The following adverse reactions are discussed in greater detail in other sections of the labeling.
- Immune-mediated enterocolitis [see WARNINGS AND PRECAUTIONS].
- Immune-mediated hepatitis [see WARNINGS AND PRECAUTIONS].
- Immune-mediated dermatitis [see WARNINGS AND PRECAUTIONS].
- Immune-mediated neuropathies [see WARNINGS AND PRECAUTIONS].
- Immune-mediated endocrinopathies [see WARNINGS AND PRECAUTIONS].
- Other immune-mediated adverse reactions, including ocular manifestations [see WARNINGS AND PRECAUTIONS].
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.
The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY 3 mg/kg for 4 doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range: 1–4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.
The most common adverse reactions ( ≥ 5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.
Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.
Table 1: Selected Adverse Reactions in Study 1
|System Organ Class/ Preferred Term||Percentage (%) of Patientsa|
|YERVOY 3 mg/kg
|YERVOY 3 mg/kg + gp100
|Any Grade||Grade 3–5||Any Grade||Grade 3–5||Any Grade||Grade 3–5|
|Skin and Subcutaneous Tissue Disorders|
|General Disorders and Administration Site Conditions|
|a Incidences presented in this table are based on reports of adverse events regardless of causality.|
Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.
Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1
|Percentage (%) of Patients|
|YERVOY 3 mg/kg
|YERVOY 3 mg/kg + gp100
|Any Immune-mediated Adverse Reaction||15||12|
|a Including fatal outcome.
bIncluding intestinal perforation.
c Underlying etiology not established.
Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.
Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.
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 YERVOY with the incidences of antibodies to other products may be misleading.