The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:
- Peripheral neuropathy [see WARNINGS AND PRECAUTIONS]
- Anaphylaxis and Infusion Reactions [see WARNINGS AND PRECAUTIONS]
- Hematologic Toxicities [see WARNINGS AND PRECAUTIONS]
- Serious Infections and Opportunistic Infections [see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Increased Toxicity in the Presence of Severe Renal Impairment [see WARNINGS AND PRECAUTIONS]
- Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Progressive Multifocal Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
- Serious Dermatologic Reactions [see WARNINGS AND PRECAUTIONS]
- Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
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.
ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, 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 trial, regardless of causality, using the NCI Common Toxicity Criteria Version 3.0, are shown in Table 2.
Experience in Hodgkin Lymphoma
ADCETRIS was studied in 102 patients with 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 27 weeks (range, 3 to 56 weeks) [see Clinical Studies].
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.
In another clinical trial in patients with 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].
Experience in Systemic Anaplastic Large Cell Lymphoma
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 24 weeks (range, 3 to 56 weeks) [see Clinical Studies].
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
|Adverse Reaction||HL Total
N = 102 % of patients
N = 58 % of patients
|Any Grade||Grade 3||Grade 4||Any Grade||Grade 3||Grade 4|
|Blood and lymphatic system disorders|
|Nervous system disorders|
|Peripheral sensory neuropathy||52||8||-||53||10||-|
|Peripheral motor neuropathy||16||4||-||7||3||-|
|General disorders and administration site conditions|
|Infections and infestations|
|Upper respiratory tract infection||47||-||-||12||-||-|
|Skin and subcutaneous tissue disorders|
|Respiratory, thoracic and mediastinal disorders|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||10||-||-||10||2||2|
|Metabolism and nutrition disorders|
|*Derived from laboratory values and adverse reaction data|
Two cases of anaphylaxis were reported in phase 1 trials. There were no Grade 3 or 4 infusion-related reactions reported in the phase 2 trials, however, Grade 1 or 2 infusion-related reactions were reported for 19 patients (12%). 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%).
Serious Adverse Reactions
In the phase 2 trials, serious adverse reactions, regardless of causality, were reported in 31% of patients receiving ADCETRIS. The most common serious adverse reactions experienced by patients with 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.
Adverse reactions that led to dose delays in more than 5% of patients were neutropenia (14%) and peripheral sensory neuropathy (11%) [see DOSAGE AND ADMINISTRATION].
Adverse reactions led to treatment discontinuation in 21% of patients. Adverse reactions that led to treatment discontinuation in 2 or more patients with HL or sALCL were peripheral sensory neuropathy (8%) and peripheral motor neuropathy (3%).
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].
Hepatobiliary disorders: hepatotoxicity [see WARNINGS AND PRECAUTIONS].
Infections: PML [see BOXED WARNING, WARNINGS AND PRECAUTIONS], serious infections and opportunistic infections [see WARNINGS AND PRECAUTIONS].
Metabolism and nutrition disorders: hyperglycemia.
Gastrointestinal disorders: Pancreatitis (including fatal outcomes). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain.
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, including fatal outcomes [see WARNINGS AND PRECAUTIONS].
Patients with HL and sALCL in the phase 2 trials [see Clinical Studies] 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 antibrentuximab 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.