Hyaluronidase (human recombinant) and Nivolumab

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. • 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. • adult patients with advanced RCC who have received prior anti-angiogenic therapy. Melanoma • adult and pediatric (12 years and older who weigh 30 kg or greater) patients with unresectable or metastatic melanoma.

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.

• 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. OPDIVO QVANTIG is for subcutaneous use only. • Administer by subcutaneous injection over 3 to 5 minutes. • Renal cell carcinoma • 600 mg/10,000 units every 2 weeks or 1,200 mg/20,000 units every 4 weeks. • 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. • 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.

None. • None.

• Immune-Mediated Adverse Reactions: 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. • 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. • Embryo-Fetal toxicity: Can cause fetal harm.

The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and Fatal Immune-Mediated Adverse Reactions • Complications of Allogeneic HSCT • 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. • 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.

Store OPDIVO QVANTIG vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake.