IMPORTANT Reminders for Patients. IMPORTANT Information for Doctors/Nurses

Transcription

1 Monitor Your Signs nd Symptoms (nivolum) is prescription medicine used in comintion with YERVOY (ipilimum) to tret type of skin cncer clled melnom tht hs spred or cnnot e removed y surgery (dvnced melnom). in comintion with YERVOY ws pproved sed on the mount of time ptients lived without their tumors worsening. There is ongoing evlution of clinicl enefit of in comintion with YERVOY for this use. It is not known if is sfe nd effective in children less thn 18 yers of ge. (10 mg/ml) nd YERVOY (5 mg/ml) re injections for intrvenous (IV) use. Plese see dditionl Importnt Sfety Informtion on pge 2 nd U.S. Full Prescriing Informtion, including Boxed Wrning regrding immune-medited side effects for YERVOY, nd Mediction Guides for nd YERVOY t the end of this document. SELECT IMPORTANT SAFETY INFORMATION cn cuse prolems tht cn sometimes ecome serious or life-thretening nd cn led to deth. Serious side effects my include lung prolems (pneumonitis); intestinl prolems (colitis) tht cn led to ters or holes in your intestine; liver prolems (heptitis); hormone glnd prolems (especilly the thyroid, pituitry, drenl glnds, nd pncres); kidney prolems, including nephritis nd kidney filure; skin prolems; inflmmtion of the rin (encephlitis); prolems in other orgns; nd severe infusion rections. Additionl serious side effects of YERVOY lone include: nerve prolems tht cn led to prlysis nd eye prolems. cn cuse severe infusion rections. Tell your doctor or nurse right wy if you get these symptoms during n infusion of : chills or shking; itching or rsh; flushing; difficulty rething; dizziness; fever; nd feeling like pssing out. Cll your oncologist right wy if you hve ny of these signs or symptoms, or if they get worse. Do not tret symptoms yourself Symptoms my occur ny time during tretment or even fter your tretment hs ended Do not feel emrrssed or tht you re othering your treting oncologist GENERAL n hedches, including those tht will not go wy or unusul hedches n drowsiness or extreme tiredness n dizziness or finting n chnges in mood or ehvior, such s decresed sex drive, irritility, or forgetfulness n feeling cold n weight gin or weight loss n hir loss n voice gets deeper n yellowing of your skin or the whites of your eyes n excessive thirst n chnge in frequency or mount of urintion n drk urine (te colored) n lood in your urine n leeding or ruising more esily thn norml n swelling in your nkles n chnges in eyesight n severe or persistent muscle or joint pins n severe muscle wekness n chills or shking n flushing n feeling like pssing out ADDITIONAL SIGNS AND SYMPTOMS ASSOCIATED WITH YERVOY n eye pin or redness n skin peeling n numness or tingling in hnds or feet n unusul wekness of legs, rms, or fce LUNG n new or worsening cough n chest pin n shortness of reth n difficulty rething SKIN n rsh n itching n skin listering n ulcers in mouth or other mucous memrnes STOMACH AND BOWEL n feeling less hungry thn usul or loss of ppetite n severe nuse or vomiting n dirrhe (loose stools) or more owel movements thn usul n lood in your stools or drk, trry, sticky stools IMPORTANT Reminders for Ptients n constiption n severe stomch re (domen) pin or tenderness n pin on the right side of your stomch re (domen) INFLAMMATION OF THE BRAIN (ENCEPHALITIS) n hedche n fever n tiredness or wekness n confusion n memory prolems n sleepiness n seeing or hering things tht re not relly there (hllucintions) n seizures n stiff neck IMPORTANT Informtion for Doctors/Nurses If you experience ny symptoms listed on this crd, or they get worse, plese notify your oncologist immeditely. Getting medicl tretment right wy my keep the prolem from ecoming more serious. Tke this crd with you if you go to the urgent cre/emergency room Be sure to tell ll helthcre providers tht you re eing treted with the + YERVOY Regimen nd SHOW THEM THIS CARD. By doing so it my help the urgent cre/er stff etter mnge ny possile side effects you my e experiencing n Your oncologist my decide to dely or completely stop the + YERVOY Regimen or give you other medicines to tret your symptoms Tke picture of this pge nd sve it on your phone to ensure it s with you t ll times This ptient is receiving the + YERVOY Regimen. Why re the + YERVOY Regimen side effects different from other tretments? The + YERVOY Regimen is n immunotherpy tht works with the ptient s immune system; therefore, the mngement of immune-medited side effects my e different from other cncer tretments. Be sure to coordinte cre with the ptient s oncologist ecuse the side effects ssocited with the + YERVOY Regimen my require tretment with corticosteroids or hormone replcement therpy or require close monitoring n If the side effects re severe, tretment with the + YERVOY Regimen my need to e delyed or completely stopped Do not wit to tret the ptient if urgent cre is required For more informtion, visit or cll ( ). For more informtion on mnging the side effects of + YERVOY, visit or cll ( ). 1

2 Importnt Sfety Informtion for (nivolum) + YERVOY (ipilimum) Importnt Sfety Informtion out (nivolum) in comintion with YERVOY (ipilimum) is medicine tht my tret certin cncers y working with your immune system. cn cuse your immune system to ttck norml orgns nd tissues in ny re of your ody nd cn ffect the wy they work. These prolems cn sometimes ecome serious or life-thretening nd cn led to deth. These prolems my hppen nytime during tretment or even fter your tretment hs ended. Some of these prolems my hppen more often when is used in comintion with YERVOY. YERVOY cn cuse serious side effects in mny prts of your ody which cn led to deth. These prolems my hppen nytime during tretment with YERVOY or fter you hve completed tretment. Serious side effects my include: n Lung prolems (pneumonitis). Symptoms of pneumonitis my include: new or worsening cough; chest pin; nd shortness of reth. n Intestinl prolems (colitis) tht cn led to ters or holes in your intestine. Signs nd symptoms of colitis my include: dirrhe (loose stools) or more owel movements thn usul; lood in your stools or drk, trry, sticky stools; nd severe stomch re (domen) pin or tenderness. n Liver prolems (heptitis). Signs nd symptoms of heptitis my include: yellowing of your skin or the whites of your eyes; severe nuse or vomiting; pin on the right side of your stomch re (domen); drowsiness; drk urine (te colored); leeding or ruising more esily thn norml; nd feeling less hungry thn usul. n Hormone glnd prolems (especilly the thyroid, pituitry, drenl glnds, nd pncres). Signs nd symptoms tht your hormone glnds re not working properly my include: hedches tht will not go wy or unusul hedches; extreme tiredness; weight gin or weight loss; dizziness or finting; chnges in mood or ehvior, such s decresed sex drive, irritility, or forgetfulness; hir loss; feeling cold; constiption; voice