HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`OPDIVO safely and effectively. See full prescribing information for
`OPDIVO.
`OPDIVO (nivolumab) injection, for intravenous use
`Initial U.S. Approval: 2014
`--------------------------RECENT MAJOR CHANGES----------------------------
`Indications and Usage (1.2)
`3/2015
`Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)
`3/2015
`---------------------------INDICATIONS AND USAGE----------------------------
`OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody
`indicated for the treatment of patients with:
` unresectable or metastatic melanoma and disease progression following
`ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. (1.1)
`This indication is approved under accelerated approval based on tumor
`response rate and durability of response. Continued approval for this
`indication may be contingent upon verification and description of clinical
`benefit in the confirmatory trials. (1.1, 14.1)
` metastatic squamous non-small cell lung cancer with progression on or
`after platinum-based chemotherapy. (1.2)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`Administer 3 mg/kg as an intravenous infusion over 60 minutes every
`2 weeks. (2.1)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Injection: 40 mg/4 mL and 100 mg/10 mL solution in a single-use vial. (3)
`------------------------------CONTRAINDICATIONS-------------------------------
`None. (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`Immune-mediated adverse reactions: Administer corticosteroids based on the
`severity of the reaction. (5.1, 5.2, 5.3, 5.4, 5.6)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 
`INDICATIONS AND USAGE 
`1.1 
`Unresectable or Metastatic Melanoma 
`1.2 
`Metastatic Squamous Non-Small Cell Lung Cancer 
`2  DOSAGE AND ADMINISTRATION 
`2.1 
`Recommended Dosage 
`2.2 
`Dose Modifications 
`2.3 
`Preparation and Administration 
`3  DOSAGE FORMS AND STRENGTHS 
`4  CONTRAINDICATIONS 
`5  WARNINGS AND PRECAUTIONS 
`5.1 
`Immune-Mediated Pneumonitis 
`5.2 
`Immune-Mediated Colitis 
`5.3 
`Immune-Mediated Hepatitis 
`5.4 
`Immune-Mediated Nephritis and Renal Dysfunction 
`5.5 
`Immune-Mediated Hypothyroidism and Hyperthyroidism 
`5.6 
`Other Immune-Mediated Adverse Reactions 
`5.7 
`Embryofetal Toxicity 
`6  ADVERSE REACTIONS 
`6.1 
`Clinical Trials Experience 
`6.2 
`Immunogenicity 
`7  DRUG INTERACTIONS 
`8  USE IN SPECIFIC POPULATIONS 
`8.1 
`Pregnancy 
`
`
`
`Reference ID: 3710966
`
` Immune-mediated pneumonitis: Withhold for moderate and permanently
`discontinue for severe or life-threatening pneumonitis. (5.1)
` Immune-mediated colitis: Withhold
`for moderate or severe and
`permanently discontinue for life-threatening colitis. (5.2)
` Immune-mediated hepatitis: Monitor for changes in liver function.
`Withhold for moderate and permanently discontinue for severe or life-
`threatening transaminase or total bilirubin elevation. (5.3)
` Immune-mediated nephritis and renal dysfunction: Monitor for changes in
`renal function. Withhold for moderate or severe and permanently
`discontinue for life-threatening serum creatinine elevation. (5.4)
` Immune-mediated hypothyroidism and hyperthyroidism: Monitor for
`changes in thyroid function. Initiate thyroid hormone replacement as
`needed. (5.5)
` Embryofetal toxicity: Can cause fetal harm. Advise of potential risk to a
`fetus and use of effective contraception. (5.7, 8.1, 8.3)
`-------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reaction (20%) in patients with melanoma was rash.
