Opdivo

Nivolumab · Injection · Intravenous

Prescription (Rx) Programmed Death Receptor-1 Blocking Antibody

Uses

1 INDICATIONS AND USAGE OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of: Melanoma
• adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. (1.1)
• for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.2) Non-Small Cell Lung Cancer (NSCLC)
• adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.3)
• adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by single-agent OPDIVO as adjuvant treatment after surgery. (1.4)
• adult patients with metastatic non-small cell lung cancer expressing PD‑L1 (≥1%) as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab. (1.5)
• adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy. (1.5)
• adult patients with metastatic non-small cell lung cancer and 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. (1.5) Malignant Pleural Mesothelioma
• adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab. (1.6) Renal Cell Carcinoma (RCC)
• adult patients with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab. (1.7)
• adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. (1.7)
• adult patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.7) Classical Hodgkin Lymphoma (cHL)
• adult and pediatric (12 years and older) patients with previously untreated, Stage III or IV classical Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine (AVD). (1.8)
• adult patients with classical Hodgkin lymphoma that has relapsed or progressed after: (1.8)
• 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 (SCCHN)
• adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. (1.9) Urothelial Carcinoma
• adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. (1.10)
• adult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.10)
• adult 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. (1.10) Colorectal Cancer
• adult and pediatric (12 years and older) patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with ipilimumab. (1.11)
• adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. ( 1.11 ) Hepatocellular Carcinoma (HCC)
• adult patients with unresectable or metastatic hepatocellular carcinoma (HCC), as a first-line treatment in combination with ipilimumab. (1.12)
• in combination with ipilimumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. ( 1.12 ) Esophageal Cancer
• adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.13)
• adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum‑containing chemotherapy whose tumors express PD-L1 (≥1). (1.13)
• adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab whose tumors express PD-L1 (≥1). (1.13)
• adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. (1.13) Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
• adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.14) 1.1 Unresectable or Metastatic Melanoma 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 unresectable or metastatic melanoma. 1.2 Adjuvant Treatment of Melanoma OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

Dosage and administration

• Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2)
• Unresectable or metastatic melanoma
• Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
• Adult and pediatric patients weighing 40 kg or greater: 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. (2.2)
• Pediatric patients weighing less than 40 kg: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
• Adjuvant treatment of melanoma
• Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2)
• Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer
• 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles. (2.2)
• Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer
• 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for up to 4 cycles, then continued as single-agent OPDIVO 480 mg every 4 weeks after surgery for up to 13 cycles (~1 year). (2.2)
• Metastatic non-small cell lung cancer
• 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
• 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2)
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Malignant pleural mesothelioma
• 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
• 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. (2.2)
• 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.2)
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Classical Hodgkin lymphoma
• Adult and pediatric patients weighing 40 kg or greater: 240 mg in combination with doxorubicin, vinblastine, and dacarbazine (AVD) every 2 weeks for 6 cycles. (2.2)
• Pediatric patients weighing less than 40 kg: 3 mg/kg in combination with AVD every 2 weeks for 6 cycles. (2.2)
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Recurrent or metastatic squamous cell carcinoma of the head and neck
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Adjuvant treatment of urothelial carcinoma
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• First-line unresectable or metastatic urothelial carcinoma
• 360 mg every 3 weeks with cisplatin and gemcitabine on the same day for up to 6 cycles, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Previously treated locally advanced or metastatic urothelial carcinoma
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
• Adult and pediatric patients weighing 40 kg or greater: 240 mg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. ( 2.2 )
• Pediatric patients weighing less than 40 kg: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. ( 2.2 )
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease.
• Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. ( 2.2 )
• Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks. ( 2.2 )
• 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. (2.2)
• Adjuvant treatment of resected esophageal or gastroesophageal cancer
• 240 mg every 2 weeks or 480 mg every 4 weeks for total treatment duration of 1 year. (2.2)
• Esophageal squamous cell carcinoma
• 240 mg every 2 weeks or 480 mg every 4 weeks in combination with chemotherapy regimen of fluoropyrimidine- and platinum-containing chemotherapy. (2.2)
• 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)
• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)
• 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. (2.2)
• 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.2)
• See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Information on FDA-authorized tests for patient selection is available at: https://www.fda.gov/CompanionDiagnostics Non-Small Cell Lung Cancer
• Select patients with metastatic NSCLC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.5) ] . Esophageal Cancer
• Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.13) ] .
• Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.13) ] .

