HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use sfely nd effectively. See full prescribing informtion for. (ipilimumb) injection, for intrvenous use Initil U.S. Approvl: 2011 WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS See full prescribing informtion for complete boxed wrning. cn result in severe nd ftl immune-medited dverse rections. These immune-medited rections my involve ny orgn system; however, the most common severe immune-medited dverse rections re enterocolitis, heptitis, dermtitis (including toxic epiderml necrolysis), neuropthy, nd endocrinopthy. The mjority of these immune-medited rections initilly mnifested during tretment; however, minority occurred weeks to months fter discontinution of. Permnently discontinue nd initite systemic high-dose corticosteroid therpy for severe immune-medited rections. (2.5) Assess ptients for signs nd symptoms of enterocolitis, dermtitis, neuropthy, nd endocrinopthy nd evlute clinicl chemistries including liver function tests, drenocorticotropic hormone (ACTH) level, nd thyroid function tests t bseline nd before ech dose. (5.1, 5.2, 5.3, 5.4, 5.5) ----------------------------- RECENT MAJOR CHANGES------------------------------ Indictions nd Usge (1) 7/2018 Dosge nd Administrtion (2) 7/2018 Wrnings nd Precutions (5) 7/2018 ------------------------------INDICATIONS AND USAGE------------------------------ is humn cytotoxic T-lymphocyte ntigen 4 (CTLA-4)-blocking ntibody indicted for: Tretment of unresectble or metsttic melnom in dults nd peditric ptients (12 yers nd older). (1.1) Adjuvnt tretment of ptients with cutneous melnom with pthologic involvement of regionl lymph nodes of more thn 1 mm who hve undergone complete resection, including totl lymphdenectomy. (1.2) Tretment of ptients with intermedite or poor risk, previously untreted dvnced renl cell crcinom, in combintion with nivolumb. (1.3) Tretment of dult nd peditric ptients 12 yers of ge nd older with microstellite instbility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer tht hs progressed following tretment with fluoropyrimidine, oxlipltin, nd irinotecn, in combintion with nivolumb. 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. (1.4) ---------------------------DOSAGE AND ADMINISTRATION--------------------------- Unresectble or metsttic melnom: 3 mg/kg dministered intrvenously over 90 minutes every 3 weeks for totl of 4 doses. (2.1) Adjuvnt melnom: 10 mg/kg dministered intrvenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 yers or until documented disese recurrence or uncceptble toxicity. (2.2) Advnced renl cell crcinom: Nivolumb 3 mg/kg dministered intrvenously over 30 minutes followed by (ipilimumb) 1 mg/kg dministered intrvenously over 30 minutes on the sme dy, every 3 weeks for 4 doses, then nivolumb 240 mg every 2 weeks or 480 mg every 4 weeks, dministered intrvenously over 30 minutes. (2.3) Microstellite instbility-high (MSI-H) or mismtch repir deficient (dmmr) metsttic colorectl cncer: Nivolumb 3 mg/kg followed by 1 mg/kg on the sme dy every 3 weeks for 4 doses, then nivolumb 240 mg every 2 weeks (2.4) Permnently discontinue for severe dverse rections. (2.5) ------------------------- DOSAGE FORMS AND STRENGTHS-------------------------- Injection: 50 mg/10 ml (5 mg/ml) nd 200 mg/40 ml (5 mg/ml) in single-use vil. (3) -------------------------------- CONTRAINDICATIONS-------------------------------- None. (4) ---------------------------WARNINGS AND PRECAUTIONS--------------------------- Immune-medited dverse rections: Permnently discontinue for severe rections. Withhold dose for moderte immune-medited dverse rections until return to bseline, improvement to mild severity, or complete resolution, nd ptient is receiving less thn 7.5 mg prednisone or equivlent per dy. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-medited rections. (5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 5.10) Immune-medited heptitis: Evlute liver function tests before ech dose of. (5.2) Withhold for moderte nd permnently discontinue for severe or life-thretening trnsminse or totl bilirubin elevtion. (5.2) Immune-medited endocrinopthies: Monitor clinicl chemistries, ACTH level, nd thyroid function tests prior to ech dose. Evlute t ech visit for signs nd symptoms of endocrinopthy. Institute hormone replcement therpy s needed. (5.5) Immune-medited pneumonitis: Withhold for moderte nd permnently discontinue for severe or life-thretening pneumonitis. (5.6) 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. (5.7) 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. (5.8) 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) 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 ( 5%) with s single gent re ftigue, dirrhe, pruritus, rsh, nd colitis. Additionl common dverse rections t the 10 mg/kg dose ( 5%) include nuse, vomiting, hedche, weight loss, pyrexi, decresed ppetite, nd insomni. (6.1) Most common dverse rections ( 20%) with in combintion with nivolumb re ftigue, rsh, dirrhe, nuse, pyrexi, musculoskeletl pin, pruritus, bdominl pin, vomiting, cough, rthrlgi, decresed ppetite, 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 during tretment with. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 7/2018 FULL PRESCRIBING INFORMATION: CONTENTS * WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom 1.2 Adjuvnt Tretment of Melnom 1.3 Advnced Renl Cell Crcinom 1.4 Microstellite Instbility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Unresectble or Metsttic Melnom 2.2 Recommended Dosing for Adjuvnt Tretment of Melnom 2.3 Recommended Dosing for RCC 2.4 Recommended Dosing for Colorectl Cncer 2.5 Recommended Dose Modifictions 2.6 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Enterocolitis/Colitis 5.2 Immune-Medited Heptitis 5.3 Immune-Medited Dermtitis/Skin Adverse Rections 5.4 Immune-Medited Neuropthies 5.5 Immune-Medited Endocrinopthies 5.6 Immune-Medited Pneumonitis 5.7 Immune-Medited Nephritis nd Renl Dysfunction 5.8 Immune-Medited Encephlitis 5.9 Infusion Rections 5.10 Other Immune-Medited Adverse Rections, Including Oculr Mnifesttions 5.11 Embryo-Fetl Toxicity 5.12 Risks Associted When Administered in Combintion with Nivolumb 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 6.3 Immunogenicity (Continued)
