Nivolumab and Hyaluronidase-Nvhy

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 nivolumab and ipilimumab. (1.10)
• adult patients with unresectable or metastatic HCC, who have been previously treated with sorafenib, following combination treatment with intravenous nivolumab and ipilimumab. (1.10)
• Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic HCC. Esophageal Cancer
• adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.11)
• adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy whose tumors express PD-L1 (≥1). (1.11)
• Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.
• adult patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy. (1.11) Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
• adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.12)

1.1 Advanced Renal Cell Carcinoma OPDIVO QVANTIG™, as monotherapy, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC) following treatment with intravenous nivolumab and ipilimumab combination therapy. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma. OPDIVO QVANTIG, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with advanced RCC who have received prior anti-angiogenic therapy.

1.2 Unresectable or Metastatic Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic melanoma. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic melanoma.

1.3 Adjuvant Treatment of Melanoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

1.4 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

1.5 Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO QVANTIG, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection.

1.6 Metastatic Non-Small Cell Lung Cancer OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with 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. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.

1.7 Squamous Cell Carcinoma of the Head and Neck OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

1.8 Urothelial Carcinoma OPDIVO QVANTIG, as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. OPDIVO QVANTIG, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic UC. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of 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.

1.9 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) following treatment with intravenous nivolumab and ipilimumab combination therapy. OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult and pediatric patients 12 years and older who weigh 30 kg or greater, with MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of unresectable or metastatic MSI-H or dMMR CRC.

1.10 Hepatocellular Carcinoma

• OPDIVO QVANTIG, as monotherapy, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) following treatment with intravenous nivolumab and ipilimumab combination therapy.
• OPDIVO QVANTIG, as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have been previously treated with sorafenib following treatment with intravenous nivolumab and ipilimumab combination therapy . Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable or metastatic HCC.

1.11 Esophageal Cancer OPDIVO QVANTIG as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT). OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, 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 (2.2) ] . Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC. OPDIVO QVANTIG as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.

1.12 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma OPDIVO QVANTIG, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.2) ] .

• 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 with OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.11) ] .

• An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma Select patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma for treatment with OPDIVO QVANTIG in combination with fluoropyrimidine-and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.12) ] .
• An FDA-approved companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is not available.