Dosage forms and strengths

Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) clear to opalescent, colorless to pale-yellow solution in a single-dose vial.
• Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) solution in a single-dose vial. (3)

Contraindications

None.
• None. (4)

Warnings and precautions

• Immune-Mediated Adverse Reactions: (5.1)
• 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.
• Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
• Withhold or permanently discontinue based on severity and type of reaction. (2.3)
• Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction. (5.2)
• 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. (5.3)
• Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.4 , 8.1 , 8.3)
• 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. (5.5) 5.1 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. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3) ] . 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. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. OPDIVO as a Single Agent Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients. Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis. OPDIVO with Ipilimumab OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients. Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab. 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 corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Side effects

The following clinically significant adverse reactions are described elsewhere in the labeling.
• Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ]
• Infusion-Related Reactions [see Warnings and Precautions (5.2) ]
• Complications of Allogeneic HSCT [see Warnings and Precautions (5.3) ] 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, vomiting, and urinary tract infection. (6.1)
• 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, constipation, decreased weight, and dizziness. (6.1)
• In combination with platinum-doublet chemotherapy: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1)
• In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1)
• In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1)
• In combination with fluoropyrimidine- and platinum-containing chemotherapy: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1) Most common adverse reactions (incidence ≥30%) in patients were:
• In combination with AVD: nausea, neutropenia, fatigue, anemia, constipation, leukopenia, musculoskeletal pain, peripheral neuropathy, transaminases increase, vomiting, and stomatitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320); and OPDIVO 240 mg or 3 mg/kg with AVD in patients enrolled in CA209-8UT (SWOG 1826) (n=490). Unresectable or Metastatic Melanoma Previously Treated Metastatic Melanoma The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1) ] . Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m 2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m 2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year. The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%). Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO.

Use in specific populations

• Lactation: Advise not to breastfeed. (8.2) 8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data) . 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. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. 8.2 Lactation Risk Summary 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. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating OPDIVO [see Use in Specific Populations (8.1) ] . Contraception OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months following the last dose. 8.4 Pediatric Use The safety and effectiveness of OPDIVO have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma, as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma in combination with ipilimumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and as a single agent for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Nivolumab exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1 , 14.11) ] . The safety and effectiveness of OPDIVO in combination with AVD have been established in patients aged 12 years and older for the treatment of cHL. Use of OPDIVO for this indication is supported by evidence from Study CA209-8UT, which included 120 pediatric patients ages ≥12 to <18 with previously untreated cHL treated with OPDIVO plus AVD. Adverse reactions reported with ≥10% higher frequency in pediatric compared to adult patients included nausea, anemia, increased transaminases, vomiting, lymphopenia, pyrexia, hyperphosphatemia, and eosinophilia [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.8) ] . The safety and effectiveness of OPDIVO have not been established for pediatric patients younger than 12 years old with melanoma, MSI-H or dMMR mCRC, or cHL. The safety and effectiveness of OPDIVO have not been established in pediatric patients with non-small cell lung cancer, malignant pleural mesothelioma, advanced renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma. 8.5 Geriatric Use Single Agent Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent OPDIVO in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1 , 14.2 , 14.5 , 14.7 , 14.10 , 14.13 , 14.14) ].