`(6.1)
`Most common adverse reactions (20%) in patients with advanced squamous
`non-small cell lung cancer were fatigue, dyspnea, musculoskeletal pain,
`decreased appetite, cough, nausea, and constipation. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
` Lactation: Discontinue breastfeeding. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 3/2015
`
`
`
`
`Lactation 
`8.2 
`Females and Males of Reproductive Potential 
`8.3 
`Pediatric Use 
`8.4 
`Geriatric Use 
`8.5 
`Renal Impairment 
`8.6 
`Hepatic Impairment 
`8.7 
`10  OVERDOSAGE 
`11  DESCRIPTION 
`12  CLINICAL PHARMACOLOGY 
`12.1  Mechanism of Action 
`12.3 
`Pharmacokinetics 
`13  NONCLINICAL TOXICOLOGY 
`13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility 
`13.2 
`Animal Toxicology and/or Pharmacology 
`14  CLINICAL STUDIES 
`14.1  Unresectable or Metastatic Melanoma 
`14.2  Metastatic Squamous Non-Small Cell Lung Cancer 
`16  HOW SUPPLIED/STORAGE AND HANDLING 
`17  PATIENT COUNSELING INFORMATION 
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`
`
`1
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`
`Unresectable or Metastatic Melanoma
`1.1
`OPDIVO (nivolumab) is indicated for the treatment of patients with unresectable or metastatic
`melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive,
`a BRAF inhibitor [see Clinical Studies (14.1)].
`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.
`
`Metastatic Squamous Non-Small Cell Lung Cancer
`1.2
`OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic squamous non-
`small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see
`Clinical Studies (14.2)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosage
`2.1
`The recommended dose of OPDIVO is 3 mg/kg administered as an intravenous infusion over
`60 minutes every 2 weeks until disease progression or unacceptable toxicity.
`
`Dose Modifications
`2.2
`There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
`Withhold OPDIVO for any of the following:
` Grade 2 pneumonitis [see Warnings and Precautions (5.1)]
` Grade 2 or 3 colitis [see Warnings and Precautions (5.2)]
` Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and
`up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to
`3 times ULN [see Warnings and Precautions (5.3)]
` Creatinine greater than 1.5 and up to 6 times ULN or greater than 1.5 times baseline
`[see Warnings and Precautions (5.4)]
` Any other severe or Grade 3 treatment-related adverse reactions [see Warnings and
`Precautions (5.6)]
`Resume OPDIVO in patients whose adverse reactions recover to Grade 0 to 1.
`Permanently discontinue OPDIVO for any of the following:
` Any life-threatening or Grade 4 adverse reaction
` Grade 3 or 4 pneumonitis [see Warnings and Precautions (5.1)]
` Grade 4 colitis [see Warnings and Precautions (5.2)]
`
`Reference ID: 3710966
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` AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN [see
`Warnings and Precautions (5.3)]
` Creatinine greater than 6 times ULN [see Warnings and Precautions (5.4)]
` Any severe or Grade 3 treatment-related adverse reaction that recurs
`
`Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per
`day within 12 weeks
` Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to
`Grade 1 or resolve within 12 weeks after last dose of OPDIVO
`
`Preparation and Administration
`2.3
`Visually inspect drug product solution for particulate matter and discoloration prior to
`administration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard the
`vial if the solution is cloudy, is discolored, or contains extraneous particulate matter other than a
`few translucent-to-white, proteinaceous particles. Do not shake the vial.
`
`Preparation
` Withdraw the required volume of OPDIVO and transfer into an intravenous container.
` Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose
`Injection, USP, to prepare an infusion with a final concentration ranging from 1 mg/mL
`to 10 mg/mL.
` Mix diluted solution by gentle inversion. Do not shake.
` Discard partially used vials or empty vials of OPDIVO.
`
`Storage of Infusion
`The product does not contain a preservative.
`After preparation, store the OPDIVO infusion either:
`
`at room temperature for no more than 4 hours from the time of preparation. This
`includes room temperature storage of the infusion in the IV container and time for
`administration of the infusion or
`under refrigeration at 2°C to 8°C (36°F-46°F) for no more than 24 hours from the time
`of infusion preparation.
`Do not freeze.
`
`
`
`Administration
`Administer the infusion over 60 minutes through an intravenous line containing a sterile, non-
`pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
`Do not coadminister other drugs through the same intravenous line.
`Flush the intravenous line at end of infusion.
`
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`DOSAGE FORMS AND STRENGTHS
`3
`Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-use vial.
`
`4
`None.
`
`5
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`Immune-Mediated Pneumonitis
`5.1
`Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO
`treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-
`mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal
`pneumonitis occurred in Trial 1 or Trial 3; all five fatal cases occurred in a dose-finding study
`with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one
`patient).
