nye-VOL-ue-mab

Therapeutic Classification: antineoplastics

Pharmacologic Classification: monoclonal antibodies, programmed death-1 inhibitors

• Unresectable/metastatic melanoma (as monotherapy or in combination with ipilimumab).
• Adjuvant treatment of melanoma in patients that have involvement of lymph nodes or metastatic disease and have undergone complete resection.
• Metastatic non–small-cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
• First-line treatment of metastatic NSCLC in patients whose tumors express PD-L1(≥1%) and have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations (in combination with ipilimumab).
• First-line treatment of metastatic or recurrent NSCLC in patients whose tumors have no EGFR or ALK genomic tumor aberrations (in combination with ipilimumab and two cycles of platinum-based chemotherapy).
• Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) NSCLC (in combination with platinum-doublet chemotherapy).
• Advanced renal cell carcinoma (RCC) in patients who have previously received anti-angiogenic therapy (as monotherapy).
• Immediate or poor risk, previously untreated advanced RCC (in combination with ipilimumab).
• First-line treatment of advanced RCC (in combination with cabozantinib).
• Classic Hodgkin's lymphoma that has relapsed or progressed after either autologous hematopoietic stem cell transplantation (HSCT) and brentuximab or ≥3 lines of systemic therapy that includes autologous HSCT.
• Recurrent or metastatic squamous cell carcinoma of the head and neck with progression on or after platinum-based therapy.
• Adjuvant treatment of urothelial carcinoma in patients who are at high risk of recurrence after undergoing radical resection of urothelial carcinoma.
• Locally advanced or metastatic urothelial carcinoma in patients who either have progression during or following platinum-based therapy or progression within 12 mo of neoadjuvant or adjuvant treatment with platinum-based therapy.
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (as monotherapy or in combination with ipilimumab).
• Hepatocellular carcinoma in patients who have been previously treated with sorafenib (in combination with ipilimumab).
• Unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy.
• First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (in combination with fluoropyrimidine- and platinum-containing chemotherapy).
• First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (in combination with ipilimumab).
• Adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy.
• Advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (in combination with fluoropyrimidine- and platinum-containing chemotherapy).
• First-line treatment of unresectable malignant pleural mesothelioma (in combination with ipilimumab).

• Programmed death receptor-1 (PD-1) blocking antibody (an IgG4 kappa immunoglobulin) that binds to PD-1 and blocks its interaction with its ligands, PD-L1 and PD-L2, resulting in activation of the immune system and decreased tumor growth.

• Decreased progression of melanoma, Hodgkin's lymphoma, urothelial carcinoma, colorectal cancer, and hepatocellular carcinoma.
• Decreased progression of and improved survival with NSCLC and advanced RCC.
• Improved survival in squamous cell carcinoma of head and neck, esophageal cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, and malignant pleural mesothelioma.

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism/Excretion: Unknown.

Half-life: 26.7 days.

Contraindicated in:

• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Patients undergoing allogeneic HSCT before or after nivolumab therapy (↑ risk of complications)
• Patients with multiple myeloma receiving a thalidomide analogue and dexamethasone (↑ risk of mortality)
• Rep: Women of reproductive potential
• Pedi: Safety and effectiveness not established in children <12 yr (MSI-H dMMR colorectal cancer and melanoma) or children <18 yr (all other indications).

CV: MYOCARDITIS, pericarditis, peripheral edema, vasculitis.

Derm: rash, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN).

EENT: iritis, uveitis.

Endo: hypothyroidism, ADRENAL INSUFFICIENCY, hyperthyroidism, hypoparathyroidism, hypophysitis, type 1 diabetes.

F and E: hyperkalemia.

GI: colitis, gastritis, HEPATITIS, pancreatitis.

GU: nephritis.

Hemat: hemolytic anemia.

MS: myositis, RHABDOMYOLYSIS.

Neuro: Guillain-Barré syndrome, autoimmune neuropathy, ENCEPHALITIS, MENINGITIS, myasthenic syndrome, myelitis.

Resp: cough, PNEUMONITIS.

Misc: INFUSION-RELATED REACTIONS.

Drug-Drug:

• None reported.

Unresectable or Metastatic Melanoma

• IV (Adults and Children ≥12 yr and ≥40 kg): As monotherapy: 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity; In combination with ipilimumab: 1 mg/kg every 3 wk for 4 doses or until unacceptable toxicity (whichever occurs first) (administer before ipilimumab on same day), then either 240 mg as monotherapy every 2 wk until disease progression or unacceptable toxicity or 480 mg as monotherapy every 4 wk until disease progression or unacceptable toxicity.
• IV (Children ≥12 yr and <40 kg): As monotherapy: 3 mg/kg every 2 wk until disease progression or unacceptable toxicity or 6 mg/kg every 4 wk until disease progression or unacceptable toxicity; In combination with ipilimumab: 1 mg/kg every 3 wk for 4 doses or until unacceptable toxicity (whichever occurs first) (administer before ipilimumab on same day), then either 3 mg/kg as monotherapy every 2 wk until disease progression or unacceptable toxicity or 6 mg/kg as monotherapy every 4 wk until disease progression or unacceptable toxicity.