gets deeper; nd excessive thirst or lots of urine. n Kidney prolems, including nephritis nd kidney filure. Signs of kidney prolems my include: decrese in the mount of urine; lood in your urine; swelling in your nkles; nd loss of ppetite. n Skin Prolems. Signs of these prolems my include: rsh; itching; skin listering; nd ulcers in the mouth or other mucous memrnes. n Inflmmtion of the rin (encephlitis). Signs nd symptoms of encephlitis my include: hedche; fever; tiredness or wekness; confusion; memory prolems; sleepiness; seeing or hering things tht re not relly there (hllucintions); seizures; nd stiff neck. n Prolems in other orgns. Signs of these prolems my include: chnges in eyesight; severe or persistent muscle or joint pins; nd severe muscle wekness. Additionl serious side effects oserved during seprte study of YERVOY lone include: n Nerve prolems tht cn led to prlysis. Symptoms of nerve prolems my include: unusul wekness of legs, rms, or fce; nd numness or tingling in hnds or feet. n Eye prolems. Symptoms my include: lurry vision, doule vision, or other vision prolems; nd eye pin or redness. Getting medicl tretment right wy my keep these prolems from ecoming more serious. Your helthcre provider will check you for these prolems during tretment. Your helthcre provider my tret you with corticosteroid or hormone replcement medicines. Your helthcre provider my lso need to dely or completely stop tretment, if you hve severe side effects. cn cuse serious side effects, including: n Severe infusion rections. Tell your doctor or nurse right wy if you get these symptoms during n infusion of : chills or shking; itching or rsh; flushing; difficulty rething; dizziness; fever; nd feeling like pssing out. Pregnncy nd Nursing: n Tell your helthcre provider if you re pregnnt or pln to ecome pregnnt. nd YERVOY cn hrm your unorn y. Femles who re le to ecome pregnnt should use n effective method of irth control during nd for t lest 5 months fter the lst dose of. Tlk to your helthcre provider out irth control methods tht you cn use during this time. Tell your helthcre provider right wy if you ecome pregnnt or think you re pregnnt during tretment. You or your helthcre provider should contct Bristol-Myers Squi t s soon s you ecome wre of the pregnncy. n Pregnncy Sfety Surveillnce Study: Femles who ecome pregnnt during tretment with YERVOY re encourged to enroll in Pregnncy Sfety Surveillnce Study. The purpose of this study is to collect informtion out the helth of you nd your y. You or your helthcre provider cn enroll in the Pregnncy Sfety Surveillnce Study y clling n Before receiving tretment, tell your helthcre provider if you re restfeeding or pln to restfeed. It is not known if either tretment psses into your rest milk. Do not restfeed during tretment nd for 3 months fter the lst dose of YERVOY. Tell your helthcre provider out: n Your helth prolems or concerns if you: hve immune system prolems such s utoimmune disese, Crohn s disese, ulcertive colitis, lupus, or srcoidosis; hve hd n orgn trnsplnt; hve lung or rething prolems; hve liver prolems; or hve ny other medicl conditions. n the medicines you tke, including prescription nd overthe-counter medicines, vitmins, nd herl supplements. The most common side effects of, when used in comintion with YERVOY include: feeling tired; dirrhe; fever; shortness of reth; rsh; nuse; nd vomiting. The most common side effects of YERVOY include: tiredness; dirrhe; itching; rsh; nuse; vomiting; hedche; weight loss; fever; decresed ppetite; nd difficulty flling or stying sleep. These re not ll the possile side effects. For more informtion, sk your helthcre provider or phrmcist. Cll your doctor for medicl dvice out side effects. You re encourged to report negtive side effects of prescription drugs to the FDA. Visit or cll FDA You my lso report side effects to Bristol-Myers Squi t Plese see U.S. Full Prescriing Informtion, including Boxed WARNING regrding immune-medited side effects, nd Mediction Guide for YERVOY t the end of this document. Plese see U.S. Full Prescriing Informtion nd Mediction Guide for t the end of this document. My Treting Oncologist Contct Informtion Nme of treting oncologist: Office phone: After-hours phone: My Nme nd Phone Dtes of Infusions, YERVOY, nd the relted logos re trdemrks of Bristol-Myers Squi Compny Bristol-Myers Squi Compny. rights reserved. 7356US /18 2

3 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescriing informtion for. (nivolum) injection, for intrvenous use Initil U.S. Approvl: RECENT MAJOR CHANGES Indictions nd Usge (1) 12/2017 Dosge nd Administrtion (2) 2/2018 Wrnings nd Precutions, Immune-Medited Heptitis (5.3) 9/2017 Wrnings nd Precutions, Other Immune-Medited Adverse Rections (5.8) 2/2018 Wrnings nd Precutions, Infusion Rections (5.9) 1/ INDICATIONS AND USAGE is progrmmed deth receptor-1 (PD-1) locking ntiody indicted for the tretment of: ptients with BRAF V600 wild-type unresectle or metsttic melnom, s single gent. (1.1) ptients with BRAF V600 muttion-positive unresectle or metsttic melnom, s single gent. (1.1) ptients with unresectle or metsttic melnom, in comintion with ipilimum. (1.1) ptients with melnom with lymph node involvement or metsttic disese who hve undergone complete resection, in the djuvnt setting. (1.2) ptients with metsttic non-smll cell lung cncer nd progression on or fter pltinum-sed chemotherpy. Ptients with EGFR or ALK genomic tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to receiving. (1.3) ptients with dvnced renl cell crcinom who hve received prior ntingiogenic therpy. (1.4) dult ptients with clssicl Hodgkin lymphom tht hs relpsed or progressed fter : (1.5) utologous hemtopoietic stem cell trnsplnttion (HSCT) nd rentuxim vedotin, or 3 or more lines of systemic therpy tht includes utologous HSCT. ptients with recurrent or metsttic squmous cell crcinom of the hed nd neck with disese progression on or fter pltinum-sed therpy. (1.6) ptients with loclly dvnced or metsttic urothelil crcinom who : hve disese progression during or following pltinum-contining chemotherpy hve disese progression within 12 months of neodjuvnt or djuvnt tretment with pltinum-contining chemotherpy. (1.7) dult nd peditric (12 yers nd older) ptients with microstellite instility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinotecn. (1.8) ptients with heptocellulr crcinom who hve een previously treted with sorfeni. (1.9) This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils. This indiction is pproved under ccelerted pprovl sed on overll response rte nd durtion of response. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils DOSAGE AND ADMINISTRATION Administer s n intrvenous infusion. Unresectle or metsttic melnom 240 mg every 2 weeks. (2.1) with ipilimum: 1 mg/kg, followed y ipilimum on the sme dy, every 3 weeks for 4 doses, then 240 mg every 2 weeks. (2.1) Adjuvnt tretment of melnom 240 mg every 2 weeks. (2.2) Metsttic non-smll cell lung cncer 240 mg every 2 weeks. (2.3) Advnced renl cell crcinom 240 mg every 2 weeks. (2.4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectle or Metsttic Melnom 1.2 Adjuvnt Tretment of Melnom 1.3 Metsttic Non-Smll Cell Lung Cncer 1.4 Renl Cell Crcinom 1.5 Clssicl Hodgkin Lymphom 1.6 Squmous Cell Crcinom of the Hed nd Neck 1.7 Urothelil Crcinom 1.8 Microstellite Instility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer 1.9 Heptocellulr Crcinom Clssicl Hodgkin lymphom (nivolum) 240 mg every 2 weeks. (2.5) Recurrent or metsttic squmous cell crcinom of the hed nd neck 240 mg every 2 weeks. (2.6) Loclly dvnced or metsttic urothelil crcinom 240 mg every 2 weeks (2.7) Microstellite instility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer 240 mg every 2 weeks. (2.8) Heptocellulr crcinom 240 mg every 2 weeks. (2.9) DOSAGE FORMS AND STRENGTHS Injection: 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 discontinue for severe or life-thretening pneumonitis. (5.1) Immune-medited colitis: Withhold when given s single gent for moderte or severe nd permnently discontinue for life-thretening colitis. Withhold when given with ipilimum for moderte nd permnently discontinue for severe or life-thretening colitis. (5.2) Immune-medited heptitis: Monitor for chnges in liver function. Withhold for moderte nd permnently discontinue for severe or life-thretening trnsminse or totl iliruin elevtion. (5.3) Immune-medited endocrinopthies: Withhold for moderte or severe nd permnently discontinue for life-thretening hypophysitis. Withhold for moderte nd permnently discontinue for severe or life-thretening drenl insufficiency. Monitor for chnges in thyroid function. Initite thyroid hormone replcement s needed. Monitor for hyperglycemi. Withhold for severe nd permnently discontinue for life-thretening hyperglycemi. (5.4) Immune-medited nephritis nd renl dysfunction: Monitor for chnges in renl function. Withhold for moderte or severe nd permnently discontinue for life-thretening serum cretinine elevtion. (5.5) Immune-medited skin dverse rections: Withhold for severe nd permnently discontinue for life-thretening rsh. (5.6) Immune-medited encephlitis: Monitor for chnges in neurologic function. Withhold for new-onset moderte to severe neurologicl signs or symptoms nd permnently discontinue for immune-medited encephlitis. (5.7) Infusion rections: Discontinue for severe nd life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. (5.9) Complictions of llogeneic HSCT fter : Monitor for hypercute grftversus-host-disese (GVHD), grde cute GVHD, steroid-requiring ferile syndrome, heptic veno-occlusive disese, nd other immune-medited dverse rections. Trnsplnt-relted mortlity hs occurred. (5.10) Emryo-fetl toxicity: Cn cuse fetl hrm. Advise of potentil risk to fetus nd use of effective contrception. (5.11, 8.1, 8.3) ADVERSE REACTIONS Most common dverse rections ( 20%) in ptients were: s single gent: ftigue, rsh, musculoskeletl pin, pruritus, dirrhe, nuse, stheni, cough, dyspne, constiption, decresed ppetite, ck pin, rthrlgi, upper respirtory trct infection, pyrexi, hedche, nd dominl pin. (6.1) with ipilimum: ftigue, rsh, dirrhe, nuse, pyrexi, vomiting, nd dyspne. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squi t or FDA t FDA-1088 or USE IN SPECIFIC POPULATIONS Lcttion: Discontinue restfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 2/ DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Unresectle or Metsttic Melnom 2.2 Recommended Dosge for Adjuvnt Tretment of Melnom 2.3 Recommended Dosge for NSCLC 2.4 Recommended Dosge for RCC 2.5 Recommended Dosge for chl 2.6 Recommended Dosge for SCCHN 2.7 Recommended Dosge for Urothelil Crcinom 2.8 Recommended Dosge for CRC 2.9 Recommended Dosge for HCC 2.10 Dose Modifictions 2.11 Preprtion nd Administrtion (Continued)

4 FULL PRESCRIBING INFORMATION: CONTENTS* (Continued) 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 Endocrinopthies 5.5 Immune-Medited Nephritis nd Renl Dysfunction 5.6 Immune-Medited Skin Adverse Rections 5.7 Immune-Medited Encephlitis 5.8 Other Immune-Medited Adverse Rections 5.9 Infusion Rections 5.10 Complictions of ogeneic HSCT fter 5.11 Emryo-Fetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 6.3 Immunogenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Unresectle or Metsttic Melnom 14.2 Adjuvnt Tretment of Melnom 14.3 Metsttic Non-Smll Cell Lung Cncer (NSCLC) 14.4 Renl Cell Crcinom 14.5 Clssicl Hodgkin Lymphom 14.6 Recurrent or Metsttic Squmous Cell Crcinom of the Hed nd Neck (SCCHN) 14.7 Urothelil Crcinom 14.8 Microstellite Instility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer 14.9 Heptocellulr Crcinom 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or susections omitted from the full prescriing informtion re not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresectle or Metsttic Melnom (nivolum) s single gent is indicted for the tretment of ptients with BRAF V600 wild-type unresectle or metsttic melnom [see Clinicl Studies (14.1)]. s single gent is indicted for the tretment of ptients with BRAF V600 muttion-positive unresectle or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils., in comintion with ipilimum, is indicted for the tretment of ptients with unresectle or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl sed on progression-free survivl. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils. 1.2 Adjuvnt Tretment of Melnom is indicted for the djuvnt tretment of ptients with melnom with involvement of lymph nodes or metsttic disese who hve undergone complete resection [see Clinicl Studies (14.2)]. 1.3 Metsttic Non-Smll Cell Lung Cncer is indicted for the tretment of ptients with metsttic non-smll cell lung cncer (NSCLC) with progression on or fter pltinum-sed chemotherpy. Ptients with EGFR or ALK genomic tumor errtions should hve disese progression on FDA-pproved therpy for these errtions prior to receiving [see Clinicl Studies (14.3)]. 1.4 Renl Cell Crcinom is indicted for the tretment of ptients with dvnced renl cell crcinom (RCC) who hve received prior nti-ngiogenic therpy [see Clinicl Studies (14.4)]. 1.5 Clssicl Hodgkin Lymphom is indicted for the tretment of dult ptients with clssicl Hodgkin lymphom (chl) tht hs relpsed or progressed fter: utologous hemtopoietic stem cell trnsplnttion (HSCT) nd rentuxim vedotin, or 3 or more lines of systemic therpy tht includes utologous HSCT. This indiction is pproved under ccelerted pprovl sed on overll response rte. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils [see Clinicl Studies (14.5)]. 1.6 Squmous Cell Crcinom of the Hed nd Neck is indicted for the tretment of ptients with recurrent or metsttic squmous cell crcinom of the hed nd neck (SCCHN) with disese progression on or fter pltinum-sed therpy [see Clinicl Studies (14.6)]. 