FULL PRESCRIBING INFORMATION: CONTENTS *(Continued) 12.1 Mechnism of Action 7 DRUG INTERACTIONS 12.3 Phrmcokinetics 8 USE IN SPECIFIC POPULATIONS 13 NONCLINICAL TOXICOLOGY 8.1 Pregnncy 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 8.2 Lcttion 14 CLINICAL STUDIES 8.3 Femles nd Mles of Reproductive Potentil 14.1 Unresectble or Metsttic Melnom 8.4 Peditric Use 14.2 Adjuvnt Tretment of Melnom 8.5 Geritric Use 14.3 Previously Untreted Advnced Renl Cell Crcinom 8.6 Renl Impirment 14.4 Microstellite Instbility-High (MSI-H) or Mismtch Repir Deficient 8.7 Heptic Impirment (dmmr) Metsttic Colorectl Cncer 10 OVERDOSAGE 16 HOW SUPPLIED/STORAGE AND HANDLING 11 DESCRIPTION 17 PATIENT COUNSELING INFORMATION 12 CLINICAL PHARMACOLOGY * Sections or subsections omitted from the full prescribing informtion re not listed. FULL PRESCRIBING INFORMATION WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS (ipilimumb) cn result in severe nd ftl immune-medited dverse rections. These immune-medited rections my involve ny orgn system; however, the most common severe immune-medited dverse rections re enterocolitis, heptitis, dermtitis (including toxic epiderml necrolysis), neuropthy, nd endocrinopthy. The mjority of these immunemedited rections initilly mnifested during tretment; however, minority occurred weeks to months fter discontinution of. Permnently discontinue nd initite systemic high-dose corticosteroid therpy for severe immune-medited rections [see Dosge nd Administrtion (2.5)]. Assess ptients for signs nd symptoms of enterocolitis, dermtitis, neuropthy, nd endocrinopthy, nd evlute clinicl chemistries including liver function tests, drenocorticotropic hormone (ACTH) level, nd thyroid function tests, t bseline nd before ech dose [see Wrnings nd Precutions (5.1, 5.2, 5.3, 5.4, 5.5)]. 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom is indicted for the tretment of unresectble or metsttic melnom in dults nd peditric ptients (12 yers nd older) [see Clinicl Studies (14.1)]. 1.2 Adjuvnt Tretment of Melnom is indicted for the djuvnt tretment of ptients with cutneous melnom with pthologic involvement of regionl lymph nodes of more thn 1 mm who hve undergone complete resection, including totl lymphdenectomy [see Clinicl Studies (14.2)]. 1.3 Advnced Renl Cell Crcinom, in combintion with nivolumb, is indicted for the tretment of ptients with intermedite or poor risk, previously untreted dvnced renl cell crcinom (RCC) [see Clinicl Studies (14.3)]. 1.4 Microstellite Instbility-High (MSI-H) or Mismtch Repir Deficient (dmmr) Metsttic Colorectl Cncer, in combintion with nivolumb, is indicted for the tretment of dult nd peditric ptients 12 yers of ge 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 (14.4)]. 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. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Unresectble or Metsttic Melnom The recommended dose of is 3 mg/kg dministered intrvenously (IV) over 90 minutes every 3 weeks for mximum of 4 doses. In the event of toxicity, doses my be delyed, but ll tretment must be dministered within 16 weeks of the first dose [see Clinicl Studies (14.1)]. 2.2 Recommended Dosing for Adjuvnt Tretment of Melnom The recommended dose of is 10 mg/kg dministered IV over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 yers [see Clinicl Studies (14.2)]. In the event of toxicity, doses re omitted, not delyed. 2.3 Recommended Dosing for RCC The recommended dose of in combintion with nivolumb is nivolumb 3 mg/kg dministered s n intrvenous infusion over 30 minutes, followed by 1 mg/kg dministered s n intrvenous infusion over 30 minutes on the sme dy, every 3 weeks for 4 doses [see Clinicl Studies (14.3)]. After completing 4 doses of the combintion, dminister nivolumb s single gent, either: 240 mg every 2 weeks, or 480 mg every 4 weeks s n intrvenous infusion over 30 minutes until disese progression or uncceptble toxicity. Review the Prescribing Informtion for nivolumb prior to initition. 2.4 Recommended Dosing for Colorectl Cncer The recommended dose of is: (ipilimumb) 1 mg/kg dministered s n intrvenous infusion over 30 minutes, immeditely following nivolumb dministered on the sme dy, every 3 weeks for up to 4 doses or until intolerble toxicity or disese progression [see Clinicl Studies (14.4)]. Review the Prescribing Informtion for nivolumb prior to initition. 2.5 Recommended Dose Modifictions Recommendtions for modifictions re provided in Tble 1. When is dministered in combintion with nivolumb, if is withheld, nivolumb should lso be withheld. Review the Prescribing Informtion for nivolumb for recommended dose modifictions. 