HIGHLIGHTS OF PRESCRIBING INFORMATION x Unresectable or metastatic melanoma: These highlights do not include all the information needed to use YERVOY o YERVOY 3 mg/kg every 3 weeks for a total of 4 doses. (2.2) safely and effectively. See full prescribing information for YERVOY. x Adjuvant melanoma: YERVOY (ipilimumab) injection, for intravenous use o YERVOY 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg Initial U.S. Approval: 2011 every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. (2.3) x Advanced renal cell carcinoma: WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS o Nivolumab 3 mg/kg followed by YERVOY 1 mg/kg on the same day, See full prescribing information for complete boxed warning. every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or YERVOY can result in severe and fatal immune-mediated adverse 480 mg every 4 weeks. (2.4) reactions. These immune-mediated reactions may involve any organ x Microsatellite instability-high (MSI-H) or mismatch repair deficient system; however, the most common severe immune-mediated adverse (dMMR) metastatic colorectal cancer: reactions are enterocolitis, hepatitis, dermatitis (including toxic o Nivolumab 3 mg/kg followed by YERVOY 1 mg/kg on the same day epidermal necrolysis), neuropathy, and endocrinopathy. The majority every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or of these immune-mediated reactions initially manifested during 480 mg every 4 weeks. (2.5) treatment; however, a minority occurred weeks to months after x Hepatocellular carcinoma: discontinuation of YERVOY. o Nivolumab 1 mg/kg followed by YERVOY 3 mg/kg on the same day Permanently discontinue YERVOY and initiate systemic high-dose every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks or corticosteroid therapy for severe immune-mediated reactions. (2.8) 480 mg every 4 weeks. (2.6) Assess patients for signs and symptoms of enterocolitis, dermatitis, x Metastatic non-small cell lung cancer neuropathy, and endocrinopathy and evaluate clinical chemistries o Nivolumab 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every including liver function tests, adrenocorticotropic hormone (ACTH) 6 weeks. (2.7) level, and thyroid function tests at baseline and before each dose. (5.1, o Nivolumab 360 mg every 3 weeks with YERVOY 1 mg/kg every 6 5.2, 5.3, 5.4, 5.5) weeks and 2 cycles of platinum-doublet chemotherapy. (2.7) x Permanently discontinue for severe adverse reactions. (2.8) --------------------------RECENT MAJOR CHANGES---------------------------- Indications and Usage (1) 5/2020 ----------------------DOSAGE FORMS AND STRENGTHS--------------------- Dosage and Administration (2) 5/2020 Injection: 50 mg/10 mL (5 mg/mL) and 200 mg/40 mL (5 mg/mL) in a single- Warnings and Precautions (5) 5/2020 use vial. (3) ---------------------------INDICATIONS AND USAGE---------------------------- ------------------------------CONTRAINDICATIONS------------------------------- YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking None. (4) antibody indicated for: Melanoma ------------------------WARNINGS AND PRECAUTIONS----------------------- x Treatment of unresectable or metastatic melanoma in adults and pediatric Immune-mediated adverse reactions: Permanently discontinue for severe patients (12 years and older). (1.1) reactions. Withhold dose for moderate immune-mediated adverse reactions x Adjuvant treatment of patients with cutaneous melanoma with pathologic until return to baseline, improvement to mild severity, or complete resolution, involvement of regional lymph nodes of more than 1 mm who have and patient is receiving less than 7.5 mg prednisone or equivalent per day. undergone complete resection, including total lymphadenectomy. (1.2) Administer systemic high-dose corticosteroids for severe, persistent, or Renal Cell Carcinoma (RCC) recurring immune-mediated reactions. (5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10) x Treatment of patients with intermediate or poor-risk, previously untreated advanced renal cell carcinoma, in combination with nivolumab. (1.3) x Immune-mediated hepatitis: Evaluate liver function tests before each dose Colorectal Cancer of YERVOY. (5.2) Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation. (5.2) x Treatment of adult and pediatric patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient x Immune-mediated endocrinopathies: Monitor clinical chemistries, ACTH (dMMR) metastatic colorectal cancer that has progressed following level, and thyroid function tests prior to each dose. Evaluate