HIGHLIGHTS OF PRESCRIBING INFORMATION

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not inlude ll the informtion needed to use sfely nd effetively. See full presriing informtion for. (nivolum) injetion, for intrvenous use Initil U.S. Approvl: RECENT MAJOR CHANGES Inditions nd Usge (1) 8/2018 Dosge nd Administrtion (2) 8/2018 Wrnings nd Preutions (5) 7/2018 Wrnings nd Preutions (5.10) 11/ INDICATIONS AND USAGE is progrmmed deth reeptor-1 (PD-1) loking ntiody indited for the tretment of: ptients with BRAF V600 wild-type unresetle or metstti melnom, s single gent. (1.1) ptients with BRAF V600 muttion-positive unresetle or metstti melnom, s single gent. (1.1) ptients with unresetle or metstti melnom, in omintion with ipilimum. (1.1) ptients with melnom with lymph node involvement or metstti disese who hve undergone omplete resetion, in the djuvnt setting. (1.2) ptients with metstti non-smll ell lung ner nd progression on or fter pltinum-sed hemotherpy. Ptients with EGFR or ALK genomi tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to reeiving. (1.3) ptients with metstti smll ell lung ner with progression fter pltinumsed hemotherpy nd t lest one other line of therpy. (1.4) ptients with dvned renl ell rinom who hve reeived prior ntingiogeni therpy. (1.5) ptients with intermedite or poor risk, previously untreted dvned renl ell rinom, in omintion with ipilimum. (1.5) dult ptients with lssil Hodgkin lymphom tht hs relpsed or progressed fter : (1.6) utologous hemtopoieti stem ell trnsplnttion (HSCT) nd rentuxim vedotin, or 3 or more lines of systemi therpy tht inludes utologous HSCT. ptients with reurrent or metstti squmous ell rinom of the hed nd nek with disese progression on or fter pltinum-sed therpy. (1.7) ptients with lolly dvned or metstti urothelil rinom who : hve disese progression during or following pltinum-ontining hemotherpy hve disese progression within 12 months of neodjuvnt or djuvnt tretment with pltinum-ontining hemotherpy. (1.8) dult nd peditri (12 yers nd older) ptients with mirostellite instility-high (MSI-H) or mismth repir defiient (dmmr) metstti oloretl ner tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinoten, s single gent or in omintion with ipilimum. (1.9) ptients with heptoellulr rinom who hve een previously treted with sorfeni. (1.10) This indition is pproved under elerted pprovl sed on progression-free survivl. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in the onfirmtory trils. This indition is pproved under elerted pprovl sed on overll response rte nd durtion of response. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in onfirmtory trils DOSAGE AND ADMINISTRATION Administer s n intrvenous infusion over 30 minutes. Unresetle or metstti melnom 240 mg every 2 weeks or 480 mg every 4 weeks. (2.1) 1 mg/kg, followed y ipilimum on the sme dy, every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.1) Adjuvnt tretment of melnom 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) Metstti non-smll ell lung ner 240 mg every 2 weeks or 480 mg every 4 weeks. (2.3) Smll ell lung ner 240 mg every 2 weeks. (2.4) Advned renl ell rinom 240 mg every 2 weeks or 480 mg every 4 weeks. (2.5) 3 mg/kg followed y ipilimum 1 mg/kg on the sme dy every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.5) Clssil Hodgkin lymphom (nivolum) 240 mg every 2 weeks or 480 mg every 4 weeks. (2.6) Reurrent or metstti squmous ell rinom of the hed nd nek 240 mg every 2 weeks or 480 mg every 4 weeks. (2.7) Lolly dvned or metstti urothelil rinom 240 mg every 2 weeks or 480 mg every 4 weeks. (2.8) Mirostellite instility-high (MSI-H) or mismth repir defiient (dmmr) metstti oloretl ner 240 mg every 2 weeks. (2.9) 3 mg/kg followed y ipilimum 1 mg/kg on the sme dy every 3 weeks for 4 doses, then 240 mg every 2 weeks. (2.9) Heptoellulr rinom 240 mg every 2 weeks or 480 mg every 4 weeks. (2.10) DOSAGE FORMS AND STRENGTHS Injetion: 40 mg/4 ml, 100 mg/10 ml, nd 240 mg/24 ml solution in single-dose vil. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Immune-medited pneumonitis: Withhold for moderte nd permnently disontinue for severe or life-thretening pneumonitis. (5.1) Immune-medited olitis: Withhold when given s single gent for moderte or severe nd permnently disontinue for life-thretening olitis. Withhold when given with ipilimum for moderte nd permnently disontinue for severe or life-thretening olitis. (5.2) Immune-medited heptitis: Monitor for hnges in liver funtion. Withhold for moderte nd permnently disontinue for severe or life-thretening trnsminse or totl iliruin elevtion. (5.3) Immune-medited endorinopthies: Withhold for moderte or severe nd permnently disontinue for life-thretening hypophysitis. Withhold for moderte nd permnently disontinue for severe or life-thretening drenl insuffiieny. Monitor for hnges in thyroid funtion. Initite thyroid hormone replement s needed. Monitor for hyperglyemi. Withhold for severe nd permnently disontinue for life-thretening hyperglyemi. (5.4) Immune-medited nephritis nd renl dysfuntion: Monitor for hnges in renl funtion. Withhold for moderte or severe nd permnently disontinue for life-thretening serum retinine elevtion. (5.5) Immune-medited skin dverse retions: Withhold for severe nd permnently disontinue for life-thretening rsh. (5.6) Immune-medited enephlitis: Monitor for hnges in neurologi funtion. Withhold for new-onset moderte to severe neurologil signs or symptoms nd permnently disontinue for immune-medited enephlitis. (5.7) Infusion retions: Disontinue for severe nd life-thretening infusion retions. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion retions. (5.9) Complitions of llogenei HSCT: Monitor for hyperute, ute, nd hroni grftversus-host-disese (GVHD), hepti veno-olusive disese, nd steroid-requiring ferile syndrome. (5.10) Emryo-Fetl toxiity: Cn use fetl hrm. Advise of potentil risk to fetus nd use of effetive ontreption. (5.11, 8.1, 8.3) ADVERSE REACTIONS Most ommon dverse retions ( 20%) in ptients were: s single gent: ftigue, rsh, musuloskeletl pin, pruritus, dirrhe, nuse, stheni, ough, dyspne, onstiption, deresed ppetite, k pin, rthrlgi, upper respirtory trt infetion, pyrexi, hedhe, nd dominl pin. (6.1) Most ommon dverse retions ( 20%) with in omintion with ipilimum re ftigue, rsh, dirrhe, nuse, pyrexi, musuloskeletl pin, pruritus, dominl pin, vomiting, ough, rthrlgi, deresed ppetite, dyspne. (6.1) To report SUSPECTED ADVERSE REACTIONS, ontt Bristol-Myers Squi t or FDA t FDA-1088 or USE IN SPECIFIC POPULATIONS Lttion: Disontinue restfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Medition Guide. Revised: 11/2018

