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 a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.
 Percentage (%) of Patients
 YERVOY
3 mg/kg
n=131 YERVOY
3 mg/kg+gp100
n=380
Any Immune-mediated Adverse Reaction 15 12
Enterocolitisa,b 7 7
Hepatotoxicitya 1 2
Dermatitisa 2 3
Neuropathya 1 <1
Endocrinopathy 4 1
Hypopituitarism 4 1
Adrenal insufficiency 0 1
Other  
Pneumonitis 0 <1
Meningitis 0 <1
Nephritis 1 0
Eosinophiliac 1 0
Pericarditisa,c 0
a Including fatal outcome.
b Including intestinal perforation.
c Underlying etiology not established.
 Percentage (%) of Patients
 YERVOY
3 mg/kg
n=131 YERVOY
3 mg/kg+gp100
n=380
Any Immune-mediated Adverse Reaction 15 12
Enterocolitisa,b 7 7
Hepatotoxicitya 1 2
Dermatitisa 2 3
Neuropathya 1 <1
Endocrinopathy 4 1
Hypopituitarism 4 1
Adrenal insufficiency 0 1
Other  
Pneumonitis 0 <1
Meningitis 0 <1
Nephritis 1 0
Eosinophiliac 1 0
Pericarditisa,c 0 <1

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.

6.2 Immunogenicity
In clinical studies, 1.1% of 1024 eva luable 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 eva luable 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.

7 DRUG INTERACTIONS
No formal drug-drug interaction studies have been conducted with YERVOY.

8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined study of embryo-fetal and peri-postnatal development, s