`In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients
`receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated
`pneumonitis, defined as requiring use of corticosteroids and no clear alternate etiology, occurred
`in 2.2% (6/268) of patients receiving OPDIVO: one with Grade 3 and five with Grade 2
`pneumonitis. The median time to onset for the six cases was 2.2 months (range: 25 days to
`3.5 months). In two patients, pneumonitis was diagnosed after discontinuation of OPDIVO for
`other reasons, and Grade 2 pneumonitis led to interruption or permanent discontinuation of
`OPDIVO in the remaining four patients. All six patients received high-dose corticosteroids (at
`least 40 mg prednisone equivalents per day); immune-mediated pneumonitis improved to Grade
`0 or 1 with corticosteroids in all six patients. There were two patients with Grade 2 pneumonitis
`that completely resolved (defined as complete resolution of symptoms with completion of
`corticosteroids) and OPDIVO was restarted without recurrence of pneumonitis.
`In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five
`Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months
`(range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another
`event and all seven patients experienced complete resolution of pneumonitis following receipt of
`high-dose corticosteroids (at least 40 mg prednisone equivalents per day).
`Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of
`1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by
`corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening
`(Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2)
`pneumonitis [see Dosage and Administration (2.2)].
`
`Immune-Mediated Colitis
`5.2
`In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18%
`(18/102) of patients receiving chemotherapy. Immune-mediated colitis, defined as requiring use
`
`Reference ID: 3710966
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`

`
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`of corticosteroids with no clear alternate etiology, occurred in 2.2% (6/268) of patients receiving
`OPDIVO: five patients with Grade 3 and one patient with Grade 2 colitis. The median time to
`onset of immune-mediated colitis from initiation of OPDIVO was 2.5 months (range: 1 to 6
`months). In three patients, colitis was diagnosed after discontinuation of OPDIVO for other
`reasons, and Grade 2 or 3 colitis led to interruption or permanent discontinuation of OPDIVO in
`the remaining three patients. Five of these six patients received high-dose corticosteroids (at least
`40 mg prednisone equivalents) for a median duration of 1.4 months (range: 3 days to 2.4 months)
`preceding corticosteroid taper. The sixth patient continued on low-dose corticosteroids started for
`another immune-mediated adverse reaction. Immune-mediated colitis improved to Grade 0 with
`corticosteroids in five patients, including one patient with Grade 3 colitis retreated after complete
`resolution (defined as improved to Grade 0 with completion of corticosteroids) without
`additional events of colitis. Grade 2 colitis was ongoing in one patient.
`In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3)
`occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The
`patient received high-dose corticosteroids and was permanently discontinued from OPDIVO.
`Complete resolution occurred.
`Monitor patients for immune-mediated colitis. 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) 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 OPDIVO for Grade 2 or 3
`immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent
`colitis upon restarting OPDIVO [see Dosage and Administration (2.2)].
`
`Immune-Mediated Hepatitis
`5.3
`In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated
`group as compared to the chemotherapy-treated group, with increases in AST (28% vs. 12%),
`alkaline phosphatase (22% vs. 13%), ALT (16% vs. 5%), and total bilirubin (9% vs. 0). Immune-
`mediated hepatitis, defined as requirement for corticosteroids and no clear alternate etiology,
`occurred in 1.1% (3/268) of patients receiving OPDIVO: two patients with Grade 3 and one
`patient with Grade 2 hepatitis. The time to onset was 97, 113, and 86 days after initiation of
`OPDIVO. In one patient, hepatitis was diagnosed after discontinuation of OPDIVO for other
`reasons. In two patients, OPDIVO was withheld. All three patients received high-dose
`corticosteroids (at least 40 mg prednisone equivalents). Liver tests improved to Grade 1 within 4
`to 15 days of initiation of corticosteroids. Immune-mediated hepatitis resolved and did not recur
`with continuation of corticosteroids in two patients; the third patient died of disease progression
`with persistent hepatitis. The two patients with Grade 3 hepatitis that resolved restarted OPDIVO
`and, in one patient, Grade 3 immune-mediated hepatitis recurred resulting in permanent
`discontinuation of OPDIVO.
`
`Reference ID: 3710966
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`
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`In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase
`(14%), ALT (12%), and total bilirubin (2.7%). No cases of immune-mediated hepatitis occurred
`in this trial.