2 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresetle or Metstti Melnom 1.2 Adjuvnt Tretment of Melnom 1.3 Metstti Non-Smll Cell Lung Cner 1.4 Smll Cell Lung Cner 1.5 Advned Renl Cell Crinom 1.6 Clssil Hodgkin Lymphom 1.7 Squmous Cell Crinom of the Hed nd Nek 1.8 Urothelil Crinom 1.9 Mirostellite Instility-High (MSI-H) or Mismth Repir Defiient (dmmr) Metstti Coloretl Cner 1.10 Heptoellulr Crinom 2 DOSAGE AND ADMINISTRATION 2.1 Reommended Dosge for Unresetle or Metstti Melnom 2.2 Reommended Dosge for Adjuvnt Tretment of Melnom 2.3 Reommended Dosge for NSCLC 2.4 Reommended Dosge for SCLC 2.5 Reommended Dosge for RCC 2.6 Reommended Dosge for HL 2.7 Reommended Dosge for SCCHN 2.8 Reommended Dosge for Urothelil Crinom 2.9 Reommended Dosge for MSI-H/dMMR CRC 2.10 Reommended Dosge for HCC 2.11 Dose Modifitions 2.12 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis 5.2 Immune-Medited Colitis 5.3 Immune-Medited Heptitis 5.4 Immune-Medited Endorinopthies 5.5 Immune-Medited Nephritis nd Renl Dysfuntion 5.6 Immune-Medited Skin Adverse Retions 5.7 Immune-Medited Enephlitis 5.8 Other Immune-Medited Adverse Retions 5.9 Infusion Retions 5.10 Complitions of ogenei Hemtopoieti Stem Cell Trnsplnttion 5.11 Emryo-Fetl Toxiity 6 ADVERSE REACTIONS 6.1 Clinil Trils Experiene 6.2 Postmrketing Experiene 6.3 Immunogeniity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnny 8.2 Lttion 8.3 Femles nd Mles of Reprodutive Potentil 8.4 Peditri Use 8.5 Geritri Use 8.6 Renl Impirment 8.7 Hepti Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mehnism of Ation 12.3 Phrmokinetis 13 NONCLINICAL TOXICOLOGY 13.1 Crinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxiology nd/or Phrmology 14 CLINICAL STUDIES 14.1 Unresetle or Metstti Melnom 14.2 Adjuvnt Tretment of Melnom 14.3 Metstti Non-Smll Cell Lung Cner (NSCLC) 14.4 Smll Cell Lung Cner 14.5 Advned Renl Cell Crinom 14.6 Clssil Hodgkin Lymphom 14.7 Reurrent or Metstti Squmous Cell Crinom of the Hed nd Nek (SCCHN) 14.8 Urothelil Crinom 14.9 Mirostellite Instility-High (MSI-H) or Mismth Repir Defiient (dmmr) Metstti Coloretl Cner Heptoellulr Crinom 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Setions or susetions omitted from the full presriing informtion re not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresetle or Metstti Melnom (nivolum) s single gent is indited for the tretment of ptients with BRAF V600 wild-type unresetle or metstti melnom [see Clinil Studies (14.1)]. s single gent is indited for the tretment of ptients with BRAF V600 muttion-positive unresetle or metstti melnom [see Clinil Studies (14.1)]. This indition is pproved under elerted pprovl sed on progression-free survivl. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in the onfirmtory trils., in omintion with ipilimum, is indited for the tretment of ptients with unresetle or metstti melnom [see Clinil Studies (14.1)]. This indition is pproved under elerted pprovl sed on progression-free survivl. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in the onfirmtory trils. 1.2 Adjuvnt Tretment of Melnom is indited for the djuvnt tretment of ptients with melnom with involvement of lymph nodes or metstti disese who hve undergone omplete resetion [see Clinil Studies (14.2)]. 1.3 Metstti Non-Smll Cell Lung Cner is indited for the tretment of ptients with metstti non-smll ell lung ner (NSCLC) with progression on or fter pltinum-sed hemotherpy. Ptients with EGFR or ALK genomi tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to reeiving [see Clinil Studies (14.3)]. 1.4 Smll Cell Lung Cner (nivolum) is indited for the tretment of ptients with metstti smll ell lung ner (SCLC) with progression fter pltinum-sed hemotherpy nd t lest one other line of therpy [see Clinil Studies (14.4)]. This indition is pproved under elerted pprovl sed on overll response rte nd durtion of response. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in onfirmtory trils. 1.5 Advned Renl Cell Crinom s single gent is indited for the tretment of ptients with dvned renl ell rinom (RCC) who hve reeived prior nti-ngiogeni therpy [see Clinil Studies (14.5)]., in omintion with ipilimum, is indited for the tretment of ptients with intermedite or poor risk, previously untreted dvned renl ell rinom (RCC) [see Clinil Studies (14.5)]. 1.6 Clssil Hodgkin Lymphom is indited for the tretment of dult ptients with lssil Hodgkin lymphom (HL) tht hs relpsed or progressed fter: utologous hemtopoieti stem ell trnsplnttion (HSCT) nd rentuxim vedotin, or 3 or more lines of systemi therpy tht inludes utologous HSCT. This indition is pproved under elerted pprovl sed on overll response rte. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in onfirmtory trils [see Clinil Studies (14.6)]. 1.7 Squmous Cell Crinom of the Hed nd Nek is indited for the tretment of ptients with reurrent or metstti squmous ell rinom of the hed nd nek (SCCHN) with disese progression on or fter pltinum-sed therpy [see Clinil Studies (14.7)].

3 (nivolum) (nivolum) 1.8 Urothelil Crinom (nivolum) is indited for the tretment of ptients with lolly dvned or metstti urothelil rinom who: hve disese progression during or following pltinum-ontining hemotherpy hve disese progression within 12 months of neodjuvnt or djuvnt tretment with pltinum-ontining hemotherpy. This indition is pproved under elerted pprovl sed on tumor response rte nd durtion of response. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in onfirmtory trils [see Clinil Studies (14.8)]. 1.9 Mirostellite Instility-High (MSI-H) or Mismth Repir Defiient (dmmr) Metstti Coloretl Cner, s single gent, is indited for the tretment of dult nd peditri ptients 12 yers nd older with mirostellite instility-high (MSI-H) or mismth repir defiient (dmmr) metstti oloretl ner (CRC) tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinoten [see Clinil Studies (14.9)]., in omintion with ipilimum, is indited for the tretment of dults nd peditri ptients 12 yers nd older with MSI-H or dmmr metstti CRC tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinoten [see Clinil Studies (14.9)]. These inditions re pproved under elerted pprovl sed on overll response rte nd durtion of response. Continued pprovl for these inditions my e ontingent upon verifition nd desription of linil enefit in onfirmtory trils Heptoellulr Crinom is indited for the tretment of ptients with heptoellulr rinom (HCC) who hve een previously treted with sorfeni. This indition is pproved under elerted pprovl sed on tumor response rte nd durility of response. Continued pprovl for this indition my e ontingent upon verifition nd desription of linil enefit in the onfirmtory trils [see Clinil Studies (14.10)]. 2 DOSAGE AND ADMINISTRATION 2.1 Reommended Dosge for Unresetle or Metstti Melnom Single Agent The reommended dose of s single gent is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. With Ipilimum The reommended dose of is 1 mg/kg dministered s n intrvenous infusion over 30 minutes, followed y ipilimum 3 mg/kg dministered s n intrvenous infusion over 90 minutes on the sme dy, every 3 weeks for mximum of 4 doses or until uneptle toxiity, whihever ours erlier. After ompleting 4 doses of the omintion, dminister s single gent, either: 240 mg every 2 weeks or 480 mg every 4 weeks s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. Review the Presriing Informtion for ipilimum for dditionl informtion prior to initition. 2.2 Reommended Dosge for Adjuvnt Tretment of Melnom The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese reurrene or uneptle toxiity for up to 1 yer. 2.3 Reommended Dosge for NSCLC The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. 2.4 Reommended Dosge for SCLC The reommended dose of is: 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uneptle toxiity. 2.5 Reommended Dosge for RCC Single Agent The reommended dose of s single gent is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. With Ipilimum The reommended dose of is 3 mg/kg dministered s n intrvenous infusion over 30 minutes, followed y ipilimum 1 mg/kg dministered s n intrvenous infusion over 30 minutes on the sme dy, every 3 weeks for 4 doses [see Clinil Studies (14.5)]. After ompleting 4 doses of the omintion, dminister s single gent, either: 240 mg every 2 weeks, or 480 mg every 4 weeks s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. Review the Presriing Informtion for ipilimum prior to initition. 2.6 Reommended Dosge for HL The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. 2.7 Reommended Dosge for SCCHN The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. 2.8 Reommended Dosge for Urothelil Crinom The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. 2.9 Reommended Dosge for MSI-H/dMMR CRC Single Agent The reommended dose of s single gent is 240 mg every 2 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. With Ipilimum The reommended dose of is 3 mg/kg dministered s n intrvenous infusion over 30 minutes, followed y ipilimum 1 mg/kg dministered s n intrvenous infusion over 30 minutes on the sme dy, every 3 weeks for 4 doses [see Clinil Studies (14.9)]. After ompleting 4 doses of the omintion, dminister 240 mg s single gent every 2 weeks s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity. Review the Presriing Informtion for ipilimum prior to initition Reommended Dosge for HCC The reommended dose of is either: 240 mg every 2 weeks or 480 mg every 4 weeks dministered s n intrvenous infusion over 30 minutes until disese progression or uneptle toxiity Dose Modifitions Reommendtions for modifitions re provided in Tle 1. When is dministered in omintion with ipilimum, if is withheld, ipilimum should lso e withheld. Review the Presriing Informtion for ipilimum for reommended dose modifitions.

4 (nivolum) There re no reommended dose modifitions for hypothyroidism or hyperthyroidism. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion retions. Disontinue in ptients with severe or life-thretening infusion retions. Tle 1: Reommended Dose Modifitions for Adverse Retion Severity* Dose Modifition Colitis Pneumonitis Heptitis/non-HCC Heptitis/HCC Hypophysitis Adrenl Insuffiieny Type 1 Dietes Mellitus Nephritis nd Renl Dysfuntion Skin Grde 2 dirrhe or olitis Grde 3 dirrhe or olitis Grde 4 dirrhe or olitis Grde 2 pneumonitis Grde 3 or 4 pneumonitis Asprtte minotrnsferse (AST) or lnine minotrnsferse (ALT) more thn 3 nd up to 5 times the upper limit of norml (ULN) or totl iliruin more thn 1.5 nd up to 3 times the ULN AST or ALT more thn 5 times the ULN or totl iliruin more thn 3 times the ULN If AST/ALT is within norml limits t seline nd inreses to more thn 3 nd up to 5 times the ULN If AST/ALT is more thn 1 nd up to 3 times ULN t seline nd inreses to more thn 5 nd up to 10 times the ULN If AST/ALT is more thn 3 nd up to 5 times ULN t seline nd inreses to more thn 8 nd up to 10 times the ULN If AST or ALT inreses to more thn 10 times the ULN or totl iliruin inreses to more thn 3 times the ULN Grde 2 or 3 hypophysitis Grde 4 hypophysitis Grde 2 drenl insuffiieny Grde 3 or 4 drenl insuffiieny Grde 3 hyperglyemi Grde 4 hyperglyemi Serum retinine more thn 1.5 nd up to 6 times the ULN Serum retinine more thn 6 times the ULN Grde 3 rsh or suspeted Stevens-Johnson syndrome (SJS) or toxi epiderml nerolysis (TEN) Grde 4 rsh or onfirmed SJS or TEN Withhold dose Withhold dose when dministered s single gent Permnently disontinue when dministered with ipilimum Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue Withhold dose Permnently disontinue (Continued) (nivolum) Tle 1: Reommended Dose Modifitions for (Continued) Adverse Retion Severity* Dose Modifition Enephlitis Other New-onset moderte or severe neurologi signs or symptoms Immune-medited enephlitis Other Grde 3 dverse retion First ourrene Reurrene of sme Grde 3 dverse retions Life-thretening or Grde 4 dverse retion Grde 3 myorditis Requirement for 10 mg per dy or greter prednisone or equivlent for more thn 12 weeks Persistent Grde 2 or 3 dverse retions lsting 12 weeks or longer Withhold dose Permnently disontinue Withhold dose Permnently disontinue Permnently disontinue Permnently disontinue Permnently disontinue Permnently disontinue * Toxiity ws grded per Ntionl Cner Institute Common Terminology Criteri for Adverse Events. Version 4.0 (NCI CTCAE v4). Resume tretment when dverse retion improves to Grde 0 or 1. HCC: heptoellulr rinom. Resume tretment when AST/ALT returns to seline Preprtion nd Administrtion Visully inspet drug produt solution for prtiulte mtter nd disolortion prior to dministrtion. is ler to oplesent, olorless to ple-yellow solution. Disrd the vil if the solution is loudy, disolored, or ontins extrneous prtiulte mtter other thn few trnsluent-to-white, proteineous prtiles. Do not shke the vil. Preprtion Withdrw the required volume of nd trnsfer into n intrvenous ontiner. Dilute with either 0.9% Sodium Chloride Injetion, USP or 5% Dextrose Injetion, USP to prepre n infusion with finl onentrtion rnging from 1 mg/ml to 10 mg/ml. The totl volume of infusion must not exeed 160 ml. For dult nd peditri ptients with ody weights less thn 40 kg, the totl volume of infusion must not exeed 4 ml/kg of ody weight. Mix diluted solution y gentle inversion. Do not shke. Disrd prtilly used vils or empty vils of. Storge of Infusion The produt does not ontin preservtive. After preprtion, store the infusion either: t room temperture for no more thn 8 hours from the time of preprtion. This inludes room temperture storge of the infusion in the IV ontiner nd time for dministrtion of the infusion or under refrigertion t 2 C to 8 C (36 F to 46 F) for no more thn 24 hours from the time of infusion preprtion. Do not freeze. Administrtion Administer the infusion over 30 minutes through n intrvenous line ontining sterile, non-pyrogeni, low protein inding in-line filter (pore size of 0.2 mirometer to 1.2 mirometer). Do not odminister other drugs through the sme intrvenous line. Flush the intrvenous line t end of infusion. When dministered in omintion with ipilimum, infuse first followed y ipilimum on the sme dy. Use seprte infusion gs nd filters for eh infusion. 3 DOSAGE FORMS AND STRENGTHS Injetion: 40 mg/4 ml (10 mg/ml), 100 mg/10 ml (10 mg/ml), nd 240 mg/24 ml (10 mg/ml) ler to oplesent, olorless to ple-yellow solution in single-dose vil. 4 CONTRAINDICATIONS None.

5 (nivolum) (nivolum) 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis n use immune-medited pneumonitis, defined s requiring use of ortiosteroids nd no ler lternte etiology. Ftl ses hve een reported. Monitor ptients for signs with rdiogrphi imging nd for symptoms of pneumonitis. Administer ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for moderte (Grde 2) or more severe (Grde ) pneumonitis, followed y ortiosteroid tper. Permnently disontinue for severe (Grde 3) or life-thretening (Grde 4) pneumonitis nd withhold until resolution for moderte (Grde 2) pneumonitis [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, immune-medited pneumonitis ourred in 3.1% (61/1994) of ptients. The medin time to onset of immune-medited pneumonitis ws 3.5 months (rnge: 1 dy to 22.3 months). Immune-medited pneumonitis led to permnent disontinution of in 1.1%, nd withholding of in 1.3% of ptients. Approximtely 89% of ptients with pneumonitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 26 dys (rnge: 1 dy to 6 months). Complete resolution of symptoms following ortiosteroid tper ourred in 67% of ptients. Approximtely 8% of ptients hd reurrene of pneumonitis fter re-initition of. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Immune-medited pneumonitis ourred in 6% (25/407) of ptients with melnom who reeived 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 1.6 months (rnge: 24 dys to 10.1 months). Immune-medited pneumonitis led to permnent disontinution or withholding of with ipilimum in 2.2% nd 3.7% of ptients, respetively. Approximtely 84% of ptients with pneumonitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 30 dys (rnge: 5 dys to 11.8 months). Complete resolution ourred in 68% of ptients. Approximtely 13% of ptients hd reurrene of pneumonitis fter re-initition of with ipilimum. 3 mg/kg with Ipilimum 1 mg/kg Immune-medited pneumonitis ourred in 4.4% (24/547) of ptients with RCC nd 1.7% (2/119) of ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset of immune-medited pneumonitis ws 2.6 months (rnge: 8 dys to 9.2 months) in ptients with RCC nd 1.9 months (rnge: 27 dys to 3 months) in ptients with CRC. Immune-medited pneumonitis led to permnent disontinution of with ipilimum in 1.8% of ptients with RCC or CRC (n=666) nd withholding of with ipilimum in 1.7%. ptients with pneumonitis required systemi ortiosteroids, inluding 92% who reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 19 dys (rnge: 4 dys to 3.2 months). Approximtely 8% required ddition of inflixim to high-dose ortiosteroids. Complete resolution of pneumonitis ourred in 81% of ptients. Pneumonitis reurred fter re-initition of with ipilimum in one ptient with CRC. 5.2 Immune-Medited Colitis n use immune-medited olitis, defined s requiring use of ortiosteroids with no ler lternte etiology. Monitor ptients for signs nd symptoms of olitis. Administer ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for severe (Grde 3) or life-thretening (Grde 4) olitis. Administer ortiosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for moderte (Grde 2) olitis of more thn 5 dys durtion; if worsening or no improvement ours despite initition of ortiosteroids, inrese dose to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte or severe (Grde 2 or 3) olitis. Permnently disontinue for life-thretening (Grde 4) or for reurrent olitis upon re-initition of [see Dosge nd Administrtion (2.11)]. When dministered in omintion with ipilimum, withhold nd ipilimum for moderte olitis (Grde 2). Permnently disontinue nd ipilimum for severe or life-thretening (Grde 3 or 4) olitis or for reurrent olitis [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, immune-medited olitis ourred in 2.9% (58/1994) of ptients; the medin time to onset ws 5.3 months (rnge: 2 dys to 20.9 months). Immune-medited olitis led to permnent disontinution of in 0.7% nd withholding of in 1% of ptients. Approximtely 91% of ptients with olitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 23 dys (rnge: 1 dy to 9.3 months). Four ptients required ddition of inflixim to high-dose ortiosteroids. Complete resolution ourred in 74% of ptients. Approximtely 16% of ptients hd reurrene of olitis fter re-initition of. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Immune-medited olitis ourred in 26% (107/407) of ptients with melnom who reeived 1 mg/kg with ipilimum 3 mg/kg every 3 weeks, inluding three ftl ses. Medin time to onset ws 1.6 months (rnge: 3 dys to 15.2 months). Immunemedited olitis led to permnent disontinution or withholding of with ipilimum in 16% nd 7% of ptients, respetively. Approximtely 96% of ptients with olitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 12 months). Approximtely 23% of ptients required ddition of inflixim to high-dose ortiosteroids. Complete resolution ourred in 75% of ptients. Approximtely 28% of ptients hd reurrene of olitis fter re-initition of with ipilimum. 3 mg/kg with Ipilimum 1 mg/kg Immune-medited olitis ourred in 10% (52/547) of ptients with RCC nd 7% (8/119) of ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset of immune-medited olitis ws 1.7 months (rnge: 2 dys to 19.2 months) in ptients with RCC nd 2.4 months (rnge: 22 dys to 5.2 months) in ptients with mcrc. Immune-medited olitis led to permnent disontinution of with ipilimum in 3.2% of ptients with RCC or CRC (n=666) nd withholding of with ipilimum in 3.9%. ptients with olitis required systemi ortiosteroids, inluding 80% who reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 21 dys (rnge: 1 dy to 27 months). Approximtely 23% of ptients with immune-medited olitis required ddition of inflixim to high-dose ortiosteroids. Complete resolution ourred in 88% of ptients. Two ptients with RCC hd reurrene of olitis fter re-initition of with ipilimum. 5.3 Immune-Medited Heptitis n use immune-medited heptitis, defined s requiring use of ortiosteroids nd no ler lternte etiology. Monitor ptients for norml liver tests prior to nd periodilly during tretment. Administer ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for severe (Grde 3) or life-thretening (Grde 4) trnsminse elevtions, with or without onomitnt elevtion in totl iliruin. Administer ortiosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) trnsminse elevtions. For ptients without heptoellulr rinom (HCC): withhold for moderte (Grde 2) immune-medited heptitis nd permnently disontinue for severe (Grde 3) or life-thretening (Grde 4) immune-medited heptitis [see Dosge nd Administrtion (2.11)]. For ptients with HCC, permnently disontinue, withhold, or ontinue sed on severity of immune-medited heptitis nd seline AST nd ALT levels s desried in Tle 1 [see Dosge nd Administrtion (2.11)]. In ddition, dminister ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper when is withheld or disontinued due to immune-medited heptitis. s Single Agent In ptients reeiving s single gent, immune-medited heptitis ourred in 1.8% (35/1994) of ptients; the medin time to onset ws 3.3 months (rnge: 6 dys to 9 months). Immune-medited heptitis led to permnent disontinution of in 0.7% nd withholding of in 1% of ptients. ptients with heptitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 23 dys (rnge: 1 dy to 2 months). Two ptients required the ddition of myophenoli id to high-dose ortiosteroids. Complete resolution ourred in 74% of ptients. Approximtely 29% of ptients hd reurrene of heptitis fter re-initition of. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Immune-medited heptitis ourred in 13% (51/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 2.1 months (rnge: 15 dys to 11 months). Immune-medited heptitis led to permnent disontinution or withholding of with ipilimum in 6% nd 5% of ptients, respetively. Approximtely 92% of ptients with heptitis reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 13.2 months). Complete resolution ourred in 75% of ptients. Approximtely 11% of ptients hd reurrene of heptitis fter re-initition of with ipilimum. 3 mg/kg with Ipilimum 1 mg/kg Immune-medited heptitis ourred in 7% (38/547) of ptients with RCC nd 8% (10/119) with CRC reeiving 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 2 months (rnge: 14 dys to 26.8 months) in ptients with RCC nd 2.2 months (rnge: 22 dys to 10.5 months) in ptients with CRC.

6 (nivolum) Immune-medited heptitis led to permnent disontinution of with ipilimum in 3.6% of ptients with RCC or CRC (n=666) nd withholding of nd ipilimum in 3.5%. ptients with heptitis required systemi ortiosteroids, inluding 94% who reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1 month (rnge: 1 dy to 7 months). Approximtely 19% of ptients with immune-medited heptitis required ddition of myophenoli id to high-dose ortiosteroids. Complete resolution ourred in 83% of ptients. No ptients hd reurrene of heptitis fter re-initition of with ipilimum. 5.4 Immune-Medited Endorinopthies Hypophysitis n use immune-medited hypophysitis. Monitor ptients for signs nd symptoms of hypophysitis. Administer hormone replement s linilly indited nd ortiosteroids t dose of 1 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for moderte (Grde 2) or greter hypophysitis. Withhold for moderte (Grde 2) or severe (Grde 3). Permnently disontinue for life-thretening (Grde 4) hypophysitis [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, hypophysitis ourred in 0.6% (12/1994) of ptients; the medin time to onset ws 4.9 months (rnge: 1.4 to 11 months). Hypophysitis led to permnent disontinution of in 0.1% nd withholding of in 0.2% of ptients. Approximtely 67% of ptients with hypophysitis reeived hormone replement therpy nd 33% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 5 to 26 dys). with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Hypophysitis ourred in 9% (36/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 2.7 months (rnge: 27 dys to 5.5 months). Hypophysitis led to permnent disontinution or withholding of with ipilimum in 1.0% nd 3.9% of ptients, respetively. Approximtely 75% of ptients with hypophysitis reeived hormone replement therpy nd 56% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 19 dys (rnge: 1 dy to 2.0 months). 3 mg/kg with Ipilimum 1 mg/kg Hypophysitis ourred in 4.6% (25/547) of ptients with RCC nd 3.4% (4/119) of ptients with CRC reeiving 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 2.8 months (rnge: 1.3 months to 7.3 months) in ptients with RCC nd 3.7 months (rnge: 2.8 to 5.5 months) in ptients with CRC. Hypophysitis led to permnent disontinution or withholding of with ipilimum in 1.2% nd 2.6% of ptients with RCC or CRC (n=666), respetively. Approximtely 72% of ptients with hypophysitis reeived hormone replement therpy nd 55% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 13 dys (rnge: 1 dy to 1.6 months). Adrenl Insuffiieny n use immune-medited drenl insuffiieny. Monitor ptients for signs nd symptoms of drenl insuffiieny. Administer ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for severe (Grde 3) or life-thretening (Grde 4) drenl insuffiieny. Withhold for moderte (Grde 2) nd permnently disontinue for severe (Grde 3) or life-thretening (Grde 4) drenl insuffiieny [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, drenl insuffiieny ourred in 1% (20/1994) of ptients nd the medin time to onset ws 4.3 months (rnge: 15 dys to 21 months). Adrenl insuffiieny led to permnent disontinution of in 0.1% nd withholding of in 0.5% of ptients. Approximtely 85% of ptients with drenl insuffiieny reeived hormone replement therpy nd 25% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 11 dys (rnge: 1 dy to 1 month). with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Adrenl insuffiieny ourred in 5% (21/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 3.0 months (rnge: 21 dys to 9.4 months). Adrenl insuffiieny led to permnent disontinution or withholding of with ipilimum in 0.5% nd 1.7% of ptients, respetively. Approximtely 57% of ptients with drenl insuffiieny reeived hormone replement therpy nd 33% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 9 dys (rnge: 1 dy to 2.7 months). 