Nivolumab

1 INDICATIONS AND USAGE OPDIVO QVANTIG is a combination of nivolumab, a programmed death receptor-1 (PD-1)-blocking antibody, and hyaluronidase, an endoglycosidase, indicated for the treatment of: Renal Cell Carcinoma (RCC) • adult patients with intermediate or poor risk advanced RCC, as a first-line treatment following combination treatment with intravenous nivolumab and ipilimumab. (1.1) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma. • adult patients with advanced RCC, as a first-line treatment in combination with cabozantinib. (1.1) • adult patients with advanced RCC who have received prior anti-angiogenic therapy. ( 1.1 ) Melanoma • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic melanoma. (1.2) • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab. (1.2) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma. • for the adjuvant treatment of adult and pediatric (12 years and older who weigh 30 kg or greater) patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.3) Non-Small Cell Lung Cancer (NSCLC) • adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.4) • adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by OPDIVO QVANTIG monotherapy as adjuvant treatment after surgery. (1.5) • adult patients with metastatic NSCLC and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO QVANTIG. (1.6) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC. Squamous Cell Carcinoma of the Head and Neck (SCCHN) • adult patients with recurrent or metastatic SCCHN with disease progression on or after a platinum-based therapy. (1.7) Urothelial Carcinoma (UC) • adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection of UC. (1.8) • adult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.8) • adult patients with locally advanced or metastatic UC who: • have disease progression during or following platinum-containing chemotherapy. • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8) Colorectal Cancer (CRC) • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC), following combination treatment with intravenous nivolumab and ipilimumab. (1.9) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC. • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. (1.9) • Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC. Hepatocellular Carcinoma (HCC) • adult patients with unresectable or metastatic HCC, as a first-line treatment following combination treatment with intravenous nivolu

12.1 Mechanism of Action Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase in OPDIVO QVANTIG acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

2 DOSAGE AND ADMINISTRATION • OPDIVO QVANTIG has different dosage and administration instructions than intravenous nivolumab products. • OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. • OPDIVO QVANTIG is to be administered by a healthcare professional only. (2.1) OPDIVO QVANTIG is for subcutaneous use only. • Administer by subcutaneous injection over 3 to 5 minutes. (2.3) • Renal cell carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.3) • Melanoma • Adult and pediatric patients (12 years and older) who weigh 40 kg or greater: 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Pediatric patients (12 years and older) who weigh 30 kg or greater but less than 40 kg: 300 mg/5,000 units every 2 weeks or 600 mg/10,000 units every 4 weeks. (2.3) • Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer • 900 mg/15,000 units with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles. (2.3) • Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer • 900 mg/15,000 units with platinum-doublet chemotherapy on the same day every 3 weeks for up to 4 cycles, then continued as single-agent OPDIVO QVANTIG 1,200 mg/20,000 units every 4 weeks after surgery for up to 13 cycles (~1 year). (2.3) • Metastatic non-small cell lung cancer • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Squamous cell carcinoma of the head and neck • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Urothelial carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • First-line unresectable or metastatic urothelial carcinoma • 900 mg/15,000 units every 3 weeks with cisplatin and gemcitabine on the same day for up to 6 cycles, then 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • MSI-H or dMMR metastatic Colorectal cancer • Adult and pediatric patients weighing 40 kg or greater: 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Pediatric patients weighing 30 kg or greater but less than 40 kg: 300 mg/5,000 units every 2 weeks or 600 mg/10,000 units every 4 weeks. (2.3) • Hepatocellular carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • Esophageal cancer • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. (2.3) • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks administered in combination with fluoropyrimidine- and platinum-containing chemotherapy. (2.3) • Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma • 600 mg/10,000 units every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.3) • 900 mg/15,000 units every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks. (2.3) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Important Dosage and Administration Information OPDIVO QVANTIG has different dosage and administration instructions than intravenously administered nivolumab products [see Dosage and Administration (2.5) ]. OPDIVO QVANTIG is for subcutaneous use only in the abdomen or thigh. Do not administer intravenously. OPDIVO QVANTIG is to be administered by a healthcare professional only. Adult patients currently receiving intravenous nivolumab as a single agent, or in combination with chemotherapy or cabozantinib, may switch to subcutaneous OPDIVO QVANTIG at their next scheduled dose. 2.2 Patient Selection Esophageal Cancer Select patients with unresectable advanced or metastatic ESCC for treatment wi

6 ADVERSE REACTIONS 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) ] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.2) ] • Most common adverse reactions (≥10%) with OPDIVO QVANTIG as monotherapy in patients with Renal Cell Carcinoma were: musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. (6.1) • Safety of OPDIVO QVANTIG for the following indications is based on safety of intravenous nivolumab in these populations. The most common adverse reactions with intravenous nivolumab for these indications are presented below. • As monotherapy for the treatment of advanced renal cell carcinoma; adjuvant treatment of completely resected Stage IIB, IIC, III, or IV melanoma; unresectable or metastatic melanoma; adjuvant treatment of NSCLC, metastatic NSCLC; squamous cell carcinoma of the head and neck; urothelial carcinoma; MSI-H or dMMR mCRC; hepatocellular carcinoma; esophageal cancer: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1) • In combination with cabozantinib for the first-line treatment of advanced renal cell carcinoma: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1) • In combination with platinum-doublet chemotherapy for the neoadjuvant treatment of NSCLC: nausea, constipation, fatigue, decreased appetite, and rash. (6.1) • In combination with cisplatin and gemcitabine for the treatment of urothelial cancer: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1) • In combination with fluoropyrimidine- and platinum- containing chemotherapy for the treatment of esophageal cancer and gastric cancer: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO QVANTIG as a single agent in 247 patients enrolled in CHECKMATE-67T, with additional data from intravenous nivolumab single-agent (1994 patients), and from intravenous nivolumab in combination with cabozantinib (320 patients) for select adverse reactions. Advanced Renal Cell Carcinoma CHECKMATE-67T was a multicenter, randomized, open-label study in adult patients with advanced or metastatic RCC. Patients received OPDIVO QVANTIG dose of 1,200 mg of nivolumab and 20,000 units of hyaluronidase subcutaneously every 4 weeks (n=247) or 3 mg/kg of nivolumab intravenously every 2 weeks (n=245). Among patients who received OPDIVO QVANTIG, 52% were exposed for 6 months or longer and 20% were exposed for greater than 1 year. Serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG. Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications.

5 WARNINGS AND PRECAUTIONS • Immune-Mediated Adverse Reactions : (5.1) o Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue based on severity and type of reaction. (2.4) • Complications of allogeneic HSCT : Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.2) • Embryo-Fetal toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.3 , 8.1 , 8.3) • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.4) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions OPDIVO QVANTIG is a combination of a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance, and inducing immune-mediated adverse reactions, and an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include 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 treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD‑1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . In general, if OPDIVO QVANTIG 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. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDIVO QVANTIG can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence

4 CONTRAINDICATIONS None. • None. (4)