Nivolumab is a PD-1 (programmed death receptor-1) blocking antibody used in the treatment of various cancers, including:

• Unresectable or metastatic melanoma (both BRAF V600 wild-type and mutation-positive) as monotherapy
• Unresectable or metastatic melanoma in combination with ipilimumab
• Adjuvant treatment of melanoma after complete surgical removal, including cases with lymph node involvement or metastasis
• Metastatic non-small cell lung cancer (NSCLC) that has progressed during or after platinum-based chemotherapy
• Patients with EGFR or ALK mutations should receive approved targeted therapy before using nivolumab
• Advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy
• Previously untreated advanced RCC (intermediate or poor risk), in combination with ipilimumab
• Classical Hodgkin lymphoma that has relapsed or progressed after stem cell transplant and brentuximab vedotin, or after multiple prior therapies
• Recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based therapy
• Locally advanced or metastatic urothelial carcinoma with progression during or after platinum chemotherapy, or within 12 months of neoadjuvant/adjuvant therapy
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (in adults and children ≥12 years) after prior chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan)
• Hepatocellular carcinoma previously treated with sorafenib

The interaction of PD-1 receptors on T-cells with their ligands (PD-L1 and PD-L2) suppresses T-cell activity and cytokine production. Many tumors increase PD-L1/PD-L2 expression to evade immune detection. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. This releases the inhibition of T-cell activity, allowing the immune system to attack tumor cells. Preclinical studies show that blocking PD-1 reduces tumor growth. When combined with ipilimumab (a CTLA-4 inhibitor), nivolumab enhances T-cell function more than either drug alone, leading to improved anti-tumor responses, especially in metastatic melanoma and advanced renal cell carcinoma.

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 progression or 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, nonpyrogenic, 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%) reported in patients include:

• Nivolumab as 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 evidence from animal studies, Nivolumab may cause harm to the fetus when given to a pregnant woman. The risk is expected to be higher during the second and third trimesters. There are no adequate human data available to determine drug-related risk. Pregnant women should be advised about the potential risk to the fetus.

Lactation: It is unknown whether Nivolumab is excreted in human milk. Since many drugs, including antibodies, are present in breast milk and may cause serious adverse effects in nursing infants, women should be advised to discontinue breastfeeding during treatment with Nivolumab.

Contraception: Based on its mechanism of action, Nivolumab may cause fetal harm when administered during pregnancy. Females of reproductive potential should use effective contraception during treatment and for at least 5 months after the last dose of Nivolumab.

Immune-mediated pneumonitis: Withhold treatment in moderate cases and permanently discontinue in severe or life-threatening pneumonitis.

Immune-mediated colitis: Withhold nivolumab when used as a single agent in moderate or severe cases and discontinue permanently if life-threatening. When combined with ipilimumab, withhold for moderate cases and discontinue permanently for severe or life-threatening colitis.

Immune-mediated hepatitis: Monitor liver function closely. Withhold in moderate cases and permanently discontinue if severe elevations in transaminases or bilirubin occur.

Immune-mediated endocrinopathies: Withhold treatment in moderate or severe cases and discontinue permanently in life-threatening hypophysitis. Withhold for moderate and discontinue for severe adrenal insufficiency. Monitor thyroid function and initiate hormone replacement when needed. Monitor blood glucose levels and discontinue permanently in life-threatening hyperglycemia.

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

Immune-mediated skin adverse reactions: Withhold treatment in severe cases and discontinue permanently if life-threatening skin reactions occur.

Immune-mediated encephalitis: Monitor neurological status. Withhold treatment in new-onset moderate to severe symptoms and discontinue permanently if encephalitis occurs.

Infusion reactions: Discontinue nivolumab in severe or life-threatening reactions. Interrupt or slow infusion in mild or moderate cases.

Complications of allogeneic HSCT after Nivolumab: Monitor for hyperacute graft-versus-host disease (GVHD), severe acute GVHD (grade 3–4), steroid-requiring febrile syndromes, hepatic veno-occlusive disease, and other immune-related complications. Transplant-related mortality has been reported.

Embryo-fetal toxicity: May cause fetal harm. Advise patients about potential risks and the need for effective contraception.

Immunological Chemotherapy, Immunosuppressant

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