Data from FDA - Curated by Marshall Pearce - Last updated 10 October 2017

Indication(s)

1 INDICATIONS AND USAGE OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of: •patients with BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent. (1.1) •patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.1) •patients with unresectable or metastatic melanoma, in combination with ipilimumab. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.1) •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. (1.2) •patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.3) •adult patients with classical Hodgkin lymphoma 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. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.4) •patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. (1.5) •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. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.6) •adult and pediatric patients (12 years and older) 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. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1.7) •patients with hepatocellular carcinoma who have been previously treated with sorafenib.This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1.8) 1.1 Unresectable or Metastatic Melanoma •OPDIVO® as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)]. •OPDIVO as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma [see Clinical Studies (14.1)]. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. •OPDIVO, in combination with ipilimumab, is indicated for the treatment of patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. 1.2 Metastatic Non-Small Cell Lung Cancer OPDIVO is indicated for the treatment of patients with metastatic non-small cell lung cancer (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 [see Clinical Studies (14.2)]. 1.3 Renal Cell Carcinoma OPDIVO is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy [see Clinical Studies (14.3)]. 1.4 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. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.4)]. 1.5 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 [see Clinical Studies (14.5)]. 1.6 Urothelial Carcinoma OPDIVO (nivolumab) 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. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.6)]. 1.7 Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer OPDIVO 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 [see Clinical Studies (14.7)]. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.8 Hepatocellular Carcinoma OPDIVO is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials [see Clinical Studies (14.8)] .

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Breakthrough Cancer Pain Learning Zone

Breakthrough Cancer Pain Learning Zone

Watch video hightlights from the BeCOn OWN 2017 event, including expert opinion, patient experience and panel discussions in the Breakthrough Cancer Pain Learning Zone.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Allergic Rhinitis

Allergic Rhinitis

Allergic rhinitis causes great strain on the workforce. Help to reduce sick days and improve productivity with appropriate treatment options.

