There is no information on overdosage with Nivolumab BMS.
None.
The following adverse reactions are discussed in greater detail in other sections of the labeling.
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 Nivolumab BMS, 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 Nivolumab BMS as a single agent. In addition, clinically significant adverse reactions of Nivolumab BMS 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 Nivolumab BMS with ipilimumab, supplemented by immunemediated adverse reaction reports in ongoing clinical trials.
The data described below reflect exposure to Nivolumab BMS as a single agent in CHECKMATE-037, CHECKMATE-066, and CHECKMATE-067, and to Nivolumab BMS 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 Nivolumab BMS data from CHECKMATE-238, a randomized trial for the adjuvant treatment of patients with completely resected Stage IIIB/C and IV melanoma, 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, multiplecohort trial in patients with HCC.
Unresectable Or Metastatic MelanomaPreviously Treated Metastatic Melanoma
The safety of Nivolumab BMS as a single agent was evaluated in CHECKMATE-037, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received 3 mg/kg of Nivolumab BMS by intravenous infusion 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. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in Nivolumab BMS-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapytreated patients. In this ongoing trial, 24% of patients received Nivolumab BMS for greater than 6 months and 3% of patients received Nivolumab BMS 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 Nivolumab BMS 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 Nivolumab BMS group with elevated LDH at baseline (51% vs. 38%).
Nivolumab BMS was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving Nivolumab BMS had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving Nivolumab BMS. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving Nivolumab BMS. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving Nivolumab BMS were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
Table 2 summarizes the adverse reactions that occurred in at least 10% of Nivolumab BMS-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 Nivolumab BMS-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 | Nivolumab BMS (n=268) | Chemotherapy (n=102) | ||
| All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
| Percentage (%) of Patients | ||||
| 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 |
| 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. | ||||
Other clinically important adverse reactions in less than 10% of patients treated with Nivolumab BMS 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 Nivolumab BMS-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)
| Laboratory Abnormality | Percentage of Patients with Worsening Laboratory Test from Baselinea | |||
| Nivolumab BMS | 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 |
| a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Nivolumab BMS group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). |
CHECKMATE-066
The safety of Nivolumab BMS 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 3 mg/kg of Nivolumab BMS by intravenous infusion every 2 weeks (n=206) or dacarbazine 1000 mg/m2 every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in Nivolumab BMStreated patients. In this trial, 47% of patients received Nivolumab BMS for greater than 6 months and 12% of patients received Nivolumab BMS 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 Nivolumab BMS 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 Nivolumab BMS group with ECOG performance status 0 (71% vs. 59%).
Adverse reactions led to permanent discontinuation of Nivolumab BMS in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of Nivolumab BMS discontinuations. Serious adverse reactions occurred in 36% of patients receiving Nivolumab BMS. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving Nivolumab BMS. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of patients receiving Nivolumab BMS were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%).
Table 4 summarizes selected adverse reactions that occurred in at least 10% of Nivolumab BMS-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 Nivolumab BMS-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 | Nivolumab BMS (n=206) | Dacarbazine (n=205) | ||
| All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
| Percentage (%) of Patients | ||||
| 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 |
| 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. | ||||
Other clinically important adverse reactions in less than 10% of patients treated with Nivolumab BMS in CHECKMATE-066 were:
Nervous System Disorders: peripheral neuropathy
Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Nivolumab BMS-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)
| Laboratory Abnormality | Percentage of Patients with Worsening Laboratory Test from Baselinea | |||
| Nivolumab BMS | 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 |
| a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Nivolumab BMS group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients). |
CHECKMATE-067
The safety of Nivolumab BMS, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067 , a randomized (1:1:1), a double-blind trial in which 937 patients with previously untreated, unresectable or metastatic melanoma received:
The median duration of exposure to Nivolumab BMS was 2.8 months (range: 1 day to 18.8 months) for the Nivolumab BMS plus ipilimumab arm and 6.6 months (range: 1 day to 17.3 months) for the Nivolumab BMS arm. In the Nivolumab BMS plus ipilimumab arm, 39% were exposed to Nivolumab BMS for ≥6 months and 24% exposed for >1 year. In the Nivolumab BMS 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 Nivolumab BMS plus ipilimumab arm relative to the Nivolumab BMS arm.