1.7 Urothelil Crcinom (nivolum) is indicted for the tretment of ptients with loclly dvnced or metsttic urothelil crcinom who: hve disese progression during or following pltinum-contining chemotherpy hve disese progression within 12 months of neodjuvnt or djuvnt tretment with pltinum-contining chemotherpy. This indiction is pproved under ccelerted pprovl sed on tumor response rte nd durtion of response. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils [see Clinicl Studies (14.7)]. 1.8 Microstellite Instility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer is indicted for the tretment of dult nd peditric ptients 12 yers nd older with microstellite instility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer (CRC) tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinotecn [see Clinicl Studies (14.8)]. This indiction is pproved under ccelerted pprovl sed on overll response rte nd durtion of response. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in confirmtory trils. 1.9 Heptocellulr Crcinom is indicted for the tretment of ptients with heptocellulr crcinom (HCC) who hve een previously treted with sorfeni. This indiction is pproved under ccelerted pprovl sed on tumor response rte nd durility of response. Continued pprovl for this indiction my e contingent upon verifiction nd description of clinicl enefit in the confirmtory trils [see Clinicl Studies (14.9)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Unresectle or Metsttic Melnom The recommended dose of s single gent is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. The recommended dose of is 1 mg/kg dministered s n intrvenous infusion over 30 minutes, followed y ipilimum on the sme dy, every 3 weeks for 4 doses [see Clinicl Studies (14.1)]. The recommended susequent dose of, s single gent, is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. Review the Full Prescriing Informtion for ipilimum prior to initition. 2.2 Recommended Dosge for Adjuvnt Tretment of Melnom The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese recurrence or uncceptle toxicity for up to 1 yer. 2.3 Recommended Dosge for NSCLC The recommended dose of is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity.

5 (nivolum) 2.4 Recommended Dosge for RCC The recommended dose of is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.5 Recommended Dosge for chl The recommended dose of is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.6 Recommended Dosge for SCCHN The recommended dose of is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.7 Recommended Dosge for Urothelil Crcinom The recommended dose of is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.8 Recommended Dosge for CRC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity. 2.9 Recommended Dosge for HCC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptle toxicity Dose Modifictions Recommendtions for modifictions re provided in Tle 1. When is dministered in comintion with ipilimum, if is withheld, ipilimum should lso e withheld. There re no recommended dose modifictions for hypothyroidism or hyperthyroidism. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections. Discontinue in ptients with severe or life-thretening infusion rections. Tle 1: Recommended Dose Modifictions for Adverse Rection Severity* Dose Modifiction Grde 2 dirrhe or colitis Withhold dose Colitis Grde 3 dirrhe or colitis Withhold dose when dministered s single gent Permnently discontinue when dministered with ipilimum Grde 4 dirrhe or colitis Permnently discontinue Pneumonitis Grde 2 pneumonitis Withhold dose Grde 3 or 4 pneumonitis Permnently discontinue Asprtte minotrnsferse (AST) or lnine minotrnsferse (ALT) more thn 3 nd up to 5 times the Withhold dose upper limit of norml (ULN) or Heptitis/non-HCC 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 Permnently discontinue thn 3 times the ULN If AST/ALT is within norml limits t seline nd increses to more thn 3 nd up to 5 times the ULN Heptitis/HCC Hypophysitis If AST/ALT is more thn 1 nd up to 3 times ULN t seline nd increses 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 increses to more thn 8 nd up to 10 times the ULN If AST or ALT increses to more thn 10 times the ULN or totl iliruin increses to more thn 3 times the ULN Grde 2 or 3 hypophysitis Grde 4 hypophysitis Withhold dose c Permnently discontinue Withhold dose Permnently discontinue (Continued) (nivolum) Tle 1: Recommended Dose Modifictions for (Continued) Adverse Rection Severity* Dose Modifiction Grde 2 drenl insufficiency Withhold dose Adrenl Insufficiency Grde 3 or 4 drenl insufficiency Permnently discontinue Type 1 Dietes Mellitus Grde 3 hyperglycemi Withhold dose Grde 4 hyperglycemi Permnently discontinue Nephritis nd Renl Dysfunction Skin Encephlitis Other Serum cretinine more thn 1.5 nd up to 6 times the ULN Serum cretinine more thn 6 times the ULN Grde 3 rsh or suspected Stevens-Johnson syndrome (SJS) or toxic epiderml necrolysis (TEN) Grde 4 rsh or confirmed SJS or TEN New-onset moderte or severe neurologic signs or symptoms Immune-medited encephlitis Other Grde 3 dverse rection First occurrence Recurrence of sme Grde 3 dverse rections Life-thretening or Grde 4 dverse rection Grde 3 myocrditis Requirement for 10 mg per dy or greter prednisone or equivlent for more thn 12 weeks Persistent Grde 2 or 3 dverse rections lsting 12 weeks or longer Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Withhold dose Permnently discontinue Permnently discontinue Permnently discontinue Permnently discontinue Permnently discontinue * Toxicity ws grded per Ntionl Cncer Institute Common Terminology Criteri for Adverse Events. Version 4.0 (NCI CTCAE v4). Resume tretment when dverse rection improves to Grde 0 or 1. HCC: heptocellulr crcinom. c Resume tretment when AST/ALT returns to seline Preprtion nd Administrtion Visully inspect drug product solution for prticulte mtter nd discolortion prior to dministrtion. is cler to oplescent, colorless to ple-yellow solution. Discrd the vil if the solution is cloudy, discolored, or contins extrneous prticulte mtter other thn few trnslucent-to-white, proteinceous prticles. Do not shke the vil. Preprtion Withdrw the required volume of nd trnsfer into n intrvenous continer. Dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepre n infusion with finl concentrtion rnging from 1 mg/ml to 10 mg/ml. Mix diluted solution y gentle inversion. Do not shke. Discrd prtilly used vils or empty vils of. Storge of Infusion The product does not contin preservtive. After preprtion, store the infusion either: t room temperture for no more thn 8 hours from the time of preprtion. This includes room temperture storge of the infusion in the IV continer 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 through n intrvenous line contining sterile, non-pyrogenic, low protein inding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).

