For Adults with Metsttic Melnom The + YERVOY Regimen ws shown to reduce the risk of disese progression by nerly 60% compred to YERVOY lone. Hlf of the ptients on + YERVOY were live t 11.5 months without their cncer spreding, growing, or getting worse, compred with 2.9 months for ptients on YERVOY lone. + YERVOY will not work for every ptient. Individul results my vry. Wht does tret? is prescription medicine used in combintion with YERVOY to tret type of skin cncer clled melnom tht hs spred or cnnot be removed by surgery (dvnced melnom). in combintion with YERVOY ws pproved bsed on the mount of time ptients lived without their tumors worsening. There is ongoing evlution of clinicl benefit of in combintion 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. Select Importnt Sfety Informtion cn cuse problems tht cn sometimes become serious or life-thretening nd cn led to deth. Serious side effects my include lung problems (pneumonitis); intestinl problems (colitis) tht cn led to ters or holes in your intestine; liver problems (heptitis); hormone glnd problems (especilly the thyroid, pituitry, drenl glnds, nd pncres); kidney problems, including nephritis nd kidney filure; skin problems; inflmmtion of the brin (encephlitis); problems in other orgns; nd severe infusion rections. Additionl serious side effects of YERVOY lone include: nerve problems tht cn led to prlysis; nd eye problems. Informtion provided in this brochure is not substitute for tlking with your helthcre professionl. Your helthcre professionl is the best source of informtion bout your disese. Plese see dditionl Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. 1
The + YERVOY Regimen It s the first immunotherpy combintion pproved for metsttic melnom The + YERVOY Regimen is unique combintion therpy. It brings together 2 metsttic melnom tretments tht work in complementry wys. It unites the brekthrough dvncement of, PD-1 (progrmmed deth receptor-1) immunotherpy, with the estblished history of YERVOY. Bristol-Myers Squibb is leder in metsttic melnom tretment We ve been t the forefront of the bttle ginst cncer since 1967, recently pving the wy in the field of immuno-oncology. Bristol-Myers Squibb first introduced YERVOY for metsttic melnom in Mrch 2011, nd continues to be leder in fighting this devstting form of cncer. Select Importnt Sfety Informtion is medicine tht my tret your melnom by working with your immune system. cn cuse your immune system to ttck norml orgns nd tissues in mny res of your body nd cn ffect the wy they work. These problems cn sometimes become serious or life-thretening nd cn led to deth. These problems my hppen nytime during tretment or even fter your tretment hs ended. Some of these problems my hppen more often when is used in combintion with YERVOY. For more informtion, cll 1-855--1 or visit www.yervoy.com All individuls depicted re models used for illustrtive purposes only. Plese see dditionl Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. 2
Proven in clinicl tril + YERVOY When they tem up, the results stnd out + YERVOY ws studied in BRAF negtive ptients (norml BRAF gene) nd BRAF positive ptients (bnorml BRAF gene), nd results were seen in both ptient types. The clinicl tril included 945 dult ptients with unresectble or metsttic melnom who were previously untreted. Ptients were treted with either the combintion of + YERVOY, lone, or YERVOY lone. Reduced the risk of disese progression by nerly 60% The + YERVOY combintion reduced the risk of cncer spreding, growing, or getting worse by nerly 60% compred with YERVOY lone. Hlf of the ptients on + YERVOY were live t 11.5 months without their cncer spreding, growing, or getting worse, compred with 2.9 months for ptients on YERVOY lone. + YERVOY will not work for every ptient. Individul results my vry. Hlf of the ptients experienced tumor shrinkge with the + YERVOY Regimen + YERVOY 50 % tumors shrunk 14 % or disppered 41% completely tumors shrunk (prtil response) tumors disppered completely (complete response) YERVOY lone 12% 9% 2% Wht re the serious side effects of when used in combintion with YERVOY? cn cuse problems tht cn sometimes become serious or life-thretening nd cn led to deth. Serious side effects my include lung problems (pneumonitis); intestinl problems (colitis) tht cn led to ters or holes in your intestine; liver problems (heptitis); hormone glnd problems (especilly the thyroid, pituitry, drenl glnds, nd pncres); kidney problems, including nephritis nd kidney filure; skin problems; inflmmtion of the brin (encephlitis); problems in other orgns; nd severe infusion rections. Additionl serious side effects of YERVOY lone include: nerve problems tht cn led to prlysis; nd eye problems. Getting medicl tretment right wy my keep these problems from becoming more serious. Wht re the most common side effects of when used in combintion with YERVOY? The most common side effects of, when used in combintion with YERVOY include: feeling tired; dirrhe; fever; shortness of breth; 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. Plese see dditionl Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. 3
