For Adults With Previously Treted Advnced Non-Smll Cell Lung Cncer (NSCLC) individuls depicted re models used for illustrtive purposes only. It cn be overwhelming to lern tht your previously treted dvnced non-smll cell lung cncer (NSCLC) hs come bck or spred fter you hve been through tretments like pltinum-bsed chemotherpy. But even when these options hve been unsuccessful, there my still be nother option for ptients like you (nivolumb). my not work for everyone. Individul results my vry. Who is for? is prescription medicine used to tret type of dvnced lung cncer clled non-smll cell lung cncer. is for dult ptients who: Hve lung cncer tht hs spred or grown; AND Hve tried chemotherpy tht contins pltinum, nd it did not work or is no longer working; AND If their tumor hs n bnorml EGFR or ALK gene, they hve tried n FDA-pproved therpy with these bnorml genes nd it did not work or is no longer working. It is not known if is sfe nd effective in children less thn 18 yers of ge. is medicine tht my tret your lung cncer by working 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 these orgns 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. Select Importnt Fcts bout cn cuse problems tht cn sometimes become serious or lifethretening 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. The most common side effects of when used lone include: feeling tired; pin in muscles, bones, nd joints; dirrhe; cough; constiption; bck pin; fever; rsh; itchy skin; nuse; shortness of breth; decresed ppetite; upper respirtory trct infection; nd wekness. is the first nd only immunotherpy the FDA pproved bsed on two phse 3 clinicl trils tht demonstrted longer life for dults with dvnced NSCLC previously treted with pltinum-bsed chemotherpy. If you hve this type of lung cncer, my be n option for you. In clinicl tril of 582 ptients whose dvnced non-squmous NSCLC hd spred or grown fter tretment with pltinum-bsed chemotherpy, 292 were treted with, nd 290 were treted with chemotherpy (docetxel). ws shown to reduce the risk of dying by 27% compred to chemotherpy (docetxel). Hlf of the ptients on were still live t 12.2 months, compred to 9.4 months with chemotherpy (docetxel). Additionlly, ws shown to prtilly or completely shrink tumors in 19% of ptients, compred to 12% with chemotherpy (docetxel). There ws no difference between the two tretments in the length of time tht ptients lived without their tumors worsening. Red bout the second tril in previously treted dvnced squmous NSCLC ptients on the next pge. Is right for me? Tht s converstion you need to hve with your oncologist. But you should know tht is different kind of tretment option tht my work for you. is pproved for dults whose dvnced NSCLC hs spred or grown fter tretment with pltinum-bsed chemotherpy. If your tumor hs n bnorml EGFR or ALK gene, you should hve lso tried n FDA-pproved therpy for tumors with these bnorml genes, nd it did not work or is no longer working. 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 Fcts bout, including serious side effects, on pges 5-6 nd ccompnying U.S. Full Prescribing Informtion nd Mediction Guide. Ask your doctor if my be right for you, or visit www.tretment.com 1
(nivolumb) chnce to live longer is the first nd only immunotherpy the FDA pproved bsed on two phse 3 clinicl trils tht demonstrted longer life for dults with dvnced NSCLC previously treted with pltinum-bsed chemotherpy ADVANCED NON-SQUAMOUS NSCLC TRIAL ADVANCED SQUAMOUS NSCLC TRIAL PATIENTS WERE GIVEN About the Clinicl Tril 582 292 290 PATIENTS WERE GIVEN CHEMOTHERAPY (DOCETAXEL) PATIENTS WERE GIVEN About the Clinicl Tril 272 135 137 PATIENTS WERE GIVEN CHEMOTHERAPY (DOCETAXEL) Demonstrted Longer Life in Clinicl Tril 27% reduced risk of dying with compred to chemotherpy (docetxel) Hlf the ptients were still live t 12.2 months COMPARED WITH 9.4 months for those who received chemotherpy In the sme study: ws shown to prtilly or completely shrink tumors in 19% of ptients, compred to 12% with chemotherpy (docetxel) There ws no difference between the two tretments in the length of time tht ptients lived without their tumors worsening Demonstrted Longer Life in Clinicl Tril 41% reduced risk of dying with compred to chemotherpy (docetxel) Hlf the ptients were still live t 9.2 months COMPARED WITH 6 months for those who received chemotherpy In the sme study: ws shown to prtilly or completely shrink tumors in 20% of ptients, compred to 9% with chemotherpy (docetxel) The length of time tht hlf of the ptients lived without their tumors worsening ws 3.5 months with nd 2.8 months for chemotherpy (docetxel) will not work for everyone. Individul results my vry. To lern more bout clinicl tril results, visit www.tretment.com/clinicl-tril-results Wht re the most common side effects of? The most common side effects of include: feeling tired, pin in muscles, bones nd joints, dirrhe, cough, constiption, bck pin, fever, rsh, itchy skin, nuse, shortness of breth, decresed ppetite, upper respirtory trct infection, wekness. These re not ll of the possible side effects of. Tlk to your helthcre tem for more informtion. You cn report ny side effects you experience to the FDA by clling 1-800-FDA-1088. Plese see dditionl Importnt Fcts bout, including serious side effects, on pges 5-6 nd ccompnying U.S. Full Prescribing Informtion nd Mediction Guide. 2
