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, 6.2).

— RECENT MAJOR CHANGES

Indications and Usage (1.2) 08/2015
Dosage and Administration (2.1) 08/2015
Warnings and Precautions (5) 03/2016

— INDICATIONS AND USAGE

ADCETRIS is a CD30-directed antibody-drug conjugate indicated for the 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.

— 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).

— DOSAGE FORMS AND STRENGTHS

For injection: 50 mg lyophilized powder in a single-use 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:

  • 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.

— 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: Breastfeeding not recommended (8.2).


See 17 for PATIENT COUNSELING INFORMATION.

Revised: 03/2016

 

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
1 INDICATIONS AND USAGE
1.1 Classical Hodgkin Lymphoma (HL)
1.2 Classical Hodgkin Lymphoma (HL) Post-auto-HSCT Consolidation
1.3 Systemic Anaplastic Large Cell Lymphoma (sALCL)
2 DOSAGE AND ADMINISTRATION
2.1 Dosage Recommendations
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
7.2 Effect of ADCETRIS on Other Drugs
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
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.

 

FULL PRESCRIBING INFORMATION

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

JC virus infection resulting in PML and death can occur in patients receiving
ADCETRIS [see Warnings and Precautions (5.9), Adverse Reactions (6.1)].

1 INDICATIONS AND USAGE

1.1 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.

2 DOSAGE AND ADMINISTRATION

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.

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 the relapsed classical HL and sALCL clinical trials, 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. 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, the infusion should be interrupted and appropriate medical management instituted. 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. Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered 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. Patients should be closely monitored 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 (CLcr) <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

Fatal and serious gastrointestinal (GI) complications including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, 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 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)]

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 Total N = 58
  % of patients % of patients
Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders            
 Neutropenia* 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 -

*Derived from laboratory values and adverse reaction data

Table 3: Most Commonly Reported (≥10% in the ADCETRIS arm) Adverse Reactions in Study 3
  ADCETRIS Placebo
  Total N = 167 Total N = 160
  % of patients % of patients
Adverse Reaction Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Blood and lymphatic system disorders            
 Neutropenia*783093464
 Thrombocytopenia*41242032
 Anemia*274-192-
Nervous system disorders
 Peripheral sensory neuropathy5610-161-
 Peripheral motor neuropathy236-21-
 Headache112-81-
Infections and infestations
 Upper respiratory tract infection26--231-
General disorders and administration site conditions
 Fatigue242-183-
 Pyrexia192-16--
 Chills10--5--
Gastrointestinal disorders
 Nausea223-8--
 Diarrhea202-101-
 Vomiting162-7--
 Abdominal pain142-3--
 Constipation132-3--
Respiratory, thoracic and mediastinal disorders
 Cough21--16--
 Dyspnea13--6-1
Investigations
 Weight decreased191-6--
Musculoskeletal and connective tissue disorders
 Arthralgia181-9--
 Muscle spasms11--6--
 Myalgia111-4--
Skin and subcutaneous tissue disorders
 Pruritus121-8--
Metabolism and nutrition disorders
 Decreased appetite121-6--

*Derived from laboratory values and adverse reaction data

 

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 HL 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, 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.

7 DRUG INTERACTIONS

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5. In vitro data indicate that MMAE is also a substrate of the efflux transporter P‑glycoprotein (P‑gp).

7.1 Effect of Other Drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: 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: 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

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.

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.

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

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.

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.

Image of ADCETRIS (brentuximab vedotin) MMAE chemical structure

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-use 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

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.

12.2 Pharmacodynamics

QT/QTc Prolongation Potential

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.

Absorption

Maximum concentrations of ADC were typically observed close to the end of infusion. A multiexponential decline in ADC serum concentrations was observed with a terminal half-life of approximately 4 to 6 days. 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 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.

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

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.

Elimination

MMAE appeared to follow metabolite kinetics, with the elimination of MMAE appearing to be limited by its rate of release from ADC. 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: [see Use in Specific Populations (8.6)].

Hepatic Impairment: [see Use in Specific Populations (8.7)].

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.

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

Clinical Trial in Relapsed Classical HL (Study 1)

The efficacy of ADCETRIS in patients with classical HL who relapsed after autologous hematopoietic stem cell transplantation was evaluated in one open-label, single-arm, multicenter trial. One hundred two 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 4. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 4: Efficacy Results in Patients with Classical Hodgkin Lymphoma (Study 1)
  N=102
  Percent (95% Cl) Duration of Response, in months
Median (95% Cl) 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+

*Not estimable
+ Follow up was ongoing at the time of data submission.