How the (nivolumb) + YERVOY (ipilimumb) Regimen works Wht re the possible side effects of the + YERVOY Regimen? + YERVOY works with your immune system to fight metsttic melnom in 2 wys Immune cells re ctivted nd directed towrd the melnom. Your oncologist my prescribe the + YERVOY Regimen becuse these 2 medictions work with your immune system to help fight cncer, but they do it in different wys. Put simply, YERVOY stimultes the kind of cells tht fight disese, nd llows these cells to recognize melnom nd ttck it. While doing so, nd YERVOY cn lso ffect non-tumor cells. The combintion of nd YERVOY gives you strong option for fighting metsttic melnom right from the strt. Some of the side effects of the + YERVOY Regimen my be life-thretening nd my need your doctor s immedite ttention. Be sure to tell your doctor bout ll side effects s soon s possible, including ny chnges in how you re feeling, so he or she cn help ddress them right wy. The most common side effects of, when used in combintion with YERVOY include: feeling tired; dirrhe; fever; shortness of breth; 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. Stimulte YERVOY helps increse the ctivity of the immune system nd stimultes more of the cells tht help fight cncer. + Recognize llows these cells to recognize melnom nd ttck it. Select Importnt Sfety Informtion Becuse + YERVOY works with your immune system, it cn cuse your immune system to ttck norml orgns nd tissues in mny res of your body nd cn ffect the wy they work. These problems cn sometimes become serious or life-thretening nd cn led to deth. These problems my hppen nytime during tretment or even fter your tretment hs ended. Some of these problems my hppen more often when is used in combintion with YERVOY. Your doctor will check you for these problems during tretment. Your helthcre provider should perform blood tests, such s liver nd thyroid function tests, before strting nd during tretment. Your doctor 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. Cll your oncologist if you hve ny of these signs or symptoms or if they get worse. Your helthcre provider my decide to dely or completely stop or give you other medicines (such s corticosteroids or hormone replcement medicines) to tret your symptoms. Symptoms my occur nytime during tretment or even fter your tretment hs ended. Lung Problems new or worsening cough chest pin shortness of breth Intestinl Problems tht cn led to ters or holes in your intestine dirrhe (loose stools) or more bowel movements thn usul blood in your stools or drk, trry, sticky stools severe stomch re (bdomen) pin or tenderness Liver Problems yellowing of your skin or the whites of your eyes Liver Problems (cont d) severe nuse or vomiting pin on the right side of your stomch re (bdomen) drowsiness drk urine (te colored) bleeding or bruising more esily thn norml feeling less hungry thn usul Hormone Glnd Problems (especilly the thyroid, pituitry, drenl glnds, nd pncres) hedches tht will not go wy or unusul hedches extreme tiredness weight gin or weight loss Getting medicl tretment right wy my keep the problem from becoming more serious. Hormone Glnd Problems (cont d) dizziness or finting chnges in mood or behvior, such s decresed sex drive, irritbility, or forgetfulness hir loss feeling cold constiption voice gets deeper excessive thirst or lots of urine Kidney Problems including nephritis nd kidney filure decrese in the mount of urine blood in your urine swelling in your nkles loss of ppetite Do not tret symptoms yourself. Skin Problems rsh itching skin blistering ulcers in mouth or other mucous membrnes Inflmmtion of the Brin hedche fever tiredness or wekness confusion memory problems sleepiness seeing or hering things tht re not relly there (hllucintions) seizures stiff neck Problems in Other Orgns chnges in eyesight severe or persistent muscle or joint pins severe muscle wekness 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 brething dizziness fever feeling like pssing out Do not feel embrrssed or worry tht you re bothering your oncologist. Plese see dditionl Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. Plese see dditionl Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. 4
Getting your tretment (nivolumb) nd YERVOY (ipilimumb) re 2 different medicines tht re delivered into your vein through n intrvenous (IV) line. Tretment begins with the combintion phse dose of ech medicine every 3 weeks for your first 4 doses. The dose tkes 60 minutes. The YERVOY dose tkes 90 minutes. After the combintion phse, tretment continues with lone, every 2 weeks. How quickly cn the + YERVOY combintion work? Your doctor cn tell you wht you my expect. As you begin nd continue tretment, it is importnt to keep ppointments with your doctor nd follow his or her recommendtions. Your doctor will do blood tests to check you for side effects. Infusion Schedule FIRST DOSE + YERVOY WEEK 3 + YERVOY WEEK 6 + YERVOY + YERVOY first infusion. Infusions will continue every 3 weeks for your first 4 doses. This prt of the tretment cn be completed in s few s 9 weeks. Wht should I tell my helthcre provider? Before you receive the + YERVOY Regimen, tell your helthcre provider if you: n hve immune system problems such s Crohn s disese, ulcertive colitis, lupus, or srcoidosis n hve hd n orgn trnsplnt n hve lung