How does (nivolumb) work with my immune system? HOW IS DIFFERENT FROM CHEMOTHERAPY? is n immunotherpy tretment tht works with the T cells of your immune system. Lerning more bout the tretment, including how it my work, cn help you hve better converstions with your helthcre tem nd be empowered to mke more-informed tretment decisions. 1 Wht do my T cells do to cncer cells? How does cncer escpe my T cells? Like rdr, your immune system s T cells re lwys serching for threts. Once T cells recognize threts like cncer cells, they become ctive nd ttck them in order to help protect your body. 2 Sometimes, cncer cells re ble to disguise themselves from T cells. If this hppens, cncer cells inctivte T cells so the T cells cnnot ttck. This llows cncer to grow more esily. RECOGNIZE ATTACK Inctive T cell Disguised cncer cells Active T cell Cncer cells HERE S A CLOSER LOOK AT HOW WORKS INSIDE YOUR BODY: 3 How does work inside my body? my help T cells recognize nd ttck cncer cells gin, by blocking cncer s bility to disguise itself. This llows your T cells to be ctive nd to ttck. While doing so, could lso cuse your T cells to ttck helthy cells in your body. Active T cell RECOGNIZE ATTACK Cncer cells Helthy cells cn cuse your T cells to ttck helthy cells contined within 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, nd my hppen nytime during tretment or even fter your tretment hs ended. Wht re the most serious side effects of? cn cuse problems tht cn sometimes become serious or life-thretening nd cn led to deth. They cn hppen nytime during tretment or even fter tretment hs ended. 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 severe infusion rections Plese see dditionl Importnt Fcts bout on pges 5-6 nd ccompnying U.S. Full Prescribing Informtion nd Mediction Guide. 3
How is (nivolumb) given? A DOSING SCHEDULE WITH A SINGLE ONE-HOUR INFUSION EVERY TWO WEEKS Week 1 At About Week 9 Receive 1st infusion. Infusions will continue every 2 weeks Receive 1st scn. Continue tretment every 2 weeks s long s it is working nd side effects re tolerble These re generl recommendtions bout tretment timing nd dosing bsed on clinicl tril. Only your doctor cn mke specific recommendtions bout your tretment with. is given through n intrvenous (IV) infusion. The medicine is given directly into the bloodstrem through needle plced in vein by helthcre professionl usully in the rm or hnd. infusions re usully given every 2 weeks. Your doctor will decide how mny tretments you need. You should sty on tretment unless the cncer grows or you hve uncceptble side effects. Your helthcre provider will do blood tests to check you for side effects, nd my tret you with corticosteroid hormone replcement medicines, nd dely or completely stop tretment with if you hve side effects tht re severe. Be sure to tlk to your helthcre tem bout side effects. The infusion tkes 60 minutes, though ctul time in the clinic my vry. Frequent communiction with your helthcre tem is n importnt prt of tretment. Use your 2-week ppointment to let them know how you re feeling nd sk ny questions you my hve. You my lso be ble to tlk with others going through similr sitution. If you miss n ppointment, cll your helthcre provider right wy. Try to schedule your ppointments for the sme dy of the week nd the sme time of dy to mke them esier to remember. It is importnt for you to keep ll ppointments with your helthcre provider. See pge 6 for informtion bout pregnncy, nursing, helth problems, nd other medicines tht you should discuss with your helthcre tem before strting. Questions nd nswers Q Wht types of lung cncer is pproved for? A is pproved for dults with dvnced NSCLC previously treted with pltinum-bsed chemotherpy. NSCLC is the most common type of lung cncer. NSCLC includes squmous nd non-squmous cncers. If your tumor hs n bnorml EGFR or ALK gene, you should hve lso tried n FDA-pproved therpy for tumors with these bnorml genes, nd it did not work or is no longer working. Q A Do people hve to be tested for the PD-L1* biomrker when considering? While does not require PD-L1 biomrker testing, your physicin my still choose to do so to help inform medicl decisions regrding tretment. People were included in the clinicl trils regrdless of their PD-L1 biomrker sttus. Q Where cn I go to get my tretments? A You nd your doctor should discuss the best plce to get your infusions, whether it s your doctor s office, n infusion center, or locl hospitl. Q How do I know if I m responding to? A While undergoing tretment with, your doctor will likely order periodic scns to evlute whether there re ny chnges in the size of your tumors. Sign up for: with You mens just tht: we re here to help you better understnd, whether you or loved one re just considering or lredy hve n prescription. This complimentry progrm includes the following resources. Sign up nd you ll receive: Helpful Informtion for You Get useful tips, tools, nd eductionl mterils tht cn help you lern more bout nd my help support your cre. Support nd Advoccy Groups We cn direct you to orgniztions tht my be helpful for the chllenges you my fce. A Cre Counselor s Close s Your Phone If you re prescribed nd sign up for this dditionl resource, you ll be ble to spek with registered nurse. This personl Cre Counselor cn nswer questions bout tretment nd help you to be more informed prtner with your doctor. Cre Counselors cnnot provide medicl dvice. Your helthcre professionl is the best source of informtion bout your helth. If you d like to sign up for the with You progrm, or if you hve generl questions bout, cll 1-855--1 (1-855-67861) 8 AM to 8 PM ET, Mondy to Fridy, or visit withyou.com. *Progrmmed deth-lignd 1. Plese see dditionl Importnt Fcts bout, including serious side effects, on pges 5-6 nd ccompnying U.S. Full Prescribing Informtion nd Mediction Guide. 4