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: Trget/Orgn System Recommended Tretment Modifictions for Immune-Medited Adverse Rections of Adverse Rection (CTCAE v4) Tretment Modifiction Endocrine Symptomtic endocrinopthy Withhold Resume in ptients with complete or prtil resolution of dverse rections (Grde 0 to 1) nd who re receiving less thn 7.5 mg prednisone or equivlent per dy. Ophthlmologic Symptomtic rections lsting 6 weeks or longer Inbility to reduce corticosteroid dose to 7.5 mg prednisone or equivlent per dy Grde 2 through 4 rections not improving to Grde 1 within 2 weeks while receiving topicl therpy or requiring systemic tretment Permnently discontinue Permnently discontinue All Other Grde 2 Withhold Resume in ptients with complete or prtil resolution of dverse rections (Grde 0 to 1) nd who re receiving less thn 7.5 mg prednisone or equivlent per dy. Grde 2 rections lsting 6 weeks or longer Inbility to reduce corticosteroid dose to 7.5 mg prednisone or equivlent per dy Grde 3 or 4 Permnently discontinue
2.6 Preprtion nd Administrtion Do not shke product. Inspect prenterl drug products visully for prticulte mtter nd discolortion prior to dministrtion. Discrd vil if solution is cloudy, there is pronounced discolortion (solution my hve ple-yellow color), or there is foreign prticulte mtter other thn trnslucent-to-white, morphous prticles. Preprtion of Solution Allow the vils to stnd t room temperture for pproximtely 5 minutes prior to preprtion of infusion. Withdrw the required volume of nd trnsfer into n intrvenous bg. Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepre diluted solution with finl concentrtion rnging from 1 mg/ml to 2 mg/ml. Mix diluted solution by gentle inversion. Store the diluted solution for no more thn 24 hours under refrigertion (2 C to 8 C, 36 F to 46 F) or t room temperture (20 C to 25 C, 68 F to 77 F). Discrd prtilly used vils or empty vils of. Administrtion Instructions Do not mix with, or dminister s n infusion with, other medicinl products. Flush the intrvenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP fter ech dose. Administer diluted solution over 90 minutes through n intrvenous line contining sterile, non-pyrogenic, low-protein-binding in-line filter. When dministered in combintion with nivolumb, infuse nivolumb first followed by on the sme dy. Use seprte infusion bgs nd filters for ech infusion. 3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/10 ml (5 mg/ml) nd 200 mg/40 ml (5 mg/ml) s cler to slightly oplescent, colorless to ple-yellow solution in single-use vil. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS cn result in severe nd ftl immune-medited rections [see Boxed Wrning]. 5.1 Immune-Medited Enterocolitis/Colitis Immune-medited enterocolitis, including ftl cses, cn occur with. Monitor ptients for signs nd symptoms of enterocolitis (such s dirrhe, bdominl pin, mucus or blood in stool, with or without fever) nd of bowel perfortion (such s peritonel signs nd ileus). In symptomtic ptients, rule out infectious etiologies nd consider endoscopic evlution for persistent or severe symptoms. Permnently discontinue in ptients with severe enterocolitis nd initite systemic corticosteroids t dose of 1 to 2 mg/kg/dy of prednisone or equivlent. Upon improvement to Grde 1 or less, initite corticosteroid tper nd continue to tper over t lest 1 month. In clinicl trils, rpid corticosteroid tpering resulted in recurrence or worsening symptoms of enterocolitis in some ptients. Consider dding nti-tnf or other immunosuppressnt gents for mngement of immune-medited enterocolitis unresponsive to systemic corticosteroids within 3 to 5 dys or recurring fter symptom improvement. Withhold dosing for moderte enterocolitis; dminister nti-dirrhel tretment nd, if persistent for more thn 1 week, initite systemic corticosteroids t dose of 0.5 mg/kg/dy prednisone or equivlent [see Dosge nd Administrtion (2.5)]. s Single Agent Metsttic Melnom In ptients receiving 3 mg/kg in MDX010-20 (NCT00094653), severe, life-thretening, or ftl (dirrhe of 7 or more stools bove bseline, fever, ileus, peritonel signs; Grde 3 to 5) immune-medited enterocolitis occurred in 34 treted ptients (7%), nd moderte (dirrhe with up to 6 stools bove bseline, bdominl pin, mucus or blood in stool; Grde 2) enterocolitis occurred in 28 treted ptients (5%). Across ll -treted ptients (n=511), 5 ptients (1%) developed intestinl perfortion, 4 ptients (0.8%) died s result of complictions, nd 26 ptients (5%) were hospitlized for severe enterocolitis. The medin time to onset of Grde 3 to 5 enterocolitis ws 1.7 months (rnge: 11 dys to 3.1 months) nd for Grde 2 enterocolitis ws 1.4 months (rnge: 2 dys to 4.3 months). Twenty-nine ptients (85%) with Grde 3 to 5 enterocolitis were treted with high-dose ( 40 mg prednisone equivlent per dy) corticosteroids, with medin dose of 80 mg/dy of prednisone or equivlent; the medin durtion of tretment ws 16 dys (rnging up to 3.2 months) followed by corticosteroid tper. Of the 28 ptients with moderte enterocolitis, 46% were not treted with systemic corticosteroids, 29% were treted with <40 mg prednisone or equivlent per dy for medin durtion of 1.2 months, nd 25% were treted with high-dose corticosteroids for medin durtion of 10 dys prior to corticosteroid tper. Infliximb ws dministered to 5 (8%) of the 62 ptients with moderte, severe, or life-thretening immune-medited enterocolitis following indequte response to corticosteroids. (ipilimumb) Of the 34 ptients with Grde 3 to 5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grde 2 severity, nd 24% did not improve. Among the 28 ptients with Grde 2 enterocolitis, 79% experienced complete resolution, 11% improved, nd 11% did not improve. Adjuvnt Tretment of Melnom