
    Trisodium Citrate Dihydrate (UNII: B22547B95K)  
    Citric Acid Monohydrate (UNII: 2968PHW8QP)  
    Polysorbate 80 (UNII: 6OZP39ZG8H)  
    Product Characteristics
    Color WHITE (off-white) Score     
    Shape Size
    Flavor Imprint Code
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:51144-050-01 1 in 1 BOX 08/25/2011
    1 10.5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA125388 08/25/2011
    Labeler - Seattle Genetics, Inc. (028484371)
    Establishment
    Name Address ID/FEI Business Operations
    PIERRE FABRE MEDICAMENT PRODUCTION 504638276 analysis(51144-050) , manufacture(51144-050)
    Establishment
    Name Address ID/FEI Business Operations
    BSP Pharmaceuticals Srl 857007830 analysis(51144-050) , manufacture(51144-050)
    Establishment
    Name Address ID/FEI Business Operations
    Seattle Genetics, Inc. 028484371 analysis(51144-050)
    Establishment
    Name Address ID/FEI Business Operations
    Covance Laboratories 213137276 analysis(51144-050)
    Establishment
    Name Address ID/FEI Business Operations
    Baxter Oncology GmbH 344276063 manufacture(51144-050) , analysis(51144-050)