2.3 Recommended Dosage The recommended dosages of OPDIVO QVANTIG as monotherapy are presented in Table 1. Administer OPDIVO QVANTIG as a subcutaneous injection over 3 to 5 minutes [see Dosage and Administration (2.5) ] . Table 1: Recommended Dosages for OPDIVO QVANTIG as Monotherapy † Dosing recommendations for monotherapy or monotherapy following intravenous nivolumab and ipilimumab combination therapy. Indication Recommended OPDIVO QVANTIG Dosage Duration of Therapy Advanced renal cell carcinoma† 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Metastatic non-small cell lung cancer Squamous cell carcinoma of the head and neck Locally advanced or metastatic urothelial carcinoma Hepatocellular carcinoma previously treated with sorafenib † Esophageal squamous cell carcinoma Unresectable or metastatic melanoma† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Adjuvant treatment of melanoma Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity, or up to 2 years Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease† Adult patients and pediatric patients age 12 years and older and weighing 40 kg or greater: 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients age 12 years and older and weighing 30 kg or greater but less than 40 kg: 300 mg nivolumab and 5,000 units hyaluronidase every 2 weeks or 600 mg nivolumab and 10,000 units hyaluronidase every 4 weeks First-line unresectable or metastatic hepatocellular carcinoma† 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease progression or unacceptable toxicity, or up to 2 years Adjuvant treatment of urothelial carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Adjuvant treatment of resected esophageal or gastroesophageal junction cancer The recommended dosages of OPDIVO QVANTIG in combination with other therapeutic agents are presented in Table 2. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO QVANTIG for the recommended dosage information, as appropriate. Table 2: Recommended Dosages for OPDIVO QVANTIG in Combination with Other Therapeutic Agents Indication Recommended OPDIVO QVANTIG Dosage Duration of Therapy Advanced renal cell carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Administer OPDIVO QVANTIG in combination with cabozantinib 40 mg orally once daily without food OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Cabozantinib: Until disease progression or unacceptable toxicity Neoadjuvant treatment of resectable non-small cell lung cancer 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks In combination with platinum-doublet chemotherapy for 3 cycles Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer Neoadjuvant: 900 mg nivolumab and 15,000 units hyaluronidase with platinum-doublet chemotherapy on the same day every 3 weeks Neoadjuvant: in combination with platinum-doublet chemotherapy until disease progression or unacceptable toxicity, for up to 4 cycles Adjuvant: 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Adjuvant: following neoadjuvant therapy and surgery, administer as a single agent until disease progression, recurrence, or unacceptable toxicity, for up to 13 cycles (up to 1 year) First-line unresectable or metastatic urothelial carcinoma 900 mg nivolumab and 15,000 units hyaluronidase every 3 weeks Administer OPDIVO QVANTIG in combination with cisplatin and gemcitabine on the same day every 3 weeks In combination with cisplatin and gemcitabine for up to 6 cycles 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose Esophageal squamous cell carcinoma 600 mg nivolumab and 10,000 units hyaluronidase every 2 weeks or 1,200 mg nivolumab and 20,000 units hyaluronidase every 4 weeks Administer OPDIVO QVANTIG in combination with fluoropyrimidine- and platinum-containing chemotherapy Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma 600 mg nivolumab and 10,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks or 900 mg nivolumab and 15,000 units hyaluronidase with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks OPDIVO QVANTIG: Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity 2.4 Dosage Modifications No dose reduction for OPDIVO QVANTIG is recommended. In general, withhold OPDIVO QVANTIG for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO QVANTIG for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, 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 OPDIVO QVANTIG or OPDIVO QVANTIG in combination with other anti-cancer agents for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4. Table 3: Recommended Dosage Modifications for Adverse Reactions a Resume in patients with complete or partial resolution (Grade 0 to 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 and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO QVANTIG based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. 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 Adverse Reaction Severity Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. Grade 2 or 3 Withhold a Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with cabozantinib, see Table 4. AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. Withhold a AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Hepatitis with tumor involvement of the liver b Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. Withhold a AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Endocrinopathies c Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grades 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy a Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO QVANTIG is withheld or discontinued when administered in combination with cabozantinib. b After recovery, rechallenge with one or both of OPDIVO QVANTIG and cabozantinib may be considered. If rechallenging with cabozantinib with or without OPDIVO QVANTIG, refer to cabozantinib Prescribing Information. Treatment Adverse Reaction Severity Dosage Modification OPDIVO QVANTIG in combination with cabozantinib Liver enzyme elevations ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN Withhold a both OPDIVO QVANTIG and cabozantinib until adverse reactions recover b to Grades 0-1 ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN Permanently discontinue a both OPDIVO QVANTIG and cabozantinib 2.5 Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is OPDIVO QVANTIG for subcutaneous use and NOT intravenous nivolumab. Do NOT administer OPDIVO QVANTIG intravenously. OPDIVO QVANTIG should be administered by a healthcare professional. Each OPDIVO QVANTIG vial is for one-time use only. It is a ready-to-use solution for injection. It should not be diluted. Visually inspect for particulate matter and discoloration prior to administration. OPDIVO QVANTIG is a clear to opalescent, colorless to yellow solution. Discard if the solution is discolored or contains extraneous particulate matter other than a few translucent-to-white particles. Do not shake. Preparation No incompatibilities were observed between OPDIVO QVANTIG and polypropylene and polycarbonate syringes, or between OPDIVO QVANTIG and polyethylene, polyurethane, polyvinyl chloride, and fluorinated ethylene propylene subcutaneous administration sets. A syringe and a transfer needle are needed to withdraw OPDIVO QVANTIG solution from the vial. OPDIVO QVANTIG may be injected subcutaneously using a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle or subcutaneous administration set (eg., winged/butterfly). Calculate the appropriate number of vials of OPDIVO QVANTIG (300 mg/5,000 units and/or 600 mg/10,000 units) needed based on the prescribed dose. Allow vial(s) to reach room temperature 20°C to 25°C (68°F to 77°F) before withdrawing dose.

