OPDIVO (nivolumab) injection

OPDIVO (nivolumab) injection

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OPDIVO (nivolumab) injection

Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated molecular mass of 146 kDa. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line.

OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-yellow liquid that may contain light (few) particles.

OPDIVO (nivolumab) injection for intravenous use is supplied in single-dose vials. Each mL of OPDIVO solution contains nivolumab 10 mg, mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6.

Indications

Unresectable or Metastatic Melanoma: OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma.

Adjuvant Treatment of Melanoma: OPDIVO is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

Metastatic Non-Small Cell Lung Cancer

  • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
  • OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
  • OPDIVO is indicated for the treatment of patients with metastatic NSCLC with 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.

Malignant Pleural Mesothelioma: OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

Advanced Renal Cell Carcinoma

  • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of patients with intermediate or poor risk advanced RCC.
  • OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced RCC.
  • OPDIVO as a single agent is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

Classical Hodgkin Lymphoma: OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:

  • autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
  • 3 or more lines of systemic therapy that includes autologous HSCT.

Squamous Cell Carcinoma of the Head and Neck: OPDIVO is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

Urothelial Carcinoma: OPDIVO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma 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.

Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer: OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Hepatocellular Carcinoma: OPDIVO, in combination with ipilimumab, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Esophageal Cancer

  • OPDIVO is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy (CRT).
  • OPDIVO is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma: OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

Mechanism of Action

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 PD1 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.

Dosage and administration

Administer by intravenous infusion based upon recommended infusion rate for each indication.

Unresectable or metastatic melanoma

  • 240 mg every 2 weeks or 480 mg every 4 weeks.
  • 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.

Adjuvant treatment of melanoma

  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Metastatic non-small cell lung cancer

  • 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.
  • 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy.
  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Malignant pleural mesothelioma

  • 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks.

Advanced renal cell carcinoma

  • 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
  • 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food.
  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Classical Hodgkin lymphoma

  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Recurrent or metastatic squamous cell carcinoma of the head and neck

  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Locally advanced or metastatic urothelial carcinoma

  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

  • Adult and pediatric patients ≥ 40 kg: 240 mg every 2 weeks or 480 mg every 4 weeks.
  • Pediatric patients < 40 kg: 3 mg/kg every 2 weeks.
  • Adult and pediatric patients ≥ 40 kg: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
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Hepatocellular carcinoma

  • 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.

Adjuvant treatment of resected esophageal or gastroesophageal cancer

  • 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks, then 480 mg every 4 weeks for total treatment duration of 1 year.

Esophageal squamous cell carcinoma

  • 240 mg every 2 weeks or 480 mg every 4 weeks.

Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC, GEJC, or EAC)

  • 360 mg every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.
  • 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks

Warnings and precautions

  • Severe and Fatal Immune-Mediated Adverse Reactions

OPDIVO is 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. 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.

Withhold or permanently discontinue OPDIVO depending on severity. In general, if OPDIVO 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.

Immune-Mediated Pneumonitis: OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology.

Immune-Mediated Colitis: OPDIVO 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 corticosteroidrefractory immune-mediated colitis.

Immune-Mediated Hepatitis and Hepatotoxicity: OPDIVO can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Adrenal Insufficiency: OPDIVO 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 depending on severity

Hypophysitis: OPDIVO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity

Thyroid Disorders: OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity

Immune-Mediated Nephritis with Renal Dysfunction: OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.

Immune-Mediated Dermatologic Adverse Reactions: OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO depending on severity

  • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction. Complications of allogeneic HSCT: Fatal and other serious complications can occur in patient who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.
  • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.
  • 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.

Adverse reactions

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

  • 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, abdominal pain, and vomiting.
  • In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness.
  • In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.
  • In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmarplantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
  • In combination with fluoropyrimidine- and platinum-containing chemotherapy: peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
Use in specific populations

Pregnancy: Based on data from animal studies and its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman.

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 are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Lactation: There are no data on the presence of nivolumab 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.

Pediatric Use: The safety and effectiveness of OPDIVO as a single agent and in combination with ipilimumab have been established in pediatric patients age 12 years and older with microsatellite instabilityhigh (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Storage

Store under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light by storing in the original package until time of use. Do not freeze or shake.

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