Ipilimumab

• Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2)
• Unresectable or Metastatic Melanoma : ∘ YERVOY 3 mg/kg every 3 weeks for a maximum of 4 doses. (2.2) ∘ YERVOY 3 mg/kg immediately following nivolumab 1 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in the Full Prescribing Information for nivolumab. (2.2)
• Adjuvant Treatment of Melanoma : YERVOY 3 mg/kg every 3 weeks for 4 doses, followed by 3 mg/kg every 12 weeks for up to 4 additional doses. (2.2)
• Advanced Renal Cell Carcinoma : YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2)
• Treatment of microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in combination with nivolumab : ∘ Adult and pediatric patients weighing 40 kg or greater: YERVOY 1 mg/kg immediately following nivolumab 240 mg on the same day every 3 weeks for a maximum of 4 doses. After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2) ∘ Pediatric patients weighing less than 40 kg: YERVOY 1 mg/kg immediately following nivolumab 3 mg/kg on the same day every 3 weeks for a maximum of 4 doses. After completing the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. ( 2.2 )
• Hepatocellular Carcinoma : YERVOY 3 mg/kg intravenously over 30 minutes immediately following nivolumab 1 mg/kg intravenously over 30 minutes on the same day, every 3 weeks for up to 4 doses. After completing up to 4 doses of the combination, administer nivolumab as a single agent as recommended in Full Prescribing Information for nivolumab. (2.2)
• Metastatic non-small cell lung cancer : ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. (2.2) ∘ YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2)
• Malignant pleural mesothelioma : YERVOY 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks. (2.2)
• Esophageal squamous cell carcinoma: YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks. (2.2)
• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.

2.1 Patient Selection Information on FDA-authorized tests for patient selection is available at: https://www.fda.gov/CompanionDiagnostics Non-Small Cell Lung Cancer

• Select patients with metastatic NSCLC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.6) ] . Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer
• Select patients with metastatic colorectal cancer for treatment with YERVOY in combination with nivolumab based on the presence of MSI-H or dMMR status in tumor specimens [see Clinical Studies (14.4) ] . Esophageal Cancer
• Select patients with unresectable or advanced or metastatic ESCC for treatment with YERVOY in combination with nivolumab based on PD-L1 expression [see Clinical Studies (14.8) ] . ∘ An FDA-authorized companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available.

2.2 Recommended Dosage The recommended dosages of YERVOY as a single agent are presented in Table 1. Administer YERVOY as a 30-minute intravenous infusion [see Preparation and Administration (2.4) ] . Table 1: Recommended Dosages for YERVOY as a Single Agent Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks Maximum of 4 doses Adjuvant treatment of melanoma 3 mg/kg every 3 weeks followed by 3 mg/kg every 12 weeks Every 3 weeks up to a maximum of 4 doses Every 12 weeks for up to 4 additional doses The recommended dosages of YERVOY in combination with other therapeutic agents are presented in Table 2. Administer YERVOY on the same day as other therapeutic agents. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with YERVOY for recommended dosage information, as appropriate. Table 2: Recommended Dosages of YERVOY in Combination with Other Therapeutic Agents* * Refer to the Prescribing Information for the agents administered in combination with YERVOY for recommended dosing information, as appropriate. † Refer to the Prescribing Information for nivolumab for dosage information after completing use in combination with YERVOY. Indication Recommended YERVOY Dosage Duration of Therapy Unresectable or metastatic melanoma 3 mg/kg every 3 weeks with nivolumab 1 mg/kg In combination with nivolumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of combination therapy, administer nivolumab as a single agent until disease progression or unacceptable toxicity. † Advanced renal cell carcinoma 1 mg/kg every 3 weeks with nivolumab 3 mg/kg In combination with nivolumab for a maximum of 4 doses. After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity. † Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Adult patients and pediatric patients age 12 years and older and weighing 40 kg or more: 1 mg/kg every 3 weeks with nivolumab 240 mg In combination with nivolumab for a maximum of 4 doses. † After completing 4 doses of combination therapy, administer nivolumab as single agent until disease progression, unacceptable toxicity, or up to 2 years. † Pediatric patients age 12 years and older and weighing less than 40 kg: 1 mg/kg every 3 weeks with nivolumab 3 mg/kg Hepatocellular carcinoma 3 mg/kg every 3 weeks with nivolumab 1 mg/kg In combination with nivolumab for a maximum of 4 doses. After completing a maximum of 4 doses of combination therapy, administer nivolumab as single agent until disease progression or unacceptable toxicity. † Metastatic non-small cell lung cancer expressing PD‑L1 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † Metastatic or recurrent non-small cell lung cancer 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks and histology-based platinum‑doublet chemotherapy every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † 2 cycles of histology-based platinum-doublet chemotherapy Malignant pleural mesothelioma 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. † Esophageal squamous cell carcinoma 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks In combination with nivolumab until disease progression, unacceptable toxicity, or up to 2 years.

2.3 Recommended Dosage Modifications for Adverse Reactions No dose reduction for YERVOY is recommended. In general, withhold YERVOY for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue YERVOY for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, persistent moderate (Grade 2) or severe (Grade 3) reactions lasting 12 weeks or longer after last YERVOY dose (excluding endocrinopathy), or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for YERVOY or YERVOY in combination with nivolumab for adverse reactions that require management different from these general guidelines are summarized in Table 3. When YERVOY is administered in combination with nivolumab, withhold or permanently discontinue both YERVOY and nivolumab for toxicity. Table 3: Recommended Dosage Modifications for Adverse Reactions ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit of normal * Based on Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 a Resume in patients with complete or partial resolution (Grade 0 or 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST/ALT are less than or equal to ULN at baseline, withhold or permanently discontinue YERVOY based on recommendations for hepatitis with no liver involvement. c This guidance is only applicable to HCC patients who are being treated with YERVOY in combination with nivolumab. d Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. Adverse Reaction Severity* Dosage Modifications Immune-Mediated Adverse Reactions [See Warnings and Precautions (5.1) ] Colitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC AST or ALT increases to more than 3 times and up to 5 times the ULN or Total bilirubin increases to more than 1.5 times and up to 3 times the ULN Withhold a AST or ALT more than 5 times the ULN or Total bilirubin more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver b /HCC c Baseline AST/ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST/ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN. Withhold a AST/ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN. Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Endocrinopathies d Grades 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Ophthalmologic Grade 2, 3, or 4 that does not improve to Grade 1 within 2 weeks while receiving topical therapy or that requires systemic treatment Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue 2.4 Preparation and Administration

• Do not shake product.
• Visually inspect for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is foreign particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution
• Allow the vial(s) to stand at room temperature for approximately 5 minutes prior to preparation of infusion.
• Withdraw the required volume of YERVOY and transfer into an intravenous bag.
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration ranging from 1 mg/mL to 2 mg/mL . Mix diluted solution by gentle inversion.
• After preparation, store the diluted solution either refrigerated at 2°C to 8°C (36°F to 46°F) or at room temperature of 20°C to 25°C (68°F to 77°F) for no more than 24 hours from the time of preparation to the time of infusion.
• Discard partially used or empty vials of YERVOY. Administration
• Do not co-administer other drugs through the same intravenous line.
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose.
• Administer diluted YERVOY solution by intravenous infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter.
• When administered in combination with nivolumab, infuse nivolumab first followed by YERVOY on the same day.
• When administered with nivolumab and platinum-doublet chemotherapy, infuse nivolumab first followed by YERVOY and then platinum-doublet chemotherapy on the same day.
• Use separate infusion bags and filters for each infusion.