 

Randomized Placebo-controlled Clinical Trial in Classical HL Post-auto-HSCT Consolidation (Study 3)

The efficacy of ADCETRIS in patients with classical HL 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 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 IRF. Standard international guidelines were followed for infection prophylaxis for HSV, VZV, and PCP post-auto-HSCT [see Clinical Studies (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 CR, 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 5. 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 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 5: Efficacy Results in Patients with Classical HL Post-auto-HSCT Consolidation (Study 3)

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)
Stratified Log-Rank Test P-value
0.57 (0.40, 0.81)
P=0.001

*Not estimable
+ Estimates are unreliable

 

Figure 1: Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival (Study 3)
Kaplan-Meier Curve of IRF-Assessed Progression-Free Survival (Study 3)

BV: Brentuximab Vedotin; BSC: Best Supportive Care

 

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 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 6. Duration of response is calculated from date of first response to date of progression or data cutoff date.

Table 6: Efficacy Results in Patients with Systemic Anaplastic Large Cell Lymphoma (Study 2)
  N=58
  Percent (95% Cl) Duration of Response, in months
Median (95% Cl) Range
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+

*Not estimable
+ Follow up was ongoing at the time of data submission.

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-use 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 procedures.1

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)].
  • Pancreatitis
    Advise patients to contact their health care provider if they develop severe abdominal pain [see Adverse Reactions (6.2)].
  • 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)].

 

SeattleGenetics logo

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

ADCETRIS, Seattle Genetics and SeaGen symbol are US registered trademarks of Seattle Genetics, Inc.

Indications

  • In classical Hodgkin lymphoma (HL), ADCETRIS is indicated for use in patients with classical HL at high risk of relapse or progression as consolidation treatment after stem cell transplantation.
  • ADCETRIS is indicated for the treatment of patients with classical HL after failure of a stem cell transplant, or for patients with classical HL who are unable to receive a stem cell transplant and have previously failed at least 2 treatments with combinations of chemotherapy medicines.
  • In systemic anaplastic large cell lymphoma (sALCL), ADCETRIS is indicated for use after failure with at least 1 previous treatment with a combination of chemotherapy medicines.

The effectiveness of ADCETRIS in sALCL is based on studies in which patients’ tumors became smaller. Currently, it is not known whether or not ADCETRIS helps patients feel better or live longer.

Important Safety Information

What is the Most Important Serious Safety Information I Should Know About ADCETRIS (brentuximab vedotin)?

  • Progressive multifocal leukoencephalopathy (PML): A rare but serious infection of the brain that can lead to death and can occur in ADCETRIS-treated patients. Cases occurred at different times from the start of ADCETRIS therapy, some within 3 months. Possible causes other than ADCETRIS-treatment include previous therapies and diseases that may weaken your immune system.
  • ADCETRIS should not be taken with bleomycin because of possible side effects in the lungs.

What are the Other Possible Serious Side Effects of ADCETRIS?