The most frequent (≥10%) serious adverse reactions in the Nivolumab BMS plus ipilimumab arm and the Nivolumab BMS 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 Nivolumab BMS plus ipilimumab arm and of Nivolumab BMS in the Nivolumab BMS 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 Nivolumab BMS plus ipilimumab arm were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea. The most common (≥20%) adverse reactions in the Nivolumab BMS arm were fatigue, rash, diarrhea, and nausea. Table 6 summarizes the incidence of adverse reactions occurring in at least 10% of patients in either Nivolumab BMS-containing arm in CHECKMATE-067.
Table 6: Adverse Reactions Occurring in ≥10% of Patients on the Nivolumab BMS plus Ipilimumab Arm or the Nivolumab BMS 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 | |||||
| Nivolumab BMS plus Ipilimumab (n=313) | Nivolumab BMS (n=313) | Ipilimumab (n=311) | ||||
| All Grades | Grades 3-4 | All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
| 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 |
| 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. | ||||||
Other clinically important adverse reactions in less than 10% of patients treated with either Nivolumab BMS with ipilimumab or single-agent Nivolumab BMS 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 Nivolumab BMS with Ipilimumab or Single-Agent Nivolumab BMS 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 | |||||
| Nivolumab BMS plus Ipilimumab | Nivolumab BMS | Ipilimumab | ||||
| Any Grade | Grade 3-4 | Any Grade | Grade 3-4 | Any Grade | Grade 3-4 | |
| 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 |
| a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Nivolumab BMS plus ipilimumab (range: 241 to 297); Nivolumab BMS (range: 260 to 306); ipilimumab (range: 253 to 304) |
The safety of Nivolumab BMS as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in which 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received 3 mg/kg of Nivolumab BMS by intravenous infusion every 2 weeks (n=452) or 10 mg/kg ipilimumab (n=453), by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to a 1 year. The median duration of exposure was 11.5 months in Nivolumab BMS-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received Nivolumab BMS for greater than 6 months.
Study therapy was discontinued for adverse reactions in 9% of Nivolumab BMS-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of Nivolumab BMS-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of Nivolumab BMStreated patients. The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of Nivolumab BMS-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of Nivolumab BMS-treated patients.
The most common adverse reactions (reported in at least 20% of Nivolumab BMS-treated patients) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Table 8 summarizes the adverse reactions that occurred in at least 10% of Nivolumab BMS-treated patients in CHECKMATE-238.