or brething problems n hve liver problems n hve ny other medicl conditions n re pregnnt or pln to become pregnnt nd YERVOY cn hrm your unborn bby. Femles who re ble to become pregnnt should use n effective method of birth control during nd for t lest 5 months fter the lst dose of. Tlk to your doctor bout birth control methods tht you cn use during this time. Tell your doctor right wy if you become pregnnt during tretment. n re brestfeeding or pln to brestfeed It is not known if either tretment psses into your brest milk. Do not brestfeed during tretment. Tell your helthcre provider bout ll the medicines you tke, including prescription nd over-the-counter medicines, vitmins, herbl supplements, nd steroids or other medicines tht lower your immune response. WEEK 9 + YERVOY 3 3 WEEK 12 Alone Continue lone. Continue tretment every 2 weeks s long s it is working nd side effects re tolerble. These re the recommendtions bout tretment timing nd dosing. Your doctor will decide how mny tretments you need. Helpful resources Turn to your helthcre provider first Tlk to your helthcre provider if you hve ny questions bout the + YERVOY Regimen. He or she is lwys the best source of informtion when it comes to your helth. Reimbursement nd co-py support Bristol-Myers Squibb is committed to helping pproprite ptients get ccess to our medictions. We hve creted Access Support to help you understnd your insurnce coverge nd how you re going to py for your medicine. We offer n Oncology Co-Py Progrm tht ssists with out-of-pocket co-pyment or co-insurnce requirements for eligible, commercilly insured ptients who hve been prescribed certin Bristol-Myers Squibb oncology products, including the + YERVOY Regimen. Ask your doctor for more informtion or visit www.bmsaccesssupport.com For more informtion, cll 1-855--1 or visit www.yervoy.com Support orgniztions Listed below re melnom support orgniztions tht provide melnom informtion, s well s ptient nd cregiver support. Bristol-Myers Squibb is not ffilited with nor endorses these orgniztions. The informtion/links provided by Bristol-Myers Squibb re ment for informtionl purposes only nd re not ment to replce physicin s medicl dvice or imply endorsement. AIM t Melnom Foundtion www.imtmelnom.org AIM t Melnom Foundtion is committed to dvncing the bttle ginst melnom. CncerCre www.cncercre.org CncerCre provides free, professionl support services to nyone ffected by cncer. Cncer Reserch Institute www.cncerreserch.org Cncer Reserch Institute is dedicted to dvncing nd rising wreness of immunotherpy for cncer. Cncer Support Community (CSC) www.cncersupportcommunity.org 1-888-793-9355 The CSC is committed to ensuring tht no one fces cncer lone. Melnom Interntionl Foundtion (MIF) www.melnominterntionl.org 1-866-463-6663 The MIF develops personlized strtegies with ptients with the gol of helping them live longer, better lives. Melnom Reserch Allince (MRA) www.curemelnom.org MRA is public chrity tht commits 100% of ll dontions to melnom reserch to ccelerte the pce of trnsltionl melnom reserch, dvnce cures for ll ptients, nd prevent more melnoms. Plese see dditionl Importnt Sfety Informtion on pge 6 nd Melnom Reserch Foundtion (MRF) www.melnom.org 1-800-673-1290 ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING The MRF hs mny resources to help ptients nvigte their for YERVOY regrding immune-medited side effects, nd Mediction Guides melnom dignosis. for nd YERVOY t the end of this brochure. 5
Importnt Sfety Informtion Importnt Sfety Informtion bout in combintion with YERVOY is medicine tht my tret your melnom by working with your immune system. cn cuse your immune system to ttck norml orgns nd tissues in mny res of your body nd cn ffect the wy they work. These problems cn sometimes become serious or life-thretening nd cn led to deth. These problems my hppen nytime during tretment or even fter your tretment hs ended. Some of these problems my hppen more often when is used in combintion with YERVOY. YERVOY cn cuse serious side effects in mny prts of your body which cn led to deth. These problems my hppen nytime during tretment with YERVOY or fter you hve completed tretment. Serious side effects my include: n Lung problems (pneumonitis). Symptoms of pneumonitis my include: new or worsening cough; chest pin; nd shortness of breth. n Intestinl problems (colitis) tht cn led to ters or holes in your intestine. Signs nd symptoms of colitis my include: dirrhe (loose stools) or more bowel movements thn usul; blood in your stools or drk, trry, sticky stools; nd severe stomch re (bdomen) pin or tenderness. n Liver problems (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 (bdomen); drowsiness; drk urine (te colored); bleeding or bruising more esily thn norml; nd feeling less hungry thn usul. n Hormone glnd problems (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 behvior, such s decresed sex drive, irritbility, or forgetfulness; hir loss; feeling cold; constiption; voice gets deeper; nd excessive thirst or lots of urine. n Kidney problems, including nephritis nd kidney filure. Signs of kidney problems my include: decrese in the mount of urine; blood in your urine; swelling in your nkles; nd loss of ppetite. n Skin problems. Signs