  • Nerve damage: Peripheral neuropathy (nerve damage) that mostly involves numbness or tingling in the hands or feet (sensory) and/or weakness in the arms or legs (motor). Symptoms increase with more doses. Your doctor may change or stop your ADCETRIS dose depending on the severity of your symptoms.
  • Allergic and infusion reactions: Allergic reactions, including severe forms, during infusion or up to 24 hours after administration of ADCETRIS. Patients who had a reaction with earlier doses should receive premedication with later doses, which may include acetaminophen, an antihistamine, and a corticosteroid.
  • Blood problems: Low number of white blood cells lasting a week or more, with or without fever. Low number of platelets (which help the blood clot) and low number of red blood cells. Your blood counts will be checked before each dose, more often if necessary. You will be monitored for fever. If your white blood cell count is too low, your doctor may delay your next infusion, lower your dose, stop your ADCETRIS therapy, or give you a medicine called growth factor with future doses of ADCETRIS.
  • Infections: Serious infections that occur when your immune system is weakened, such as pneumonia, bacteremia, and sepsis or septic shock (including deaths).
  • Tumor lysis syndrome (TLS): You will be closely monitored for TLS if you have a tumor that grows quickly or have many tumor cells throughout your body.
  • Patients with severe kidney disease: May have more side effects and deaths compared to patients with normal kidney function and should avoid use of ADCETRIS.
  • Patients with moderate or severe liver disease: May have more side effects and deaths compared to patients with normal liver function and should avoid use of ADCETRIS.
  • Liver injury: Liver problems (including deaths) have been reported after the first dose of ADCETRIS and after ADCETRIS was stopped and restarted. Your liver function will be monitored. Having liver problems, raised liver enzymes, and some medicines may increase the risk. Your doctor may delay your next infusion, lower your dose, or stop your ADCETRIS therapy if you have liver problems.
  • Lung problems: Lung problems, including deaths, have been reported. If you have symptoms, your doctor may hold your ADCETRIS therapy until they improve.
  • Skin problems: Rare but serious skin conditions (including deaths) called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). If either occurs, your doctor will stop ADCETRIS and treat you for symptoms.
  • Gastrointestinal (GI) problems: Stomach and intestine problems, including deaths, have been reported. Lymphoma that involves the stomach or intestine may increase the risk of GI perforation (hole in the stomach or intestine).
  • Fetal harm: ADCETRIS can harm a fetus (unborn baby). Women should not become pregnant while taking ADCETRIS and for at least 6 months after the last dose of ADCETRIS.

What Were the Most Common Side Effects in Clinical Trials?

ADCETRIS was studied by itself in 160 patients in two clinical trials in patients with relapsed classical HL and relapsed sALCL. Across both trials, the most common side effects were a low number of white blood cells, tingling or numbness in the hands or feet, feeling tired, nausea, a low number of red blood cells, an infection in the upper respiratory tract, diarrhea, fever, rash, a low number of platelets (which help the blood clot), cough, and vomiting.

ADCETRIS was studied in a trial with 329 patients with classical HL at high risk of relapse or progression after stem cell transplantation. The most common side effects in patients who received ADCETRIS (167 patients), were a low number of white blood cells, tingling or numbness in the hands or feet, a low number of platelets (which help the blood clot), a low number of red blood cells, an infection in the upper respiratory tract, feeling tired, trouble moving the hands or feet, nausea, cough, and diarrhea.

What Should I Tell My Doctor Before I Start Treatment with ADCETRIS® (brentuximab vedotin) for Injection?

  • Tell your doctor about all of your medical conditions. ADCETRIS should be avoided if you have severe kidney disease or moderate or severe liver disease or other liver problems.
  • Tell your doctor about any medicine you are taking (including over-the-counter drugs, vitamins, and herbal supplements) because it is possible for ADCETRIS to interact with certain types of drugs.
  • Tell your doctor if you are pregnant or plan to become pregnant. You should not take ADCETRIS while pregnant or breastfeeding.
  • Women should use effective birth control while taking ADCETRIS and for at least 6 months after the final dose of ADCETRIS.
  • Men with female partners should use effective birth control while taking ADCETRIS and for at least 6 months after the final dose of ADCETRIS.

Contact Your Doctor if You Experience Any of the Following:

  • Symptoms of nerve damage: Tingling, burning, or numbness in the hands or feet. Changes in sense of touch or trouble moving the hands or feet.
  • Symptoms of infection: Fever of 100.5° or higher, chills, cough, or pain upon urination.
  • Symptoms of infusion reaction: Fever, chills, rash, or breathing problems within 24 hours of infusion.
  • Symptoms of liver injury: Fatigue, anorexia, upper stomach pain, dark urine, yellowing of the skin and eyes (jaundice).
  • Symptoms of PML: Changes in mood or usual behavior. Confusion, thinking problems, or loss of memory. Changes in vision, speech, or walking. Decreased strength or weakness on one side of the body.
  • Symptoms of pancreatitis: Severe abdominal pain.
  • Symptoms of lung problems: New or worsening cough or shortness of breath.
  • Symptoms of GI problems: Severe stomach pain, chills, fever, nausea, vomiting, or diarrhea.
  • Pregnancy: Pregnant or breastfeeding women should not receive ADCETRIS.
  • Any other side effects that are bothersome or do not go away.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/Safety/MedWatch or call 1-800-FDA-1088.


For additional Important Safety Information, including BOXED WARNING, please see the full Prescribing Information for ADCETRIS.