Adverse Reactions Occurring in ≥10% of Nivolumab BMS-Treated Patients (CHECKMATE-238)
| Adverse Reaction | Nivolumab BMS (n=452) | Ipilimumab 10 mg/kg (n=453) | ||
| All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
| Percentage (%) of Patients | ||||
| General Disorders and Administration Site Conditions | ||||
| Fatiguea | 57 | 0.9 | 55 | 2.4 |
| Gastrointestinal Disorders | ||||
| Diarrhea | 37 | 2.4 | 55 | 11 |
| Nausea | 23 | 0.2 | 28 | 0 |
| Abdominal painb | 21 | 0.2 | 23 | 0.9 |
| Constipation | 10 | 0 | 9 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rashc | 35 | 1.1 | 47 | 5.3 |
| Pruritus | 28 | 0 | 37 | 1.1 |
| Infections and Infestations | ||||
| Upper respiratory tract infectiond | 22 | 0 | 15 | 0.2 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal paine | 32 | 0.4 | 27 | 0.4 |
| Arthralgia | 19 | 0.4 | 13 | 0.4 |
| Nervous System Disorders | ||||
| Headache | 23 | 0.4 | 31 | 2.0 |
| Dizzinessf | 11 | 0 | 8 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough/productive cough | 19 | 0 | 19 | 0 |
| Dyspnea/exertional dyspnea | 10 | 0.4 | 10 | 0.2 |
| Endocrine Disorders | ||||
| Hypothyroidismg | 12 | 0.2 | 7.5 | 0.4 |
| Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness. c Includes dermatitis also described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption. d Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis. e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity. f Includes postural dizziness and vertigo. g Includes secondary hypothyroidism and autoimmune hypothyroidism. | ||||
Table 9: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Nivolumab BMS-Treated Patients (CHECKMATE-238)
| Laboratory Abnormality | Percentage of Patients with Worsening Laboratory Test from Baselinea | |||
| Nivolumab BMS | Ipilimumab 10mg/kg | |||
| All Grades | Grades 3-4 | All Grades | Grades 3-4 | |
| Hematology | ||||
| Lymphopenia | 27 | 0.4 | 12 | 0.9 |
| Anemia | 26 | 0 | 34 | 0.5 |
| Leukopenia | 14 | 0 | 2.7 | 0.2 |
| Neutropenia |
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.
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.
Nivolumab BMS is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
Metastatic Non-Small Cell Lung CancerNivolumab BMS 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 Nivolumab BMS.
Renal Cell CarcinomaNivolumab BMS is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.
Classical Hodgkin LymphomaNivolumab BMS is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:
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.
Squamous Cell Carcinoma Of The Head And NeckNivolumab BMS is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.
Urothelial CarcinomaNivolumab BMS (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
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.
Microsatellite Instability-High (MSI-H) Or Mismatch Repair Deficient (dMMR) Metastatic Colorectal CancerNivolumab BMS 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.
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.
Hepatocellular CarcinomaNivolumab BMS 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.
Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in safety and efficacy between a nivolumab dose of 240 mg or 3 mg/kg every 2 weeks in patients with melanoma, NSCLC, RCC, urothelial carcinoma, MSI-H CRC, and HCC.
Nivolumab pharmacokinetics (PK) was assessed using a population PK approach for both single-agent Nivolumab BMS and Nivolumab BMS with ipilimumab.
Nivolumab BMS As A Single AgentThe PK of single-agent nivolumab was studied in patients over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of Nivolumab BMS as a 60- minute intravenous infusion every 2 or 3 weeks. Nivolumab clearance decreases over time, with a mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 24.5% (47.6%) resulting in a geometric mean steady state clearance (CLss) (CV%) of 8.2 mL/h (53.9%) in patients with metastatic tumors; the decrease in CLss is not considered clinically relevant. Nivolumab clearance does not decrease over time in patients with completely resected melanoma, as the geometric mean population clearance is 24% lower in this patient population compared with patients with metastatic melanoma at steady-state. The geometric mean volume of distribution at steady state (Vss) (CV%) is 6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). Steady-state concentrations of nivolumab were reached by 12 weeks when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 3.7-fold. The exposure to nivolumab increases dose proportionally over the dose range of 0.1 to 10 mg/kg administered every 2 weeks. The predicted exposure of nivolumab after a 30-minute infusion is comparable to that observed with a 60-minute infusion.
Nivolumab BMS With IpilimumabThe geometric mean (CV%) CL, Vss, and terminal half-life of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), respectively. When administered in combination, the CL of nivolumab was increased by 24%, whereas there was no effect on the clearance of ipilimumab.
When administered in combination, the clearance of nivolumab increased by 42% in the presence of anti-nivolumab antibodies. There was no effect of anti-ipilimumab antibodies on the clearance of ipilimumab.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Immune-Mediated PneumonitisNivolumab BMS can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology. Fatal cases have been reported.
Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 3-4) pneumonitis, followed by corticosteroid taper. Permanently discontinue Nivolumab BMS for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold Nivolumab BMS until resolution for moderate (Grade 2) pneumonitis.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. The median time to onset of immune-mediated pneumonitis was 3.5 months (range: 1 day to 22.3 months). Immune-mediated pneumonitis led to permanent discontinuation of Nivolumab BMS in 1.1%, and withholding of Nivolumab BMS in 1.3% of patients. Approximately 89% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 26 days (range: 1 day to 6 months). Complete resolution of symptoms following corticosteroid taper occurred in 67% of patients. Approximately 8% of patients had recurrence of pneumonitis after re-initiation of Nivolumab BMS.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS with ipilimumab, immune-mediated pneumonitis occurred in 6% (25/407) of patients. The median time to onset of immune-mediated pneumonitis was 1.6 months (range: 24 days to 10.1 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 2.2% and 3.7% of patients, respectively. Approximately 84% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 30 days (range: 5 days to 11.8 months). Complete resolution occurred in 68% of patients. Approximately 13% of patients had recurrence of pneumonitis after re-initiation of Nivolumab BMS with ipilimumab.
Immune-Mediated ColitisNivolumab BMS can cause immune-mediated colitis, defined as requiring use of corticosteroids with no clear alternate etiology.
Monitor patients for signs and symptoms of colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or lifethreatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents.
Withhold Nivolumab BMS for moderate or severe (Grade 2 or 3) colitis. Permanently discontinue Nivolumab BMS for life-threatening (Grade 4) or for recurrent colitis upon re-initiation of Nivolumab BMS.
When administered in combination with ipilimumab, withhold Nivolumab BMS and ipilimumab for moderate colitis (Grade 2). Permanently discontinue Nivolumab BMS and ipilimumab for severe or lifethreatening (Grade 3 or 4) colitis or for recurrent colitis.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, immune-mediated colitis occurred in 2.9% (58/1994) of patients; the median time to onset was 5.3 months (range: 2 days to 20.9 months). Immune-mediated colitis led to permanent discontinuation of Nivolumab BMS in 0.7% and withholding of Nivolumab BMS in 1% of patients. Approximately 91% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 23 days (range: 1 day to 9.3 months). Four patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 16% of patients had recurrence of colitis after re-initiation of Nivolumab BMS.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS with ipilimumab, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. The median time to onset of immune-mediated colitis was 1.6 months (range: 3 days to 15.2 months). Immune-mediated colitis led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 16% and 7% of patients, respectively. Approximately 96% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 12 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 75% of patients. Approximately 28% of patients had recurrence of colitis after re-initiation of Nivolumab BMS with ipilimumab.
Immune-Mediated HepatitisNivolumab BMS can cause immune-mediated hepatitis, defined as requiring use of corticosteroids and no clear alternate etiology. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or without concomitant elevation in total bilirubin. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) transaminase elevations.
For patients without hepatocellular carcinoma (HCC): withhold Nivolumab BMS for moderate (Grade 2) immune-mediated hepatitis and permanently discontinue Nivolumab BMS for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. For patients with HCC, permanently discontinue, withhold, or continue Nivolumab BMS based on severity of immune-mediated hepatitis and baseline AST and ALT levels as described in Table 1. In addition, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper when Nivolumab BMS is withheld or discontinued due to immune-mediated hepatitis.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients; the median time to onset was 3.3 months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent discontinuation of Nivolumab BMS in 0.7% and withholding of Nivolumab BMS in 1% of patients. All patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74% of patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation of Nivolumab BMS.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS with ipilimumab, immune-mediated hepatitis occurred in 13% (51/407) of patients; the median time to onset was 2.1 months (range: 15 days to 11 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 6% and 5% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 13.2 months). Complete resolution occurred in 75% of patients. Approximately 11% of patients had recurrence of hepatitis after re-initiation of Nivolumab BMS with ipilimumab.