3 mg/kg with Ipilimum 1 mg/kg (nivolum) Adrenl insuffiieny ourred in 7% (41/547) of ptients with RCC nd 5.9% (7/119) ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 3.4 months (rnge: 2.0 months to 22.3 months) in RCC nd 3.7 months (rnge: 2.5 to 13.4 months) in CRC. Adrenl insuffiieny led to permnent disontinution of nd ipilimum in 1.2% of ptients with RCC or CRC (n=666) nd withholding of nd ipilimum in 2.6%. Approximtely 94% of ptients with drenl insuffiieny reeived hormone replement therpy nd 27% reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 12 dys (rnge: 2 dys to 5.6 months). Hypothyroidism nd Hyperthyroidism n use utoimmune thyroid disorders. Monitor thyroid funtion prior to nd periodilly during tretment. Administer hormone-replement therpy for hypothyroidism. Initite medil mngement for ontrol of hyperthyroidism. There re no reommended dose djustments of for hypothyroidism or hyperthyroidism. s Single Agent In ptients reeiving s single gent, hypothyroidism or thyroiditis resulting in hypothyroidism ourred in 9% (171/1994) of ptients; the medin time to onset ws 2.9 months (rnge: 1 dy to 16.6 months). Approximtely 79% of ptients with hypothyroidism reeived levothyroxine nd 4% lso required ortiosteroids. Resolution ourred in 35% of ptients. Hyperthyroidism ourred in 2.7% (54/1994) of ptients reeiving s single gent; the medin time to onset ws 1.5 months (rnge: 1 dy to 14.2 months). Approximtely 26% of ptients with hyperthyroidism reeived methimzole, 9% reeived rimzole, 4% reeived propylthiouril, nd 9% reeived ortiosteroids. Resolution ourred in 76% of ptients. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Hypothyroidism or thyroiditis resulting in hypothyroidism ourred in 22% (89/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 2.1 months (rnge: 1 dy to 10.1 months). Approximtely 73% of ptients with hypothyroidism or thyroiditis reeived levothyroxine. Resolution ourred in 45% of ptients. Hyperthyroidism ourred in 8% (34/407) of ptients with melnom who reeived with ipilimum; the medin time to onset ws 23 dys (rnge: 3 dys to 3.7 months). Approximtely 29% of ptients with hyperthyroidism reeived methimzole nd 24% reeived rimzole. Resolution ourred in 94% of ptients. 3 mg/kg with Ipilimum 1 mg/kg Hypothyroidism or thyroiditis resulting in hypothyroidism ourred in 22% (119/547) of ptients with RCC nd 15% (18/119) of ptients with CRC who reeived 3 mg/kg nd ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 2.2 months (rnge: 1 dy to 21.4 months) in ptients with RCC nd 2.3 months (rnge: 22 dys to 9.8 months) in ptients with CRC. Of the 137 ptients with RCC or CRC who developed hypothyroidism, pproximtely 81% of ptients with RCC nd 78% with CRC reeived levothyroxine. Hyperthyroidism ourred in 12% (66/547) of ptients with RCC nd 12% (14/119) of ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 1.4 months (rnge: 6 dys to 14.2 months) in RCC nd 1.1 months (rnge: 21 dys to 5.4 months) in CRC. Of the 80 ptients with RCC or CRC who developed hyperthyroidism, pproximtely 15% reeived methimzole nd 2% reeived rimzole. Type 1 Dietes Mellitus n use Type 1 dietes mellitus. Monitor for hyperglyemi. Withhold in ses of severe (Grde 3) hyperglyemi until metoli ontrol is hieved. Permnently disontinue for life-thretening (Grde 4) hyperglyemi [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, dietes ourred in 0.9% (17/1994) of ptients inluding two ses of dieti ketoidosis. Medin time to onset ws 4.4 months (rnge: 15 dys to 22 months). with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Dietes ourred in 1.5% (6/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 2.5 months (rnge: 1.3 to 4.4 months). with ipilimum ws withheld in ptient nd permnently disontinued in seond ptient who developed dietes.

7 (nivolum) (nivolum) 3 mg/kg with Ipilimum 1 mg/kg Dietes ourred in 2.7% (15/547) of ptients with RCC reeiving 3 mg/kg with ipilimum 1 mg/kg every 3 weeks; the medin time to onset ws 3.2 months (rnge: 19 dys to 16.8 months). with ipilimum ws withheld in 33% of ptients nd permnently disontinued in 20% of ptients who developed dietes. 5.5 Immune-Medited Nephritis nd Renl Dysfuntion n use immune-medited nephritis, defined s renl dysfuntion or Grde 2 inresed retinine, requirement for ortiosteroids, nd no ler lternte etiology. Monitor ptients for elevted serum retinine prior to nd periodilly during tretment. Administer ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for life-thretening (Grde 4) inresed serum retinine. Administer ortiosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) or severe (Grde 3) inresed serum retinine, if worsening or no improvement ours, inrese dose of ortiosteroids to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte (Grde 2) or severe (Grde 3) inresed serum retinine. Permnently disontinue for life-thretening (Grde 4) inresed serum retinine [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, immune-medited nephritis nd renl dysfuntion ourred in 1.2% (23/1994) of ptients; the medin time to onset ws 4.6 months (rnge: 23 dys to 12.3 months). Immune-medited nephritis nd renl dysfuntion led to permnent disontinution of in 0.3% nd withholding of in 0.8% of ptients. ptients reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 21 dys (rnge: 1 dy to 15.4 months). Complete resolution ourred in 48% of ptients. No ptients hd reurrene of nephritis or renl dysfuntion fter re-initition of. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Immune-medited nephritis nd renl dysfuntion ourred in 2.2% (9/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 2.7 months (rnge: 9 dys to 7.9 months). Immune-medited nephritis nd renl dysfuntion led to permnent disontinution or withholding of with ipilimum in 0.7% nd 0.5% of ptients, respetively. Approximtely 67% of ptients reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 13.5 dys (rnge: 1 dy to 1.1 months). Complete resolution ourred in ll ptients. Two ptients resumed with ipilimum without reurrene of nephritis or renl dysfuntion. 