`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 for Grade 2 or greater
`transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold
`OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or
`life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) and
`Adverse Reactions (6.1)].
`
`Immune-Mediated Nephritis and Renal Dysfunction
`5.4
`In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group
`as compared to the chemotherapy-treated group (13% vs. 9%). Grade 2 or 3 immune-mediated
`nephritis or renal dysfunction (defined as  Grade 2 increased creatinine, requirement for
`corticosteroids, and no clear alternate etiology) occurred in 0.7% (2/268) of patients at 3.5 and
`6 months after OPDIVO initiation, respectively. OPDIVO was permanently discontinued in both
`patients; both received high-dose corticosteroids (at least 40 mg prednisone equivalents).
`Immune-mediated nephritis resolved and did not recur with continuation of corticosteroids in one
`patient. Renal dysfunction was ongoing in one patient.
`In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction
`(Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 0.8 months.
`The patient received high-dose corticosteroids. OPDIVO was withheld, and the patient
`discontinued due to disease progression prior to receiving additional OPDIVO. Immune-
`mediated renal dysfunction was ongoing.
`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) serum creatinine elevation and permanently
`discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation,
`withhold OPDIVO and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone
`equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase
`dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue
`OPDIVO [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
`
`Immune-Mediated Hypothyroidism and Hyperthyroidism
`5.5
`In Trial 1, where patients were evaluated at baseline and during the trial for thyroid function,
`Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none
`of the 102 patients receiving chemotherapy. The median time to onset was 2.5 months (range:
`24 days to 11.7 months). Seventeen of the 21 patients with hypothyroidism received
`levothyroxine. Fifteen of 17 patients received subsequent OPDIVO dosing while continuing to
`receive levothyroxine.
`
`Reference ID: 3710966
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`
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`Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1%
`(1/102) of patients receiving chemotherapy. The median time to onset in OPDIVO-treated
`patients was 1.6 months (range: 0 to 3.3 months). Four of five patients with Grade 1
`hyperthyroidism and two of three patients with Grade 2 hyperthyroidism had documented
`resolution of hyperthyroidism; all three patients received medical management for Grade 2
`hyperthyroidism.
`In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and
`every 6 weeks. Hypothyroidism occurred in 4.3% (5/117) of patients. The median time to onset
`for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with
`hypothyroidism received levothyroxine. Complete resolution of hypothyroidism occurred in one
`patient allowing discontinuation of levothyroxine. Interruption of OPDIVO did not occur in
`these five patients.
`Hyperthyroidism occurred in 1.7% (2/117) of patients. One patient experienced Grade 2
`hyperthyroidism 5.2 months after the first dose of OPDIVO, requiring treatment with high-dose
`corticosteroids and methimazole. Thyroid laboratory tests returned to normal 4.7 months later.
`Monitor thyroid function prior to and periodically during treatment. Administer hormone
`replacement
`therapy for hypothyroidism. Initiate medical management for control of
`hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism
`or hyperthyroidism.
`
`Other Immune-Mediated Adverse Reactions
`5.6
`Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated
`adverse reactions may occur after discontinuation of OPDIVO therapy.
`The following clinically significant, immune-mediated adverse reactions occurred in less than
`2% of OPDIVO-treated patients in Trials 1 and 3 (n=385): adrenal insufficiency, uveitis,
`pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor
`dysfunction, and vasculitis.
`Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following
`additional clinically significant,
`immune-mediated adverse
`reactions were
`identified:
`hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic
`syndrome.
`For any suspected immune-mediated adverse reactions, exclude other causes. Based on the
`severity of the adverse reaction, withhold OPDIVO, 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 OPDIVO
`after completion of corticosteroid taper based on the severity of the event [see Dosage and
`Administration (2.2)].
`
`Reference ID: 3710966
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`Embryofetal Toxicity
`5.7
`Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm
`when administered to a pregnant woman. In animal reproduction studies, administration of
`nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in
`increased abortion and premature infant death. Advise pregnant women of the potential risk to a
`fetus. Advise females of reproductive potential to use effective contraception during treatment
`with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific
`Populations (8.1, 8.3)].