Immune-Mediated Endocrinopathies HypophysitisNivolumab BMS can cause immune-mediated hypophysitis. Monitor patients for signs and symptoms of hypophysitis. Administer hormone replacement as clinically indicated and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Withhold Nivolumab BMS for moderate (Grade 2) or severe (Grade 3). Permanently discontinue Nivolumab BMS for life-threatening (Grade 4) hypophysitis.
In patients receiving Nivolumab BMS as a single agent, hypophysitis occurred in 0.6% (12/1994) of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months). Hypophysitis led to permanent discontinuation of Nivolumab BMS in 0.1% and withholding of Nivolumab BMS in 0.2% of patients. Approximately 67% of patients with hypophysitis received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days).
In patients receiving Nivolumab BMS with ipilimumab, hypophysitis occurred in 9% (36/407) of patients; the median time to onset was 2.7 months (range: 27 days to 5.5 months). Hypophysitis led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 1.0% and 3.9% of patients, respectively. Approximately 75% of patients with hypophysitis received hormone replacement therapy and 56% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 1 day to 2.0 months).
Adrenal InsufficiencyNivolumab BMS can cause immune-mediated adrenal insufficiency. Monitor patients for signs and symptoms of adrenal insufficiency. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold Nivolumab BMS for moderate (Grade 2) and permanently discontinue Nivolumab BMS for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency.
In patients receiving Nivolumab BMS as a single agent, adrenal insufficiency occurred in 1% (20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 months). Adrenal insufficiency led to permanent discontinuation of Nivolumab BMS in 0.1% and withholding of Nivolumab BMS in 0.5% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy and 25% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days (range: 1 day to 1 month).
In patients receiving Nivolumab BMS with ipilimumab, adrenal insufficiency occurred in 5% (21/407) of patients and the median time to onset was 3.0 months (range: 21 days to 9.4 months). Adrenal insufficiency led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 0.5% and 1.7% of patients, respectively. Approximately 57% of patients with adrenal insufficiency received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 9 days (range: 1 day to 2.7 months).
Hypothyroidism And HyperthyroidismNivolumab BMS can cause autoimmune thyroid disorders. Monitor thyroid function prior to and periodically during Nivolumab BMS treatment. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of Nivolumab BMS for hypothyroidism or hyperthyroidism.
In patients receiving Nivolumab BMS as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients.
Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving Nivolumab BMS as a single agent; the median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients.
In patients receiving Nivolumab BMS with ipilimumab, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients; the median time to onset was 2.1 months (range: 1 day to 10.1 months). Approximately 73% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45% of patients.
Hyperthyroidism occurred in 8% (34/407) of patients receiving Nivolumab BMS with ipilimumab: the median time to onset was 23 days (range: 3 days to 3.7 months). Approximately 29% of patients with hyperthyroidism received methimazole and 24% received carbimazole. Resolution occurred in 94% of patients.
Type 1 Diabetes MellitusNivolumab BMS can cause Type 1 diabetes mellitus. Monitor for hyperglycemia. Withhold Nivolumab BMS in cases of severe (Grade 3) hyperglycemia until metabolic control is achieved. Permanently discontinue Nivolumab BMS for life-threatening (Grade 4) hyperglycemia.
In patients receiving Nivolumab BMS as a single agent, diabetes occurred in 0.9% (17/1994) of patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months (range: 15 days to 22 months).
In patients receiving Nivolumab BMS with ipilimumab, diabetes occurred in 1.5% (6/407) of patients; the median time to onset was 2.5 months (range: 1.3 to 4.4 months). Nivolumab BMS with ipilimumab was withheld in a patient and permanently discontinued in a second patient who developed diabetes.
Immune-Mediated Nephritis And Renal DysfunctionNivolumab BMS can cause immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 increased creatinine, requirement for corticosteroids, and no clear alternate etiology. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents.