In ptients receiving 10 mg/kg in CA184-029 (NCT00636168), Grde 3 to 5 immune-medited enterocolitis occurred in 76 ptients (16%) nd Grde 2 enterocolitis occurred in 68 ptients (14%). Seven ptients (1.5%) developed intestinl perfortion nd 3 ptients (0.6%) died s result of complictions [see Adverse Rections (6.1)]. The medin time to onset for Grde 3 to 4 enterocolitis ws 1.1 months (rnge: 1 dy to 33.1 months) nd for Grde 2 enterocolitis ws 1.1 months (rnge: 1 dy to 20.6 months). Seventy-one ptients (95%) with Grde 3 to 4 enterocolitis were treted with systemic corticosteroids. The medin durtion of tretment ws 4.7 months (rnging up to 52.3 months). Of the 68 ptients with moderte enterocolitis, 51 ptients (75%) were treted with systemic corticosteroids with medin durtion of tretment of 3.5 months (rnging up to 52.2 months). Non-corticosteroids immunosuppression, consisting lmost exclusively of infliximb, ws used to tret 36% of ptients with Grde 3 to 4 enterocolitis nd 15% of ptients with Grde 2 event. Of the 75 ptients with Grde 3 to 4 immune-medited enterocolitis, 86% experienced complete resolution, 3% experienced improvement to Grde 1, nd 11% did not improve. Among the 68 ptients with Grde 2 enterocolitis, 94% experienced complete resolution, 3% experienced improvement to Grde 1, nd 3% did not improve. 1 mg/kg dministered with nivolumb 3 mg/kg Immune-medited colitis occurred in 10% (52/547) of ptients with RCC nd 7% (8/119) of ptients with CRC. Medin time to onset of immune-medited colitis ws 1.7 months (rnge: 2 dys to 19.2 months) in ptients with RCC nd 2.4 months (rnge: 22 dys to 5.2 months) in ptients with CRC. Immune-medited colitis led to permnent discontinution of nd nivolumb in 3.2% of ptients with RCC or CRC (n=666) nd withholding of both nd nivolumb in 3.9% [see Dosge nd Administrtion (2.5)]. All ptients with colitis required systemic corticosteroids, including 80% who received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 21 dys (rnge: 1 dy to 27 months). Approximtely 23% of ptients with immune-medited colitis required ddition of infliximb to high-dose corticosteroids. Complete resolution occurred in 88% of ptients. Two ptients with RCC hd recurrence of colitis fter re-initition of nivolumb with. 5.2 Immune-Medited Heptitis Immune-medited heptitis, including ftl cses, cn occur with. Monitor liver function tests (heptic trnsminse nd bilirubin levels) nd ssess ptients for signs nd symptoms of heptotoxicity before ech dose of. In ptients with heptotoxicity, rule out infectious or mlignnt cuses nd increse frequency of liver function test monitoring until resolution. Permnently discontinue in ptients with Grde 3 to 4 heptotoxicity nd dminister systemic corticosteroids t dose of 1 to 2 mg/kg/dy of prednisone or equivlent. When liver function tests show sustined improvement or return to bseline, initite corticosteroid tpering nd continue to tper over 1 month. Across the clinicl development progrm for, mycophenolte tretment hs been dministered in ptients who hve persistent severe heptitis despite high-dose corticosteroids. Withhold in ptients with Grde 2 heptotoxicity [see Dosge nd Administrtion (2.5)]. s Single Agent Metsttic Melnom In ptients receiving 3 mg/kg in MDX010-20, severe, life-thretening, or ftl heptotoxicity (AST or ALT elevtions of more thn 5 times the upper limit of norml or totl bilirubin elevtions more thn 3 times the upper limit of norml; Grde 3 to 5) occurred in 8 -treted ptients (2%), with ftl heptic filure in 0.2% nd hospitliztion in 0.4% of -treted ptients. An dditionl 13 ptients (2.5%) experienced moderte heptotoxicity mnifested by liver function test bnormlities (AST or ALT elevtions of more thn 2.5 times but not more thn 5 times the upper limit of norml or totl bilirubin elevtion of more thn 1.5 times but not more thn 3 times the upper limit of norml; Grde 2). The underlying pthology ws not scertined in ll ptients but in some instnces included immune-medited heptitis. There were insufficient numbers of ptients with biopsy-proven heptitis to chrcterize the clinicl course of this event. Adjuvnt Tretment of Melnom In ptients receiving 10 mg/kg in CA184-029, Grde 3 to 4 immune-medited heptitis occurred in 51 ptients (11%) nd moderte Grde 2 immune-medited heptitis occurred in 22 ptients (5%). Liver biopsy performed in 6 ptients with Grde 3 to 4 heptitis showed evidence of toxic or utoimmune heptitis. The medin time to onset for Grde 3 to 4 heptitis ws 2.0 months (rnge: 1 dy to 4.2 months) nd for Grde 2 heptitis ws 1.4 months (rnge: 13 dys to 6.5 months). Of the 51 ptients with Grde 3 to 4 immune-medited heptitis, 94% experienced complete resolution, 4% experienced improvement to Grde 1, nd 2% did not improve. Of the 22 ptients with Grde 2 immune-medited heptitis, 91% experienced complete resolution nd 9% did not improve.