6 (nivolum) Do not codminister other drugs through the sme intrvenous line. Flush the intrvenous line t end of infusion. When dministered in comintion with ipilimum, infuse first followed y ipilimum on the sme dy. Use seprte infusion gs nd filters for ech infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 40 mg/4 ml (10 mg/ml), 100 mg/10 ml (10 mg/ml), nd 240 mg/24 ml (10 mg/ml) cler to oplescent, colorless to ple-yellow solution in single-dose vil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis cn cuse immune-medited pneumonitis, defined s requiring use of corticosteroids nd no cler lternte etiology. Ftl cses hve een reported. Monitor ptients for signs with rdiogrphic imging nd for symptoms of pneumonitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for moderte (Grde 2) or more severe (Grde ) pneumonitis, followed y corticosteroid tper. Permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) pneumonitis nd withhold until resolution for moderte (Grde 2) pneumonitis [see Dosge nd Administrtion (2.10)]. s Single Agent In ptients receiving s single gent, immune-medited pneumonitis occurred 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 discontinution of in 1.1%, nd withholding of in 1.3% of ptients. Approximtely 89% of ptients with pneumonitis received high-dose corticosteroids (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 corticosteroid tper occurred in 67% of ptients. Approximtely 8% of ptients hd recurrence of pneumonitis fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited pneumonitis occurred in 6% (25/407) of ptients. The medin time to onset of immune-medited pneumonitis ws 1.6 months (rnge: 24 dys to 10.1 months). Immune-medited pneumonitis led to permnent discontinution or withholding of with ipilimum in 2.2% nd 3.7% of ptients, respectively. Approximtely 84% of ptients with pneumonitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 30 dys (rnge: 5 dys to 11.8 months). Complete resolution occurred in 68% of ptients. Approximtely 13% of ptients hd recurrence of pneumonitis fter re-initition of with ipilimum. 5.2 Immune-Medited Colitis cn cuse immune-medited colitis, defined s requiring use of corticosteroids with no cler lternte etiology. Monitor ptients for signs nd symptoms of colitis. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) colitis. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents followed y corticosteroid tper for moderte (Grde 2) colitis of more thn 5 dys durtion; if worsening or no improvement occurs despite initition of corticosteroids, increse dose to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte or severe (Grde 2 or 3) colitis. Permnently discontinue for life-thretening (Grde 4) or for recurrent colitis upon re-initition of [see Dosge nd Administrtion (2.10)]. When dministered in comintion with ipilimum, withhold nd ipilimum for moderte colitis (Grde 2). Permnently discontinue nd ipilimum for severe or life-thretening (Grde 3 or 4) colitis or for recurrent colitis [see Dosge nd Administrtion (2.10)]. s Single Agent In ptients receiving s single gent, immune-medited colitis occurred 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 colitis led to permnent discontinution of in 0.7% nd withholding of in 1% of ptients. Approximtely 91% of ptients with colitis received high-dose corticosteroids (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 corticosteroids. Complete resolution occurred in 74% of ptients. Approximtely 16% of ptients hd recurrence of colitis fter re-initition of. (nivolum) with Ipilimum In ptients receiving with ipilimum, immune-medited colitis occurred in 26% (107/407) of ptients including three ftl cses. The medin time to onset of immune-medited colitis ws 1.6 months (rnge: 3 dys to 15.2 months). Immunemedited colitis led to permnent discontinution or withholding of with ipilimum in 16% nd 7% of ptients, respectively. Approximtely 96% of ptients with colitis received high-dose corticosteroids (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 corticosteroids. Complete resolution occurred in 75% of ptients. Approximtely 28% of ptients hd recurrence of colitis fter re-initition of with ipilimum. 5.3 Immune-Medited Heptitis cn cuse immune-medited heptitis, defined s requiring use of corticosteroids nd no cler lternte etiology. Monitor ptients for norml liver tests prior to nd periodiclly during tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) trnsminse elevtions, with or without concomitnt elevtion in totl iliruin. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) trnsminse elevtions. For ptients without heptocellulr crcinom (HCC): withhold for moderte (Grde 2) immune-medited heptitis nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) immune-medited heptitis [see Dosge nd Administrtion (2.10)]. For ptients with HCC, permnently discontinue, withhold, or continue sed on severity of immune-medited heptitis nd seline AST nd ALT levels s descried in Tle 1 [see Dosge nd Administrtion (2.10)]. In ddition, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper when is withheld or discontinued due to immune-medited heptitis. s Single Agent In ptients receiving s single gent, immune-medited heptitis occurred 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 discontinution of in 0.7% nd withholding of in 1% of ptients. ptients with heptitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents) for medin durtion of 23 dys (rnge: 1 dy to 2 months). Two ptients required the ddition of mycophenolic cid to high-dose corticosteroids. Complete resolution occurred in 74% of ptients. Approximtely 29% of ptients hd recurrence of heptitis fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited heptitis occurred in 13% (51/407) of ptients; the medin time to onset ws 2.1 months (rnge: 15 dys to 11 months). Immune-medited heptitis led to permnent discontinution or withholding of with ipilimum in 6% nd 5% of ptients, respectively. Approximtely 92% of ptients with heptitis received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1.1 month (rnge: 1 dy to 13.2 months). Complete resolution occurred in 75% of ptients. Approximtely 11% of ptients hd recurrence of heptitis fter re-initition of with ipilimum. 5.4 Immune-Medited Endocrinopthies Hypophysitis cn cuse immune-medited hypophysitis. Monitor ptients for signs nd symptoms of hypophysitis. Administer hormone replcement s cliniclly indicted nd corticosteroids t dose of 1 mg/kg/dy prednisone equivlents followed y corticosteroid tper for moderte (Grde 2) or greter hypophysitis. Withhold for moderte (Grde 2) or severe (Grde 3). Permnently discontinue for life-thretening (Grde 4) hypophysitis [see Dosge nd Administrtion (2.10)]. In ptients receiving s single gent, hypophysitis occurred 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 discontinution of in 0.1% nd withholding of in 0.2% of ptients. Approximtely 67% of ptients with hypophysitis received hormone replcement therpy nd 33% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 5 to 26 dys). In ptients receiving with ipilimum, hypophysitis occurred in 9% (36/407) of ptients; the medin time to onset ws 2.7 months (rnge: 27 dys to 5.5 months). Hypophysitis led to permnent discontinution or withholding of with ipilimum in 1.0% nd 3.9% of ptients, respectively. Approximtely 75% of ptients with hypophysitis received hormone replcement therpy nd 56% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 19 dys (rnge: 1 dy to 2.0 months).