Withhold Nivolumab BMS for moderate (Grade 2) or severe (Grade 3) increased serum creatinine. Permanently discontinue Nivolumab BMS for life-threatening (Grade 4) increased serum creatinine.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 months (range: 23 days to 12.3 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Nivolumab BMS in 0.3% and withholding of Nivolumab BMS in 0.8% of patients. All patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 48% of patients. No patients had recurrence of nephritis or renal dysfunction after re-initiation of Nivolumab BMS.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS with ipilimumab, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients; the median time to onset was 2.7 months (range: 9 days to 7.9 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 0.7% and 0.5% of patients, respectively. Approximately 67% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 13.5 days (range: 1 day to 1.1 months). Complete resolution occurred in all patients. Two patients resumed Nivolumab BMS with ipilimumab without recurrence of nephritis or renal dysfunction.
Immune-Mediated Skin Adverse ReactionsNivolumab BMS can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. For symptoms or signs of SJS or TEN, withhold Nivolumab BMS and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue Nivolumab BMS.
For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) rash. Withhold Nivolumab BMS for severe (Grade 3) rash and permanently discontinue Nivolumab BMS for lifethreatening (Grade 4) rash.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, immune-mediated rash occurred in 9% (171/1994) of patients; the median time to onset was 2.8 months (range: <1 day to 25.8 months). Immunemediated rash led to permanent discontinuation of Nivolumab BMS in 0.3% and withholding of Nivolumab BMS in 0.8% of patients. Approximately 16% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8.9 months) and 85% received topical corticosteroids. Complete resolution occurred in 48% of patients. Recurrence of rash occurred in 1.4% of patients who resumed Nivolumab BMS after resolution of rash.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS with ipilimumab, immune-mediated rash occurred in 22.6% (92/407) of patients; the median time to onset was 18 days (range: 1 day to 9.7 months). Immunemediated rash led to permanent discontinuation or withholding of Nivolumab BMS with ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately 17% of patients with rash received highdose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 2 days to 4.7 months). Complete resolution occurred in 47% of patients. Approximately 6% of patients who resumed Nivolumab BMS and ipilimumab after resolution had recurrence of rash.
Immune-Mediated EncephalitisNivolumab BMS can cause immune-mediated encephalitis with no clear alternate etiology. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture.
Withhold Nivolumab BMS in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue Nivolumab BMS for immune-mediated encephalitis.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a single agent, encephalitis occurred in 0.2% (3/1994). Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of Nivolumab BMS and administration of corticosteroids. In the other two patients, encephalitis occurred post-allogeneic HSCT.
Nivolumab BMS With IpilimumabEncephalitis occurred in one patient receiving Nivolumab BMS with ipilimumab (0.2%) after 1.7 months of exposure.
Other Immune-Mediated Adverse ReactionsNivolumab BMS can cause other clinically significant and potentially fatal immune-mediated adverse reactions. Immune-mediated adverse reactions may occur after discontinuation of Nivolumab BMS therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold Nivolumab BMS, administer high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting Nivolumab BMS after completion of corticosteroid taper based on the severity of the event.
Across clinical trials of Nivolumab BMS administered as a single agent or in combination with ipilimumab, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in less than 1.0% of patients receiving Nivolumab BMS: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, and myasthenic syndrome.
Infusion ReactionsNivolumab BMS can cause severe infusion reactions, which have been reported in less than 1.0% of patients in clinical trials. Discontinue Nivolumab BMS in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions.
Nivolumab BMS As A Single AgentIn patients receiving Nivolumab BMS as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.
In a study assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received Nivolumab BMS as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of Nivolumab BMS.
Nivolumab BMS With IpilimumabIn patients receiving Nivolumab BMS as a 60-minute intravenous infusion prior to the infusion of ipilimumab, infusion-related reactions occurred in 2.5% (10/407) of patients.