Forty-six ptients (90%) with Grde 3 to 4 heptitis were treted with systemic corticosteroids. The medin durtion of tretment ws 4.4 months (rnging up to 56.1 months). Sixteen ptients (73%) with moderte heptitis were treted with systemic corticosteroids. The medin durtion of tretment ws 2.6 months (rnging up to 41.4 months). Concurrent Administrtion with Vemurfenib In dose-finding tril, Grde 3 increses in trnsminses with or without concomitnt increses in totl bilirubin occurred in 6 of 10 ptients who received concurrent (3 mg/kg) nd vemurfenib (960 mg BID or 720 mg BID). 1 mg/kg dministered with nivolumb 3 mg/kg Immune-medited heptitis occurred in 7% (38/547) of ptients with RCC nd 8% (10/119) with CRC. Medin time to onset ws 2 months (rnge: 14 dys to 26.8 months) in ptients with RCC nd 2.2 months (rnge: 22 dys to 10.5 months) in ptients with CRC. Immune-medited heptitis led to permnent discontinution of nd nivolumb in 3.6% of ptients with RCC or CRC (n=666) nd withholding of both nd nivolumb in 3.5% [see Dosge nd Administrtion (2.5)]. All ptients with heptitis required systemic corticosteroids, including 94% who received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 1 month (rnge: 1 dy to 7 months). Approximtely 19% of ptients with immune-medited heptitis required ddition of mycophenolic cid to high-dose corticosteroids. Complete resolution occurred in 83% of ptients. No ptients hd recurrence of heptitis fter re-initition of nivolumb with or nivolumb lone. 5.3 Immune-Medited Dermtitis/Skin Adverse Rections Immune-medited dermtitis, including ftl cses, cn occur with. Monitor ptients for signs nd symptoms of dermtitis, such s rsh nd pruritus. Unless n lternte etiology hs been identified, signs or symptoms of dermtitis should be considered immune-medited. Permnently discontinue in ptients with Stevens-Johnson syndrome, toxic epiderml necrolysis, or rsh complicted by full thickness derml ulcertion, or necrotic, bullous, or hemorrhgic mnifesttions. Administer systemic corticosteroids t dose of 1 to 2 mg/kg/dy of prednisone or equivlent. When dermtitis is controlled, corticosteroid tpering should occur over period of t lest 1 month. Withhold dosing in ptients with moderte to severe signs nd symptoms [see Dosge nd Administrtion (2.5)]. For mild to moderte dermtitis, such s loclized rsh nd pruritus, tret symptomticlly. Administer topicl or systemic corticosteroids if there is no improvement of symptoms within 1 week. s Single Agent Metsttic Melnom In ptients receiving 3 mg/kg in MDX010-20, severe, life-thretening, or ftl immune-medited dermtitis (e.g., Stevens-Johnson syndrome, toxic epiderml necrolysis, or rsh complicted by full thickness derml ulcertion, or necrotic, bullous, or hemorrhgic mnifesttions; Grde 3 to 5) occurred in 13 -treted ptients (2.5%). One ptient (0.2%) died s result of toxic epiderml necrolysis nd one dditionl ptient required hospitliztion for severe dermtitis. There were 63 ptients (12%) with moderte (Grde 2) dermtitis. The medin time to onset of moderte, severe, or life-thretening immune-medited dermtitis ws 22 dys nd rnged up to 4.0 months from the initition of. Seven -treted ptients (54%) with severe dermtitis received high-dose corticosteroids (medin dose 60 mg prednisone/dy or equivlent) for up to 3.4 months followed by corticosteroid tper. Of these 7 ptients, 6 hd complete resolution; time to resolution rnged up to 3.6 months. Of the 63 ptients with moderte dermtitis, 25 (40%) were treted with systemic corticosteroids (medin of 60 mg/dy of prednisone or equivlent) for medin of 15 dys, 7 (11%) were treted with only topicl corticosteroids, nd 31 (49%) did not receive systemic or topicl corticosteroids. Forty-four ptients (70%) with moderte dermtitis were reported to hve complete resolution, 7 (11%) improved to mild (Grde 1) severity, nd 12 (19%) hd no reported improvement. Adjuvnt Tretment of Melnom In ptients receiving 10 mg/kg in CA184-029, Grde 3 to 4 immune-medited dermtitis occurred in 19 ptients (4%). There were 99 ptients (21%) with moderte (Grde 2) dermtitis. The medin time to onset for Grde 3 to 4 dermtitis ws 14 dys (rnge: 5 dys to 11.3 months) nd for Grde 2 dermtitis ws 11 dys (rnge: 1 dy to 16.6 months). Sixteen ptients (84%) with Grde 3 to 4 dermtitis were treted with systemic corticosteroids for medin of 21 dys (rnging up to 49.2 months) resulting in complete resolution of dermtitis within medin time of 4.3 months (rnge up to 44.4 months). Of the 3 ptients (16%) not treted with systemic or topicl corticosteroids, 2 (11%) hd complete resolution nd 1 hd improvement to Grde 1. Of the 99 ptients with Grde 2 dermtitis, 67 (68%) were treted with systemic corticosteroids for medin of 2.6 months, 16 (16%) were treted with only topicl corticosteroids nd 16 (16%) did not receive systemic or topicl corticosteroids. Seventy-seven ptients (78%) hd complete resolution, 15 (15%) improved to mild (Grde 1) severity, nd 7 (7%) did not improve. (ipilimumb) 1 mg/kg dministered with nivolumb 3 mg/kg Immune-medited rsh occurred in 16% (90/547) of ptients with RCC nd 14% (17/119) of ptients with CRC. Medin time to onset ws 1.5 months (rnge: 1 dy to 20.9 months) in RCC nd 26 dys (rnge: 5 dys to 9.8 months) in CRC. Immune-medited rsh led to permnent discontinution or withholding of nd nivolumb in 0.5% of ptients with RCC or CRC (n=666) nd withholding of nd nivolumb in 2.6% of ptients [see Dosge nd Administrtion (2.5)]. All ptients with immune-medited rsh required systemic corticosteroids, including 19% who received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 22 dys (rnge: 1 dy to 23 months). Complete resolution occurred in 66% of ptients. Immune-medited rsh recurred in pproximtely 3% (3/98) of ptients who resumed nivolumb. 