5 WARNINGS AND PRECAUTIONS

• Severe and Fatal Immune-Mediated Adverse Reactions : Immune-mediated adverse reactions (IMAR) can occur in any organ system or tissue, including the following: immune-mediated colitis, immune-mediated hepatitis, immune-mediated dermatologic adverse reactions, immune-mediated endocrinopathies, immune-mediated pneumonitis, and immune-mediated nephritis with renal dysfunction, and can occur at any time during treatment or after discontinuation. Monitor for symptoms and signs that may be clinical manifestations of IMAR. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level and thyroid function including at baseline and before each dose. In general, withhold YERVOY for severe (grade 3) and permanently discontinue for life-threatening (grade 4) immune-mediated adverse reactions. See Full Prescribing Information for additional dosage modifications. ( 2.3 , 5.1 )
• Infusion-Related Reactions : Discontinue for severe and life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions. ( 2.3 , 5.2 )
• Complications of allogeneic HSCT : Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with YERVOY. (5.3)
• Embryo-Fetal Toxicity : Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 )

5.1 Severe and Fatal Immune-Mediated Adverse Reactions YERVOY is a fully human monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response with the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting YERVOY. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of YERVOY. Early identification and management are essential to ensure safe use of YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3) ]. In general, if YERVOY requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Immune-Mediated Colitis YERVOY can cause immune-mediated colitis, which may be fatal. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. YERVOY 3 mg/kg as a Single Agent Immune-mediated colitis occurred in 12% (62/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (7%) and Grade 2 (5%). Colitis led to permanent discontinuation of YERVOY in 4.3% and withholding of at least one dose of YERVOY in 0.2% of patients. Systemic corticosteroids were required in 74% (46/62) of patients with immune-mediated colitis. Five patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 76% of the 62 patients. One patient was withheld one or more doses of YERVOY for colitis, and no patient received additional treatment after symptom improvement. YERVOY 1 mg/kg with 3 mg/kg Nivolumab Immune-mediated colitis occurred in 9% (60/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (4.4%), and Grade 2 (3.7%). Colitis led to permanent discontinuation of YERVOY and nivolumab in 3.2% and withholding of YERVOY and nivolumab in 2.7% of patients. In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated colitis. Systemic corticosteroids were therefore required in 100% (60/60) of patients with immune-mediated colitis. Approximately 23% of patients required coadministration of another immunosuppressant with corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom YERVOY or nivolumab was withheld for colitis, 16 received additional treatment after symptom improvement; of these, 10 had recurrence of colitis. YERVOY 3 mg/kg with 1 mg/kg Nivolumab Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of YERVOY with nivolumab in 14% and withholding of treatment in 4.4% of patients. Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of 115 patients. Of the 20 patients in whom YERVOY with nivolumab was withheld for colitis, 16 reinitiated treatment after symptom improvement, and 9 had recurrence of colitis. Immune-Mediated Hepatitis YERVOY 3 mg/kg as a Single Agent Immune-mediated hepatitis occurred in 4.1% (21/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (1.6%) and Grade 2 (2.5%). Hepatitis led to permanent discontinuation of YERVOY in 0.4% of patients and withholding of at least one dose of YERVOY in none of the patients. Systemic corticosteroids were required in 29% (6/21) of patients with immune-mediated hepatitis. No patients required the coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 86% of the 21 patients. YERVOY 3 mg/kg with Vemurafenib The safety and effectiveness of YERVOY in combination with vemurafenib have not been established [see Indications and Usage (1) ] . In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg or 720 mg twice daily). YERVOY 1 mg/kg with 3 mg/kg Nivolumab Immune-mediated hepatitis occurred in 7% (48/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%). Hepatitis led to permanent discontinuation of YERVOY and nivolumab in 3.6% and withholding of YERVOY and nivolumab in 2.6% of patients. In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated hepatitis. Systemic corticosteroids were therefore required in 100% (48/48) of patients with immune-mediated hepatitis. Approximately 19% of patients required coadministration of another immunosuppressant with corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom YERVOY or nivolumab was withheld for hepatitis, 14 received additional treatment after symptom improvement; of these, 10 had recurrence of hepatitis. YERVOY 3 mg/kg with 1 mg/kg Nivolumab Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of YERVOY with nivolumab in 8% and withholding of treatment in 3.5% of patients. Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom YERVOY with nivolumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement, and 8 had recurrence of hepatitis. Immune-Mediated Dermatologic Adverse Reactions YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, Stevens Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms). Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3) ] . YERVOY 3 mg/kg as a Single Agent Immune-mediated rash occurred in 15% (76/511) of patients who received YERVOY 3 mg/kg as a single agent, including Grade 3-5 (2.5%) and Grade 2 (12%). Rash led to permanent discontinuation of YERVOY in 0.2% and withholding of at least one dose of YERVOY in 1.4% of patients. Systemic corticosteroids were required in 43% (33/76) of patients with immune-mediated rash. Rash resolved in 71% of the 76 patients. Of the 7 patients in whom YERVOY was withheld for rash, 3 received additional treatment after symptom improvement; of these, 1 had recurrence of rash. YERVOY 1 mg/kg with 3 mg/kg Nivolumab Immune-mediated rash occurred in 16% (108/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (3.5%) and Grade 2 (4.2%). Rash led to permanent discontinuation of YERVOY and nivolumab in 0.5% of patients and withholding of YERVOY and nivolumab in 2.0% of patients. In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated rash. Systemic corticosteroids were therefore required in 100% (108/108) of patients. Rash resolved in 75% of 108 patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for rash, 11 received additional treatment after symptom improvement; of these, 5 had recurrence of rash. YERVOY 3 mg/kg with 1 mg/kg Nivolumab Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of YERVOY with nivolumab in 0.4% and withholding of treatment in 3.9% of patients. Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 of patients. Of the 18 patients in whom YERVOY with nivolumab was withheld for rash, 15 reinitiated treatment after symptom improvement, and 8 had recurrence of rash. Immune-Mediated Endocrinopathies YERVOY 3 mg/kg as a Single Agent Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients who received YERVOY 3 mg/kg as a single agent. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 patients (1.8%). All 9 of these patients had hypopituitarism with some patients having additional concomitant endocrinopathies, such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushing’s syndrome. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 required long-term hormone replacement therapy, including adrenal hormones (n=10) and thyroid hormones (n=13). YERVOY 1 mg/kg with 3 mg/kg Nivolumab Hypophysitis: YERVOY can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue YERVOY depending on severity [see Dosage and Administration (2.3) ]. Hypophysitis occurred in 4.4% (29/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%). Hypophysitis led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 72% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 72% (21/29) of patients with immune-mediated hypophysitis. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for hypophysitis, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of hypophysitis. Adrenal Insufficiency: Adrenal insufficiency occurred in 7% (48/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 1.2% and withholding of YERVOY with nivolumab in 2.1% of patients. Approximately 94% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 94% (45/48) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom YERVOY or nivolumab was withheld for adrenal insufficiency, 11 received additional treatment after symptom improvement; of these, 2 had recurrence of adrenal insufficiency. Hyperthyroidism: Hyperthyroidism occurred in 12% (80/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (0.6%) and Grade 2 (4.5%). No patients discontinued YERVOY for hyperthyroidism. Hyperthyroidism led to withholding of YERVOY with nivolumab in 2.3% of patients. Approximately 19% received a thyroid synthesis inhibitor. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom YERVOY or nivolumab was withheld for hyperthyroidism, 11 received additional treatment after symptom improvement; of these, 3 had recurrence of hyperthyroidism. Hypothyroidism: Hypothyroidism occurred in 18% (122/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (0.6%) and Grade 2 (11%). Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 1.4% of patients. Approximately 82% received thyroid hormone replacement. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom YERVOY or nivolumab was withheld for hypothyroidism, 5 received additional treatment after symptom improvement; of these, one patient had recurrence of hypothyroidism. Thyroiditis: Thyroiditis occurred in 2.7% (22/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (4.5%) and Grade 2 (2.2%). Thyroiditis led to permanent discontinuation of YERVOY with nivolumab in 0.2% and withholding of YERVOY with nivolumab in 0.8% of patients. Systemic corticosteroids were required in 18% (4/22) of patients with thyroiditis. Thyroiditis resolved in 64% of the 22 patients. Of the 5 patients in whom YERVOY or nivolumab was withheld for thyroiditis, 5 received additional treatment after symptom improvement; of these, no patients had recurrence of thyroiditis. Type 1 Diabetes Mellitus: Diabetes occurred in 2.7% (15/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%). Diabetes led to the permanent discontinuation of YERVOY with nivolumab in 0.5% and withholding of YERVOY with nivolumab in 0.5% of patients. Systemic corticosteroids were required in 7% (1/15) of patients with diabetes. Diabetes resolved in 27% of the 15 patients. Of the 3 patients in whom YERVOY or nivolumab was withheld for diabetes, 2 received additional treatment after symptom improvement; of these, none had recurrence of diabetes. YERVOY 3 mg/kg with 1 mg/kg Nivolumab Hypophysitis: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of YERVOY with nivolumab in 0.9% and withholding of treatment in 4.2% of patients. Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom YERVOY with nivolumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement, and 1 had recurrence of hypophysitis. Adrenal Insufficiency: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of YERVOY with nivolumab in 0.4% of patients and withholding of treatment in 2.0% of patients. Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom YERVOY with nivolumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement, and all required hormone replacement therapy for their ongoing adrenal insufficiency. Hypothyroidism: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of YERVOY with nivolumab in 0.9% of patients and withholding of treatment in 0.9% of patients. Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom YERVOY with nivolumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement, and none had recurrence of hypothyroidism. Hyperthyroidism: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC receiving YERVOY 3 mg/kg with nivolumab 1 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to permanent discontinuation of YERVOY with nivolumab in no patients and withholding of treatment in 2.4% of patients. Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom YERVOY with nivolumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement, and 1 had recurrence of hyperthyroidism. Immune-Mediated Pneumonitis YERVOY 1 mg/kg with 3 mg/kg Nivolumab Immune-mediated pneumonitis occurred in 3.9% (26/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 3 (1.4%) and Grade 2 (2.6%). Pneumonitis led to permanent discontinuation of YERVOY and nivolumab in 1.8% and withholding of YERVOY and nivolumab in 1.5% of patients. In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated pneumonitis. Systemic corticosteroids were therefore required in 100% (26/26) of patients with immune-mediated pneumonitis. Approximately 8% required coadministration of another immunosuppressant with corticosteroids. Pneumonitis resolved in 92% of the 26 patients. Of the 10 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of pneumonitis. In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. The median duration was 1.5 months (range: 5 days to 25+ months). Immune-mediated pneumonitis led to permanent discontinuation of YERVOY with nivolumab in 5% of patients and withholding of YERVOY with nivolumab in 3.6% of patients. Systemic corticosteroids were required in 100% of patients with pneumonitis followed by a corticosteroid taper. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after re-initiation of YERVOY with nivolumab. YERVOY 3 mg/kg with 1 mg/kg Nivolumab Immune-mediated pneumonitis occurred in 7% (31/456) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC or melanoma, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). Immune-mediated pneumonitis led to permanent discontinuation or withholding of treatment in 2.9% and 3.9% of patients, respectively. Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 94% of the patients. Of the 13 patients in whom YERVOY or nivolumab was withheld for pneumonitis, 13 received additional treatment after symptom improvement, and 4 had recurrence of pneumonitis. Immune-Mediated Nephritis with Renal Dysfunction YERVOY 1 mg/kg with 3 mg/kg Nivolumab Immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or mCRC, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%). Nephritis with renal dysfunction led to permanent discontinuation of YERVOY and nivolumab in 1.2% and withholding of nivolumab and YERVOY in 1.8% of patients. In patients who received YERVOY 1 mg/kg with nivolumab, use of systemic corticosteroids was one of the diagnostic criteria required to identify immune-mediated nephritis with renal dysfunction. Systemic corticosteroids were therefore required in 100% (27/27) of patients with immune-mediated nephritis with renal dysfunction. Nephritis with renal dysfunction resolved in 67% of the 27 patients. Of the 12 patients in whom YERVOY or nivolumab was withheld for nephritis, 10 received additional treatment after symptom improvement; of these, 4 had recurrence of nephritis. Other Immune-Mediated Adverse Reactions Across clinical trials of YERVOY administered as a single agent or in combination with nivolumab, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified, as shown below: Nervous System: Autoimmune neuropathy (2%), meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, nerve paresis, motor dysfunction Cardiovascular: Angiopathy, myocarditis, pericarditis, temporal arteritis, vasculitis Ocular: Blepharitis, episcleritis, iritis, orbital myositis, scleritis, uveitis. Some cases can be associated with retinal detachment. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss. Gastrointestinal: Duodenitis, gastritis, pancreatitis (1.3%) Musculoskeletal and Connective Tissue: Arthritis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysis Hematologic/Immune: Aplastic anemia, conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), hypersensitivity vasculitis, meningitis, neurosensory hypoacusis, psoriasis, sarcoidosis, systemic inflammatory response syndrome, and solid organ transplant rejection. Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reported as the co-occurrence of either two or all three adverse reactions .