+ 4 more

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. •Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)] •Immune-Mediated Colitis [see Warnings and Precautions (5.2)] •Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)] •Immune-Mediated Endocrinopathies [see Warnings and Precautions (5.4)] •Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions (5.5)] •Immune-Mediated Skin Adverse Reactions [see Warnings and Precautions (5.6)] •Immune-Mediated Encephalitis [see Warnings and Precautions (5.7)] •Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.8)] •Infusion Reactions [see Warnings and Precautions (5.9)] •Complications of Allogeneic HSCT after OPDIVO [see Warnings and Precautions (5.10)] Most common adverse reactions (≥20%) in patients were: •OPDIVO as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia. (6.1) •OPDIVO with ipilimumab: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. (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 the Warnings and Precautions section reflect exposure to OPDIVO, as a single agent, for clinically significant adverse reactions in 1994 patients enrolled in the CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 trials or a single-arm trial in NSCLC (n=117) administering OPDIVO as a single agent [see Warnings and Precautions (5.1, 5.8)]. In addition, clinically significant adverse reactions of OPDIVO administered with ipilimumab were evaluated in 407 patients with melanoma enrolled in CHECKMATE-067 (n=313) or a Phase 2 randomized study (n=94), administering OPDIVO with ipilimumab, supplemented by immune-mediated adverse reaction reports in ongoing clinical trials [see Warnings and Precautions (5.1, 5.8)]. The data described below reflect exposure to OPDIVO as a single agent in CHECKMATE-037, CHECKMATE-066, and CHECKMATE-067, and to OPDIVO with ipilimumab in CHECKMATE-067, which are randomized, active-controlled trials conducted in patients with unresectable or metastatic melanoma. Also described below are single-agent OPDIVO data from CHECKMATE-017 and CHECKMATE-057, which are randomized trials in patients with metastatic NSCLC, CHECKMATE-025, which is a randomized trial in patients with advanced RCC, CHECKMATE-205 and CHECKMATE-039, which are open-label, multiple-cohort trials in patients with cHL, CHECKMATE-141, a randomized trial in patients with recurrent or metastatic SCCHN, CHECKMATE-275, which is a single-arm trial in patients with urothelial carcinoma, and CHECKMATE-040, which is an open-label, multiple-cohort trial in patients with HCC. Unresectable or Metastatic Melanoma Previously Treated Metastatic Melanoma The safety of OPDIVO as a single agent was evaluated in CHECKMATE-037, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1)]. 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 greater than 6 months and 3% of patients received OPDIVO for greater than 1 year. In CHECKMATE-037, 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. The trial 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 LDH at baseline (51% vs. 38%). OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Table 2 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated patients in CHECKMATE-037. The most common adverse reaction (reported in at least 20% of patients) was rash. Table 2: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-037) Adverse Reaction OPDIVO (n=268) Chemotherapy (n=102) All Grades Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Toxicity was graded per NCI CTCAE v4. a Rash is a composite term which includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis. b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis. Skin and Subcutaneous Tissue Disorders Rasha 21 0.4 7 0 Pruritus 19 0 3.9 0 Respiratory, Thoracic, and Mediastinal Disorders Cough 17 0 6 0 Infections Upper respiratory tract infectionb 11 0 2.0 0 General Disorders and Administration Site Conditions Peripheral edema 10 0 5 0 Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in CHECKMATE-037 were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis Table 3: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-037) a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baseline a OPDIVO Chemotherapy All Grades Grades 3-4 All Grades Grades 3-4 Increased AST 28 2.4 12 1.0 Increased alkaline phosphatase 22 2.4 13 1.1 Hyponatremia 25 5 18 1.1 Increased ALT 16 1.6 5 0 Hyperkalemia 15 2.0 6 0 Previously Untreated Metastatic Melanoma CHECKMATE-066 The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in which 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=206) or dacarbazine 1000 mg/m2 every 3 weeks (n=205) [see Clinical Studies (14.1)]. The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for greater than 6 months and 12% of patients received OPDIVO for greater than 1 year. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% white, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%). Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). Table 4 summarizes selected adverse reactions that occurred in at least 10% of OPDIVO-treated patients. The most common adverse reactions (reported in at least 20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus. Table 4: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-066) Adverse Reaction OPDIVO (n=206) Dacarbazine (n=205) All Grades Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction. d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis. General Disorders and Administration Site Conditions Fatigue 49 1.9 39 3.4 Edemaa 12 1.5 4.9 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal painb 32 2.9 25 2.4 Skin and Subcutaneous Tissue Disorders Rashc 28 1.5 12 0 Pruritus 23 0.5 12 0 Erythema 10 0 2.9 0 Vitiligo 11 0 0.5 0 Infections Upper respiratory tract infectiond 17 0 6 0 Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in CHECKMATE-066 were: Nervous System Disorders: peripheral neuropathy Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-066) a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients). Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baseline a OPDIVO Dacarbazine All Grades Grades 3-4 All Grades Grades 3-4 Increased ALT 25 3.0 19 0.5 Increased AST 24 3.6 19 0.5 Increased alkaline phosphatase 21 2.6 14 1.6 Increased bilirubin 13 3.1 6 0 CHECKMATE-067 The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067 [see Clinical Studies (14.1)], a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received: •OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by OPDIVO 3 mg/kg as a single agent every 2 weeks (OPDIVO plus ipilimumab arm; n=313), •OPDIVO 3 mg/kg every 2 weeks (OPDIVO arm; n=313), or •Ipilimumab 3 mg/kg every 3 weeks for up to 4 doses (ipilimumab arm; n=311). The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 18.8 months) for the OPDIVO plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the OPDIVO arm. In the OPDIVO plus ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 24% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 32% for >1 year. CHECKMATE-067 excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. The trial population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with AJCC Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy. In CHECKMATE-067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus ipilimumab arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO plus ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were diarrhea (8% and 1.9%), colitis (8% and 0.6%), increased ALT (4.8% and 1.3%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the OPDIVO plus ipilimumab arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, diarrhea, and nausea. Table 6 summarizes the incidence of adverse reactions occurring in at least 10% of patients in either OPDIVO-containing arm in CHECKMATE-067. Table 6: Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO plus Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-067) Adverse Reaction Percentage (%) of Patients OPDIVO plus Ipilimumab (n=313) OPDIVO (n=313) Ipilimumab (n=311) All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 Toxicity was graded per NCI CTCAE v4. a Fatigue is a composite term which includes asthenia and fatigue. b Rash is a composite term which includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, erythema, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, pruritic rash, and seborrheic dermatitis. General Disorders and Administration Site Conditions Fatiguea 59 6 53 1.9 50 3.9 Pyrexia 37 1.6 14 0 17 0.6 Skin and Subcutaneous Tissue Disorders Rashb 53 5 40 1.6 42 3.9 Gastrointestinal Disorders Diarrhea 52 11 31 3.8 46 8 Nausea 40 3.5 28 0.6 29 1.9 Vomiting 28 3.5 17 1.0 16 1.6 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 20 2.2 12 1.3 13 0.6 Other clinically important adverse reactions in less than 10% of patients treated with either OPDIVO with ipilimumab or single-agent OPDIVO in CHECKMATE-067 were: Gastrointestinal Disorders: stomatitis, intestinal perforation Skin and Subcutaneous Tissue Disorders: vitiligo Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy Nervous System Disorders: neuritis, peroneal nerve palsy Table 7: Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients Treated with OPDIVO with Ipilimumab