Nivolumab and Hyaluronidase

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. […]

Injection: 300 mg nivolumab and 5,000 units hyaluronidase per 2.5 mL (120 mg/2,000 units per mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial. Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL), as a clear to opalescent, colorless to yellow solution in a single-dose vial.

• Injection: 300 mg nivolumab and 5,000 units hyaluronidase per 2.5 mL (120 mg/2,000 units per mL) in a single-dose vial. (3)
• Injection: 600 mg nivolumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL) in a single-dose vial. (3)

None.

• None. (4)

• 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) ] . […]

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) ] . […]

• 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. […]

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.