40 ML ipilimumab 5 MG/ML Injection

INDICATIONS AND USAGE YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: Melanoma • Treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older as a single agent or in combination with nivolumab. (1.1) • Adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. (1.2) Renal Cell Carcinoma (RCC) • Treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab. (1.3) Colorectal Cancer • Treatment of adults and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with nivolumab. (1.4) Hepatocellular Carcinoma • adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) as first-line treatment in combination with nivolumab. ( 1.5 ) • in combination with nivolumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. (1.5) Non-Small Cell Lung Cancer (NSCLC) • Treatment of adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with nivolumab. (1.6) • Treatment of adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy. (1.6) Malignant Pleural Mesothelioma • Treatment of adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with nivolumab. (1.7) Esophageal Cancer • Treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, as first line treatment in combination with nivolumab whose tumors express PD-L1 (≥1). (1.8) 1.1 Unresectable or Metastatic Melanoma YERVOY, as a single agent or in combination with nivolumab, is indicated for the treatment of unresectable or metastatic melanoma in adult and pediatric patients 12 years and older. 1.2 Adjuvant Treatment of Melanoma YERVOY is indicated for the adjuvant treatment of adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. 1.3 Advanced Renal Cell Carcinoma YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC). 1.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer • YERVOY, in combination with nivolumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer ( CRC ). 1.5 Hepatocellular Carcinoma • YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC). • YERVOY, in combination with nivolumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. 1.6 Metastatic Non-Small Cell Lung Cancer YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , with no EGFR or ALK genomic tumor aberrations. YERVOY, in combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations. 1.7 Malignant Pleural Mesothelioma YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. 1.8 Esophageal Cancer YERVOY, in combination with nivolumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.1) ] .

DOSAGE AND ADMINISTRATION • 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-approved 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) ] . 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-approved 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 Y

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 Nivolu

CONTRAINDICATIONS None. • None. (4)

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.