Adjuvant Treatment of Melanoma

• IV (Adults and Children ≥12 yr and ≥40 kg): 240 mg every 2 wk until disease progression or unacceptable toxicity for up to 1 yr or 480 mg every 4 wk until disease progression or unacceptable toxicity for up to 1 yr.
• IV (Children ≥12 yr and <40 kg): 3 mg/kg every 2 wk until disease progression or unacceptable toxicity or 6 mg/kg every 4 wk until disease progression or unacceptable toxicity.

Hepatocellular Carcinoma

• IV (Adults): 1 mg/kg every 3 wk for 4 doses (administer before ipilimumab on same day), then 240 mg as monotherapy every 2 wk or 480 mg as monotherapy every 4 wk until disease progression or unacceptable toxicity.

Adjuvant Treatment of Urothelial Carcinoma

• IV (Adults): 240 mg every 2 wk until disease progression or unacceptable toxicity for up to 1 yr or 480 mg every 4 wk until disease progression or unacceptable toxicity for up to 1 yr.

Classical Hodgkin's Lymphoma, Urothelial Carcinoma, or Squamous Cell Carcinoma of Head and Neck

• IV (Adults): 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity.

Esophageal Squamous Cell Carcinoma

• IV (Adults): As monotherapy: 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity. In combination with fluoropyrimidine- and platinum-containing chemotherapy: 240 mg every 2 wk until disease progression, unacceptable toxicity, or for up to 2 yr or 480 mg every 4 wk until disease progression, unacceptable toxicity, or for up to 2 yr. In combination with ipilimumab: 3 mg/kg every 2 wk until disease progression, unacceptable toxicity, or for up to 2 yr (administer before ipilimumab on same day) or 360 mg every 3 wk until disease progression, unacceptable toxicity, or for up to 2 yr (administer before ipilimumab on same day).

Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer

• IV (Adults): 240 mg every 2 wk until disease progression or unacceptable toxicity for a total treatment duration of 1 yr or 480 mg every 4 wk until disease progression or unacceptable toxicity for a total treatment duration of 1 yr.

Metastatic Non–Small-Cell Lung Cancer

• IV (Adults): As monotherapy: 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity; In combination with ipilimumab (for metastatic tumors expressing PD-L1): 3 mg/kg every 3 wk until disease progression, unacceptable toxicity or for up to 2 yr (if no disease progression) (administer before ipilimumab on same day). In combination with ipilimumab (for metastatic or recurrent tumors not expressing PD-L1): 360 mg every 3 wk until disease progression, unacceptable toxicity or for up to 2 yr (if no disease progression) (when given just with platinum-based chemotherapy on same day, administer nivolumab then platinum-based chemotherapy; when given with ipilimumab and platinum-based chemotherapy on same day, administer nivolumab, then ipilimumab, then platinum-based chemotherapy).

Neoadjuvant Treatment of Resectable Non-Small-Cell Lung Cancer

• IV (Adults): 360 mg every 3 wk (when given with platinum-doublet chemotherapy on same day) for 3 cycles.

Advanced Renal Cell Carcinoma

• IV (Adults): As monotherapy: 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity; In combination with ipilimumab: 3 mg/kg every 3 wk for 4 doses (administer before ipilimumab on same day), then 240 mg as monotherapy every 2 wk until disease progression or unacceptable toxicity or 480 mg as monotherapy every 4 wk until disease progression or unacceptable toxicity. In combination with cabozantinib: 240 mg every 2 wk until disease progression, unacceptable toxicity, or up to 2 yr or 480 mg every 4 wk until disease progression, unacceptable toxicity, or up to 2 yr.

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

• IV (Adults and Children ≥12 yr and ≥40 kg): As monotherapy: 240 mg every 2 wk until disease progression or unacceptable toxicity or 480 mg every 4 wk until disease progression or unacceptable toxicity; In combination with ipilimumab: 3 mg/kg every 3 wk for 4 doses (administer before ipilimumab on same day), then 240 mg as monotherapy every 2 wk until disease progression or unacceptable toxicity or 480 mg as monotherapy every 4 wk until disease progression or unacceptable toxicity.
• IV (Children ≥12 yr and <40 kg): As monotherapy: 3 mg/kg every 2 wk until disease progression or unacceptable toxicity; In combination with ipilimumab: 3 mg/kg every 3 wk for 4 doses (administer before ipilimumab on same day), then 3 mg/kg as monotherapy every 2 wk until disease progression or unacceptable toxicity.