5.2 Infusion-Related Reactions Severe infusion-related reactions can occur with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions [see Dosage and Administration (2.3) ] . Infusion-related reactions occurred in 0.6% (3/511) of patients who received single-agent YERVOY 3 mg/kg for the unresectable or metastatic treatment of melanoma. Infusion-related reactions occurred in 5% (33/666) of patients who received YERVOY 1 mg/kg with nivolumab for the treatment of RCC or CRC. Infusion-related reactions occurred in 8% (4/49) of patients who received YERVOY 3 mg/kg with nivolumab for the treatment of HCC. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks.

5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplant after YERVOY Fatal or serious graft-versus-host disease (GVHD) can occur in patients who receive YERVOY either before or after allogeneic hematopoietic stem cell transplantation (HSCT). These complications may occur despite intervening therapy between CTLA-4 receptor blocking antibody and allogeneic HSCT. Follow patients closely for evidence of GVHD and intervene promptly [see Adverse Reactions (6.2) ] . Consider the benefit versus risks of treatment with YERVOY after allogeneic HSCT.

5.4 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, YERVOY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight) and higher incidences of infant mortality in a dose-related manner. The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3 )] .

5.5 Risks Associated When Administered in Combination with Nivolumab YERVOY is indicated for use in combination with nivolumab for patients with advanced RCC, MSI-H or dMMR mCRC, HCC, and NSCLC. Refer to the nivolumab Full Prescribing Information for additional risk information that applies to the combination use treatment.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1) ] .
• Infusion-related reactions [see Warnings and Precautions (5.2) ] . Most common adverse reactions (≥20%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. (6.1) Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (6.1) Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab and platinum-doublet chemotherapy are fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data described in the Warnings and Precautions section reflect exposure to YERVOY 3 mg/kg as a single agent (or in combination with an investigational gp100 peptide vaccine) in 511 patients in Study MDX010-20; YERVOY 1 mg/kg administered with nivolumab 3 mg/kg in 1,362 patients in CHECKMATE-214, CHECKMATE-142, CHECKMATE-227, and CHECKMATE-743; YERVOY 3 mg/kg administered with nivolumab 1 mg/kg in 456 patients enrolled in CHECKMATE-067, CHECKMATE-040, and another randomized trial; and to YERVOY 1 mg/kg, administered in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA. Unresectable or Metastatic Melanoma The safety of YERVOY was evaluated in 643 previously treated patients with unresectable or metastatic melanoma in Study MDX010-20 [see Clinical Studies (14.1) ] . Study MDX010-20 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Patients received YERVOY 3 mg/kg by intravenous infusion for 4 doses as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses). The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% White, and baseline ECOG performance status 0 (56%). YERVOY was discontinued for adverse reactions in 10% of patients. Table 4 presents adverse reactions from Study MDX010-20. Table 4: Selected Adverse Reactions (≥5%) in Patients Receiving YERVOY with a Difference Between Arms of >5% for All Grades and >1% for Grades 3 to 5 Compared to gp100 Peptide Vaccine in Study MDX010-20 Adverse Reactions YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg and gp100 n=380 gp100 n=132 All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%) All Grades (%) Grade 3 to 5 (%) General and Administration-Site Conditions Fatigue 41 7 34 5 31 3 Gastrointestinal Diarrhea 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Dermatologic Pruritus 31 0 21 <1 11 0 Rash 29 2 25 2 8 0 Unresectable or Metastatic Melanoma: In Combination with Nivolumab The safety of YERVOY, administered with nivolumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1) ] . The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. Patients were randomized to receive:

• YERVOY 3 mg/kg by intravenous infusion over 90 minutes with nivolumab 1 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (YERVOY and nivolumab arm; n=313), or
• Nivolumab 3 mg/kg by intravenous infusion every 2 weeks (nivolumab arm; n=313), or
• YERVOY 3 mg/kg by intravenous infusion over 90 minutes every 3 weeks for up to 4 doses (YERVOY arm; n=311). The median duration of exposure to nivolumab was 2.8 months (range: 1 day to 36.4 months) for the YERVOY and nivolumab arm. In the YERVOY and nivolumab arm, 39% were exposed to nivolumab for ≥6 months and 30% exposed for >1 year. Serious adverse reactions (74%), adverse reactions leading to permanent discontinuation (47%) or to dosing delays (58%), and Grade 3 or 4 adverse reactions (72%) occurred in patients treated with YERVOY and nivolumab. The most frequent (≥10%) serious adverse reactions in the YERVOY and nivolumab arm were diarrhea (13%), colitis (10%), and pyrexia (10%). The most frequent adverse reactions leading to discontinuation of both drugs in the YERVOY and nivolumab arm were colitis (10%), diarrhea (8%), increased ALT (4.8%), increased AST (4.5%), and pneumonitis (1.9%). The most common (≥20%) adverse reactions in the YERVOY and nivolumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. Tables 5 and 6 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067. Table 5: Adverse Reactions Occurring in ≥10% of Patients on the YERVOY and Nivolumab Arm or the Nivolumab Arm and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 Toxicity was graded per NCI CTCAE v4. a Includes asthenia and fatigue. b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash. c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. e Includes hypertension and blood pressure increased. Adverse Reaction YERVOY and Nivolumab (n=313) Nivolumab (n=313) YERVOY (n=311) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 62 7 59 1.6 51 4.2 Pyrexia 40 1.6 16 0 18 0.6 Gastrointestinal Diarrhea 54 11 36 5 47 7 Nausea 44 3.8 30 0.6 31 1.9 Vomiting 31 3.8 20 1.0 17 1.6 Skin and Subcutaneous Tissue Rash b 53 6 40 1.9 42 3.5 Vitiligo 9 0 10 0.3 5 0 Musculoskeletal and Connective Tissue Musculoskeletal pain c 32 2.6 42 3.8 36 1.9 Arthralgia 21 0.3 21 1.0 16 0.3 Metabolism and Nutrition Decreased appetite 29 1.9 22 0 24 1.3 Respiratory, Thoracic and Mediastinal Cough/productive cough 27 0.3 28 0.6 22 0 Dyspnea/exertional dyspnea 24 2.9 18 1.3 17 0.6 Infections Upper respiratory tract infection d 23 0 22 0.3 17 0 Endocrine Hypothyroidism 19 0.6 11 0 5 0 Hyperthyroidism 11 1.3 6 0 1 0 Investigations Decreased weight 12 0 7 0 7 0.3 Vascular Hypertension e 7 2.2 11 5 9 2.3 Clinically important adverse reactions in <10% of patients who received YERVOY with nivolumab: Gastrointestinal Disorders: stomatitis, intestinal perforation Skin and Subcutaneous Tissue Disorders: vitiligo Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis) Nervous System Disorders: neuritis, peroneal nerve palsy Table 6: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥20% of Patients Treated with YERVOY with Nivolumab or Single-Agent Nivolumab and at a Higher Incidence than in the YERVOY Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab (range: 75 to 297); nivolumab (range: 81 to 306); YERVOY (range: 61 to 301) Laboratory Abnormality YERVOY and Nivolumab Nivolumab YERVOY All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Increased ALT 55 16 25 3.0 29 2.7 Hyperglycemia 53 5 46 7 26 0 Increased AST 52 13 29 3.7 29 1.7 Hyponatremia 45 10 22 3.3 26 7 Increased lipase 43 22 32 12 24 7 Increased alkaline phosphatase 41 6 27 2.0 23 2.0 Hypocalcemia 31 1.1 15 0.7 20 0.7 Increased amylase 27 10 19 2.7 15 1.6 Increased creatinine 26 2.7 19 0.7 17 1.3 Hematology Anemia 52 2.7 41 2.6 41 6 Lymphopenia 39 5 41 4.9 29 4.0 Adjuvant Treatment of Melanoma The safety of YERVOY was evaluated in Study E1609, an open-label, multicenter, randomized trial for the adjuvant treatment of patients with completely resected node positive cutaneous melanoma [see Clinical Studies (14.2) ] . Patients received YERVOY 3 mg/kg intravenously every 3 weeks for 4 doses followed by 3 mg/kg every 12 weeks for up to 4 additional doses, or high-dose interferon-α2b (HDI). Among patients who received YERVOY, 55% were exposed for 6 months or longer and 42% were exposed for greater than 1 year. Fatal adverse reactions occurred in 1.4% of patients who received YERVOY, including gastric perforation (0.2%), and cardiac arrest (0.2%). Permanent discontinuation of YERVOY due to an adverse reaction occurred in 35% of patients. The most common adverse reactions (≥20%) in the YERVOY arm were fatigue, diarrhea, rash, pruritus, nausea, and headache. Table 7 summarizes adverse reactions in E1609. Table 7: Adverse Reactions (>10%) in Patients Receiving YERVOY 3 mg/kg in E1609 Adverse Reaction YERVOY 3 mg/kg n=516 HDI n=520 All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) General disorders and administration site conditions Fatigue 56 3 87 22 Decreased appetite 14 0.6 53 2.1 Pyrexia 10 0 31 0.8 Gastrointestinal Diarrhea 49 10 34 0.8 Nausea 29 1.2 66 4.2 Abdominal Pain 19 1 9 0.4 Vomiting 11 0.6 26 2.3 Colitis 10 8 1 0.4 Dermatologic Rash 46 4 18 1 Pruritus 41 2 15 0 Nervous System Disorders Headache 25 2 45 3 Endocrine Endocrine disorders, other 19 4.1 2 0 Hypothyroidism 11 0.6 10 0.2 Adrenal insufficiency 10 2 0.6 0 Other Clinical Experience Across clinical studies in which patients received YERVOY as a single agent at doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence <1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Advanced Renal Cell Carcinoma: In Combination with Nivolumab The safety of YERVOY in combination with nivolumab was evaluated in 1082 patients with previously untreated advanced RCC in CHECKMATE-214 [see Clinical Studies (14.3) ] . Patients received YERVOY 1 mg/kg with nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses followed by nivolumab as a single agent at a dose of 3 mg/kg every 2 weeks (n=547) or sunitinib 50 mg orally daily for first 4 weeks of each 6-week cycle (n=535). The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in YERVOY and nivolumab arm. In this trial, 57% of patients in the YERVOY and nivolumab arm were exposed to treatment for greater than 6 months and 38% of patients were exposed to treatment for greater than 1 year. Serious adverse reactions occurred in 59% of patients receiving YERVOY with nivolumab. The most frequent serious adverse reactions reported in ≥2% of patients treated with YERVOY and nivolumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In patients who received YERVOY with nivolumab, study therapy was discontinued for adverse reactions in 31% and delayed for adverse reactions in 54%. The most common adverse reactions (≥20%) in the YERVOY and nivolumab arm were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, vomiting, dyspnea, and decreased appetite. Table 8 summarizes adverse reactions in CHECKMATE-214. Table 8: Adverse Reactions (>15%) in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema, peripheral swelling. c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. Adverse Reaction YERVOY 1 mg/kg and Nivolumab n=547 Sunitinib n=535 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) General and Administration Site Conditions Fatigue a 58 8 69 13 Pyrexia 25 0.7 17 0.6 Edema b 16 0.5 17 0.6 Skin and Subcutaneous Tissue Rash c 39 3.7 25 1.1 Pruritus/generalized pruritus 33 0.5 11 0 Gastrointestinal Diarrhea 38 4.6 58 6 Nausea 30 2.0 43 1.5 Vomiting 20 0.9 28 2.1 Abdominal pain 19 1.6 24 1.9 Constipation 17 0.4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4.0 40 2.6 Arthralgia 23 1.3 16 0 Respiratory, Thoracic, and Mediastinal Cough/productive cough 28 0.2 25 0.4 Dyspnea/exertional dyspnea 20 2.4 21 2.1 Metabolism and Nutrition Decreased appetite 21 1.8 29 0.9 Nervous System Headache 19 0.9 23 0.9 Endocrine Hypothyroidism 18 0.4 27 0.2 Table 9 summarizes the laboratory abnormalities in CHECKMATE-214. Table 9: Laboratory Abnormalities (>15%) Worsening from Baseline in Patients Receiving YERVOY and Nivolumab in CHECKMATE-214 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: nivolumab and YERVOY group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). Laboratory Abnormality YERVOY 1 mg/kg and Nivolumab a Sunitinib a Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased lipase 48 20 51 20 Increased creatinine 42 2.1 46 1.7 Increased ALT 41 7 44 2.7 Increased AST 40 4.8 60 2.1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2.0 32 1.0 Hyperkalemia 29 2.4 28 2.9 Hypocalcemia 21 0.4 35 0.6 Hypomagnesemia 16 0.4 26 1.6 Hematology Anemia 43 3.0 64 9 Lymphopenia 36 5 63 14 In addition, among patients with TSH ≤ ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the YERVOY with nivolumab group compared to the sunitinib group (31% and 61%, respectively). MSI-H or dMMR Metastatic Colorectal Cancer Treatment of MSI -H or dMMR mCRC: In Combination with Nivolumab The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naïve patients with MSI-H or dMMR mCRC [see Clinical Studies (14.4) ] . Patients received one of the following:
• YERVOY 1 mg/kg every 3 weeks and nivolumab 240 mg every 3 weeks for a maximum of 4 doses, then nivolumab 480 mg every 4 weeks.
• Nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks.