of these problems my include: rsh; itching; skin blistering; nd ulcers in the mouth or other mucous membrnes. n Inflmmtion of the brin (encephlitis). Signs nd symptoms of encephlitis my include: hedche; fever; tiredness or wekness; confusion; memory problems; sleepiness; seeing or hering things tht re not relly there (hllucintions); seizures; nd stiff neck. n Problems in other orgns. Signs of these problems my include: chnges in eyesight; severe or persistent muscle or joint pins; nd severe muscle wekness. Additionl serious side effects observed during seprte study of YERVOY lone include: n Nerve problems tht cn led to prlysis. Symptoms of nerve problems my include: unusul wekness of legs, rms, or fce; nd numbness or tingling in hnds or feet. n Eye problems. Symptoms my include: blurry vision, double vision, or other vision problems; nd eye pin or redness. Getting medicl tretment right wy my keep these problems from becoming more serious. Your helthcre provider will check you for these problems 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 brething; dizziness; fever; nd feeling like pssing out. Pregnncy nd Nursing: n Tell your helthcre provider if you re pregnnt or pln to become pregnnt. nd YERVOY cn hrm your unborn bby. Femles who re ble to become pregnnt should use n effective method of birth control during nd for t lest 5 months fter the lst dose of. Tlk to your helthcre provider bout birth control methods tht you cn use during this time. Tell your helthcre provider right wy if you become pregnnt or think you re pregnnt during tretment. You or your helthcre provider should contct Bristol-Myers Squibb t 1-800-721-5072 s soon s you become wre of the pregnncy. n Pregnncy Sfety Surveillnce Study: Femles who become pregnnt during tretment with YERVOY re encourged to enroll in Pregnncy Sfety Surveillnce Study. The purpose of this study is to collect informtion bout the helth of you nd your bby. You or your helthcre provider cn enroll in the Pregnncy Sfety Surveillnce Study by clling 1-844-593-7869. n Before receiving tretment, tell your helthcre provider if you re brestfeeding or pln to brestfeed. It is not known if either tretment psses into your brest milk. Do not brestfeed during tretment nd for 3 months fter the lst dose of YERVOY. Tell your helthcre provider bout: n Your helth problems or concerns if you: hve immune system problems such s utoimmune disese, Crohn s disese, ulcertive colitis, lupus, or srcoidosis; hve hd n orgn trnsplnt; hve lung or brething problems; hve liver problems; or hve ny other medicl conditions. n All the medicines you tke, including prescription nd over-the-counter medicines, vitmins, nd herbl supplements. The most common side effects of, when used in combintion with YERVOY include: feeling tired; dirrhe; fever; shortness of breth; 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 possible side effects. For more informtion, sk your helthcre provider or phrmcist. Cll your doctor for medicl dvice bout side effects. You re encourged to report negtive side effects of prescription drugs to the FDA. Visit www.fd.gov/medwtch or cll 1-800-FDA-1088. You my lso report side effects to Bristol-Myers Squibb t 1-800-721-5072. Plese see ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. 6
For Adults with Metsttic Melnom Support for your fight ginst metsttic melnom Sign up for: We re committed to providing you with ongoing support during tretment. Tht s why we ve creted this complimentry progrm, offering: Support Resources Receive helpful tools nd mterils in your milbox or inbox. Personlized Cre Counselor Support Ptients cn sign up for the option to spek with registered nurse who cn respond to questions bout tretment nd help you to be n informed prtner with your doctor. Cre Counselors cnnot offer medicl dvice. Your helthcre professionl is the best source of informtion bout your helth. Ptient Cll Center Cll 1-855--1 (1-855-67861) 8AM to 8PM ET, Mondy to Fridy, to sk generl questions bout + YERVOY. Visit www.withyou.com or cll 1-855--1 (1-855-67861) + YERVOY is not pproved for ptients less thn 18 yers of ge. Plese see Importnt Sfety Informtion on pge 6 nd ccompnying U.S. Full Prescribing Informtion, including Boxed WARNING for YERVOY regrding immune-medited side effects, nd Mediction Guides for nd YERVOY t the end of this brochure. Bristol-Myers Squibb is committed to helping ptients throughout their + YERVOY Regimen tretment. 2018 Bristol-Myers Squibb Compny. All rights reserved., YERVOY, Access Support, nd the relted logos re trdemrks of Bristol-Myers Squibb Compny. 7356US1600186-15-01 01/18 7