• 300 mg nivolumab and 5,000 units hyaluronidase ∘ Withdraw 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into the syringe.
• 600 mg nivolumab and 10,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial of OPDIVO QVANTIG into the syringe.
• 900 mg nivolumab and 15,000 units hyaluronidase ∘ Withdraw 5 mL from the 600 mg/10,000 units vial and 2.5 mL from the 300 mg/5,000 units vial of OPDIVO QVANTIG into a single syringe for a total volume of 7.5 mL .
• 1,200 mg nivolumab and 20,000 units hyaluronidase ∘ Withdraw 5 mL from each vial of 600 mg/10,000 units OPDIVO QVANTIG into a single syringe for a total volume of 10 mL . Select the appropriate syringe label provided in the carton that matches the prescribed dose and apply to the prepared syringe. Discard partially used or empty vials of OPDIVO QVANTIG. If the dose is not to be used immediately, attach a tip cap to the syringe prior to storage. To avoid clogging of the hypodermic injection needle, attach a 23G to 25G (3/8 to 5/8 inch) hypodermic injection needle to the syringe immediately prior to administration. Storage in Syringe Once withdrawn into the syringe, OPDIVO QVANTIG should be used immediately. If not used immediately, store the syringe:
• In the refrigerator at 2°C to 8°C (36°F to 46°F), protected from light for up to 72 hours ; do not freeze, or
• At room temperature 20°C to 25°C (68°F to 77°F) for up to 8 hours. Storage at room temperature for this duration does not require protection from light.
• Discard if storage time exceeds these limits.
• If stored in the refrigerator, allow the solution to come to room temperature before administration. Administration
• Administer the full contents of the syringe into the subcutaneous tissue of 1 of the 4 quadrants of the abdomen, or thigh over a period of 3 to 5 minutes.
• Alternate injection sites across the 4 quadrants of the abdomen or thighs for successive injections. Do not inject into areas where the skin is tender, red, or bruised, or areas where there are scars or moles. If the administration of OPDIVO QVANTIG is interrupted, continue administering at the same site, or at an alternate site.
• During treatment with OPDIVO QVANTIG, do not administer other subcutaneous medications at the same site used for OPDIVO QVANTIG.