3 mg/kg with Ipilimum 1 mg/kg Immune-medited nephritis nd renl dysfuntion ourred in 4.6% (25/547) of ptients with RCC nd 1.7% (2/119) of ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 3 months (rnge: 1 dy to 13.2 months) mong these 27 ptients. Immune-medited nephritis nd renl dysfuntion led to permnent disontinution of with ipilimum in 1.2% of ptients with RCC or CRC (n=666) nd withholding of nd ipilimum in 2.3%. Approximtely 78% of ptients with immunemedited nephritis nd renl dysfuntion reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 17 dys (rnge: 1 dy to 6 months). Complete resolution ourred in 63% of ptients. One of 16 ptients with RCC hd reurrene of nephritis or renl dysfuntion fter re-initition of with ipilimum. 5.6 Immune-Medited Skin Adverse Retions n use immune-medited rsh, inluding Stevens-Johnson syndrome (SJS) nd toxi epiderml nerolysis (TEN), some ses with ftl outome. For symptoms or signs of SJS or TEN, withhold nd refer the ptient for speilized re for ssessment nd tretment. If SJS or TEN is onfirmed, permnently disontinue [see Dosge nd Administrtion (2.11)]. For immune-medited rsh, dminister ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y ortiosteroid tper for severe (Grde 3) or life-thretening (Grde 4) rsh. Withhold for severe (Grde 3) rsh nd permnently disontinue for life-thretening (Grde 4) rsh. s Single Agent In ptients reeiving s single gent, immune-medited rsh ourred in 9% (171/1994) of ptients; the medin time to onset ws 2.8 months (rnge: <1 dy to 25.8 months). Immune-medited rsh led to permnent disontinution of in 0.3% nd withholding of in 0.8% of ptients. Approximtely 16% of ptients with rsh reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 12 dys (rnge: 1 dys to 8.9 months) nd 85% reeived topil ortiosteroids. Complete resolution ourred in 48% of ptients. Reurrene of rsh ourred in 1.4% of ptients who resumed fter resolution of rsh. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Immune-medited rsh ourred in 22.6% (92/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. Medin time to onset ws 18 dys (rnge: 1 dy to 9.7 months). Immune-medited rsh led to permnent disontinution or withholding of with ipilimum in 0.5% nd 3.9% of ptients, respetively. Approximtely 17% of ptients with rsh reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 2 dys to 4.7 months). Complete resolution ourred in 47% of ptients. Approximtely 6% of ptients who resumed nd ipilimum fter resolution hd reurrene of rsh. 3 mg/kg with Ipilimum 1 mg/kg Immune-medited rsh ourred in 16% (90/547) of ptients with RCC nd 14% (17/119) of ptients with CRC who reeived 3 mg/kg with ipilimum 1 mg/kg every 3 weeks. Medin time to onset ws 1.5 months (rnge: 1 dy to 20.9 months) in RCC nd 26 dys (rnge: 5 dys to 9.8 months) in CRC. Immune-medited rsh led to permnent disontinution or withholding of with ipilimum in 0.5% of ptients with RCC or CRC (n=666) nd withholding of with ipilimum in 2.6% of ptients. ptients with immune-medited rsh required systemi ortiosteroids, inluding 19% who reeived high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 22 dys (rnge: 1 dy to 23 months). Complete resolution ourred in 66% of ptients. Immunemedited rsh reurred in pproximtely 3% (3/98) of ptients who resumed nd ipilimum. 5.7 Immune-Medited Enephlitis n use immune-medited enephlitis with no ler lternte etiology. Evlution of ptients with neurologi symptoms my inlude, ut not e limited to, onsulttion with neurologist, rin MRI, nd lumr punture. Withhold in ptients with new-onset moderte to severe neurologi signs or symptoms nd evlute to rule out infetious or other uses of moderte to severe neurologi deteriortion. If other etiologies re ruled out, dminister ortiosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for ptients with immune-medited enephlitis, followed y ortiosteroid tper. Permnently disontinue for immune-medited enephlitis [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s single gent, enephlitis ourred in 0.2% (3/1994). Ftl limi enephlitis ourred in one ptient fter 7.2 months of exposure despite disontinution of nd dministrtion of ortiosteroids. In the other two ptients, enephlitis ourred post-llogenei HSCT [see Wrnings nd Preutions (5.10)]. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Enephlitis ourred in one ptient (0.2%) with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks fter 1.7 months of exposure. 3 mg/kg with Ipilimum 1 mg/kg Enephlitis ourred in one ptient (0.2%) with RCC fter pproximtely 4 months of exposure nd one ptient (0.8%) with CRC fter 15 dys of exposure. The ptient with CRC required inflixim nd high-dose ortiosteroids (t lest 40 mg prednisone equivlents per dy). 5.8 Other Immune-Medited Adverse Retions n use other linilly signifint nd potentilly ftl immune-medited dverse retions. Immune-medited dverse retions my our fter disontinution of therpy. For ny suspeted immune-medited dverse retions, exlude other uses. Bsed on the severity of the dverse retion, permnently disontinue or withhold, dminister high-dose ortiosteroids, nd if pproprite, initite hormone-replement therpy. Upon improvement to Grde 1 or less, initite ortiosteroid tper nd ontinue to tper over t lest 1 month. Consider restrting fter ompletion of ortiosteroid tper sed on the severity of the event [see Dosge nd Administrtion (2.11)]. Aross linil trils of dministered s single gent or in omintion with ipilimum, the following linilly signifint immune-medited dverse retions, some with ftl outome, ourred in less thn 1.0% of ptients reeiving : myorditis, rhdomyolysis, myositis, uveitis, iritis, pnretitis, fil nd duens nerve presis, demyelintion, polymylgi rheumti, utoimmune neuropthy, Guillin-Brré syndrome, hypopituitrism, systemi inflmmtory response syndrome, gstritis, duodenitis, sroidosis, histioyti nerotizing lymphdenitis (Kikuhi lymphdenitis), motor dysfuntion, vsulitis, plsti nemi, perirditis, nd mystheni syndrome. If uveitis ours in omintion with other immune-medited dverse retions, onsider Vogt-Koyngi-Hrd-like syndrome, whih hs een oserved in ptients reeiving or in omintion with ipilimum nd my require tretment with systemi steroids to redue the risk of permnent vision loss.