7 (nivolum) Adrenl Insufficiency cn cuse immune-medited drenl insufficiency. Monitor ptients for signs nd symptoms of drenl insufficiency. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) drenl insufficiency [see Dosge nd Administrtion (2.10)]. In ptients receiving s single gent, drenl insufficiency occurred in 1% (20/1994) of ptients nd the medin time to onset ws 4.3 months (rnge: 15 dys to 21 months). Adrenl insufficiency led to permnent discontinution of in 0.1% nd withholding of in 0.5% of ptients. Approximtely 85% of ptients with drenl insufficiency received hormone replcement therpy nd 25% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 11 dys (rnge: 1 dy to 1 month). In ptients receiving with ipilimum, drenl insufficiency occurred in 5% (21/407) of ptients nd the medin time to onset ws 3.0 months (rnge: 21 dys to 9.4 months). Adrenl insufficiency led to permnent discontinution or withholding of with ipilimum in 0.5% nd 1.7% of ptients, respectively. Approximtely 57% of ptients with drenl insufficiency received hormone replcement therpy nd 33% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 9 dys (rnge: 1 dy to 2.7 months). Hypothyroidism nd Hyperthyroidism cn cuse utoimmune thyroid disorders. Monitor thyroid function prior to nd periodiclly during tretment. Administer hormone-replcement therpy for hypothyroidism. Initite medicl mngement for control of hyperthyroidism. There re no recommended dose djustments of for hypothyroidism or hyperthyroidism. In ptients receiving s single gent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred 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 received levothyroxine nd 4% lso required corticosteroids. Resolution occurred in 35% of ptients. Hyperthyroidism occurred in 2.7% (54/1994) of ptients receiving 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 received methimzole, 9% received crimzole, 4% received propylthiourcil, nd 9% received corticosteroids. Resolution occurred in 76% of ptients. In ptients receiving with ipilimum, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of ptients; the medin time to onset ws 2.1 months (rnge: 1 dy to 10.1 months). Approximtely 73% of ptients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45% of ptients. Hyperthyroidism occurred in 8% (34/407) of ptients receiving with ipilimum: the medin time to onset ws 23 dys (rnge: 3 dys to 3.7 months). Approximtely 29% of ptients with hyperthyroidism received methimzole nd 24% received crimzole. Resolution occurred in 94% of ptients. Type 1 Dietes Mellitus cn cuse Type 1 dietes mellitus. Monitor for hyperglycemi. Withhold in cses of severe (Grde 3) hyperglycemi until metolic control is chieved. Permnently discontinue for life-thretening (Grde 4) hyperglycemi [see Dosge nd Administrtion (2.10)]. In ptients receiving s single gent, dietes occurred in 0.9% (17/1994) of ptients including two cses of dietic ketocidosis. The medin time to onset ws 4.4 months (rnge: 15 dys to 22 months). In ptients receiving with ipilimum, dietes occurred in 1.5% (6/407) of ptients; the medin time to onset ws 2.5 months (rnge: 1.3 to 4.4 months). with ipilimum ws withheld in ptient nd permnently discontinued in second ptient who developed dietes. 5.5 Immune-Medited Nephritis nd Renl Dysfunction cn cuse immune-medited nephritis, defined s renl dysfunction or Grde 2 incresed cretinine, requirement for corticosteroids, nd no cler lternte etiology. Monitor ptients for elevted serum cretinine prior to nd periodiclly during tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for life-thretening (Grde 4) incresed serum cretinine. Administer corticosteroids t dose of 0.5 to 1 mg/kg/dy prednisone equivlents for moderte (Grde 2) or severe (Grde 3) incresed serum cretinine, if worsening or no improvement occurs, increse dose of corticosteroids to 1 to 2 mg/kg/dy prednisone equivlents. Withhold for moderte (Grde 2) or severe (Grde 3) incresed serum cretinine. Permnently discontinue for life-thretening (Grde 4) incresed serum cretinine [see Dosge nd Administrtion (2.10)]. (nivolum) s Single Agent In ptients receiving s single gent, immune-medited nephritis nd renl dysfunction occurred 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 dysfunction led to permnent discontinution of in 0.3% nd withholding of in 0.8% of ptients. ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 21 dys (rnge: 1 dy to 15.4 months). Complete resolution occurred in 48% of ptients. No ptients hd recurrence of nephritis or renl dysfunction fter re-initition of. with Ipilimum In ptients receiving with ipilimum, immune-medited nephritis nd renl dysfunction occurred in 2.2% (9/407) of ptients; the medin time to onset ws 2.7 months (rnge: 9 dys to 7.9 months). Immune-medited nephritis nd renl dysfunction led to permnent discontinution or withholding of with ipilimum in 0.7% nd 0.5% of ptients, respectively. Approximtely 67% of ptients received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 13.5 dys (rnge: 1 dy to 1.1 months). Complete resolution occurred in ll ptients. Two ptients resumed with ipilimum without recurrence of nephritis or renl dysfunction. 