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 of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO QVANTIG in 1.6% and withholding of OPDIVO QVANTIG in 1.6% of patients. Systemic corticosteroids were required in 100% (7/7) of patients with pneumonitis. Pneumonitis resolved in 27% of the 7 patients. Of the 4 patients in whom OPDIVO QVANTIG was withheld for pneumonitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had recurrence of pneumonitis. Immune-Mediated Colitis OPDIVO QVANTIG can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. 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. Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions. Colitis led to withholding of OPDIVO QVANTIG in 2.0% of patients. Systemic corticosteroids were required in 100% (7/7) of patients with colitis. Colitis resolved in 71% of the 7 patients. Of the 5 patients in whom OPDIVO QVANTIG was withheld for colitis, 3 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 2 (67%) had recurrence of colitis. Immune-Mediated Hepatitis and Hepatotoxicity OPDIVO QVANTIG can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology. Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO QVANTIG in 0.8% and withholding of OPDIVO QVANTIG in 1.6% of patients. Systemic corticosteroids were required in 100% (6/6) of patients with hepatitis. Hepatitis resolved in 67% of the 6 patients. Of the 2 patients in whom OPDIVO QVANTIG was withheld for hepatitis, 2 reinitiated OPDIVO QVANTIG after symptom improvement; of these, 1 (50%) had recurrence of hepatitis. Intravenous Nivolumab with Cabozantinib Nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to nivolumab alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt nivolumab and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.4) ] . With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% (35/320) of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either intravenous nivolumab (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving intravenous nivolumab, 2 patients receiving cabozantinib, and 7 patients receiving both intravenous nivolumab and cabozantinib. Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO QVANTIG in 0.4% of patients and withholding of OPDIVO QVANTIG in 0.4% of patients. Systemic corticosteroids were required in 100% (5/5) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 20% of the 5 patients. Intravenous Nivolumab with Cabozantinib Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of intravenous nivolumab and cabozantinib in 0.9% and withholding of intravenous nivolumab and cabozantinib in 2.8% of patients with RCC. Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom intravenous nivolumab with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency. Hypophysitis OPDIVO QVANTIG can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . Intravenous Nivolumab Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Hypophysitis led to permanent discontinuation of intravenous nivolumab in <0.1% and withholding of intravenous nivolumab in 0.2% of patients. Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom intravenous nivolumab was withheld for hypophysitis, 2 reinitiated intravenous nivolumab after symptom improvement; of these, none had recurrence of hypophysitis. Thyroid Disorders OPDIVO QVANTIG can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . Thyroiditis Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade 1 (0.4%) adverse reaction. Systemic corticosteroids were not required in the patient with thyroiditis. Thyroiditis did not resolve in this patient. Hyperthyroidism Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (0.4%) adverse reactions. Systemic corticosteroids were not required in patients with hyperthyroidism. Hyperthyroidism resolved in 50% of the 2 patients. Hypothyroidism Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (5.7%) adverse reactions. Hypothyroidism led to withholding of OPDIVO QVANTIG in 0.8% of patients. Systemic corticosteroids were not required in patients with hypothyroidism. Hypothyroidism resolved in 4.3% of the 23 patients. Of the 1 patient in whom OPDIVO QVANTIG was withheld for hypothyroidism, OPDIVO QVANTIG was not reinitiated after symptom improvement. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG. No patients with diabetes required systemic corticosteroids. Diabetes did not resolve in this patient. Immune-Mediated Nephritis with Renal Dysfunction OPDIVO QVANTIG can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology. Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG. Immune-mediated nephritis and renal dysfunction led to withholding of OPDIVO QVANTIG in 1.2% of patients. Systemic corticosteroids were required in 100% (3/3) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 100% of the 3 patients. Of the 3 patients in whom OPDIVO QVANTIG was withheld for nephritis or renal dysfunction, 1 reinitiated OPDIVO QVANTIG after symptom improvement without recurrence of nephritis or renal dysfunction. Immune-Mediated Dermatologic Adverse Reactions OPDIVO QVANTIG can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity [see Dosage and Administration (2.4) ] . Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade 2 (2.8%) adverse reactions. Immune-mediated rash led to withholding of OPDIVO QVANTIG in 1.2% of patients. Systemic corticosteroids were required in 47% (8/17) of patients with immune-mediated rash. Rash resolved in 77% of the 17 patients. Of the 3 patients in whom OPDIVO QVANTIG was withheld for immune-mediated rash, all reinitiated OPDIVO QVANTIG after symptom improvement; of these, all (100%) had recurrence of immune-mediated rash. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as a single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular : Myocarditis, pericarditis, vasculitis Nervous System : Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy Ocular : Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss Gastrointestinal : Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis Musculoskeletal and Connective Tissue : Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic Endocrine : Hypoparathyroidism Hematologic/Immune : Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection. Other: Myocarditis-Myositis-Myasthenia Gravis (or Myasthenia-Like) Overlap Syndrome, reporting as the co-occurrence of either two or all three adverse reactions.

5.2 Complications of Allogeneic Hematopoietic Stem Cell Transplantation Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1) ] . These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

5.3 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for 5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

5.4 Increased Mortality in Patients with Multiple Myeloma when Nivolumab Is Added to a Thalidomide Analogue and Dexamethasone In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. 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.