Pregnancy

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data) . 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. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of OPDIVO have been established in pediatric patients aged 12 years and older for the following indications: as a single agent and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma, as a single agent for the adjuvant treatment of completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma in combination with ipilimumab for the treatment of MSI-H or dMMR unresectable and metastatic CRC, and as a single agent for the treatment of MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO for these indications is supported by evidence from adequate and well-controlled studies in adults with melanoma or MSI-H or dMMR mCRC and additional pharmacokinetic data in pediatric patients. Nivolumab exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of melanoma and MSI-H or dMMR mCRC are similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.1 , 14.11) ] . The safety and effectiveness of OPDIVO in combination with AVD have been established in patients aged 12 years and older for the treatment of cHL. Use of OPDIVO for this indication is supported by evidence from Study CA209-8UT, which included 120 pediatric patients ages ≥12 to <18 with previously untreated cHL treated with OPDIVO plus AVD. Adverse reactions reported with ≥10% higher frequency in pediatric compared to adult patients included nausea, anemia, increased transaminases, vomiting, lymphopenia, pyrexia, hyperphosphatemia, and eosinophilia [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.8) ] . The safety and effectiveness of OPDIVO have not been established for pediatric patients younger than 12 years old with melanoma, MSI-H or dMMR mCRC, or cHL. The safety and effectiveness of OPDIVO have not been established in pediatric patients with non-small cell lung cancer, malignant pleural mesothelioma, advanced renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial carcinoma, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastroesophageal cancer and esophageal adenocarcinoma.

Geriatric use

8.5 Geriatric Use Single Agent Of 3569 patients with melanoma, NSCLC, renal cell carcinoma, urothelial carcinoma, ESCC, and esophageal or gastroesophageal junction cancer who were randomized to single agent OPDIVO in clinical studies, 41% were 65 years and over and 10% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients [see Clinical Studies (14.1 , 14.2 , 14.5 , 14.7 , 14.10 , 14.13 , 14.14) ]. In patients with cHL, recurrent head and neck SCC, or dMMR or MSI-H metastatic CRC (mCRC) who were treated with single agent OPDIVO in clinical studies did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients [see Clinical Studies (14.8 , 14.9 , 14.11) ]. OPDIVO in Combination with Ipilimumab Of the 314 patients with melanoma who were randomized to OPDIVO in combination with ipilimumab, 41% were 65 years or older and 11% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients [see Clinical Studies (14.1) ]. Of the 576 patients with NSCLC who were randomized to OPDIVO in combination with ipilimumab, 48% were 65 years or older and 10% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there was a higher discontinuation rate due to adverse reactions in patients aged 75 years or older (29%) relative to all patients who received OPDIVO with ipilimumab (18%). Of the 396 patients in the primary efficacy population (PD-L1 ≥1%) randomized to OPDIVO in combination with ipilimumab, the hazard ratio for overall survival was 0.70 (95% CI: 0.55, 0.89) in the 199 patients younger than 65 years compared to 0.91 (95% CI: 0.72, 1.15) in the 197 patients 65 years or older [see Clinical Studies (14.3) ]. Of the 303 patients with malignant pleural mesothelioma who were randomized to OPDIVO in combination with ipilimumab, 77% were 65 years old or older and 26% were 75 years or older. No overall difference in safety was reported between older patients and younger patients; however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (68% and 35%, respectively) relative to all patients who received OPDIVO with ipilimumab (54% and 28%, respectively). For patients aged 75 years or older who received chemotherapy, the rate of serious adverse reactions was 34% and the discontinuation rate due to adverse reactions was 26% relative to 28% and 19% respectively for all patients. The hazard ratio for overall survival was 0.76 (95% CI: 0.52, 1.11) in the 71 patients younger than 65 years compared to 0.74 (95% CI: 0.59, 0.93) in the 232 patients 65 years or older randomized to OPDIVO in combination with ipilimumab [see Clinical Studies (14.6) ]. Of the 550 patients with renal cell carcinoma who were randomized to OPDIVO in combination with ipilimumab, 38% were 65 years or older and 8% were 75 years or older. 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 [see Clinical Studies (14.7) ]. Of the 354 patients with dMMR or MSI-H metastatic CRC (mCRC) who were randomized to OPDIVO in combination with ipilimumab, 44% were 65 years or older and 14% were 75 years or older. Of the 353 patients randomized to OPDIVO, as a single agent, 45% were 65 years or older and 13% were 75 years or older. There was a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving OPDIVO in combination with ipilimumab compared to those younger than 65 receiving the combination (42%). There was also a higher incidence of any Grade 3 or 4 adverse reactions (55%) in patients aged 65 years or older receiving OPDIVO in combination with ipilimumab relative to patients aged 65 years or older receiving single-agent OPDIVO (41%). There was a similar incidence of any Grade 3 or 4 adverse reactions in patients receiving single-agent OPDIVO aged 65 years or older (41%) relative to patients younger than 65 years (45%). Patients 65 years or older who received OPDIVO with ipilimumab discontinued treatment due to adverse reaction at a higher rate (23%) relative to patients 65 years or older receiving nivolumab (15%). No overall differences in effectiveness were reported between elderly patients and younger patients receiving either OPDIVO in combination with ipilimumab or single-agent OPDIVO [see Clinical Studies (14.11) ] . Of the 335 patients with unresectable hepatocellular carcinoma who were randomized to OPDIVO in combination with ipilimumab, 52% were 65 years or older and 14% were 75 years or older. No overall difference in safety was reported between elderly patients and younger patients, however, there were higher rates of serious adverse reactions and discontinuation due to adverse reactions in patients aged 75 years or older (67% and 35%, respectively) relative to all patients who received OPDIVO with ipilimumab (53% and 27%, respectively). Of the 49 patients with hepatocellular carcinoma who were treated with OPDIVO in combination with ipilimumab, 29% were between 65 years and 74 years of age and 8% were 75 years or older. Clinical studies of OPDIVO in combination with ipilimumab did not include sufficient numbers of patients with hepatocellular carcinoma aged 65 and over to determine whether they respond differently from younger patients [see Clinical Studies (14.12) ]. Of the 325 patients with ESCC who were randomized to OPDIVO in combination with ipilimumab, 43% were 65 years old or older and 7% were 75 years or older.