Complications Of Allogeneic HSCT After Nivolumab BMSComplications, including fatal events, occurred in patients who received allogeneic HSCT after Nivolumab BMS. Outcomes were evaluated in 17 patients from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after discontinuing Nivolumab BMS (15 with reduced-intensity conditioning, two with myeloablative conditioning). The median age at HSCT was 33 (range: 18 to 56), and a median of 9 doses of Nivolumab BMS had been administered (range: 4 to 16). Six of 17 patients (35%) died from complications of allogeneic HSCT after Nivolumab BMS. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 5/17 patients (29%). Hyperacute GVHD, defined as GVHD occurring within 14 days after stem cell infusion, was reported in 2 patients (20%). A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in six patients (35%) within the first 6 weeks post-transplantation, with five patients responding to steroids. Two cases of encephalitis were reported: one case of Grade 3 lymphocytic encephalitis without an identified infectious cause, which occurred and resolved on steroids, and one case of Grade 3 suspected viral encephalitis which was resolved with antiviral treatment. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.
Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported.
These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.
Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.
Embryo-Fetal ToxicityBased on its mechanism of action and data from animal studies, Nivolumab BMS 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. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an Nivolumab BMS-containing regimen and for at least 5 months after the last dose of Nivolumab BMS.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and withholding or discontinuation of Nivolumab BMS, including:
No studies have been performed to assess the potential of nivolumab for carcinogenicity or genotoxicity. Fertility studies have not been performed with nivolumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.
Use In Specific Populations Pregnancy Risk SummaryBased on its mechanism of action and data from animal studies, Nivolumab BMS 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. 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 Nivolumab BMS 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.
DataAnimal 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.
Lactation Risk SummaryIt is not known whether Nivolumab BMS 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 Nivolumab BMS, advise women to discontinue breastfeeding during treatment with Nivolumab BMS.
Females And Males Of Reproductive Potential ContraceptionBased on its mechanism of action, Nivolumab BMS can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Nivolumab BMS and for at least 5 months following the last dose of Nivolumab BMS.
Pediatric UseThe safety and effectiveness of Nivolumab BMS 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 Nivolumab BMS for this indication is supported by evidence from adequate and well-controlled studies of Nivolumab BMS 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. The safety and effectiveness of Nivolumab BMS have not been established (1) in pediatric patients less than 12 years old with MSI-H or dMMR mCRC or (2) in pediatric patients less than 18 years old for the other approved indications.
Geriatric UseOf the 1359 patients randomized to single-agent Nivolumab BMS 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.
In CHECKMATE-238 (Adjuvant Treatment of Melanoma), 26% of patients were 65 years or older and 3% 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, a
The recommended dose of Nivolumab BMS as a single agent is 240 mg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
The recommended dose of Nivolumab BMS is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses. The recommended subsequent dose of Nivolumab BMS, as a single agent, is 240 mg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity. Review the Full Prescribing Information for ipilimumab prior to initiation.
Recommended Dosage For Adjuvant Treatment Of MelanomaThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease recurrence or unacceptable toxicity for up to 1 year.
Recommended Dosage For NSCLCThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For RCCThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For cHLThe recommended dose of Nivolumab BMS is 3 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For SCCHNThe recommended dose of Nivolumab BMS is 3 mg/kg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For Urothelial CarcinomaThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For CRCThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Recommended Dosage For HCCThe recommended dose of Nivolumab BMS is 240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
Dose ModificationsRecommendations for Nivolumab BMS modifications are provided in Table 1. When Nivolumab BMS is administered in combination with ipilimumab, if Nivolumab BMS 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 Nivolumab BMS in patients with severe or life-threatening infusion reactions.
Table 1: Recommended Dose Modifications for Nivolumab BMS
| 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 |
| 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. |
Visually inspect drug product solution for particulate matter and discoloration prior to administration. Nivolumab BMS 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.
PreparationThe product does not contain a preservative.
After preparation, store the Nivolumab BMS infusion either:
Do not freeze.
AdministrationAdminister the infusion 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 Nivolumab BMS first followed by ipilimumab on the same day. Use separate infusion bags and filters for each infusion.
