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. The total volume of infusion must not exceed 160 mL.
• For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL.
• For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight.

•

Mix diluted solution by gentle inversion. Do not shake.

•

Discard partially used vials or empty vials of OPDIVO.

•

The product does not contain a preservative.

•

After preparation, store the diluted solution either:
• at room temperature and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or
• under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation.

•

Do not freeze.

Administration

•

Administer the infusion, after dilution, over 30 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).

•

Administer OPDIVO in combination with other therapeutic agents as follows:

o

With ipilimumab: administer OPDIVO first followed by ipilimumab on the same day.

o

With platinum-doublet chemotherapy: administer OPDIVO first followed by platinum-doublet chemotherapy on the same day

o

With ipilimumab and platinum-doublet chemotherapy: administer OPDIVO first followed by ipilimumab and then platinum-doublet chemotherapy on the same day.

o

With fluoropyrimidine- and platinum-containing chemotherapy: administer OPDIVO first followed by fluoropyrimidine- and platinum-containing chemotherapy on the same day.

•

Use separate infusion bags and filters for each infusion.

•

Flush the intravenous line at end of infusion.

•

Do not co-administer other drugs through the same intravenous line.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

OPDIVO as a Single Agent

Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients.

Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis.

OPDIVO with Ipilimumab

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients.

Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

OPDIVO as a Single Agent

Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients.

Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients.

Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis.

Immune-Mediated Hepatitis and Hepatotoxicity

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

OPDIVO as a Single Agent

Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients.

Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients.

Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis.

OPDIVO with Cabozantinib

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt OPDIVO and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3)].

With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1)]. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either OPDIVO (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients.

Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2.0% of patients.

Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency.

OPDIVO with Cabozantinib

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO and cabozantinib in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom OPDIVO with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Hypophysitis

OPDIVO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO in 0.2% of patients.

Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients.

Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC.

Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis.

Thyroid Disorders

OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

Thyroiditis

OPDIVO as a Single Agent

Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients.

Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis.

Hyperthyroidism

OPDIVO as a Single Agent

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients.

Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients.

Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC.

Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism.

Hypothyroidism

OPDIVO as a Single Agent

Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients.

Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients.

Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC.

Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism.

Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients.

No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology.

OPDIVO as a Single Agent

Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients.

Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3)].

OPDIVO as a Single Agent

Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients.

Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients.

Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC.

Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO or OPDIVO in combination with ipilimumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic

Endocrine: Hypoparathyroidism

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

OPDIVO as a Single Agent

In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.

In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO 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) of 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 OPDIVO.

OPDIVO with Ipilimumab

OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg

Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks.

OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg

Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.

Unresectable or Metastatic Melanoma

Previously Treated Metastatic Melanoma

The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)]. Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year.

The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%).

Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash.

Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037.

Clinically important adverse reactions in <10% of patients who received OPDIVO 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

Previously Untreated Metastatic Melanoma

CHECKMATE-066

The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m2 intravenously every 3 weeks (n=205). 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 >6 months and 12% of patients received OPDIVO for >1 year.

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%).

Serious adverse reactions occurred in 36% of patients receiving OPDIVO. 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. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus.

Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066.

Clinically important adverse reactions in <10% of patients who received OPDIVO were:

Nervous System Disorders: peripheral neuropathy

CHECKMATE-067

The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1)]. The trial 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.

Patients were randomized to receive:

•

OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or

•

OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or

•

Ipilimumab 3 mg/kg by intravenous infusion 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 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 40% for >1 year.

The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (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.

Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO and ipilimumab arm relative to the OPDIVO arm.

The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1.0%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%).

The most common (≥20%) adverse reactions in the OPDIVO and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting.

Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067.

Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO as a single agent were:

Gastrointestinal Disorders: stomatitis, intestinal perforation

Skin and Subcutaneous Tissue Disorders: vitiligo

Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis)

Nervous System Disorders: neuritis, peroneal nerve palsy

Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer

The safety of OPDIVO in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.3)]. Patients received either OPDIVO 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles.