Description

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.

Mechanism of action

12.1 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 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.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING OPDIVO ® (nivolumab) Injection is a clear to opalescent, colorless to pale-yellow solution in a single-dose vial available as follows: Carton Contents NDC 40 mg/4 mL (10 mg/mL) single-dose vial 0003-3772-11 100 mg/10 mL (10 mg/mL) single-dose vial 0003-3774-12 120 mg/12 mL (10 mg/mL) single-dose vial 0003-3756-14 240 mg/24 mL (10 mg/mL) single-dose vial 0003-3734-13 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.

Patient information

Advise the patient to read the FDA-approved patient labeling (Medication Guide) . Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of OPDIVO, including:
• Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1) ] .
• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.1) ] .
• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.1) ] .
• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, and diabetes mellitus [see Warnings and Precautions (5.1) ] .
• Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions (5.1) ] .
• Skin Adverse Reactions: Advise patients to contact their healthcare provider immediately for rash [see Warnings and Precautions (5.1) ] . Infusion-Related Reactions
• Advise patients of the potential risk of infusion-related reactions [see Warnings and Precautions (5.2) ] . Complications of Allogeneic HSCT
• Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3) ]. Embryo-Fetal Toxicity
• Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] .
• Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose [see Use in Specific Populations (8.3) ] . Lactation
• Advise women not to breastfeed during treatment with OPDIVO and for 5 months after the last dose [see Use in Specific Populations (8.2) ] . Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713

Label text from the FDA structured product label by E.R. Squibb & Sons, L.L.C. (revised Aug 12, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Opdivo NDC products (4)

NDCStrength & formLabelerType
0003-3734Nivolumab 10 mg/mL
Injection		E.R. Squibb & Sons, L.L.C.BLA
0003-3756Nivolumab 10 mg/mL
Injection		E.R. Squibb & Sons, L.L.C.BLA
0003-3772Nivolumab 10 mg/mL
Injection		E.R. Squibb & Sons, L.L.C.BLA
0003-3774Nivolumab 10 mg/mL
Injection		E.R. Squibb & Sons, L.L.C.BLA

Frequently asked questions

What is Opdivo used for?

1 INDICATIONS AND USAGE OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of: Melanoma • adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. (1.1) • for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB,…

What are the side effects of Opdivo?

The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] • Infusion-Related Reactions [see Warnings and Precautions (5.2) ] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%) in patients were: • As a… See the full label for the complete list.

Who makes Opdivo?

Opdivo is listed by 1 labeler in the FDA NDC directory, including E.R. Squibb & Sons, L.L.C..