or Single-Agent OPDIVO and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-067) Laboratory Abnormality Percentage (%) of Patientsa OPDIVO plus Ipilimumab OPDIVO Ipilimumab Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade 3-4 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO plus ipilimumab (range: 241 to 297); OPDIVO (range: 260 to 306); ipilimumab (range: 253 to 304). Chemistry Increased ALT 53 15 23 3.0 28 2.7 Increased AST 47 13 27 3.7 27 1.7 Hyponatremia 42 9 20 3.3 25 7 Increased lipase 41 20 29 9 23 7 Increased alkaline phosphatase 40 6 24 2.0 22 2.0 Hypocalcemia 29 1.1 13 0.7 21 0.7 Increased amylase 25 9.1 15 1.9 14 1.6 Increased creatinine 23 2.7 16 0.3 16 1.3 Hematology Anemia 50 2.7 39 2.6 40 6 Lymphopenia 35 4.8 39 4.3 27 3.4 Metastatic Non-Small Cell Lung Cancer The safety of OPDIVO in metastatic NSCLC was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.2)]. Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The median duration of therapy in OPDIVO-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for greater than 6 months and 20% of patients received OPDIVO for greater than 1 year. CHECKMATE-017 and CHECKMATE-057 excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were white. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%). OPDIVO was discontinued in 11% of patients, and was delayed in 28% of patients for an adverse reaction. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Across both trials, the most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Table 8 summarizes selected adverse reactions occurring more frequently in at least 10% of OPDIVO-treated patients. Table 8: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-017 and CHECKMATE-057) Adverse Reaction OPDIVO (n=418) Docetaxel (n=397) All Grades Grades 3-4 All Grades Grades 3-4 Percentage (%) of Patients Toxicity was graded per NCI CTCAE v4. Respiratory, Thoracic, and Mediastinal Disorders Cough 31 0.7 24 0 Metabolism and Nutrition Disorders Decreased appetite 28 1.4 23 1.5 Skin and Subcutaneous Tissue Disorders Pruritus 10 0.2 2.0 0 Other clinically important adverse reactions observed in patients treated with OPDIVO and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% Grade 1-4, 5% Grade 3-4), musculoskeletal pain (33%), pleural effusion (4.5%), pulmonary embolism (3.3%). Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of OPDIVO-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3-4]) (CHECKMATE-017 and CHECKMATE-057) a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients); TSH: OPDIVO group n=314 and docetaxel group n=297. b Not graded per NCI CTCAE v4. Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baseline a OPDIVO Docetaxel All Grades Grades 3-4 All Grades Grades 3-4 Chemistry Hyponatremia 35 7 34 4.9 Increased AST 27 1.9 13 0.8 Increased alkaline phosphatase 26 0.7 18 0.8 Increased ALT 22 1.7 17 0.5 Increased creatinine 18 0 12 0.5 Increased TSHb 14 N/A 6 N/A Renal Cell Carcinoma The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in which 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimens received OPDIVO 3 mg/kg every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.3)]. The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients and 19% of everolimus patients. Forty-four percent (44%) of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. Rate of death on treatment or within 30 days of the last dose of study drug was 4.7% on the OPDIVO arm versus 8.6% on the everolimus arm. The most common adverse reactions (reported in at least 20% of patients) were asthenic conditions, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. Table 10 summarizes adverse reactions that occurred in greater than 15% of OPDIVO-treated patients. Table 10: Grade 1-4 Adverse Reactions in >15% of Patients Receiving OPDIVO (CHECKMATE-025) Toxicity was graded per NCI CTCAE v4. a Asthenic conditions covering PTs asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral URI. c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema. OPDIVO (n=406) Everolimus (n=397) Percentage (%) of Patients Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Adverse Reaction 98 56 96 62 General Disorders and Administration Site Conditions Asthenic conditionsa 56 6 57 7 Pyrexia 17 0.7 20 0.8 Respiratory, Thoracic and Mediastinal Disorders Cough/productive cough 34 0 38 0.5 Dyspnea/exertional dyspnea 27 3.0 31 2.0 Upper respiratory infectionb 18 0 11 0 Gastrointestinal Disorders Nausea 28 0.5 29 1 Diarrheac 25 2.2 32 1.8 Constipation 23 0.5 18 0.5 Vomiting 16 0.5 16 0.5 Skin and Subcutaneous Tissue Disorders Rashd 28 1.5 36 1.0 