8 (nivolum) (nivolum) 5.9 Infusion Retions n use severe infusion retions, whih hve een reported in less thn 1.0% of ptients in linil trils. Disontinue in ptients with severe or life-thretening infusion retions. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion retions [see Dosge nd Administrtion (2.11)]. s Single Agent In ptients reeiving s 60-minute intrvenous infusion, infusion-relted retions ourred in 6.4% (127/1994) of ptients. In study ssessing the phrmokinetis nd sfety of more rpid infusion, in whih ptients reeived s 60-minute intrvenous infusion or 30-minute intrvenous infusion, infusion-relted retions ourred in 2.2% (8/368) nd 2.7% (10/369) of ptients, respetively. Additionlly, 0.5% (2/368) nd 1.4% (5/369) of ptients, respetively, experiened dverse retions within 48 hours of infusion tht led to dose dely, permnent disontinution or withholding of. with Ipilimum 1 mg/kg with Ipilimum 3 mg/kg Infusion-relted retions ourred in 2.5% (10/407) of ptients with melnom reeiving 1 mg/kg with ipilimum 3 mg/kg every 3 weeks. 3 mg/kg with Ipilimum 1 mg/kg Infusion-relted retions ourred in 5.1% (28/547) of ptients with RCC nd 4.2% (5/119) of ptients with CRC reeiving 3 mg/kg with ipilimum 1 mg/kg every 3 weeks, respetively Complitions of ogenei Hemtopoieti Stem Cell Trnsplnttion Ftl nd other serious omplitions n our in ptients who reeive llogenei hemtopoieti stem ell trnsplnttion (HSCT) efore or fter eing treted with PD-1 reeptor loking ntiody. Trnsplnt-relted omplitions inlude hyperute grft-versus-host-disese (GVHD), ute GVHD, hroni GVHD, hepti veno-olusive disese (VOD) fter redued intensity onditioning, nd steroid-requiring ferile syndrome (without n identified infetious use) [see Adverse Retions (6.1)]. These omplitions my our despite intervening therpy etween PD-1 lokde nd llogenei HSCT. Follow ptients losely for evidene of trnsplnt-relted omplitions nd intervene promptly. Consider the enefit versus risks of tretment with PD-1 reeptor loking ntiody prior to or fter n llogenei HSCT Emryo-Fetl Toxiity Bsed on its mehnism of tion nd dt from niml studies, n use fetl hrm when dministered to pregnnt womn. In niml reprodution studies, dministrtion of nivolum to ynomolgus monkeys from the onset of orgnogenesis through delivery resulted in inresed ortion nd premture infnt deth. Advise pregnnt women of the potentil risk to fetus. Advise femles of reprodutive potentil to use effetive ontreption during tretment with n -ontining regimen nd for t lest 5 months fter the lst dose of [see Use in Speifi Popultions (8.1, 8.3)]. 6 ADVERSE REACTIONS The following dverse retions re disussed in greter detil in other setions of the leling. Immune-Medited Pneumonitis [see Wrnings nd Preutions (5.1)] Immune-Medited Colitis [see Wrnings nd Preutions (5.2)] Immune-Medited Heptitis [see Wrnings nd Preutions (5.3)] Immune-Medited Endorinopthies [see Wrnings nd Preutions (5.4)] Immune-Medited Nephritis nd Renl Dysfuntion [see Wrnings nd Preutions (5.5)] Immune-Medited Skin Adverse Retions [see Wrnings nd Preutions (5.6)] Immune-Medited Enephlitis [see Wrnings nd Preutions (5.7)] Other Immune-Medited Adverse Retions [see Wrnings nd Preutions (5.8)] Infusion Retions [see Wrnings nd Preutions (5.9)] Complitions of ogenei HSCT [see Wrnings nd Preutions (5.10)] 6.1 Clinil Trils Experiene Beuse linil trils re onduted under widely vrying onditions, dverse retion rtes oserved in the linil trils of drug nnot e diretly ompred to rtes in the linil trils of nother drug nd my not reflet the rtes oserved in prtie. The dt in the Wrnings nd Preutions setion reflet exposure to s single gent in 1994 ptients enrolled in the CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 trils or single-rm tril in NSCLC (n=117); 1 mg/kg with ipilimum 3 mg/kg in ptients enrolled in CHECKMATE-067 (n=313) or nother rndomized study (n=94); nd 3 mg/kg dministered with ipilimum 1 mg/kg in 666 ptients enrolled in CHECKMATE-214 or CHECKMATE-142. The dt desried elow reflet exposure to s single gent in 13 linil trils (n=3063), with 3 mg/kg ipilimum in 1 linil tril (n=313), nd with 1 mg/kg ipilimum in 2 linil trils (n=666) [see Clinil Studies (14)]. Unresetle or Metstti Melnom Previously Treted Metstti Melnom The sfety of s single gent ws evluted in CHECKMATE-037, rndomized, open-lel tril in whih 370 ptients with unresetle or metstti melnom reeived 3 mg/kg of y intrvenous infusion every 2 weeks (n=268) or investigtor s hoie of hemotherpy (n=102), either drzine 1000 mg/m 2 every 3 weeks or the omintion of ropltin AUC 6 every 3 weeks plus plitxel 175 mg/m 2 every 3 weeks [see Clinil Studies (14.1)]. The medin durtion of exposure ws 5.3 months (rnge: 1 dy to months) in -treted ptients nd ws 2 months (rnge: 1 dy to 9.6+ months) in hemotherpy-treted ptients. In this ongoing tril, 24% of ptients reeived for greter thn 6 months nd 3% of ptients reeived for greter thn 1 yer. In CHECKMATE-037, ptients hd doumented disese progression following tretment with ipilimum nd, if BRAF V600 muttion positive, BRAF inhiitor. The tril exluded ptients with utoimmune disese, prior ipilimum-relted Grde 4 dverse retions (exept for endorinopthies) or Grde 3 ipilimum-relted dverse retions tht hd not resolved or were indequtely ontrolled within 12 weeks of the inititing event, ptients with ondition requiring hroni systemi tretment with ortiosteroids (>10 mg dily prednisone equivlent) or other immunosuppressive meditions, positive test for heptitis B or C, nd history of HIV. The tril popultion hrteristis in the group nd the hemotherpy group were similr: 66% mle, medin ge 59.5 yers, 98% White, seline Estern Coopertive Onology Group (ECOG) performne sttus 0 (59%) or 1 (41%), 74% with M1 stge disese, 73% with utneous melnom, 11% with muosl melnom, 73% reeived two or more prior therpies for dvned or metstti disese, nd 18% hd rin metstsis. There were more ptients in the group with elevted LDH t seline (51% vs. 38%). ws disontinued for dverse retions in 9% of ptients. Twenty-six perent of ptients reeiving hd drug dely for n dverse retion. Serious dverse retions ourred in 41% of ptients reeiving. Grde 3 nd 4 dverse retions ourred in 42% of ptients reeiving. The most frequent Grde 3 nd 4 dverse retions reported in 2% to less thn 5% of ptients reeiving were dominl pin, hypontremi, inresed sprtte minotrnsferse, nd inresed lipse. Tle 2 summrizes the dverse retions tht ourred in t lest 10% of treted ptients in CHECKMATE-037. The most ommon dverse retion (reported in t lest 20% of ptients) ws rsh. Tle 2: Adverse Retion Adverse Retions Ourring in 10% of -Treted Ptients nd t Higher Inidene thn in the Chemotherpy Arm (Between Arm Differene of 5% [ ] or 2% [ ]) (CHECKMATE-037) Skin nd Suutneous Tissue (n=268) Chemotherpy (n=102) Perentge (%) of Ptients Rsh Pruritus Respirtory, Thori, nd Medistinl Cough Infetions Upper respirtory trt infetion Generl nd Administrtion Site Conditions Peripherl edem Toxiity ws grded per NCI CTCAE v4. Rsh is omposite term whih inludes muloppulr rsh, erythemtous rsh, pruriti rsh, folliulr rsh, mulr rsh, ppulr rsh, pustulr rsh, vesiulr rsh, nd neiform dermtitis. Upper respirtory trt infetion is omposite term whih inludes rhinitis, phryngitis, nd nsophryngitis.