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in greater detail in other sections of the labeling.
`
`Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)]
`
`Immune-Mediated Colitis [see Warnings and Precautions (5.2)]
`
`Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)]
`
`Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions
`(5.4)]
`Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and
`Precautions (5.5)]
` Other Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.6)]
`
`
`
`Clinical Trials Experience
`6.1
`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 clinical practice.
`The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure
`to OPDIVO in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma
`and in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer
`(NSCLC).
`Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials
`1, 3, or an additional dose finding study (n=306) administering OPDIVO at doses of 0.1 to
`10 mg/kg every 2 weeks [see Warnings and Precautions (5.1, 5.6)].
`
`Unresectable or Metastatic Melanoma
`The safety of OPDIVO was evaluated in Trial 1, a randomized, open-label trial in which
`370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every
`2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine
`1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus
`paclitaxel 175 mg/m2 every 3 weeks [see Clinical Studies (14.1)]. The median duration of
`exposure was 5.3 months (range: 1 day to 13.8+ months) with a median of eight doses (range: 1
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`to 31) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in
`chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for
`greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.
`In Trial 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.
`The study population characteristics in the OPDIVO group and the chemotherapy group were
`similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status
`0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with
`mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic
`disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with
`elevated LDH at baseline (51% vs. 38%).
`OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of
`patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions
`occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in
`42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported
`in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia,
`increased aspartate aminotransferase, and increased lipase.
`Table 1 summarizes the adverse reactions that occurred in at least 10% of OPDIVO-treated
`patients. The most common adverse reaction (reported in at least 20% of patients) was rash.
`
`Table 1:
`
`
`
`Adverse Reaction
`
`Selected Adverse Reactions Occurring in 10% of OPDIVO-
`Treated Patients and at a Higher Incidence than in the
`Chemotherapy Arm (Between Arm Difference of % [All Grades]
`or 2% [Grades 3-4]) (Trial 1)
`OPDIVO
`(n=268)
`
`Chemotherapy
`(n=102)
`
`
`Skin and Subcutaneous Tissue Disorders
`Rasha
`
`
`Pruritus
`Respiratory, Thoracic, and Mediastinal
`Disorders
`
`Cough
`
`All
`Grades
`
`
`21
`19
`
`
`17
`
`All
`Grades
`Grades
`3-4
`Percentage (%) of Patients
`
`
`0.4
`7
`0
`3.9
`
`
`
`0
`
`6
`
`Grades
`3-4
`
`
`0
`0
`
`
`0
`
`Reference ID: 3710966
`
`9
`
`

`

`
`
`Table 1:
`
`
`
`Adverse Reaction
`
`Selected Adverse Reactions Occurring in 10% of OPDIVO-
`Treated Patients and at a Higher Incidence than in the
`Chemotherapy Arm (Between Arm Difference of % [All Grades]
`or 2% [Grades 3-4]) (Trial 1)
`OPDIVO
`(n=268)
`
`Chemotherapy
`(n=102)
`
`All
`Grades
`
`
`11
`
`
`All
`Grades
`Grades
`3-4
`Percentage (%) of Patients
`
`
`0
`2.0
`
`
`
`
`Infections and Infestations
`Upper respiratory tract infectionb
`
`General Disorders and Administration
`Site Conditions
`0
`5
`0
`10
`
`Peripheral edema
`a Rash is a composite term which includes maculopapular rash, rash erythematous, rash pruritic, rash follicular,
`rash macular, rash papular, rash pustular, rash vesicular, and dermatitis acneiform.
`b Upper respiratory tract infection is a composite term which includes rhinitis, pharyngitis, and nasopharyngitis.
`
`Grades
`3-4
`
`
`0
`
`
`Other clinically important adverse reactions in less than 10% of patients treated with OPDIVO in
`Trial 1 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.