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma

• IV (Adults): 240 mg every 2 wk until disease progression, unacceptable toxicity or for up to 2 yr (administer before fluoropyrimidine- and platinum-containing chemotherapy on same day) or 360 mg every 3 wk until disease progression, unacceptable toxicity or for up to 2 yr (administer before fluoropyrimidine- and platinum-containing chemotherapy on same day).

Malignant Pleural Mesothelioma

• IV (Adults): 360 mg/kg every 3 wk until disease progression, unacceptable toxicity or for up to 2 yr (if no disease progression) (administer before ipilimumab on same day).

• Solution for injection: 10 mg/mL;

• Monitor for signs and symptoms of immune-mediated pneumonitis (shortness of breath, chest pain, new or worse cough) periodically during therapy. Treat with corticosteroids 1–2 mg/kg/day prednisone equivalents for ≥Grade 2 pneumonitis followed by corticosteroid taper. If Grade 2 pneumonitis occurs, hold nivolumab; resume therapy when recovery to Grade 0–1. If Grade 3 or 4 pneumonitis occurs, permanently discontinue nivolumab.
• Assess for signs and symptoms of infusion reactions (chills or shaking, itching or rash, flushing, difficulty breathing, dizziness, fever, feeling faint) periodically during therapy. If Grade 1 or 2 infusion reactions occur, hold or slow infusion. If Grade 3 or 4 infusion reactions occur, discontinue therapy.
• Monitor for signs and symptoms of immune-mediated colitis (diarrhea, abdominal pain, mucus or blood in stool, with or without fever). Treat with corticosteroids at doses of 1–2 mg/kg/day of prednisone or equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. If Grade 2 or 3 colitis occurs, hold nivolumab. Resume with complete or partial resolution (Grade 0–1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 wk of last dose or inability to reduce prednisone to ≤10 mg per day (or equivalent) within 12 wk of initiating steroids. If Grade 4 colitis occurs, permanently discontinue nivolumab. If administered with ipilimumab, hold for Grade 2 colitis. For moderate or severe (Grade 3 or 4) or recurrent colitis, permanently discontinue nivolumab and ipilimumab.
• Monitor for signs and symptoms of hepatitis (yellowing of skin or whites of eyes, severe nausea or vomiting, right-sided abdominal pain, drowsiness, dark urine, unusual bleeding or bruising, anorexia) periodically during therapy.
• Assess for rash periodically during therapy. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. May cause SJS and TEN. If rash, itching, blistering, or ulcers in mouth or other mucous membranes occur and SJS, TEN, or DRESS are suspected, hold dose and refer for assessment and treatment. If SJS, TEN, or DRESS are confirmed, permanently discontinue therapy. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia. For immune-mediated rash, administer corticosteroids at doses of 1–2 mg/kg/day of prednisone or equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) rash. Withhold for severe rash; permanently discontinue for life-threatening rash.
• Monitor for signs and symptoms of hypophysitis (headaches, photophobia, visual field defects, extreme tiredness, weight gain or loss, dizziness or fainting, mood changes, hair loss, feeling cold, constipation, deepening voice, excessive thirst and urination) periodically during therapy. Administer hormone replacement and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate or severe hypophysitis. Withhold therapy for moderate or severe hypophysitis. Discontinue for life-threatening Grade 4.
• Monitor for signs and symptoms of adrenal insufficiency. Administer corticosteroids at a dose of 1–2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) symptoms. Withhold for moderate (Grade 2) and permanently discontinue therapy for severe or life-threatening adrenal insufficiency.
• Monitor for signs and symptoms of encephalitis (headache, fever, tiredness or weakness, confusion, memory problems, sleepiness, hallucinations, seizures, stiff neck) periodically during therapy. If Grade 2 neurological toxicities occur, hold therapy for patients with new-onset moderate to severe neurologic symptoms during diagnosis. If Grade 3 or 4 neurological toxicities occur, permanently discontinue nivolumab and administer corticosteroids at dose of 1–2 mg/kg/day prednisone equivalents for immune-mediated encephalitis, followed by corticosteroid taper.
• Monitor for signs and symptoms of kidney dysfunction (decrease in amount of urine, blood in urine, swelling in ankles, anorexia) periodically during therapy.
• Monitor for signs and symptoms of myocarditis (chest pain, dyspnea) during therapy. If Grade 2, 3 or 4 myocarditis occurs, permanently discontinue nivolumab.