Importnt Fcts bout (nivolumb) This is summry of importnt informtion tht you need to know bout. Your helthcre tem cn work with you to help nswer ny questions you my hve bout. Keep this informtion in sfe plce, so you cn refer to it before nd during your tretment. Look out for the following icons s you red: Tlk to your helthcre tem Cll helthcre provider right wy Helpful informtion to remember Wht is? is prescription medicine used to tret type of dvnced stge lung cncer clled non-smll cell lung cncer. is for dult ptients who: Hve lung cncer tht hs spred or grown; AND Hve tried chemotherpy tht contins pltinum, nd it did not work or is no longer working; AND If their tumor hs n bnorml EGFR or ALK gene, they hve lso tried n FDA-pproved therpy for tumors with these bnorml genes nd it did not work or is no longer working. It is not known if is sfe nd effective in children less thn 18 yers. is medicine tht my tret your lung cncer by working 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 these orgns work. Wht re the serious side effects of? A serious side effect is side effect tht cn sometimes become life-thretening nd cn led to deth. They cn hppen nytime during tretment or even fter your tretment hs ended. Get medicl help immeditely if you develop ny of these symptoms or they get worse. It my keep these problems from becoming more serious. Your helthcre tem will check you for side effects during tretment with, nd my tret you with corticosteroid or hormone replcement medicines. If you hve serious side effect, your helthcre tem my need to dely or completely stop your tretment. Lung problems (pneumonitis) Things to look out for my include: new or worsening cough chest pin shortness of breth Intestinl problems (colitis) tht cn led to ters or holes in your intestine Things to look out for my include: 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 (heptitis) Things to look out for 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 feeling less hungry thn usul Hormone glnd problems (especilly the thyroid, pituitry, drenl glnds, nd pncres) Things to look out for 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 excessive thirst or lots of urine Kidney problems, including nephritis nd kidney filure Things to look out for my include: decrese in the mount of urine blood in your urine swelling in your nkles loss of ppetite Skin problems Things to look out for my include: rsh itching skin blistering ulcers in the mouth or other mucous membrnes Inflmmtion of the brin (encephlitis) Things to look out for my include: 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 Things to look out for my include: chnges in eyesight severe or persistent muscle or joint pins severe muscle wekness Plese see dditionl Importnt Fcts bout on pge 6 nd ccompnying U.S. Full Prescribing Informtion nd Mediction Guide. 5
Importnt Fcts bout (nivolumb), continued Severe infusion rections Things to look out for my include: chills or shking itching or rsh flushing difficulty brething dizziness fever feeling like pssing out Tlk to your helthcre tem right wy if you get ny of the symptoms of severe infusion rection during or fter n infusion of. Wht should I discuss with my helthcre tem bout pregnncy nd nursing before strting? Tell your helthcre tem if you re pregnnt or pln to become pregnnt. 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. Tell your helthcre tem bout birth control methods tht you cn use during this time. Tell your helthcre tem right wy if you become pregnnt during tretment. Tell your helthcre tem if you re brestfeeding or pln to brestfeed. It is not known if psses into your brest milk. Do not brestfeed during tretment. Wht should I discuss with my helthcre tem before strting? Tlk to your helthcre tem bout ll of your helth problems or concerns, including if you: hve immune system problems such s Crohn s disese, ulcertive colitis, or lupus hve hd n orgn trnsplnt hve lung or brething problems hve liver problems hve ny other medicl conditions Wht re the common side effects of? The most common side effects of include: feeling tired rsh pin in muscles, bones, itchy skin nd joints nuse dirrhe shortness of breth cough decresed ppetite constiption upper respirtory trct bck pin infection fever wekness These re not ll of the possible side effects of. Tlk to your helthcre tem for more informtion. You cn report ny side effects you experience to the FDA by clling 1-800-FDA-1088. How will I receive? is prescription medicine tht is given s n intrvenous (IV) infusion by your helthcre tem. An IV infusion is when medicine is given directly into the bloodstrem through needle plced in vein by helthcre professionl - usully in the rm or hnd. 60 minutes intrvenous (IV) infusion time, though ctul time in the clinic my vry. is usully given every 2 weeks. Your doctor will decide how mny tretment cycles you will receive, nd do blood tests to check you for side effects. Cll your doctor right wy to reschedule your ppointment if you miss ny of your ppointments. For more informtion, plese see U.S. Full Prescribing Informtion nd Mediction Guide for, or tlk to your helthcre tem. Tlk to your helthcre tem bout ll of the medicines you re tking, including: prescription medicines over-the-counter medicines vitmins herbl supplements 2017 Bristol-Myers Squibb Compny. rights reserved. nd the relted logo re trdemrks of Bristol-Myers Squibb Compny. 1506US1605793-01-01 01/17 6
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) 11/2016 Dosge nd Administrtion (2) 11/2016 Wrnings nd Precutions (5) 10/2016 ----------------------------- 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) BRAF V600 muttion-positive unresectble or metsttic melnom, s single gent. This indiction is pproved under ccelerted pprovl bsed on progressionfree survivl. Continued pprovl for this indiction my be contingent upon verifiction nd description of clinicl benefit in the confirmtory trils. (1.1) Unresectble or metsttic melnom, in combintion with ipilimumb. 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. (1.1) 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. (1.2) Advnced renl cell crcinom who hve received prior nti-ngiogenic therpy. (1.3) Clssicl Hodgkin lymphom tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion brentuximb vedotin. 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. (1.4) Recurrent or metsttic squmous cell crcinom of the hed nd neck with disese progression on or fter pltinum-bsed therpy. (1.5) -------------------------- DOSAGE AND ADMINISTRATION--------------------------- Administer s n intrvenous infusion over 60 minutes. 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) Metsttic non-smll cell lung cncer 240 mg every 2 weeks. (2.2) Advnced renl cell crcinom 240 mg every 2 weeks. (2.3) Clssicl Hodgkin lymphom 3 mg/kg every 2 weeks. (2.4) Recurrent or metsttic squmous cell crcinom of the hed nd neck 3 mg/kg every 2 weeks. (2.5) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom 1.2 Metsttic Non-Smll Cell Lung Cncer 1.3 Renl Cell Crcinom 1.4 Clssicl Hodgkin Lymphom 1.5 Squmous Cell Crcinom of the Hed nd Neck 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom 2.2 Recommended Dosge for NSCLC 2.3 Recommended Dosge for RCC 2.4 Recommended Dosge for chl 2.5 Recommended Dosge for SCCHN 2.6 Dose Modifictions 2.7 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Pneumonitis 5.2 Immune-Medited Colitis 5.3 Immune-Medited Heptitis 5.4 Immune-Medited 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 Embryo-Fetl Toxicity -------------------------DOSAGE FORMS AND STRENGTHS------------------------- Injection: 40 mg/4 ml nd 100 mg/10 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 (nivolumb) 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 grft-versushost-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. (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: 11/2016 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 Metsttic Non-Smll Cell Lung Cncer (NSCLC) 14.3 Renl Cell Crcinom 14.4 Clssicl Hodgkin Lymphom 14.5 Recurrent or Metsttic Squmous Cell Crcinom of the Hed nd Neck (SCCHN) 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 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 (14.2)]. 1.3 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 (14.3)]. 1.4 Clssicl Hodgkin Lymphom is indicted for the tretment of ptients with clssicl Hodgkin lymphom (chl) tht hs relpsed or progressed fter utologous hemtopoietic stem cell trnsplnttion (HSCT) nd post-trnsplnttion brentuximb vedotin [see Clinicl Studies (14.4)]. 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 (14.4)]. 1.5 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 (14.5)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosge for Melnom The recommended dose of s single gent is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. The recommended dose of is 1 mg/kg dministered s n intrvenous infusion over 60 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 60 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 NSCLC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.3 Recommended Dosge for RCC The recommended dose of is 240 mg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.4 Recommended Dosge for chl The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.5 Recommended Dosge for SCCHN The recommended dose of is 3 mg/kg dministered s n intrvenous infusion over 60 minutes every 2 weeks until disese progression or uncceptble toxicity. 2.6 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. (nivolumb) 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 upper limit of norml or totl Withhold dose Heptitis bilirubin more thn 1.5 nd up to 3 times the upper limit of norml AST or ALT more thn 5 times the upper limit of norml or totl bilirubin more thn 3 times Permnently discontinue the upper limit of norml Hypophysitis Grde 2 or 3 hypophysitis Withhold dose Grde 4 hypophysitis Permnently discontinue 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 upper limit of norml Serum cretinine more thn 6 times the upper limit of norml 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 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 * Toxicity ws grded per Ntionl Cncer Institute Common Terminology Criteri for Adverse Events. Version 4.0 (NCI CTCAE v4). Resume tretment when dverse rection returns to Grde 0 or 1. 2.7 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.
(nivolumb) 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 4 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 over 60 minutes through n intrvenous line contining sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). 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) nd 100 mg/10 ml (10 mg/ml) 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 (2.6)]. 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 (2.6)]. (nivolumb) 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 (2.6)]. 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. 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). Immune-medited 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. Withhold for moderte (Grde 2) nd permnently discontinue for severe (Grde 3) or life-thretening (Grde 4) immune-medited heptitis [see Dosge nd Administrtion (2.6)]. 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 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 (2.6)]. 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).
(nivolumb) 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 by 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 (2.6)]. 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 ipilimumb, 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 ipilimumb 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 crbimzole, 4% received propylthiourcil, nd 9% received corticosteroids. Resolution occurred in 76% of ptients. In ptients receiving with ipilimumb, 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 ipilimumb: 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 crbimzole. Resolution occurred in 94% of ptients. Type 1 Dibetes Mellitus cn cuse Type 1 dibetes mellitus. Monitor for hyperglycemi. Withhold in cses of severe (Grde 3) hyperglycemi until metbolic control is chieved. Permnently discontinue for life-thretening (Grde 4) hyperglycemi [see Dosge nd Administrtion (2.6)]. In ptients receiving s single gent, dibetes occurred in 0.9% (17/1994) of ptients including two cses of dibetic ketocidosis. The medin time to onset ws 4.4 months (rnge: 15 dys to 22 months). In ptients receiving with ipilimumb, dibetes 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 ipilimumb ws withheld in ptient nd permnently discontinued in second ptient who developed dibetes. 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 by 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 (2.6) nd Adverse Rections (6.1)]. 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 (nivolumb) 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 Ipilimumb In ptients receiving with ipilimumb, 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 ipilimumb 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 ipilimumb 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 (2.6)]. For immune-medited rsh, dminister 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) 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 Ipilimumb In ptients receiving with ipilimumb, 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 ipilimumb 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 ipilimumb 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, but not be limited to, consulttion with neurologist, brin MRI, nd lumbr 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 by corticosteroid tper. Permnently discontinue for immune-medited encephlitis [see Dosge nd Administrtion (2.6)]. s Single Agent In ptients receiving s single gent, encephlitis occurred in 0.2% (3/1994). Ftl limbic 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 Ipilimumb Encephlitis occurred in one ptient receiving with ipilimumb (0.2%) fter 1.7 months of exposure. 5.8 Other Immune-Medited Adverse Rections cn cuse other cliniclly significnt 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 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 bsed on the severity of the event [see Dosge nd Administrtion (2.6)]. Across clinicl trils of dministered s single gent or in combintion with ipilimumb, the following cliniclly significnt immune-medited dverse rections occurred in less thn 1.0% of ptients receiving : uveitis, iritis, pncretitis, fcil nd bducens nerve presis, demyelintion, polymylgi rheumtic, utoimmune neuropthy, Guillin-Brré syndrome, hypopituitrism, systemic inflmmtory response syndrome, gstritis, duodenitis, srcoidosis, histiocytic necrotizing lymphdenitis (Kikuchi lymphdenitis), myositis, myocrditis, rhbdomyolysis, motor dysfunction, vsculitis, nd mysthenic syndrome.