5.4 Immune-Medited Neuropthies Immune-medited neuropthies, including ftl cses, cn occur with. Monitor for symptoms of motor or sensory neuropthy such s unilterl or bilterl wekness, sensory ltertions, or presthesi. Permnently discontinue in ptients with severe neuropthy (interfering with dily ctivities) such s Guillin-Brré-like syndromes. Institute medicl intervention s pproprite for mngement of severe neuropthy. Consider initition of systemic corticosteroids t dose of 1 to 2 mg/kg/dy prednisone or equivlent for severe neuropthies. Withhold dosing in ptients with moderte neuropthy (not interfering with dily ctivities) [see Dosge nd Administrtion (2.5)]. s Single Agent Metsttic Melnom In ptients receiving 3 mg/kg in MDX010-20, 1 cse of ftl Guillin-Brré syndrome nd 1 cse of severe (Grde 3) peripherl motor neuropthy were reported. Across the clinicl development progrm of, mystheni grvis nd dditionl cses of Guillin-Brré syndrome hve been reported. Adjuvnt Tretment of Melnom In ptients receiving 10 mg/kg in CA184-029, Grde 3 to 5 immune-medited neuropthy occurred in 8 ptients (2%); the sole ftlity ws due to complictions of Guillin-Brré syndrome [see Adverse Rections (6.1)]. Moderte Grde 2 immunemedited neuropthy occurred in 1 ptient (0.2%). The time to onset cross the 9 ptients with Grde 2 to 5 immune-medited neuropthy rnged from 1.4 to 27.4 months. All 8 ptients with Grde 3 to 5 neuropthy were treted with systemic corticosteroids (rnge: 3 dys to 38.3 months) nd 3 lso received tcrolimus. Four of the 8 ptients with Grde 3 to 5 immune-medited neuropthy experienced complete resolution, 1 improved to Grde 1, nd 3 did not improve. The single ptient with Grde 2 immune-medited neuropthy experienced complete resolution without the use of corticosteroids. 1 mg/kg dministered with nivolumb 3 mg/kg Among 547 RCC ptients, there were 3 cses of Grde 3 presthesi/hypoesthesi. 5.5 Immune-Medited Endocrinopthies Immune-medited endocrinopthies, including life-thretening cses, cn occur with. Monitor ptients for clinicl signs nd symptoms of hypophysitis, drenl insufficiency (including drenl crisis), nd hyper- or hypothyroidism. Ptients my present with ftigue, hedche, mentl sttus chnges, bdominl pin, unusul bowel hbits, nd hypotension, or nonspecific symptoms which my resemble other cuses such s brin metstsis or underlying disese. Unless n lternte etiology hs been identified, signs or symptoms of endocrinopthies should be considered immune-medited. Monitor clinicl chemistries, drenocorticotropic hormone (ACTH) level, nd thyroid function tests t the strt of tretment, before ech dose, nd s cliniclly indicted bsed on symptoms. In limited number of ptients, hypophysitis ws dignosed by imging studies through enlrgement of the pituitry glnd. Withhold dosing in symptomtic ptients nd consider referrl to n endocrinologist. Initite systemic corticosteroids t dose of 1 to 2 mg/kg/dy of prednisone or equivlent, nd initite pproprite hormone replcement therpy [see Dosge nd Administrtion (2.5)]. s Single Agent Metsttic Melnom In ptients receiving 3 mg/kg in MDX010-20, severe to life-thretening immunemedited endocrinopthies (requiring hospitliztion, urgent medicl intervention, or interfering with ctivities of dily living; Grde 3 to 4) occurred in 9 -treted ptients (1.8%). All 9 ptients hd hypopituitrism nd some hd dditionl concomitnt endocrinopthies such s drenl insufficiency, hypogondism, nd hypothyroidism. Six of the 9 ptients were hospitlized for severe endocrinopthies. Moderte endocrinopthy (requiring hormone replcement or medicl intervention; Grde 2) occurred in 12 ptients (2.3%) nd consisted of hypothyroidism, drenl insufficiency, hypopituitrism, nd 1 cse ech of hyperthyroidism nd Cushing s syndrome. The medin time to onset of moderte to severe immune-medited endocrinopthy ws 2.5 months nd rnged up to 4.4 months fter the initition of. Of the 21 ptients with moderte to life-thretening endocrinopthy, 17 ptients required long-term hormone replcement therpy including, most commonly, drenl hormones (n=10) nd thyroid hormones (n=13).
Adjuvnt Tretment of Melnom In ptients receiving 10 mg/kg in CA184-029, Grde 3 to 4 immune-medited endocrinopthies occurred in 39 ptients (8%) nd Grde 2 immune-medited endocrinopthies in 93 ptients (20%). Of the 39 ptients with Grde 3 to 4 immunemedited endocrinopthies, 35 ptients hd hypopituitrism (ssocited with one or more secondry endocrinopthies, e.g., drenl insufficiency, hypogondism, nd hypothyroidism), 3 ptients hd hyperthyroidism, nd 1 hd primry hypothyroidism. The medin time to onset of Grde 3 to 4 immune-medited endocrinopthy ws 2.2 months (rnge: 2 dys to 8 months). Twenty-seven of the 39 ptients (69%) were hospitlized for immune-medited endocrinopthies, nd 4 ptients (10%) were reported to hve resolution. Of the 93 ptients with Grde 2 immune-medited endocrinopthy, 74 hd primry hypopituitrism (ssocited with one or more secondry endocrinopthy, e.g., drenl insufficiency, hypogondism, nd hypothyroidism), 9 hd primry hypothyroidism, 3 hd hyperthyroidism, 3 hd thyroiditis with hypo- or hyperthyroidism, 2 hd hypogondism, 1 hd both hyperthyroidism nd hypopituitrism, nd 1 subject developed Grves ophthlmopthy. The medin time to onset of Grde 2 immune-medited endocrinopthy ws 2.1 months (rnge: 9 dys to 19.3 months), nd 20% were reported to hve resolution. One hundred twenty-four ptients received systemic corticosteroids s immunosuppression nd/or drenl hormone replcement for Grde 2 to 4 immunemedited endocrinopthy. Of these, 42 (34%) were ble to discontinue corticosteroids. Seventy-three ptients received thyroid hormones for tretment of Grde 2 to 4 immunemedited hypothyroidism. Of these, 14 ptients (19%) were ble to discontinue thyroid replcement therpy. 