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. Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition results in enhanced T-cell function that is greater than the effects of either antibody alone, and results in improved anti-tumor responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity.

Recommended Dosage for Unresectable or Metastatic Melanoma: Single Agent: The recommended dose of Nivolumab as a single agent is either: 240 mg every 2 weeks or 480 mg every 4 weeks. Administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. With Ipilimumab : The recommended dose of Nivolumab is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by ipilimumab 3 mg/kg administered as an intravenous infusion over 90 minutes on the same day, every 3 weeks for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of the combination, administer Nivolumab as a single agent, either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for Adjuvant Treatment of Melanoma: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease recurrence or unacceptable toxicity for up to 1 year.

Recommended Dosage for NSCLC: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for RCC: The recommended dose of Nivolumab as a single agent is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for cHL: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for SCCHN: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for Urothelial Carcinoma: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progressionor unacceptable toxicity.

Recommended Dosage for CRC: The recommended dose of Nivolumab is 240 mg every 2 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Recommended Dosage for HCC: The recommended dose of Nivolumab is either: 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

Visually inspect drug product solution for particulate matter and discoloration prior to administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake the vial.

Preparation: Withdraw the required volume of Nivolumab and transfer into an intravenous container. Dilute Nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL. Mix diluted solution by gentle inversion. Do not shake. Discard partially used vials or empty vials of Nivolumab.

Administration: Administer the infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter. Do not co-administer other drugs through the same intravenous line.

Storage of Infusion: The product does not contain a preservative. After preparation, store the Nivolumab infusion either: at room temperature for no more than 8 hours from the time of preparation. This includes room temperature storage of the infusion in the IV container and time for administration of the infusion or under refrigeration at 2°C to 8°C for no more than 24 hours from the time of infusion preparation. Do not freeze.

Pediatric Use: The safety and effectiveness of Nivolumab have not been established in pediatric patients less than 12 years old with MSI-H or dMMR mCRC or in pediatric patients less than 18 years old for the other approved indications.

Geriatric Use: No overall difference in safety was reported between elderly patients and younger patients. In elderly patients with intermediate or poor risk, no overall difference in effectiveness was reported.

Most common adverse reactions (≥20%) in patients were:

• Nivolumabas a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.
• Nivolumab with ipilimumab for melanoma: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea.
• Nivolumab with ipilimumab for renal cell carcinoma: fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite.

Pregnancy: Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman. The effects of Nivolumab are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Lactation: It is not known whether Nivolumab is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nivolumab, advise women to discontinue breastfeeding during treatment with Nivolumab.

Contraception: Based on its mechanism of action, Nivolumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Nivolumab and for at least 5 months following the last dose of Nivolumab.

Immune-mediated pneumonitis: Withhold for moderate and permanently discontinue for severe or life-threatening pneumonitis.

Immune-mediated colitis: Withhold Nivolumab when given as a single agent for moderate or severe and permanently discontinue for life-threatening colitis. Withhold Nivolumab when given with ipilimumab for moderate and permanently discontinue for severe or life-threatening colitis.

Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation.

Immune-mediated endocrinopathies: Withhold for moderate or severe and permanently discontinue for life-threatening hypophysitis. Withhold for moderate and permanently discontinue for severe or life-threatening adrenal insufficiency. Monitor for changes in thyroid function. Initiate thyroid hormone replacement as needed. Monitor for hyperglycemia. Withhold for severe and permanently discontinue for life-threatening hyperglycemia.

Immune-mediated nephritis and renal dysfunction: Monitor for changes in renal function. Withhold for moderate or severe and permanently discontinue for life-threatening serum creatinine elevation.

Immune-mediated skin adverse reactions: Withhold for severe and permanently discontinue for life-threatening rash.

Immune-mediated encephalitis: Monitor for changes in neurologic function. Withhold forb new-onset moderate to severe neurological signs or symptoms and permanently discontinue for immune-mediated encephalitis.

Infusion reactions: Discontinue Nivolumab for severe and life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.

Complications of allogeneic HSCT after Nivolumab: Monitor for hyperacute graft-versus-host-disease (GVHD), grade 3-4 acute GVHD, steroid requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. Transplant-related mortality has occurred.

Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception.

Store vials under refrigeration at 2°C-8°C in original carton to protect from light. Do not freeze or shake. Keep out of the reach of children.