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. Permanent discontinuation of OPDIVO QVANTIG due to an adverse reaction occurred in 10% of patients. The most common adverse reaction which resulted in permanent discontinuation was pneumonitis (2%). Dosage interruptions of OPDIVO QVANTIG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in >2% of patients included COVID-19 (4.5%), increased blood creatinine (2.8%), anemia, diarrhea, and fatigue (2.4% each). The most common adverse reactions (≥10%) were musculoskeletal pain, fatigue, pruritus, rash, hypothyroidism, diarrhea, cough, and abdominal pain. Tables 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-67T. Table 5: Adverse Reactions* in ≥5% of Adult Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T * Toxicity was graded per NCI CTCAE v5. a Includes multiple related terms Adverse Reaction OPDIVO QVANTIG (n=247) Intravenous Nivolumab (n=245) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 20 2.4 25 3.3 Injection site reaction a 8 0 0 0 Edema 5 0.4 11 0.8 Musculoskeletal and Connective Tissue Musculoskeletal pain a 31 1.6 39 3.3 Skin and Subcutaneous Tissue Pruritus 16 0.4 21 0 Rash a 15 1.2 13 1.2 Gastrointestinal Diarrhea a 11 0.4 14 0.4 Abdominal pain a 10 0 10 0.4 Nausea 8 0 9 0 Constipation 8 0 6 0 Vomiting 6 0.4 4.9 0 Respiratory, Thoracic, and Mediastinal Cough 11 0 11 0 Endocrine Hypothyroidism a 12 0 17 0 Metabolism and Nutrition Hyperglycemia 9 2.4 13 2.0 Decreased appetite 9 0 11 0.8 Clinically important adverse reactions in <5% of patients who received OPDIVO QVANTIG include: Cardiac: myocarditis Respiratory, thoracic, and mediastinal: pneumonitis, dyspnea Endocrine: adrenal insufficiency, hyperthyroidism, thyroiditis Gastrointestinal: colitis, pancreatitis Hepatobiliary: hepatitis Nervous system: peripheral neuropathy Skin and subcutaneous tissue: psoriasis, erythema Musculoskeletal and connective tissue: arthritis Blood and lymphatic system: eosinophilia Eye disorders: uveitis Immune system: hypersensitivity Table 6: Laboratory Values Worsening from Baseline a (≥20%) in Patients with RCC Receiving OPDIVO QVANTIG in CHECKMATE-67T a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO QVANTIG group (range: 232 to 235 patients) and intravenous nivolumab group (range: 240 to 244 patients). Laboratory Abnormality OPDIVO QVANTIG Intravenous Nivolumab All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Hemoglobin decreased 46 7 48 9 Lymphocytes decreased 36 6 45 9 Chemistry Creatinine increased 38 1.3 43 0.4 Sodium decreased 34 2.6 40 2.5 Potassium increased 34 3.0 45 2.9 Alkaline phosphatase increased 32 2.1 33 2.0 Calcium increased 29 2.1 31 4.1 Albumin decreased 25 1.7 35 0.4 ALT increased 21 1.3 26 4.1 Adverse Reactions in Patients Treated with Intravenous Nivolumab The safety of OPDIVO QVANTIG for its approved indications [see Indications and Usage (1) ] has been established in adequate and well-controlled clinical studies of intravenous nivolumab. Below is a description of adverse reactions in these adequate and well-controlled clinical studies. First-line Renal Cell Carcinoma CHECKMATE-214 The safety of intravenous nivolumab with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC; patients received intravenous nivolumab 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by intravenous nivolumab as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.1) ] . The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in intravenous nivolumab and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the intravenous nivolumab and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of intravenous nivolumab and ipilimumab patients. Fifty-four percent (54%) of patients receiving intravenous nivolumab and ipilimumab had a dose interruption for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of intravenous nivolumab and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Tables 7 and 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of intravenous nivolumab and ipilimumab‑treated patients in CHECKMATE-214. Table 7: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Ipilimumab - 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 Intravenous Nivolumab and Ipilimumab (n=547) Sunitinib (n=535) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 99 65 99 76 General 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 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 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 8: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on Intravenous Nivolumab and Ipilimumab - 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: intravenous nivolumab and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). Laboratory Abnormality Intravenous Nivolumab and Ipilimumab Sunitinib 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 32 1 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 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 intravenous nivolumab and ipilimumab group compared to the sunitinib group (31% and 61%, respectively). CHECKMATE-9ER The safety of intravenous nivolumab with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received intravenous nivolumab 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.1) ] . Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in intravenous nivolumab and cabozantinib-treated patients. In this trial, 82% of patients in the intravenous nivolumab and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. Adverse reactions leading to discontinuation of either intravenous nivolumab or cabozantinib occurred in 20% of patients: 7% intravenous nivolumab only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either intravenous nivolumab or cabozantinib occurred in 83% of patients: 3% intravenous nivolumab only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially. The most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab and cabozantinib were 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. Tables 9 and 10 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER. Table 9: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER Toxicity was graded per NCI CTCAE v4. a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b Includes gastroesophageal reflux disease. c Includes asthenia. d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. e Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes blood pressure increased, blood pressure systolic increased. h Includes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, rhinitis. Adverse Reaction Intravenous Nivolumab and Cabozantinib (n=320) Sunitinib (n=320) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Diarrhea 64 7 47 4.4 Nausea 27 0.6 31 0.3 Abdominal pain a 22 1.9 15 0.3 Vomiting 17 1.9 21 0.3 Dyspepsia b 15 0 22 0.3 General Fatigue c 51 8 50 8 Hepatobiliary Hepatotoxicity d 44 11 26 5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 40 8 41 8 Stomatitis e 37 3.4 46 4.4 Rash f 36 3.1 14 0 Pruritus 19 0.3 4.4 0 Vascular Hypertension g 36 13 39 14 Endocrine Hypothyroidism h 34 0.3 30 0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain i 33 3.8 29 3.1 Arthralgia 18 0.3 9 0.3 Metabolism and Nutrition Decreased appetite 28 1.9 20 1.3 Nervous System Dysgeusia 24 0 22 0 Headache 16 0 12 0.6 Respiratory, Thoracic and Mediastinal Cough j 20 0.3 17 0 Dysphonia 17 0.3 3.4 0 Infections and Infestations Upper respiratory tract infection k 20 0.3 8 0.3 Table 10: Laboratory Values Worsening from Baseline a Occurring in >20% of Patients on Intravenous Nivolumab and Cabozantinib - CHECKMATE-9ER a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). Laboratory Abnormality Intravenous Nivolumab and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased ALT 79 9.8 39 3.5 Increased AST 77 7.9 57 2.6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1.9 24 0.6 Hypomagnesemia 47 1.3 25 0.3 Hyperglycemia 44 3.5 44 1.7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2.8 37 1.6 Increased creatinine 39 1.3 42 0.6 Hyperkalemia 35 4.7 27 1 Hypoglycemia 26 0.8 14 0.4 Hematology Lymphopenia 42 6.6 45 10 Thrombocytopenia 41 0.3 70 9.7 Anemia 37 2.5 61 4.8 Leukopenia 37 0.3 66 5.1 Neutropenia 35 3.2 67 12 Previously Treated Renal Cell Carcinoma CHECKMATE-025 The safety of intravenous nivolumab was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received intravenous nivolumab 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.1) ] . The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in intravenous nivolumab-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients. Rate of death on treatment or within 30 days of the last dose was 4.7% on the intravenous nivolumab arm. Serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab. Study therapy was discontinued for adverse reactions in 16% of intravenous nivolumab patients. Forty-four percent (44%) of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the intravenous nivolumab group compared to the everolimus group (26% and 14%, respectively). Tables 11 and 12 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025. Table 11: Adverse Reactions in >15% of Patients Receiving Intravenous Nivolumab - CHECKMATE-025 Toxicity was graded per NCI CTCAE v4. a Includes asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI). c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema. Adverse Reaction Intravenous Nivolumab (n=406) Everolimus (n=397) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 98 56 96 62 General Fatigue a 56 6 57 7 Pyrexia 17 0.7 20 0.8 Respiratory, Thoracic and Mediastinal Cough/productive cough 34 0 38 0.5 Dyspnea/exertional