1 mg/kg dministered with nivolumb 3 mg/kg Hypophysitis. Hypophysitis occurred in 4.6% (25/547) of ptients with RCC nd 3.4% (4/119) of ptients with CRC. Medin time to onset ws 2.8 months (rnge: 1.3 months to 7.3 months) in ptients with RCC nd 3.7 months (rnge: 2.8 to 5.5 months) in ptients with CRC. Hypophysitis led to permnent discontinution or withholding of nd nivolumb in 1.2% nd 2.6% of ptients with RCC or CRC (n=666), respectively [see Dosge nd Administrtion (2.5)]. Approximtely 72% of ptients with hypophysitis received hormone replcement therpy nd 55% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 13 dys (rnge: 1 dy to 1.6 months). Adrenl Insufficiency. Adrenl insufficiency occurred in 7% (41/547) of ptients with RCC nd 5.9% (7/119) ptients with CRC. Medin time to onset ws 3.4 months (rnge: 2.0 months to 22.3 months) in RCC nd 3.7 months (rnge: 2.5 to 13.4 months) in CRC. Adrenl insufficiency led to permnent discontinution of nd nivolumb in 1.2% of ptients with RCC or CRC (n=666) nd withholding of nd nivolumb in 2.6% [see Dosge nd Administrtion (2.5)]. Approximtely 94% of ptients with drenl insufficiency received hormone replcement therpy nd 27% received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 12 dys (rnge: 2 dys to 5.6 months). Hypothyroidism nd Hyperthyroidism. Hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of ptients with RCC nd 15% (18/119) of ptients with CRC. Medin time to onset ws 2.2 months (rnge: 1 dy to 21.4 months) in ptients with RCC nd 2.3 months (rnge: 22 dys to 9.8 months) in ptients with CRC. Of the 137 ptients with RCC or CRC who developed hypothyroidism, pproximtely 81% of ptients with RCC nd 78% with CRC received levothyroxine. Hyperthyroidism occurred in 12% (66/547) of ptients with RCC nd 12% (14/119) of ptients with CRC. Medin time to onset ws 1.4 months (rnge: 6 dys to 14.2 months) in RCC nd 1.1 months (rnge: 21 dys to 5.4 months) in CRC. Of the 80 ptients with RCC or CRC who developed hyperthyroidism, pproximtely 15% received methimzole nd 2% received crbimzole. Type 1 Dibetes Mellitus. Dibetes occurred in 2.7% (15/547) of ptients with RCC. Medin time to onset ws 3.2 months (rnge: 19 dys to 16.8 months). Both nd nivolumb were withheld in 33% of ptients nd both were permnently discontinued in 20% of ptients who developed dibetes [see Dosge nd Administrtion (2.5)]. 5.6 Immune-Medited Pneumonitis Immune-medited pneumonitis, including ftl cses, cn occur with nivolumb with. 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 3-4) pneumonitis, followed by corticosteroid tper. Withhold dosing in ptients with moderte to severe signs nd symptoms. Permnently discontinue for life-thretening (Grde 4) pneumonitis [see Dosge nd Administrtion (2.5)]. 1 mg/kg dministered with nivolumb 3 mg/kg Immune-medited pneumonitis occurred in 4.4% (24/547) of ptients with RCC nd 1.7% (2/119) of ptients with CRC. Medin time to onset of immune-medited pneumonitis ws 2.6 months (rnge: 8 dys to 9.2 months) in ptients with RCC nd 1.9 months (rnge: 27 dys to 3 months) in ptients with CRC. (ipilimumb) Immune-medited pneumonitis led to permnent discontinution of nd nivolumb in 1.8% of ptients with RCC or CRC (n=666) nd withholding of nd nivolumb in 1.7% [see Dosge nd Administrtion (2.5)]. All ptients with pneumonitis required systemic corticosteroids, including 92% who received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 19 dys (rnge: 4 dys to 3.2 months). Approximtely 8% required ddition of infliximb to high-dose corticosteroids. Complete resolution of pneumonitis occurred in 81% of ptients. 5.7 Immune-Medited Nephritis nd Renl Dysfunction Immune-medited nephritis cn occur with nivolumb with. 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 dosing in ptients with moderte to severe signs nd symptoms. Permnently discontinue for life-thretening (Grde 4) incresed serum cretinine [see Dosge nd Administrtion (2.5)]. 1 mg/kg dministered with nivolumb 3 mg/kg Immune-medited nephritis nd renl dysfunction occurred in 4.6% (25/547) of ptients with RCC nd 1.7% (2/119) of ptients with CRC. Medin time to onset ws 3 months (rnge: 1 dy to 13.2 months) mong these 27 ptients. Immune-medited nephritis nd renl dysfunction led to permnent discontinution of nd nivolumb in 1.2% of ptients with RCC or CRC (n=666) nd withholding of nivolumb nd in 2.3% of ptients with RCC or CRC [see Dosge nd Administrtion (2.5)]. Approximtely 78% of ptients with immune-medited nephritis nd renl dysfunction received high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy) for medin durtion of 17 dys (rnge: 1 dy to 6 months). Complete resolution occurred in 63% of ptients. 5.8 Immune-Medited Encephlitis Immune-medited encephlitis cn occur with. 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 (2.5)]. 1 mg/kg dministered with nivolumb 3 mg/kg Encephlitis occurred in one ptient (0.2%) with RCC pproximtely 4 months fter initition of nd in one ptient (0.8%) with CRC 15 dys fter initition of. The ptient with CRC required infliximb nd high-dose corticosteroids (t lest 40 mg prednisone equivlents per dy). 5.9 Infusion Rections Severe infusion rections cn occur with nivolumb with. Discontinue in ptients with severe or life-thretening infusion rections. Interrupt or slow the rte of infusion in ptients with mild or moderte infusion rections [see Dosge nd Administrtion (2.5)]. 