`
`Reference ID: 3710966
`
`10
`
`

`

`
`
`
`
`Table 2:
`
`Selected Laboratory Abnormalities Worsening from Baseline
`Occurring in 10% of OPDIVO-Treated Patients and at a Higher
`Incidence than in the Chemotherapy Arm (Between Arm Difference
`of % [All Grades] or 2% [Grades 3-4]) (Trial 1)
`Percentage of Patients with Worsening Laboratory Test from Baselinea
`OPDIVO
`Chemotherapy
`All Grades
`Grades 3-4
`All Grades
`Grades 3-4
`Test
`28
`2.4
`12
`1.0
`Increased AST
`22
`2.4
`13
`1.1
`Increased alkaline phosphatase
`25
`5
`18
`1.1
`Hyponatremia
`16
`1.6
`5
`0
`Increased ALT
`15
`2.0
`6
`0
`Hyperkalemia
`a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory
`measurement available: OPDIVO group (range 252 to 256 patients) and chemotherapy group (range 94 to 96
`patients).
`
`Metastatic Squamous Non-Small Cell Lung Cancer
`The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in
`117 patients with metastatic squamous NSCLC and progression on both a prior platinum-based
`therapy and at least one additional systemic therapy [see Clinical Studies (14.2)]. Patients
`received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks. The
`median duration of therapy was 2.3 months (range: 1 day to 16.1+ months). Patients received a
`median of 6 doses (range: 1 to 34).
`Trial 3 excluded patients with active autoimmune disease, symptomatic interstitial lung disease,
`or untreated brain metastasis. The median age of patients was 65 years (range: 37 to 87) with
`50% 65 years of age and 14% 75 years of age. The majority of patients were male (73%) and
`white (85%). All patients received two or more prior systemic treatments. Baseline disease
`characteristics of the population were recurrent Stage IIIb (6%), Stage IV (94%), and brain
`metastases (1.7%). Baseline ECOG performance status was 0 (22%) or 1 (78%).
`OPDIVO was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of
`patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions
`occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse reactions
`reported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary
`disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.
`Table 3 summarizes adverse reactions that occurred in at least 10% of patients. The most
`common adverse reactions (reported in at least 20% of patients) were fatigue, dyspnea,
`musculoskeletal pain, decreased appetite, cough, nausea, and constipation.
`
`Reference ID: 3710966
`
`11
`
`

`

`
`
`Table 3:
`
`Adverse Reactions Occurring in 10% of Patients for All NCI
`CTCAE* Grades or 5% for Grades 3-4 (Trial 3)
`
`OPDIVO
`(n=117)
`
`Adverse Reaction
`
`
`General Disorders and Administration Site Conditions
`
`Fatigue
`
`Asthenia
`Edemaa
`
`
`Pyrexia
`Chest painb
`
`
`Pain
`Respiratory, Thoracic, and Mediastinal Disorders
`
`Dyspnea
`
`Cough
`Musculoskeletal and Connective Tissue Disorders
` Musculoskeletal painc
`Arthralgiad
`
`Metabolism and Nutrition Disorders
`
`Decreased appetite
`Gastrointestinal Disorders
`
`Nausea
`
`Constipation
`
`Vomiting
`
`Diarrhea
`Abdominal paine
`
`Skin and Subcutaneous Tissue Disorders
`Rashf
`
`
`Pruritus
`Investigations
`
`Decreased weight
`
`Grades 3-4
`All Grades
`Percentage (%) of Patients
`
`
`50
`7
`19
`1.7
`17
`1.7
`17
`0
`13
`0
`10
`2.6
`
`
`38
`9
`32
`1.7
`
`
`36
`6
`13
`0
`
`
`35
`2.6
`
`
`29
`1.7
`24
`0
`19
`0.9
`18
`2.6
`16
`1.7
`
`
`16
`0.9
`11
`0.9
`
`
`13
`0.9
`
`Reference ID: 3710966
`
`12
`
`

`

`
`
`Table 3:
`
`Adverse Reactions Occurring in 10% of Patients for All NCI
`CTCAE* Grades or 5% for Grades 3-4 (Trial 3)
`
`OPDIVO
`(n=117)
`
`
`
`Adverse Reaction
`
`Grades 3-4
`All Grades
`Percentage (%) of Patients
`Infections and Infestations
`
`
`Pneumoniag
`10
`5
`
`* National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.
`a Includes face edema, peripheral edema, local swelling, localized edema, lymphoedema.
`b Includes chest discomfort and noncardiac chest pain.
`c Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain.
`d Includes arthritis and osteoarthritis.
`e Incl