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (nivolumb) injection, for intrvenous use Initil U.S. Approvl: 2014 -----------------------------RECENT MAJOR CHANGES ---------------------------- Indictions nd Usge (1) 12/2017 Dosge nd Administrtion (2) 1/2018 Wrnings nd Precutions, Immune-Medited Heptitis (5.3) 9/2017 Wrnings nd Precutions, Other Immune-Medited Adverse Rections (5.8) 9/2017 Wrnings nd Precutions, Infusion Rections (5.9) 1/2018 ----------------------------- INDICATIONS AND USAGE ----------------------------- is progrmmed deth receptor-1 (PD-1) blocking ntibody indicted for the tretment of: ptients with BRAF V600 wild-type unresectble or metsttic melnom, s single gent. (1.1) ptients with BRAF V600 muttion-positive unresectble or metsttic melnom, s single gent. (1.1) ptients with unresectble or metsttic melnom, in combintion with ipilimumb. (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-bsed chemotherpy. Ptients with EGFR or ALK genomic tumor berrtions should hve disese progression on FDA-pproved therpy for these berrtions 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 b : (1.5) utologous hemtopoietic stem cell trnsplnttion (HSCT) nd brentuximb 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-bsed therpy. (1.6) ptients with loclly dvnced or metsttic urothelil crcinom who b : 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 instbility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinotecn. b (1.8) ptients with heptocellulr crcinom who hve been previously treted with sorfenib. b (1.9) This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. b This indiction is pproved under ccelerted pprovl bsed on overll response rte nd durtion of response. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in confirmtory trils. -------------------------- DOSAGE AND ADMINISTRATION -------------------------- Administer s n intrvenous infusion. Unresectble or metsttic melnom 240 mg every 2 weeks. (2.1) with ipilimumb: 1 mg/kg, followed by ipilimumb 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 Unresectble 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 Instbility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer 1.9 Heptocellulr Crcinom Clssicl Hodgkin lymphom (nivolumb) 3 mg/kg every 2 weeks. (2.5) Recurrent or metsttic squmous cell crcinom of the hed nd neck 3 mg/kg every 2 weeks. (2.6) Loclly dvnced or metsttic urothelil crcinom 240 mg every 2 weeks (2.7) Microstellite instbility-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 ipilimumb 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 bilirubin 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 febrile syndrome, heptic veno-occlusive disese, nd other immune-medited dverse rections. Trnsplnt-relted mortlity hs occurred. (5.10) Embryo-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, bck pin, rthrlgi, upper respirtory trct infection, pyrexi, hedche, nd bdominl pin. (6.1) with ipilimumb: ftigue, rsh, dirrhe, nuse, pyrexi, vomiting, nd dyspne. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Bristol-Myers Squibb t 1-800-721-5072 or FDA t 1-800-FDA-1088 or www.fd.gov/medwtch. -------------------------- USE IN SPECIFIC POPULATIONS -------------------------- Lcttion: Discontinue brestfeeding. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 1/2018 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Unresectble 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)
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 Allogeneic HSCT fter 5.11 Embryo-Fetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 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 12.2 Phrmcodynmics 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 Unresectble 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 Instbility-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 subsections omitted from the full prescribing informtion re not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom (nivolumb) s single gent is indicted for the tretment of ptients with BRAF V600 wild-type unresectble or metsttic melnom [see Clinicl Studies (14.1)]. s single gent is indicted for the tretment of ptients with BRAF V600 muttion-positive unresectble or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils., in combintion with ipilimumb, is indicted for the tretment of ptients with unresectble or metsttic melnom [see Clinicl Studies (14.1)]. This indiction is pproved under ccelerted pprovl bsed on progression-free survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit 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-bsed chemotherpy. Ptients with EGFR or ALK genomic tumor berrtions should hve disese progression on FDA-pproved therpy for these berrtions 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 brentuximb vedotin, or 3 or more lines of systemic therpy tht includes utologous HSCT. This indiction is pproved under ccelerted pprovl bsed on overll response rte. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit 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-bsed therpy [see Clinicl Studies (14.6)]. 1.7 Urothelil Crcinom (nivolumb) 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 bsed on tumor response rte nd durtion of response. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in confirmtory trils [see Clinicl Studies (14.7)]. 1.8 Microstellite Instbility-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 instbility-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 bsed on overll response rte nd durtion of response. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in confirmtory trils. 1.9 Heptocellulr Crcinom is indicted for the tretment of ptients with heptocellulr crcinom (HCC) who hve been previously treted with sorfenib. This indiction is pproved under ccelerted pprovl bsed on tumor response rte nd durbility of response. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils [see Clinicl Studies (14.9)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Unresectble 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 uncceptble toxicity. The recommended dose of is 1 mg/kg dministered s n intrvenous infusion over 30 minutes, followed by ipilimumb on the sme dy, every 3 weeks for 4 doses [see Clinicl Studies (14.1)]. The recommended subsequent dose of, s single gent, is 240 mg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptble toxicity. Review the Full Prescribing Informtion for ipilimumb 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 uncceptble 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 uncceptble toxicity.