The median age of patients who received OPDIVO in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African-American.

Serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy.

Study therapy with OPDIVO in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of OPDIVO in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%).

The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia.

Tables 13 and 14 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816.

Metastatic Non-Small Cell Lung Cancer

First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab

The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.4)]. The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received OPDIVO 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received OPDIVO and ipilimumab for >6 months and 23% of patients received OPDIVO and ipilimumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology.

Serious adverse reactions occurred in 58% of patients. OPDIVO and ipilimumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.

Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227.

Other clinically important adverse reactions in CHECKMATE-227 were:

Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo

Gastrointestinal: stomatitis, pancreatitis, gastritis

Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis

Nervous System: peripheral neuropathy, autoimmune encephalitis

Blood and Lymphatic System: eosinophilia

Eye Disorders: blurred vision, uveitis

Cardiac: atrial fibrillation, myocarditis

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

The safety of OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.4)]. Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year.

Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

Study therapy with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA.

Second-line Treatment of Metastatic NSCLC

The safety of OPDIVO 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 (14.4)]. These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m2 intravenously 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 >6 months and 20% of patients received OPDIVO for >1 year.

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%).

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. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

Tables 19 and 20 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057.

Other clinically important adverse reactions observed in OPDIVO-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades).

Malignant Pleural Mesothelioma

The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.5)]. Patients received either OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received OPDIVO and ipilimumab for >6 months and 24% of patients received OPDIVO and ipilimumab for >1 year.

Serious adverse reactions occurred in 54% of patients who were treated with OPDIVO in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis and encephalitis.

Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction.

The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus.

Tables 21 and 22 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743.

Advanced Renal Cell Carcinoma

First-line Renal Cell Carcinoma

CHECKMATE-214

The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.6)]. The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the OPDIVO and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 59% of patients receiving OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia.

Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab-treated patients in CHECKMATE-214.

In addition, among patients with TSH ≤ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively).

CHECKMATE-9ER

The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.6)]. Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year.

Serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

Adverse reactions leading to discontinuation of either OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially.

The most common adverse reactions reported in ≥20% of patients treated with OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysaesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER.

Previously Treated Renal Cell Carcinoma

CHECKMATE-025

The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.6)]. 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.

Rate of death on treatment or within 30 days of the last dose was 4.7% on the OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO had a dose interruption for an adverse reaction.

The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. 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, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively).

Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025.

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

Classical Hodgkin Lymphoma

The safety of OPDIVO was evaluated in 266 adult patients with cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies (14.7)]. Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks 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).

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. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients.

The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus.

Tables 29 and 30 summarize the adverse reactions and laboratory abnormalities, respectively, in 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 nasopharyngitis, pharyngitis, rhinitis, and sinusitis.
c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia.
d Includes asthenia.
e Includes colitis.
f Includes abdominal discomfort and upper abdominal pain.
g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity.
h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform.
i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events.

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: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days.

Complications of allogeneic HSCT after OPDIVO: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure.

Table 30 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase.

Squamous Cell Carcinoma of the Head and Neck

The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.8)]. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year.

The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy.

Serious adverse reactions occurred in 49% of patients receiving OPDIVO. OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC.

The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH.

Adjuvant Treatment of Urothelial Carcinoma

The safety of OPDIVO was evaluated in CHECKMATE-274, a randomized, double-blind, multicenter trial of adjuvant OPDIVO versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.9)]. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of OPDIVO treatment was 8.8 months (range: 0 to 12.5).

Serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). OPDIVO was discontinued for adverse reactions in 18% of patients. OPDIVO was delayed for adverse reaction in 33% of patients.

The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274.

Table 31: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274

Table 32: Laboratory Abnormalities Worsening from Baselinea Occurring in ≥10% of Patients - CHECKMATE-274

Advanced or Metastatic Urothelial Carcinoma

The safety of OPDIVO was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic urothelial carcinoma had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.9)]. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction.

Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO was discontinued for adverse reactions in 17% of patients.

The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite.

Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275.