at each visit for treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in signs and symptoms of endocrinopathy. Institute hormone replacement combination with nivolumab. This indication is approved under accelerated therapy as needed. (5.5) approval based on overall response rate and duration of response. Continued x Immune-mediated pneumonitis: Withhold for moderate and permanently approval for this indication may be contingent upon verification and discontinue for severe or life-threatening pneumonitis. (5.6) description of clinical benefit in confirmatory trials. (1.4) x Immune-mediated nephritis and renal dysfunction: Monitor for changes in Hepatocellular Carcinoma renal function. Withhold for moderate or severe and permanently x Treatment of patients with hepatocellular carcinoma who have been discontinue for life-threatening serum creatinine elevation. (5.7) previously treated with sorafenib, in combination with nivolumab. This x Immune-mediated encephalitis: Monitor for changes in neurologic function. indication is approved under accelerated approval based on overall response Withhold for new-onset moderate to severe neurological signs or symptoms rate and duration of response. Continued approval for this indication may be and permanently discontinue for immune-mediated encephalitis. (5.8) contingent upon verification and description of clinical benefit in Infusion reactions: Discontinue for severe and life-threatening infusion confirmatory trials. (1.5) x reactions. Interrupt or slow the rate of infusion in patients with mild or Non-Small Cell Lung Cancer (NSCLC) moderate infusion reactions. (5.9) x Treatment of adult patients with metastatic non-small cell lung cancer Embryo-Fetal toxicity: Can cause fetal harm. Advise of potential risk to a expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no x fetus and use of effective contraception. (5.11, 8.1, 8.3) EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6) -------------------------------ADVERSE REACTIONS------------------------------ x Treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line Most common adverse reactions (t5%) with YERVOY as a single agent are treatment, in combination with ipilimumab and 2 cycles of platinum-doublet fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse chemotherapy (1.6) reactions at the 10 mg/kg dose (t5%) include nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia. (6.1) ------------------------DOSAGE AND ADMINISTRATION---------------------- Most common adverse reactions (t20%) with YERVOY in combination with x Administer by intravenous infusion based upon recommended infusion rate nivolumab are fatigue, rash, pruritus, diarrhea, musculoskeletal pain, cough, for each indication. (2) 1 Reference ID: 4614238 pyrexia, decreased appetite, nausea, abdominal pain, arthralgia, headache, To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers vomiting, dyspnea, dizziness, hypothyroidism, and decreased weight. (6.1) Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab and platinum-doublet chemotherapy are fatigue, musculoskeletal ------------------------USE IN SPECIFIC POPULATIONS----------------------- pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1) x Lactation: Discontinue breastfeeding during treatment with YERVOY. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 5/2020 FULL PRESCRIBING INFORMATION: CONTENTS * WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS 5.12 Risks Associated When Administered in Combination with 1 INDICATIONS AND USAGE Nivolumab 1.1 Unresectable or Metastatic Melanoma 6 ADVERSE REACTIONS 1.2 Adjuvant Treatment of Melanoma 6.1 Clinical Trials Experience 1.3 Advanced Renal Cell Carcinoma 6.2 Immunogenicity 1.4 Microsatellite Instability-High (MSI-H) or Mismatch Repair 6.3 Postmarketing Experience Deficient (dMMR) Metastatic Colorectal Cancer 7 DRUG INTERACTIONS 1.5 Hepatocellular Carcinoma 8 USE IN SPECIFIC POPULATIONS 1.6 Metastatic Non-Small Cell Lung Cancer 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Patient Selection 8.3 Females and Males of Reproductive Potential 2.2 Recommended Dosing for Unresectable or Metastatic 8.4 Pediatric Use Melanoma 8.5 Geriatric Use 2.3 Recommended Dosing for Adjuvant Treatment of 8.6 Renal Impairment Melanoma 8.7 Hepatic Impairment 2.4 Recommended Dosing for Renal Cell Carcinoma 10 OVERDOSAGE 2.5 Recommended Dosing for Colorectal Cancer 11 DESCRIPTION 2.6 Recommended Dosing for Hepatocellular Carcinoma 12 CLINICAL PHARMACOLOGY 2.7 Recommended Dosing for Metastatic NSCLC 12.1