 Immune-mediated pneumonitis: Withhold for moderate and permanently
`discontinue for severe or life-threatening pneumonitis. (5.1)
`for moderate or severe and
` Immune-mediated colitis: Withhold
`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 and permanently discontinue for
`
`severe or 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%) was rash. (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: 12/2014
`
`
`
`
`
`
` 
` 
`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
` 
` 
`Animal Toxicology and/or Pharmacology
`13.2
` 
` 
`14 CLINICAL STUDIES
` 
` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
` 
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`1
`
` 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
` ---------------------------INDICATIONS AND USAGE----------------------------
`
`OPDIVO is a human 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.
`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, 14)
`-----------------------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
` 
` 
`2 DOSAGE AND ADMINISTRATION
`
` 
` 
`Recommended Dosage
`2.1
` 
` 
`2.2
`Dose Modifications
` 
` 
`2.3
`Preparation and Administration
` 
` 
`3 DOSAGE FORMS AND STRENGTHS
` 
` 
`4 CONTRAINDICATIONS
` 
` 
`5 WARNINGS AND PRECAUTIONS
` 
` 
`Immune-Mediated Pneumonitis
`5.1
` 
` 
`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: 3677021
`
`Ex. 1112-0001
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`INDICATIONS AND USAGE
`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)].
`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.
`
`
`
`
`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 0-1.
`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)]
`
`
` 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
`
`
`
`Reference ID: 3677021
`
`2
`
`Ex. 1112-0002
`
`

`
`
`
`
` Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade
`0-1 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.
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`Injection: 40 mg/4 mL (10 mg/mL) and 100 mg/10 mL (10 mg/mL) solution in a single-use vial.
`
`CONTRAINDICATIONS
`
`
`4
`None.
`
`Reference ID: 3677021
`
`3
`
`Ex. 1112-0003
`
`

`
`
`
`5
`
`
`
` 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 574 patients with solid tumors, fatal immune-
`mediated pneumonitis occurred in 0.9% (5/574) of patients receiving OPDIVO. No cases of fatal
`pneumonitis occurred in Trial 1; 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
`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 improved to Grade 0 with completion of corticosteroids)
`and OPDIVO was restarted without recurrence of pneumonitis.
`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
`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: 1-6
`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-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.
`
`
`
`Reference ID: 3677021
`
`4
`
`Ex. 1112-0004
`
`

`
`
`
`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)].
`
`
`
`
`5.3
`Immune-Mediated Hepatitis
`
`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
`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.
`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.
`
`Reference ID: 3677021
`
`5
`
`Ex. 1112-0005
`
`

`
`
`
`
`
`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-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.
`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: 0-3.3 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.
`
`Monitor thyroid function prior to and periodically during treatment. Administer hormone
`therapy for hypothyroidism. Initiate medical management for control of
`replacement
`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
`1% of OPDIVO-treated patients in Trial 1: pancreatitis, uveitis, demyelination, autoimmune
`neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.
`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
`
`
`
`Reference ID: 3677021
`
`6
`
`Ex. 1112-0006
`
`

`
`
`
`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)].
`
` 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)].
`
`
`
`
`
`
`6
`ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling.
`
`Immune-Mediated Pneumonitis [see Warnings and Precautions (5.1)]
`
`
`
`
`Immune-Mediated Colitis [see Warnings and Precautions (5.2)]
`
`
`
`
`Immune-Mediated Hepatitis [see Warnings and Precautions (5.3)]
`
`
`
`
`Immune-Mediated 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, the 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, 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)]. The median duration of exposure was 5.3 months (range: 1 day-13.8+ months) with a
`median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range:
`1 day-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.
`Clinically significant adverse reactions were also evaluated in 574 patients with solid tumors
`enrolled in two clinical trials receiving OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks,
`
`Reference ID: 3677021
`
`7
`
`Ex. 1112-0007
`
`

`
`
`
`
`
` supplemented by immune-mediated adverse reaction reports across ongoing clinical trials [see
`Warnings and Precautions (5.1, 5.6)].
`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: 3677021
`
`8
`
`Ex. 1112-0008
`
`

`
`
`
`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
`
`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: 3677021
`
`9
`
`Ex. 1112-0009
`
`