Pruritus/generalized pruritus 19 0 14 0 Metabolism and Nutrition Disorders Decreased appetite 23 1.2 30 1.5 Musculoskeletal and Connective Tissue Disorders Arthralgia 20 1.0 14 0.5 Back pain 21 3.4 16 2.8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: peripheral edema/edema Gastrointestinal Disorders: abdominal pain/discomfort Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain Nervous System Disorders: headache/migraine, peripheral neuropathy Investigations: weight decreased Skin Disorders: Palmar-plantar erythrodysesthesia The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, elevated triglycerides, and hyperkalemia. Table 11 summarizes the laboratory abnormalities that occurred in greater than 15% of OPDIVO-treated patients. Table 11: Grade 1-4 Laboratory Values Worsening from Baseline Occurring in >15% of Patients on OPDIVO (CHECKMATE-025) a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients). Laboratory Abnormality Percentage of Patients with Worsening Laboratory Test from Baseline a OPDIVO Everolimus Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Hematology Lymphopenia 42 6 53 11 Anemia 39 8 69 16 Chemistry Increased creatinine 42 2.0 45 1.6 Increased AST 33 2.8 39 1.6 Increased alkaline phosphatase 32 2.3 32 0.8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4.0 20 2.1 Hypocalcemia 23 0.9 26 1.3 Increased ALT 22 3.2 31 0.8 Hypercalcemia 19 3.2 6 0.3 Lipids Increased triglycerides 32 1.5 67 11 Increased cholesterol 21 0.3 55 1.4 In addition, among patients with TSH less than ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH greater than ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively). Classical Hodgkin Lymphoma The safety of OPDIVO 3 mg/kg every 2 weeks was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials). Treatment could continue until disease progression, maximal clinical benefit, or unacceptable toxicity. The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months). OPDIVO was discontinued due to adverse reactions in 7% of patients. Dose delay for an adverse reaction occurred in 34% of patients. Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in at least 1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. The most common adverse reactions (reported in at least 20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus. Table 12 summarizes the adverse reactions, excluding laboratory terms, that occurred in at least 10% of patients in the safety population. Table 12: Non-Laboratory Adverse Reactions Occurring in ≥10% of Patients with cHL(CHECKMATE-205 and CHECKMATE-039) Toxicity was graded per NCI CTCAE v4. a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course. b Includes asthenia. c Includes colitis. d Includes abdominal discomfort and upper abdominal pain. e Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis. f Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia. g Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform. h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity. i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events. OPDIVO cHL Safety Population (n=266) Adverse Reactiona Percentage (%) All Grades Grades 3-4 General Disorders and Administration Site Conditions Fatigueb 39 1.9 Pyrexia 29 <1 Gastrointestinal Disorders Diarrheac 33 1.5 Nausea 20 0 Vomiting 19 <1 Abdominal paind 16 <1 Constipation 14 0.4 Infections Upper respiratory tract infectione 44 0.8 Pneumonia/bronchopneumoniaf 13 3.8 Nasal congestion 11 0 Respiratory, Thoracic and Mediastinal Disorders Cough/productive cough 36 0 Dyspnea/exertional dyspnea 15 1.5 Skin and Subcutaneous Tissue Disorders Rashg 24 1.5 Pruritus 20 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal painh 26 1.1 Arthralgia 16 <1 Endocrine Disorders Hypothyroidism/thyroiditis 12 0 Nervous System Disorders Headache 17 <1 Neuropathy peripherali 12 <1 Injury, Poisoning and Procedural Complications Infusion-related reaction 14 <1 Additional information regarding clinically important adverse reactions: Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis. Peripheral neuropathy: In CHECKMATE-205 and CHECKMATE-039, treatment-emergent peripheral neuropathy was reported in 14% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy, and 3 of 40 patients had worsening of neuropathy from baseline. These adverse reactions were Grade 1 or 2, except for 1 Grade 3 event (<1%). The median time to onset was 50 (range: 1 to 309) days. Complications of allogeneic HSCT after OPDIVO: [see Warnings and Precautions (5.10)]. Table 13 summarizes laboratory abnormalities that developed or worsened in at least 10% of patients with cHL. The most