• Verify negative pregnancy test before starting therapy.Patient selection for NSCLC in combination with ipilimumab is based on PD-L1 expression. Information on FDA-approved tests for the determination of PD-L1 expression in NSCLC is available at: www.fda.gov/CompanionDiagnostics.Monitor for abnormal liver tests prior to and periodically during therapy. For hepatitis with no tumor involvement: If AST/ALT >3 and ≤8 times (or ≤5 if given with ipilimumab) upper limit of normal (ULN) or total bilirubin >1.5 and ≤3 times ULN, hold nivolumab. Resume with complete or partial resolution (Grade 0–1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 wk of last dose or inability to reduce prednisone to ≤10 mg per day (or equivalent) within 12 wk of starting steroids. If AST or ALT >8 times (or >5 if given with ipilimumab) ULN or total bilirubin >3 times ULN, permanently discontinue nivolumab. For hepatitis with tumor involvement of the liver: If 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, hold nivolumab. If AST/ALT >10 times ULN or total bilirubin >3 times ULN, discontinue nivolumab permanently. If given with cabozantinib and ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN, hold nivolumab and cabozantinib until recovery to Grade 0–1. If given with cabozantinib and AST or ALT >10 times ULN or >3 times with concurrent bilirubin ≥2 times ULN, permanently discontinue nivolumab and cabozantinib.
  • Monitor for ↑ serum creatinine prior to and periodically during therapy. If Grade 2 or 3 increases in blood creatinine occur, hold nivolumab. Resume in patients with complete or partial resolution (Grade 0–1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 wk of last dose or inability to reduce prednisone to ≤10 mg per day (or equivalent) within 12 wk of starting steroids. If Grade 4 increases in blood creatinine occur, permanently discontinue nivolumab.
  • Monitor thyroid function prior to and periodically during therapy. Treat hypothyroidism with replacement therapy. Use medical management for hyperthyroidism. Immune-mediated thyroid dysfunction does not require dose modification of nivolumab.
  • Monitor for hyperglycemia. If severe, withhold therapy until metabolic control achieved. If life-threatening, permanently discontinue nivolumab.

IV Administration:

• Intermittent Infusion:
  Diluent: 0.9% NaCl or D5W.Concentration: 1–10 mg/mL. Mix by gentle inversion; do not shake. Solution is clear to slightly opalescent, colorless to slightly yellow; do not administer solution if discolored or contains particulate matter other than translucent to white proteinaceous particles. Solution is stable at room temperature for up to 4 hr and 24 hr if refrigerated.
• Rate: Infuse through a sterile, nonpyrogenic, low-protein binding 0.2–1.2 micrometer in-line filter over 60 min. Flush line at end of infusion.
• Y-Site Incompatibility: Do not administer other drugs through same infusion line.

• Explain purpose of nivolumab to patient.
• Advise patient to notify health care professional immediately if signs and symptoms of pneumonitis, colitis, hepatitis (jaundice, severe nausea or vomiting, pain on right side of abdomen, lethargy, easy bruising or bleeding), kidney problems (decreased urine output, blood in urine, swollen ankles, loss of appetite), hormone gland problems (rapid heartbeat, weight loss, increased sweating, weight gain, hair loss, feeling cold, constipation, deepening of voice, muscle aches, dizziness or fainting, persistent or unusual headache) occur.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Rep: May cause fetal harm. Advise females of reproductive potential to use highly effective contraception and avoid breastfeeding during and for 5 mo after last dose. Advise patient to notify healthcare professional immediately if pregnancy is planned or suspected.
• Emphasize importance of keeping scheduled appointments for blood work or other laboratory tests.

• Decreased progression of melanoma, Hodgkin's lymphoma, urothelial carcinoma, colorectal cancer, and hepatocellular carcinoma.
• Decreased progression of and improved survival with NSCLC and advanced RCC.
• Improved survival in squamous cell carcinoma of head and neck, esophageal cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, and malignant pleural mesothelioma.

Opdivo

NDC Code^*

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-3734- OPDIVO
    • 0003-3734-13- 1 VIAL, SINGLE-DOSE in 1 CARTON (0003-3734-13) > 24 mL in 1 VIAL, SINGLE-DOSE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-3772- OPDIVO
    • 0003-3772-11- 1 VIAL, SINGLE-DOSE in 1 CARTON (0003-3772-11) > 4 mL in 1 VIAL, SINGLE-DOSE

• 0003- E.R. Squibb and Sons, L.L.C.
  • 0003-3774- OPDIVO
    • 0003-3774-12- 1 VIAL, SINGLE-DOSE in 1 CARTON (0003-3774-12) > 10 mL in 1 VIAL, SINGLE-DOSE