`
`
`
`Table 2:
`
`Selected Laboratory Abnormalities Increased 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
`
`Chemotherapy
`OPDIVO
`
`Test
`Grades 3-4
`All Grades
`All Grades
`Grades 3-4
`
`
`
`
`Increased AST
`1.0
`12
`28
`2.4
`
`
`
`
`
`Increased alkaline phosphatase
`13
`1.1
`22
`2.4
`
`
`
`
`
`
`
`
`
`Hyponatremia
`18
`1.1
`25
`5
`Increased ALT
`16
`0
`5
`1.6
`
`
`
`Hyperkalemia
`0
`6
`2.0
`15
`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).
`
`
`
`
`
` Immunogenicity
`6.2
`
`As with all therapeutic proteins, there is a potential for immunogenicity.
` Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the
`
`presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent
`anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies
`were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile
`or toxicity profile with anti-product binding antibody development based on the population
`pharmacokinetic and exposure-response analyses.
`The detection of antibody formation is highly dependent on the sensitivity and specificity of the
`
`assay. Additionally, the observed incidence of antibody (including neutralizing antibody)
`positivity in an assay may be influenced by several factors including assay methodology, sample
`handling, timing of sample collection, concomitant medications, and underlying disease. For
`
`these reasons, comparison of incidence of antibodies to OPDIVO with the incidences of
`
`antibodies to other products may be misleading.
`
`7
`DRUG INTERACTIONS
`
`No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`Risk Summary
`
`Based on its mechanism of action [see Clinical Pharmacology (12.1)] and data from animal
`studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical
`Pharmacology (12.1)]. In animal reproduction studies, administration of nivolumab to
`
`Reference ID: 3677021
`
`10
`
`
`Ex. 1112-0010
`
`

`
`
`
`cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased
`abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental
`barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential
`
`to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to
`
`be greater during the second and third trimesters of pregnancy. There are no available human
`
`data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
`The background risk of major birth defects and miscarriage for the indicated population is
`unknown; however, the background risk in the U.S. general population of major birth defects is
`2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
`Data
`Animal Data
`A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal
`
`immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models
`of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab
`on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice
`weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and
`42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on
`AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion
`and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab
`may increase the risk of developing immune-mediated disorders or altering the normal immune
`
`response and immune-mediated disorders have been reported in PD-1 knockout mice. In
`surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus
`monkeys treated with nivolumab, there were no apparent malformations and no effects on
`neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month
`postnatal period.
`
`Lactation
`8.2
`Risk Summary
`It is not known whether OPDIVO is present in human milk. Because many drugs, including
`antibodies are excreted in human milk and because of the potential for serious adverse reactions
`in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment
`with OPDIVO.
`
`Females and Males of Reproductive Potential
`8.3
`Contraception
`Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a
`pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive
`potential to use effective contraception during treatment with OPDIVO and for at least 5 months
`
`following the last dose of OPDIVO.
`
`Reference ID: 3677021
`
`11
`
`
`Ex. 1112-0011
`
`

`
`
`
`Pediatric Use
`8.4
`The safety and effectiveness of OPDIVO have not been established in pediatric patients.
`
`Geriatric Use
`8.5
`Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and
`older to determine whether they respond differently from younger patients. Of the 272 patients
`randomized to OPDIVO in Trial 1, 35% of patients were 65 years or older and 15% were
`75 years or older.
`
`Renal Impairment
`8.6
`Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients
`
`with renal impairment [see Clinical Pharmacology (12.3)].
`
`Hepatic Impairment
`8.7
`
`Based on a population pharmacokinetic analysis, no dose adjustment is recommended for
`patients with mild hepatic impairment. OPDIVO has not been studied in patients with moderate
`or severe hepatic impairment [see Clinical Pharmacology (12.3)].
`
`OVERDOSAGE
`10
`There is no information on overdosage with OPDIVO.
`
`DESCRIPTION
`11
`Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its
`ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated
`molecular mass of 146 kDa.
`OPDIVO is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to pale-
`yellow liquid that may contain light (few) particles. OPDIVO injection for intravenous infusion
`
`is supplied in single-use vials. Each mL of OPDIVO solution contains nivolumab 10 mg,
`mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 (0.2 mg), sodium chloride (2.92 mg),
`sodium citrate dihydrate (5.88 mg), and Water for Injection, USP. May contain hydrochloric acid
`and/or sodium hydroxide to adjust pH to 6.
`
`12
`
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`12.1
`Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 recept