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Administer as an intravenous infusion over 60 minutes. •Unresectable or metastatic melanoma •OPDIVO 240 mg every 2 weeks. (2.1) •OPDIVO with ipilimumab: OPDIVO 1 mg/kg, followed by ipilimumab on the same day, every 3 weeks for 4 doses, then OPDIVO 240 mg every 2 weeks. (2.1) •Metastatic non-small cell lung cancer •OPDIVO 240 mg every 2 weeks. (2.2) •Advanced renal cell carcinoma •OPDIVO 240 mg every 2 weeks. (2.3) •Classical Hodgkin lymphoma •OPDIVO 3 mg/kg every 2 weeks. (2.4) •Recurrent or metastatic squamous cell carcinoma of the head and neck •OPDIVO 3 mg/kg every 2 weeks. (2.5) •Locally advanced or metastatic urothelial carcinoma •OPDIVO 240 mg every 2 weeks. (2.6) •Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer •OPDIVO 240 mg every 2 weeks. (2.7) •Hepatocellular carcinoma •OPDIVO 240 mg every 2 weeks. (2.8) 2.1 Recommended Dosage for Melanoma The recommended dose of OPDIVO as a single agent is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses [see Clinical Studies (14.1)]. The recommended subsequent dose of OPDIVO, as a single agent, is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing Information for ipilimumab prior to initiation. 2.2 Recommended Dosage for NSCLC The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for RCC The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for cHL The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for SCCHN The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Urothelial Carcinoma The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.7 Recommended Dosage for CRC The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.8 Recommended Dosage for HCC The recommended dose of OPDIVO is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. 2.9 Dose Modifications Recommendations for OPDIVO modifications are provided in Table 1. When OPDIVO is administered in combination with ipilimumab, if OPDIVO is withheld, ipilimumab should also be withheld. There are no recommended dose modifications for hypothyroidism or hyperthyroidism. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Discontinue OPDIVO in patients with severe or life-threatening infusion reactions. Table 1: Recommended Dose Modifications for OPDIVO Adverse Reaction Severity* Dose Modification Colitis Grade 2 diarrhea or colitis Withhold dosea Grade 3 diarrhea or colitis Withhold dosea when administered as a single agent Permanently discontinue when administered with ipilimumab Grade 4 diarrhea or colitis Permanently discontinue Pneumonitis Grade 2 pneumonitis Withhold dosea Grade 3 or 4 pneumonitis Permanently discontinue Hepatitis/non-HCCb Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 3 and up to 5 times the upper limit of normal (ULN) or total bilirubin more than 1.5 and up to 3 times the ULN Withhold dosea AST or ALT more than 5 times the ULN or total bilirubin more than 3 times the ULN Permanently discontinue Hepatitis/HCCb •If AST/ALT is within normal limits at baseline and increases to more than 3 and up to 5 times the ULN •If AST/ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times the ULN •If AST/ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times the ULN Withhold dosec If AST or ALT increases to more than 10 times the ULN or total bilirubin increases to more than 3 times the ULN Permanently discontinue Hypophysitis Grade 2 or 3 hypophysitis Withhold dosea Grade 4 hypophysitis Permanently discontinue Adrenal Insufficiency Grade 2 adrenal insufficiency Withhold dosea Grade 3 or 4 adrenal insufficiency Permanently discontinue Type 1 Diabetes Mellitus Grade 3 hyperglycemia Withhold dosea Grade 4 hyperglycemia Permanently discontinue Nephritis and Renal Dysfunction Serum creatinine more than 1.5 and up to 6 times the ULN Withhold dosea Serum creatinine more than 6 times the ULN Permanently discontinue Skin Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) Withhold dosea Grade 4 rash or confirmed SJS or TEN Permanently discontinue Encephalitis New-onset moderate or severe neurologic signs or symptoms Withhold dosea Immune-mediated encephalitis Permanently discontinue Other Other Grade 3 adverse reaction First occurrence Withhold dosea Recurrence of same Grade 3 adverse reactions Permanently discontinue Life-threatening or Grade 4 adverse reaction Permanently discontinue Grade 3 myocarditis Permanently discontinue Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks Permanently discontinue Persistent Grade 2 or 3 adverse reactions lasting 12 weeks or longer Permanently discontinue * Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4). a Resume treatment when adverse reaction improves to Grade 0 or 1. b HCC: hepatocellular carcinoma. c Resume treatment when AST/ALT returns to baseline. 2.10 Preparation and Administration Visually inspect drug product solution for particulate matter and discoloration prior to administration. OPDIVO 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 OPDIVO and transfer into an intravenous container. •Dilute OPDIVO 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. •Mix diluted solution by gentle inversion. Do not shake. •Discard partially used vials or empty vials of OPDIVO. Storage of Infusion The product does not contain a preservative. After preparation, store the OPDIVO 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 (36°F to 46°F) for no more than 24 hours from the time of infusion preparation. Do not freeze. Administration Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). Do not coadminister other drugs through the same intravenous line. Flush the intravenous line at end of infusion. When administered in combination with ipilimumab, infuse OPDIVO first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding. (8.2) 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, 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 of nivolumab (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 It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, 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 at least 5 months following the last dose of OPDIVO. 8.4 Pediatric Use The safety and effectiveness of OPDIVO have been established in pediatric patients age 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Use of OPDIVO for this indication is supported by evidence from adequate and well-controlled studies of OPDIVO in adults with MSI-H or dMMR mCRC with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of nivolumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MSI-H or dMMR mCRC is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater for this indication is the same as that in adults [see Dosage and Administration (2.7) , Clinical Pharmacology (12.3), and Clinical Studies (14)]. The safety and effectiveness of OPDIVO have not been established (1) in pediatric patients less than 12 years old with MSI-H or dMMR mCRC or (2) in pediatric patients for the other approved indications. 8.5 Geriatric Use Of the 1359 patients randomized to single-agent OPDIVO in CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, and CHECKMATE-067, 39% were 65 years or older and 9% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. In CHECKMATE-275 (Urothelial Cancer), 55% of patients were 65 years or older and 14% were 75 years or older. No overall differences in safety or effectiveness were reported between elderly patients and younger patients. CHECKMATE-037, CHECKMATE-205, CHECKMATE-039, CHECKMATE-141, and CHECKMATE-142, and CHECKMATE-040 did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 314 patients randomized to OPDIVO administered with ipilimumab in CHECKMATE-067, 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. 8.6 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild or moderate hepatic impairment. OPDIVO has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO.

More information

Category Value
Authorisation number BLA125554
Agency product number 31YO63LBSN
Orphan designation No
Product NDC 0003-3772,0003-3774
Date Last Revised 22-09-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder E.R. Squibb & Sons, L.L.C.