dyspnea 27 3 31 2 Upper respiratory infection b 18 0 11 0 Gastrointestinal Nausea 28 0.5 29 1 Diarrhea c 25 2.2 32 1.8 Constipation 23 0.5 18 0.5 Vomiting 16 0.5 16 0.5 Skin and Subcutaneous Tissue Rash d 28 1.5 36 1 Pruritus/generalized pruritus 19 0 14 0 Metabolism and Nutrition Decreased appetite 23 1.2 30 1.5 Musculoskeletal and Connective Tissue Arthralgia 20 1 14 0.5 Back pain 21 3.4 16 2.8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: peripheral edema/edema Gastrointestinal Disorders: abdominal pain/discomfort Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain Nervous System Disorders: headache/migraine, peripheral neuropathy Investigations: weight decreased Skin Disorders: palmar-plantar erythrodysesthesia Table 12: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on Intravenous Nivolumab - CHECKMATE-025 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients). Laboratory Abnormality Intravenous Nivolumab Everolimus Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Lymphopenia 42 6 53 11 Anemia 39 8 69 16 Chemistry Increased creatinine 42 2 45 1.6 Increased AST 33 2.8 39 1.6 Increased alkaline phosphatase 32 2.3 32 0.8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4 20 2.1 Hypocalcemia 23 0.9 26 1.3 Increased ALT 22 3.2 31 0.8 Hypercalcemia 19 3.2 6 0.3 Lipids Increased triglycerides 32 1.5 67 11 Increased cholesterol 21 0.3 55 1.4 Unresectable or Metastatic Melanoma Previously Treated Metastatic Melanoma CHECKMATE-037 The safety of intravenous nivolumab was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.2) ] . Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m 2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m 2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in intravenous nivolumab‑treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received intravenous nivolumab for >6 months and 3% of patients received intravenous nivolumab for >1 year. The population characteristics in the intravenous nivolumab group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the intravenous nivolumab group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%). Serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab. Intravenous nivolumab was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving intravenous nivolumab had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash. Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037. Table 13: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 Toxicity was graded per NCI CTCAE v4. a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis. b Includes rhinitis, pharyngitis, and nasopharyngitis. Adverse Reaction Intravenous Nivolumab (n=268) Chemotherapy (n=102) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 21 0.4 7 0 Pruritus 19 0 3.9 0 Respiratory, Thoracic and Mediastinal Cough 17 0 6 0 Infections Upper respiratory tract infection b 11 0 2 0 General Peripheral edema 10 0 5 0 Clinically important adverse reactions in <10% of patients who received intravenous nivolumab were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis Table 14: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: intravenous nivolumab group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). Laboratory Abnormality Intravenous Nivolumab Chemotherapy All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Increased AST 28 2.4 12 1 Hyponatremia 25 5 18 1.1 Increased alkaline phosphatase 22 2.4 13 1.1 Increased ALT 16 1.6 5 0 Hyperkalemia 15 2 6 0 Previously Untreated Metastatic Melanoma CHECKMATE-066 The safety of intravenous nivolumab was also evaluated in CHECKMATE-066, a randomized, double-blind, active‑controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.2) ] . The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received intravenous nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m 2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in intravenous nivolumab-treated patients. In this trial, 47% of patients received intravenous nivolumab for >6 months and 12% of patients received intravenous nivolumab for >1 year. The trial population characteristics in the intravenous nivolumab group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the intravenous nivolumab group with ECOG performance status 0 (71% vs. 59%). Serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab. Adverse reactions led to permanent discontinuation of intravenous nivolumab in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of intravenous nivolumab discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus. Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066. Table 15: Adverse Reactions Occurring in ≥10% of Intravenous Nivolumab-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066 Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug …

• Lactation: Advise not to breastfeed. (8.2)

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data) . Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO QVANTIG are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO QVANTIG use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data OPDIVO QVANTIG for subcutaneous injection contains nivolumab and hyaluronidase [see Description (11) ] . Nivolumab A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab intravenously twice weekly from the onset of organogenesis through delivery, at exposure levels of between 4 and 15 times higher than those observed at the clinical dose of 600 mg once every 2 weeks, 900 mg once every 3 weeks, or 1,200 mg once every 4 weeks (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response, and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Hyaluronidase In an embryo-fetal development study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is at least 6,600 times higher than the human dose of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when administered with nivolumab. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is at least 1,080 times higher than the human dose of 10,000 U once every 2 weeks, 15,000 U once every 3 weeks, or 20,000 U once every 4 weeks (U/kg basis), when administered with nivolumab.

8.2 Lactation Risk Summary There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO QVANTIG.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO QVANTIG [see Use in Specific Populations (8.1) ] . Contraception OPDIVO QVANTIG 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 OPDIVO QVANTIG and for 5 months following the last dose.

8.4 Pediatric Use The safety and effectiveness of OPDIVO QVANTIG have been established in pediatric patients aged 12 years and older who weigh 30 kg or greater for the following indications:

• Unresectable or metastatic melanoma [see Indications and Usage (1.2) ]
• Unresectable or metastatic melanoma following combination treatment with intravenous nivolumab and ipilimumab [see Indications and Usage (1.2) ]
• Completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma as adjuvant treatment [see Indications and Usage (1.3) ]
• Unresectable or metastatic MSI-H or dMMR CRC following combination treatment with intravenous nivolumab and ipilimumab [see Indications and Usage (1.9) ]
• MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, irinotecan [see Indications and Usage (1.9) ] Use of OPDIVO QVANTIG in pediatric patients for these indications is supported by evidence from adequate and well-controlled studies for intravenous nivolumab in adults and additional pharmacokinetic and safety data for intravenous nivolumab in pediatric patients 12 years and older who weigh 30 kg or greater [see Adverse Reactions (6.1) and Clinical Studies (14) ] . Nivolumab exposure in pediatric patients 12 years and older who receive OPDIVO QVANTIG is predicted to be within range of those observed/predicted in adult patients at the recommended dosage [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) ] . The safety and effectiveness of OPDIVO QVANTIG have not been established for pediatric patients younger than 12 years old with melanoma or MSI-H or dMMR mCRC. The safety and effectiveness of OPDIVO QVANTIG have not been established in pediatric patients for other approved adult indications [see Indications and Usage (1) ] .

8.5 Geriatric Use Monotherapy Of the 248 patients who were randomized to monotherapy OPDIVO QVANTIG in clinical studies, 48% were 65 years and over and 14% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients . Single Agent Intravenous Nivolumab Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent intravenous nivolumab in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.6 , 14.8 , 14.11 , 14.12) ] . Clinical studies in patients with recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent intravenous nivolumab did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.7 , 14.9) ] . Intravenous Nivolumab in Combination with Platinum-Containing Chemotherapy Of the 179 patients with NSCLC who were randomized to intravenous nivolumab in combination with platinum-doublet chemotherapy, 48% were 65 years old or older and 6% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years [see Clinical Studies (14.4) ] . Of the 229 patients with NSCLC who were randomized to intravenous nivolumab 360 mg in combination with platinum-doublet chemotherapy every 3 weeks for up to 4 cycles, followed by intravenous nivolumab 480 mg every 4 weeks, 56% were 65 years old or older and 7% were 75 years old or older. No overall differences in safety or effectiveness were reported between patients older and younger than 65 years. Of the 1,110 patients with ESCC, GC, GEJC, or EAC who were randomized to intravenous nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy, 42% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.11 , 14.12) ] . Of the 304 patients with UC who were treated with intravenous nivolumab in combination with gemcitabine and platinum-doublet chemotherapy, 40% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age and over and younger patients. Clinical studies of intravenous nivolumab with platinum-doublet chemotherapy did not include sufficient numbers of patients aged 75 years and over to determine whether safety and effectiveness differs compared to younger patients. [see Clinical Studies (14.8) ] . In Combination with Cabozantinib Of the 320 patients with renal cell carcinoma who were treated with intravenous nivolumab in combination with cabozantinib, 41% were 65 years or older and 9% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients [see Clinical Studies (14.1) ] .