(nivolumb) 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 uncceptble toxicity. 2.5 Recommended Dosge for chl The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.6 Recommended Dosge for SCCHN The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 30 minutes every 2 weeks until disese progression or uncceptble 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 uncceptble 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 uncceptble 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 uncceptble toxicity. 2.10 Dose Modifictions Recommendtions for modifictions re provided in Tble 1. When is dministered in combintion with ipilimumb, if is withheld, ipilimumb should lso be 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. Tble 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 ipilimumb 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 b totl bilirubin more thn 1.5 nd up to 3 times the ULN AST or ALT more thn 5 times the ULN or totl bilirubin more Permnently discontinue thn 3 times the ULN If AST/ALT is within norml limits t bseline nd increses to more thn 3 nd up to 5 times the ULN Heptitis/HCC b Hypophysitis If AST/ALT is more thn 1 nd up to 3 times ULN t bseline 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 bseline 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 bilirubin 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) (nivolumb) Tble 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 Dibetes 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. b HCC: heptocellulr crcinom. c Resume tretment when AST/ALT returns to bseline. 2.11 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 by 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 binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer).
(nivolumb) Do not codminister other drugs through the sme intrvenous line. Flush the intrvenous line t end of infusion. When dministered in combintion with ipilimumb, infuse first followed by ipilimumb on the sme dy. Use seprte infusion bgs 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 been 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 by 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 Ipilimumb In ptients receiving with ipilimumb, 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 ipilimumb 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 ipilimumb. 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 by 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 by 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 combintion with ipilimumb, withhold nd ipilimumb for moderte colitis (Grde 2). Permnently discontinue nd ipilimumb 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 infliximb to high-dose corticosteroids. Complete resolution occurred in 74% of ptients. Approximtely 16% of ptients hd recurrence of colitis fter re-initition of. (nivolumb) with Ipilimumb In ptients receiving with ipilimumb, 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 ipilimumb 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 infliximb to high-dose corticosteroids. Complete resolution occurred in 75% of ptients. Approximtely 28% of ptients hd recurrence of colitis fter re-initition of with ipilimumb. 5.3 Immune-Medited Heptitis cn cuse immune-medited heptitis, defined s requiring use of corticosteroids nd no cler lternte etiology. Monitor ptients for bnorml liver tests prior to nd periodiclly during tretment. Administer corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed by corticosteroid tper for severe (Grde 3) or life-thretening (Grde 4) trnsminse elevtions, with or without concomitnt elevtion in totl bilirubin. 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 bsed on severity of immune-medited heptitis nd bseline AST nd ALT levels s described in Tble 1 [see Dosge nd Administrtion (2.10)]. In ddition, dminister corticosteroids t dose of 1 to 2 mg/kg/dy prednisone equivlents followed by 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. All 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 Ipilimumb In ptients receiving with ipilimumb, 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 ipilimumb 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 ipilimumb. 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 by 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 ipilimumb, 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 ipilimumb 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).