• Investigator’s choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.4) ] . In the YERVOY and nivolumab arm, the median duration of exposure to YERVOY was 2.1 months (range 1 day to 3.7 months); patients received a median of 4 doses (range 1-4). The median duration of treatment in the YERVOY and nivolumab arm was 20.5 months (range: 1 day to 35.9 months); 70% were exposed to treatment for >6 months, and 63% were exposed for >1 year. The median duration of treatment was 16.4 months (range: 1 day to 36 months) in the nivolumab-only arm; 64% were exposed to treatment for >6 months, and 54% were exposed for >1 year. Serious adverse reactions occurred in 46% of patients receiving YERVOY in combination with nivolumab, and 39% of patients receiving nivolumab alone. The most frequent serious adverse reactions reported in ≥1% of patients who received YERVOY with nivolumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune-mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as a single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%). Fatal adverse reactions occurred in 2 (0.6%) patients who received YERVOY in combination with nivolumab; these included myocarditis, and pneumonitis (1 each). YERVOY and/or nivolumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune-mediated enterocolitis (1.1%), and pneumonitis (1.1%). Nivolumab was permanently discontinued in 13% of patients receiving single agent nivolumab. Adverse reactions leading to the delay of YERVOY and/or nivolumab occurred in 48% of patients receiving the combination; single agent nivolumab was delayed in 37% of patients due to adverse reactions. The most common adverse reactions reported in ≥20% of patients treated with YERVOY in combination with nivolumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in ≥20% of patients treated with nivolumab as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 10 and 11 summarize the adverse reactions and selected laboratory abnormalities, for YERVOY in combination with nivolumab and nivolumab arms respectively, in CHECKMATE-8HW. Table 10: Adverse Reactions in ≥10% in Patient and a Difference Between Arms of >5% for All Grades in - CHECKMATE-8HW Toxicity was graded per NCI CTCAE v5. a Includes colitis, diarrhea, enterocolitis, immune-mediated enterocolitis Adverse Reaction YERVOY and Nivolumab (n=352) Nivolumab (n=351) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Diarrhea a 35 4.5 30 3.4 Skin and Subcutaneous Tissue Pruritus 30 0 23 0 Musculoskeletal and Connective Tissue Arthralgia 20 0.6 15 0.6 Endocrine Hypothyroidism 18 0.6 10 0 Hyperthyroidism 12 0 5 0 Table 11: Laboratory Values Worsening from Baseline a in ≥10% of Patients and a Difference Between Arms of >5% for All Grades - CHECKMATE-8HW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 108 to 343 patients) or nivolumab group (range: 102 to 348 patients). Laboratory Abnormality a YERVOY and Nivolumab (n=352) Nivolumab (n=351) All Grades (%) Grades 3-or 4 (%) All Grades (%) Grades 3 or -4 (%) Hematology Lymphocytes decreased 30 5 37 4 Neutrophils decreased 21 1.7 12 0.6 Chemistry Lipase increased 44 10 32 11 Amylase increased 41 4.6 33 5 ALT increased 39 3.5 32 1.4 AST increased 38 3.2 29 1.4 Sodium decreased 36 3.2 30 2.3 Creatinine increased 32 2 25 1.4 Potassium increased 29 1.2 35 0.9 Glucose decreased 17 0 12 0 Hepatocellular Carcinoma: In Combination with Nivolumab Unresectable or Metastatic Hepatocellular Carcinoma (HCC) The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14.5) ] . Patients received YERVOY in combination with nivolumab (n=332) or investigator’s choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage:
• YERVOY 3 mg/kg administered intravenously over 30 minutes in combination with nivolumab 1 mg/kg administered intravenously over 30 minutes every 3 weeks, for a maximum of 4 doses, followed by single agent nivolumab at 480 mg administered intravenously over 30 minutes every 4 weeks, or
• Investigator’s choice: o Lenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight ≥60 kg), or o Sorafenib 400 mg orally twice daily In the YERVOY and nivolumab arm, the median duration of exposure to nivolumab was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with YERVOY in combination with nivolumab. The most frequent non-liver-related serious adverse reactions reported in ≥2% were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%). Liver-related serious adverse reactions occurred in 17% of patients treated with YERVOY in combination with nivolumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%). Fatal adverse reactions occurred in 12 (3.6%) patients who received YERVOY in combination with nivolumab; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure. Permanent discontinuation due to an adverse reaction occurred in 27% of patients treated with YERVOY in combination with nivolumab. Adverse reactions leading to permanent discontinuation in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), and hepatic failure (1.2%). Dosage interruptions due to an adverse reaction occurred in 62% of patients treated with YERVOY in combination with nivolumab. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%). The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea. Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW. Table 12: Adverse Reactions Occurring in ≥10% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW Toxicity was graded per NCI CTCAE v5 a Represents a composite of multiple related terms. Adverse Reaction YERVOY and Nivolumab (n=332) Lenvatinib or Sorafenib (n=325) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 3.6 15 1.2 Pruritus 34 1.5 7 0.3 General Fatigue a 33 2.4 39 4 Pyrexia a 15 0.6 9 1.5 Edema a 13 1.2 13 1.5 Gastrointestinal Diarrhea 25 6 39 3.4 Abdominal pain a 14 1.2 27 2.5 Nausea 10 0.3 16 0.9 Musculoskeletal and Connective Tissue Musculoskeletal pain a 17 0.6 23 0.3 Arthralgia 12 0.3 13 0.6 Metabolism and Nutrition Decreased appetite 16 1.2 28 1.8 Endocrine Hypothyroidism a 14 0 27 0 Hyperthyroidism 11 0.6 1.5 0 Respiratory, Thoracic and Mediastinal Cough a 13 0 8 0 Clinically important adverse reactions reported in <10% of patients who received YERVOY with nivolumab were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%). Table 13: Laboratory Values Worsening from Baseline a Occurring in ≥20% of YERVOY in combination with Nivolumab-Treated Patients - CHECKMATE-9DW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: YERVOY and nivolumab group (range: 168 to 331 patients) and lenvatinib or sorafenib group (range: 145 to 315 patients). Laboratory Abnormality YERVOY and Nivolumab (n=332) Lenvatinib or Sorafenib (n=325) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased AST 62 29 51 14 Increased ALT 61 17 46 9 Increased lipase 58 16 39 5 Decreased albumin 48 0.9 57 0.6 Hyponatremia 45 6 42 3.8 Hyperglycemia 44 15 32 2.1 Increased bilirubin 44 10 44 8 Increased amylase 41 6 26 1 Increased alkaline phosphatase 36 1.2 38 5 Hypocalcemia 29 0.9 46 0 Increased creatinine 26 2.4 23 0.6 Hypokalemia 21 2.1 20 2.6 Hematology Anemia 44 5 40 3.8 Lymphopenia 40 6.1 40 8 Thrombocytopenia 27 4 44 4.8 Neutropenia 24 4 32 3.5 Previously Treated Hepatocellular Carcinoma The safety of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in a subgroup of 49 patients with HCC and Child-Pugh Class A cirrhosis who progressed on or were intolerant to sorafenib enrolled in Cohort 4 of CHECKMATE-040. YERVOY and nivolumab were administered every 3 weeks for four doses, followed by single-agent nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the YERVOY and nivolumab combination period, 33 of 49 (67%) patients received all four planned doses of YERVOY and nivolumab. During the entire treatment period, the median duration of exposure to YERVOY was 2.1 months (range: 0 to 4.5 months) and to nivolumab was 5.1 months (range: 0 to 35+ months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Table 14 summarizes the adverse reactions and Table 15 summarizes the laboratory abnormalities of YERVOY in combination with nivolumab in CHECKMATE-040. Table 14: Adverse Reactions Occurring in ≥10% of Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Adverse Reaction YERVOY and Nivolumab (n=49) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash 53 8 Pruritus 53 4 Musculoskeletal and Connective Tissue Musculoskeletal pain 41 2 Arthralgia 10 0 Gastrointestinal Diarrhea 39 4 Abdominal pain 22 6 Nausea 20 0 Ascites 14 6 Constipation 14 0 Dry mouth 12 0 Dyspepsia 12 2 Vomiting 12 2 Stomatitis 10 0 Respiratory, Thoracic and Mediastinal Cough 37 0 Dyspnea 14 0 Pneumonitis 10 2 Metabolism and Nutrition Decreased appetite 35 2 General Fatigue 27 2 Pyrexia 27 0 Malaise 18 2 Edema 16 2 Influenza-like illness 14 0 Chills 10 0 Nervous System Headache 22 0 Dizziness 20 0 Endocrine Hypothyroidism 20 0 Adrenal insufficiency 18 4 Investigations Weight decreased 20 0 Psychiatric Insomnia 18 0 Blood and Lymphatic System Anemia 10 4 Infections Influenza 10 2 Vascular Hypotension 10 0 Clinically important adverse reactions reported in <10% of patients receiving YERVOY with nivolumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 15: Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving YERVOY in Combination with Nivolumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality YERVOY and Nivolumab (n=47) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 53 13 Anemia 43 4.3 Neutropenia 43 9 Leukopenia 40 2.1 Thrombocytopenia 34 4.3 Chemistry Increased AST 66 40 Increased ALT 66 21 Increased bilirubin 55 11 Increased lipase 51 26 Hyponatremia 49 32 Hypocalcemia 47 0 Increased alkaline phosphatase 40 4.3 Increased amylase 38 15 Hypokalemia 26 2.1 Hyperkalemia 23 4.3 Increased creatinine 21 0 Hypomagnesemia 11 0 In patients who received YERVOY with nivolumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline. First-line Treatment of Metastatic NSCLC: In Combination with Nivolumab The safety of YERVOY in combination with nivolumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.6) ] . The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received YERVOY 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks and nivolumab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in YERVOY and nivolumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received YERVOY and nivolumab for >6 months and 23% of patients received YERVOY and nivolumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology. Serious adverse reactions occurred in 58% of patients. YERVOY and nivolumab were discontinued for adverse reactions in 24% of …

• Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , YERVOY can cause fetal harm when administered to a pregnant woman. There is insufficient human data for YERVOY exposure in pregnant women. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data ) . The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Bristol-Myers Squibb at 1-844-593-7869. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the humans exposure based on area under the curve at a dose of 3 mg/kg). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.

8.2 Lactation Risk Summary There are no data on the presence of YERVOY in human milk or its effects on the breastfed child or milk production. In monkeys, ipilimumab was present in milk (see Data ) . Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with YERVOY and for 3 months following the last dose. Data In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state serum concentration of the drug.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating YERVOY [see Use in Specific Populations (8.1) ] . Contraception YERVOY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose.

8.4 Pediatric Use The safety and effectiveness of YERVOY have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with nivolumab for unresectable or metastatic melanoma, in combination with nivolumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and in combination with nivolumab for MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of YERVOY for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Ipilimumab exposures in pediatric patients 12 years and older are comparable to that of adults, and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.4) ] . The safety and effectiveness of YERVOY have not been established in pediatric patients younger than 12 years old with unresectable or metastatic melanoma or MSI-H or dMMR mCRC. The safety and effectiveness of YERVOY have not been established in pediatric patients for the adjuvant treatment of melanoma or for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma, metastatic non-small cell lung cancer, malignant pleural mesothelioma and esophageal cancer. In a dose-finding trial (NCT01445379), 33 patients aged 2 to 21 years (median 13 years) with relapsed or refractory solid tumors were evaluated including unresectable stage IIIc or stage IV melanoma (12), progressive or refractory sarcomas (17), renal or bladder carcinoma (3), and neuroblastoma (1). No responses in the patients with non-melanoma solid tumors and no new safety signals were observed in pediatric patients in this study.

8.5 Geriatric Use Single Agent Of the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. In Combination with Nivolumab Of the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. Of the 576 patients randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.6) ] . Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab. Of the 550 patients randomized to YERVOY 1 mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed. Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as a single agent, 45% were 65 years or older and 13% were 75 years or older. There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was a higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14.4) ] . Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. Of the 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort 4 of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients. Of the 325 patients who received YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients. Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In Combination with Nivolumab and Platinum-Doublet Chemotherapy Of the 361 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

Single Agent Of the 511 patients treated with YERVOY in Study MDX010-20 (unresectable or metastatic melanoma), 28% were 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. In Combination with Nivolumab Of the 314 patients randomized to YERVOY administered with nivolumab in CHECKMATE-067, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. Of the 576 patients randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227 (NSCLC), 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received YERVOY with nivolumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to YERVOY 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-227, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.6) ] . Of the 303 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-743 (malignant pleural mesothelioma), 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation rate due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received YERVOY with nivolumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and discontinuation due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to YERVOY in combination with nivolumab. Of the 550 patients randomized to YERVOY 1 mg/kg with nivolumab in CHECKMATE-214 (renal cell carcinoma), 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety was observed between these patients and younger patients. In geriatric patients with intermediate or poor risk, no overall difference in effectiveness was observed. Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to YERVOY in combination with nivolumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to nivolumab, as a single agent, 45% were 65 years or older and 13% were 75 years or older. There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving YERVOY in combination with nivolumab compared to those younger than 65 receiving the combination (42%). There was a higher incidence of adverse reactions leading to discontinuation in patients aged 65 years or older receiving YERVOY in combination with nivolumab (23%) compared to those younger than 65 receiving the combination (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving YERVOY in combination with nivolumab [see Clinical Studies (14.4) ] . Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to YERVOY in combination with nivolumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients. Of the 49 patients who received YERVOY 3 mg/kg with nivolumab in Cohort 4 of CHECKMATE-040 (previously treated hepatocellular carcinoma), 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of YERVOY in combination with nivolumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients. Of the 325 patients who received YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 3 mg/kg every 2 weeks in CHECKMATE-648 (ESCC), 43% were 65 years old or older and 7% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (38%) relative to all patients who received YERVOY with nivolumab (23%). For patients aged 75 years or older who received chemotherapy, the discontinuation rate due to adverse reactions was 33% relative to 23% for all patients. Study CA184-029 (adjuvant treatment of melanoma) and CHECKMATE-142 (metastatic colorectal cancer) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In Combination with Nivolumab and Platinum-Doublet Chemotherapy Of the 361 patients randomized to YERVOY 1 mg/kg every 6 weeks in combination with nivolumab 360 mg every 3 weeks and platinum-doublet chemotherapy every 3 weeks (for 2 cycles) in CHECKMATE-9LA (NSCLC), 51% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (43%) relative to all patients who received YERVOY with nivolumab and chemotherapy (24%). For patients aged 75 years or older who received chemotherapy only, the discontinuation rate due to adverse reactions was 16% relative to all patients who had a discontinuation rate of 13%. Based on an updated analysis for overall survival, of the 361 patients randomized to YERVOY in combination with nivolumab and platinum-doublet chemotherapy in CHECKMATE-9LA, the hazard ratio for overall survival was 0.61 (95% CI: 0.47, 0.80) in the 176 patients younger than 65 years compared to 0.73 (95% CI: 0.56, 0.95) in the 185 patients 65 years or older.