5.6 Immune-Medited Skin Adverse Rections cn cuse immune-medited rsh, including Stevens-Johnson syndrome (SJS) nd toxic epiderml necrolysis (TEN), some cses with ftl outcome. For symptoms or signs of SJS or TEN, withhold nd refer the ptient for specilized cre for ssessment nd tretment. If SJS or TEN is confirmed, permnently discontinue [see Dosge nd Administrtion (2.10)]. For immune-medited rsh, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed y corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) rsh. Withhold for severe (Grde 3) rsh nd permnently discontinue for life-thretening (Grde 4) rsh. s Single Agent In ptients receiving s single gent, immune-medited rsh occurred 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 discontinution of in 0.3% nd withholding of in 0.8% of ptients. Approximtely 16% of ptients with rsh received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 12 dys (rnge: 1 dys to 8.9 months) nd 85% received topicl corticosteroids. Complete resolution occurred in 48% of ptients. Recurrence of rsh occurred in 1.4% of ptients who resumed fter resolution of rsh. with Ipilimum In ptients receiving with ipilimum, immune-medited rsh occurred in 22.6% (92/407) of ptients; the medin time to onset ws 18 dys (rnge: 1 dy to 9.7 months). Immune-medited rsh led to permnent discontinution or withholding of with ipilimum in 0.5% nd 3.9% of ptients, respectively. Approximtely 17% of ptients with rsh received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 14 dys (rnge: 2 dys to 4.7 months). Complete resolution occurred in 47% of ptients. Approximtely 6% of ptients who resumed nd ipilimum fter resolution hd recurrence of rsh. 5.7 Immune-Medited Encephlitis cn cuse immune-medited encephlitis with no cler lternte etiology. Evlution of ptients with neurologic symptoms my include, ut not e limited to, consulttion with neurologist, rin MRI, nd lumr puncture. Withhold in ptients with new-onset moderte to severe neurologic signs or symptoms nd evlute to rule out infectious or other cuses of moderte to severe neurologic deteriortion. If other etiologies re ruled out, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents for ptients with immune-medited encephlitis, followed y corticosteroid tper. Permnently discontinue for immune-medited encephlitis [see Dosge nd Administrtion (2.10)]. s Single Agent In ptients receiving s single gent, encephlitis occurred in 0.2% (3/1994). Ftl limic encephlitis occurred in one ptient fter 7.2 months of exposure despite discontinution of nd dministrtion of corticosteroids. In the other two ptients, encephlitis occurred post-llogeneic HSCT [see Wrnings nd Precutions (5.10)]. with Ipilimum Encephlitis occurred in one ptient receiving with ipilimum (0.2%) fter 1.7 months of exposure. 5.8 Other Immune-Medited Adverse Rections cn cuse other cliniclly significnt nd potentilly ftl immune-medited dverse rections. Immune-medited dverse rections my occur fter discontinution of therpy. For ny suspected immune-medited dverse rections, exclude other cuses. Bsed on the severity of the dverse rection, permnently discontinue or withhold, dminister high-dose corticosteroids, nd if pproprite, initite

8 (nivolum) hormone-replcement therpy. Upon improvement to Grde 1 or less, initite corticosteroid tper nd continue to tper over t lest 1 month. Consider restrting fter completion of corticosteroid tper sed on the severity of the event [see Dosge nd Administrtion (2.10)]. Across clinicl trils of dministered s single gent or in comintion with ipilimum, the following cliniclly significnt immune-medited dverse rections, some with ftl outcome, occurred in less thn 1.0% of ptients receiving : myocrditis, rhdomyolysis, myositis, uveitis, iritis, pncretitis, fcil nd ducens nerve presis, demyelintion, polymylgi rheumtic, utoimmune neuropthy, Guillin-Brré syndrome, hypopituitrism, systemic inflmmtory response syndrome, gstritis, duodenitis, srcoidosis, histiocytic necrotizing lymphdenitis (Kikuchi lymphdenitis), motor dysfunction, vsculitis, nd mysthenic syndrome. If uveitis occurs in comintion with other immune-medited dverse rections, consider Vogt-Koyngi-Hrd-like syndrome, which hs een oserved in ptients receiving or in comintion with ipilimum nd my require tretment with systemic steroids to reduce the risk of permnent vision loss. 5.9 Infusion Rections cn cuse severe infusion rections, which hve een reported in less thn 1.0% of ptients in clinicl trils. Discontinue in ptients with severe or life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections [see Dosge nd Administrtion (2.10)]. s Single Agent In ptients receiving s 60-minute intrvenous infusion, infusion-relted rections occurred in 6.4% (127/1994) of ptients. In study ssessing the phrmcokinetics nd sfety of more rpid infusion, in which ptients received s 60-minute intrvenous infusion or 30-minute intrvenous infusion, infusion-relted rections occurred in 2.2% (8/368) nd 2.7% (10/369) ptients, respectively. Additionlly, 0.5% (2/368) nd 1.4% (5/369) of ptients, respectively, experienced dverse rections within 48 hours of infusion tht led to dose dely, permnent discontinution or withholding of. with Ipilimum In ptients receiving s 60-minute intrvenous infusion prior to the infusion of ipilimum, infusion-relted rections occurred in 2.5% (10/407) of ptients Complictions of ogeneic HSCT fter Complictions, including ftl events, occurred in ptients who received llogeneic HSCT fter. Outcomes were evluted in 17 ptients from the CHECKMATE-205 nd CHECKMATE-039 trils who underwent llogeneic HSCT fter discontinuing (15 with reduced-intensity conditioning, two with myeloltive conditioning). The medin ge t HSCT ws 33 (rnge: 18 to 56), nd medin of 9 doses of hd een dministered (rnge: 4 to 16). Six of 17 ptients (35%) died from complictions of llogeneic HSCT fter. Five deths occurred in the setting of severe or refrctory GVHD. Grde 3 or higher cute GVHD ws reported in 5/17 ptients (29%). Hypercute GVHD, defined s GVHD occurring within 14 dys fter stem cell infusion, ws reported in 2 ptients (20%). A steroid-requiring ferile syndrome, without n identified infectious cuse, ws reported in six ptients (35%) within the first 6 weeks post-trnsplnttion, with five ptients responding to steroids. Two cses of encephlitis were reported: one cse of Grde 3 lymphocytic encephlitis without n identified infectious cuse, which occurred nd resolved on steroids, nd one cse of Grde 3 suspected virl encephlitis which ws resolved with ntivirl tretment. Heptic veno-occlusive disese (VOD) occurred in one ptient, who received reducedintensity conditioned llogeneic HSCT nd died of GVHD nd multi-orgn filure. Other cses of heptic VOD fter reduced-intensity conditioned llogeneic HSCT hve lso een reported in ptients with lymphom who received PD-1 receptor locking ntiody efore trnsplnttion. Cses of ftl hypercute GVHD hve lso een reported. These complictions my occur despite intervening therpy etween PD-1 lockde nd llogeneic HSCT. Follow ptients closely for erly evidence of trnsplnt-relted complictions such s hypercute GVHD, severe (Grde 3 to 4) cute GVHD, steroid-requiring ferile syndrome, heptic VOD, nd other immune-medited dverse rections, nd intervene promptly Emryo-Fetl Toxicity Bsed on its mechnism of ction nd dt from niml studies, cn cuse fetl hrm when dministered to pregnnt womn. In niml reproduction studies, dministrtion of nivolum to cynomolgus monkeys from the onset of orgnogenesis through delivery resulted in incresed ortion nd premture infnt deth. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with n -contining regimen nd for t lest 5 months fter the lst dose of [see Use in Specific Popultions (8.1, 8.3)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the leling. (nivolum) Immune-Medited Pneumonitis [see Wrnings nd Precutions (5.1)] Immune-Medited Colitis [see Wrnings nd Precutions (5.2)] Immune-Medited Heptitis [see Wrnings nd Precutions (5.3)] Immune-Medited Endocrinopthies [see Wrnings nd Precutions (5.4)] Immune-Medited Nephritis nd Renl Dysfunction [see Wrnings nd Precutions (5.5)] Immune-Medited Skin Adverse Rections [see Wrnings nd Precutions (5.6)] Immune-Medited Encephlitis [see Wrnings nd Precutions (5.7)] Other Immune-Medited Adverse Rections [see Wrnings nd Precutions (5.8)] Infusion Rections [see Wrnings nd Precutions (5.9)] Complictions of ogeneic HSCT fter [see Wrnings nd Precutions (5.10)] 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. The dt in the Wrnings nd Precutions section reflect exposure to, s single gent, for cliniclly significnt dverse rections 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) dministering s single gent [see Wrnings nd Precutions (5)]. In ddition, cliniclly significnt dverse rections of dministered with ipilimum were evluted in 407 ptients with melnom enrolled in CHECKMATE-067 (n=313) or Phse 2 rndomized study (n=94), dministering with ipilimum, supplemented y immune-medited dverse rection reports in ongoing clinicl trils [see Wrnings nd Precutions (5)]. The dt descried elow reflect exposure to s single gent in CHECKMATE-037, CHECKMATE-066, nd CHECKMATE-067, nd to with ipilimum in CHECKMATE-067, which re rndomized, ctive-controlled trils conducted in ptients with unresectle or metsttic melnom. Also descried elow re single-gent dt from CHECKMATE-238, rndomized tril for the djuvnt tretment of ptients with completely resected Stge IIIB/C nd IV melnom, CHECKMATE-017 nd CHECKMATE-057, which re rndomized trils in ptients with metsttic NSCLC, CHECKMATE-025, which is rndomized tril in ptients with dvnced RCC, CHECKMATE-205 nd CHECKMATE-039, which re open-lel, multiple-cohort trils in ptients with chl, CHECKMATE-141, rndomized tril in ptients with recurrent or metsttic SCCHN, CHECKMATE-275, which is single-rm tril in ptients with urothelil crcinom, nd CHECKMATE-040, which is n open-lel, multiple-cohort tril in ptients with HCC. Unresectle or Metsttic Melnom Previously Treted Metsttic Melnom The sfety of s single gent ws evluted in CHECKMATE-037, rndomized, open-lel tril in which 370 ptients with unresectle or metsttic melnom received 3 mg/kg of y intrvenous infusion every 2 weeks (n=268) or investigtor s choice of chemotherpy (n=102), either dcrzine 1000 mg/m 2 every 3 weeks or the comintion of cropltin AUC 6 every 3 weeks plus pclitxel 175 mg/m 2 every 3 weeks [see Clinicl 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 chemotherpy-treted ptients. In this ongoing tril, 24% of ptients received for greter thn 6 months nd 3% of ptients received for greter thn 1 yer. In CHECKMATE-037, ptients hd documented disese progression following tretment with ipilimum nd, if BRAF V600 muttion positive, BRAF inhiitor. The tril excluded ptients with utoimmune disese, prior ipilimum-relted Grde 4 dverse rections (except for endocrinopthies) or Grde 3 ipilimum-relted dverse rections tht hd not resolved or were indequtely controlled within 12 weeks of the inititing event, ptients with condition requiring chronic systemic tretment with corticosteroids (>10 mg dily prednisone equivlent) or other immunosuppressive medictions, positive test for heptitis B or C, nd history of HIV. The tril popultion chrcteristics in the group nd the chemotherpy group were similr: 66% mle, medin ge 59.5 yers, 98% white, seline Estern Coopertive Oncology Group (ECOG) performnce sttus 0 (59%) or 1 (41%), 74% with M1c stge disese, 73% with cutneous melnom, 11% with mucosl melnom, 73% received two or more prior therpies for dvnced or metsttic disese, nd 18% hd rin metstsis. There were more ptients in the group with elevted LDH t seline (51% vs. 38%). ws discontinued for dverse rections in 9% of ptients. Twenty-six percent of ptients receiving hd drug dely for n dverse rection. Serious dverse rections occurred in 41% of ptients receiving. Grde 3 nd 4 dverse rections occurred in 42% of ptients receiving. The most frequent Grde 3 nd 4 dverse rections reported in 2% to less thn 5% of ptients receiving were dominl pin, hypontremi, incresed sprtte minotrnsferse, nd incresed lipse.