12.1 Mechanism of Action CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response.

12.3 Pharmacokinetics The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 mg/kg to 10 mg/kg. Following administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean minimum concentration (C min ) at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. Elimination The mean (percent coefficient of variation) terminal half-life (t 1/2 ) was 15.4 days (34%) and then mean (percent coefficient of variation) clearance (CL) was 16.8 mL/h (38%). The CL of ipilimumab was unchanged in presence of anti-ipilimumab antibodies. Specific Populations The CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, performance status, renal impairment (glomerular filtration rate ≥15 mL/min/1.73 m 2 ), mild hepatic impairment (total bilirubin [TB] >1 to 1.5 times the upper limit of normal [ULN] or AST > ULN), previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-White racial groups. YERVOY has not been studied in patients with moderate (TB >1.5 to 3 times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment. Pediatric Patients The exposures of ipilimumab in pediatric patients 12 years and older are comparable to those in adult patients at the recommended dosage. Drug Interaction Studies Ipilimumab with Nivolumab When YERVOY 1 mg/kg was administered with nivolumab 3 mg/kg every 3 weeks, the CL of ipilimumab was unchanged compared to when YERVOY was administered alone. When YERVOY 3 mg/kg every 3 weeks was administered in combination with nivolumab 1 mg/kg every 3 weeks, the CL of ipilimumab was unchanged compared to ipilimumab administered alone and the CL of nivolumab was increased by 29% compared to nivolumab administered alone. When YERVOY 1 mg/kg every 6 weeks was administered in combination with nivolumab 3 mg/kg every 2 weeks, the CL of ipilimumab increased by 30% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone. When YERVOY 1 mg/kg every 6 weeks was administered in combination with nivolumab 360 mg every 3 weeks and chemotherapy, the CL of ipilimumab increased by 22% compared to YERVOY administered alone and the CL of nivolumab was unchanged compared to nivolumab administered alone.

12.6 Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of YERVOY or of other ipilimumab products. Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab developed anti-ipilimumab antibodies and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for anti-ipilimumab antibodies using an ECL assay with improved drug tolerance. No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for anti-ipilimumab antibodies. Of the 499 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-214 and CHECKMATE-142, 27 (5.4%) were positive for anti-ipilimumab antibodies; there were no patients with neutralizing antibodies against ipilimumab. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies. Of 483 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-227 Part 1, 8.5% were positive for treatment-emergent anti-ipilimumab antibodies. No patients had neutralizing antibodies against ipilimumab. In Part 1 of the same study, of 491 patients evaluable for anti-nivolumab antibodies, 36.7% were positive for anti-nivolumab antibodies and 1.4% had neutralizing antibodies against nivolumab. Of 305 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-9LA, 8% were positive for anti-ipilimumab antibodies and 1.6% were positive for anti-ipilimumab neutralizing antibodies. There was no evidence of increased incidence of infusion reactions to YERVOY in patients with anti-ipilimumab antibodies. Of 308 patients evaluable for anti-nivolumab antibodies in CHECKMATE-9LA, 34% were positive for anti-nivolumab antibodies and 2.6% had neutralizing antibodies against nivolumab. Of 271 patients evaluable for anti-ipilimumab antibodies in CHECKMATE-743, 13.7% were positive for anti-ipilimumab antibodies and 0.4% were positive for anti-ipilimumab neutralizing antibodies. Of 269 patients evaluable for anti-nivolumab antibodies in CHECKMATE-743, 25.7% were positive for anti-nivolumab antibodies and 0.7% had neutralizing antibodies against nivolumab. Anti-drug antibody and neutralizing antibody responses were monitored throughout the treatment period where the benefit to risk ratio was assessed. Incidence of anti-drug antibodies and neutralizing antibodies are presented in Table 24. Table 24: YERVOY Anti-Drug Antibody (ADA) and Neutralizing Antibody (NAb) Incidence a Details of each treatment regimen are described in Section 14 [see Clinical Studies (14) ]. b NAb incidence is reported among the subset of patients positive for ADA. ADA = treatment-emergent anti-ipilimumab antibodies, NAb = neutralizing antibodies, HCC = hepatocellular carcinoma, RCC = renal cell carcinoma, CRC = colorectal cancer, NSCLC = non-small cell lung cancer. Treatment Regimen a Indication(s) ADA NAb b YERVOY as a single agent Melanoma 1.1% (11/1024) 0 (0/11) Adjuvant Melanoma 4.9 (7/144) 0 (0/7) YERVOY with nivolumab for 4 doses followed by nivolumab as a single agent Melanoma 8.4% (33/391) 3% (1/33) HCC 5.3% (13/244) 0 (0/13) RCC and CRC 5.4% (27/499) 0% (0/27) YERVOY with nivolumab Malignant Pleural Mesothelioma 13.7% (37/271) 2.7% (1/37) NSCLC 8.5% (41/483) 0 (0/41) YERVOY with nivolumab and 2 cycles of platinum-doublet chemotherapy NSCLC 7.5% (23/305) 21.7% (5/23) Effects of Anti-Drug Antibodies Presence of treatment-emergent anti-ipilimumab antibodies did not affect ipilimumab clearance after administration of ipilimumab as monotherapy or in combination with nivolumab. These anti-drug antibody-associated pharmacokinetic changes were not considered to be clinically significant. There was no identified clinically significant effect of anti-drug antibodies on incidence of infusion-related reactions. In hepatocellular carcinoma, there was no identified clinically significant effect of anti-drug antibodies on efficacy for ipilimumab in combination with nivolumab. For other indications, the effects of anti-drug antibodies on effectiveness have not been fully characterized.