1 mg/kg dministered with nivolumb 3 mg/kg Infusion-relted rections occurred in 5.1% (28/547) of ptients with RCC nd 4.2% (5/119) of ptients with CRC. 5.10 Other Immune-Medited Adverse Rections, Including Oculr Mnifesttions s Single Agent Permnently discontinue for cliniclly significnt or severe immune-medited dverse rections. Initite systemic corticosteroids t dose of 1 to 2 mg/kg/dy prednisone or equivlent for severe immune-medited dverse rections. Monitor ptients for signs or symptoms of oculr toxicity, which my include blurred vision nd reduced visul cuity. Immune-medited oculr toxicity my be ssocited with retinl detchment or permnent vision loss. Administer corticosteroid eye drops to ptients who develop uveitis, iritis, or episcleritis. Permnently discontinue for immune-medited oculr disese tht is unresponsive to locl immunosuppressive therpy [see Dosge nd Administrtion (2.5)]. If uveitis occurs in combintion with other immune-medited dverse rections, consider Vogt-Koyngi-Hrd-like syndrome, which hs been observed in ptients receiving nd my require tretment with systemic steroids to reduce the risk of permnent vision loss. Metsttic Melnom In MDX010-20, the following cliniclly significnt immune-medited dverse rections were seen in less thn 1% of -treted ptients: cytopenis, nephritis, pneumonitis, meningitis, pericrditis, uveitis, nd iritis.
Adjuvnt Tretment of Melnom In CA184-029, the following cliniclly significnt immune-medited dverse rections were seen in less thn 1% of -treted ptients unless specified: cytopenis, eosinophili (2.1%), pncretitis (1.3%), meningitis, pneumonitis, srcoidosis, pericrditis, uveitis, nd ftl myocrditis [see Adverse Rections (6.1)]. Other Clinicl Experience Across 21 dose-rnging trils dministering t doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-medited dverse rections were lso reported with less thn 1% incidence unless specified: ngiopthy, temporl rteritis, vsculitis, polymylgi rheumtic, conjunctivitis, blephritis, episcleritis, scleritis, iritis, leukocytoclstic vsculitis, erythem multiforme, psorisis, rthritis, utoimmune thyroiditis, neurosensory hypocusis, utoimmune centrl neuropthy (encephlitis), myositis, polymyositis, oculr myositis, cytopenis (2.5%), nd nephritis. 1 mg/kg dministered with nivolumb 3 mg/kg cn cuse other cliniclly significnt nd potentilly ftl immune-medited dverse rections. Immune-medited dverse rections my occur fter discontinution of therpy. For ny suspected immune-medited dverse rections, exclude other cuses. Bsed on the severity of the dverse rection, permnently discontinue or withhold, dminister high-dose corticosteroids, nd if pproprite, initite 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. Across clinicl trils of dministered with nivolumb or in trils of nivolumb dministered s single gent, the following cliniclly significnt immunemedited dverse rections, some with ftl outcome, occurred in less thn 1.0% of ptients: myocrditis, rhbdomyolysis, myositis, 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), motor dysfunction, vsculitis, plstic nemi, pericrditis, nd mysthenic syndrome. 5.11 Embryo-Fetl Toxicity Bsed on its mechnism of ction nd dt from niml studies, cn cuse fetl hrm when dministered to pregnnt womn. In niml reproduction studies, dministrtion of ipilimumb to cynomolgus monkeys from the onset of orgnogenesis through delivery resulted in higher incidences of bortion, stillbirth, premture delivery (with corresponding lower birth weight), nd higher incidences of infnt mortlity in dose-relted mnner. The effects of ipilimumb re likely to be greter during the second nd third trimesters of pregnncy. Advise pregnnt women of the potentil risk to fetus. Advise femles of reproductive potentil to use effective contrception during tretment with -contining regimen nd for 3 months fter the lst dose of [see Use in Specific Popultions (8.1, 8.3)]. 5.12 Risks Associted When Administered in Combintion with Nivolumb When is dministered in combintion with nivolumb, refer to the nivolumb prescribing informtion for dditionl risk informtion tht pplies to the combintion use. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lbeling. Immune-medited enterocolitis/colitis [see Wrnings nd Precutions (5.1)]. Immune-medited heptitis [see Wrnings nd Precutions (5.2)]. Immune-medited dermtitis/skin dverse rections [see Wrnings nd Precutions (5.3)]. Immune-medited neuropthies [see Wrnings nd Precutions (5.4)]. Immune-medited endocrinopthies [see Wrnings nd Precutions (5.5)]. Immune-medited pneumonitis [see Wrnings nd Precutions (5.6)]. Immune-medited nephritis nd renl dysfunction [see Wrnings nd Precutions (5.7)]. Immune-medited encephlitis [see Wrnings nd Precutions (5.8)]. Infusion rections [see Wrnings nd Precutions (5.9)]. Other immune-medited dverse rections, including oculr mnifesttions [see Wrnings nd Precutions (5.10)]. Embryo-fetl toxicity [see Wrnings nd Precutions (5.11)]. In ptients receiving 3 mg/kg for unresectble or metsttic melnom in MDX010-20, 15% of ptients receiving monotherpy nd 12% of ptients treted in combintion with gp100 peptide vccine experienced Grde 3 to 5 immune-medited rections. In ptients receiving 10 mg/kg for djuvnt tretment of melnom in CA184-029, 41% experienced Grde 3 to 5 immune-medited rections. 6.1 Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, the dverse rection rtes observed cnnot be directly compred with rtes in other clinicl trils or experience with therpeutics in the sme clss nd my not reflect the rtes observed in clinicl prctice. (ipilimumb) The dt described below reflect exposure to 3 mg/kg s single gent in MDX010-20, rndomized tril in ptients with unresectble or metsttic melnom; to 10 mg/kg s single gent in CA184-029, rndomized tril in ptients with resected Stge IIIA (>1 mm nodl involvement), IIIB, nd IIIC (with no in-trnsit metstses) cutneous melnom; nd to 1 mg/kg, dministered in combintion with nivolumb, in two trils: CHECKMATE-214 (NCT02231749), rndomized tril in previously untreted ptients with dvnced renl cell crcinom, nd CHECKMATE-142 (NCT02060188), n open-lbel, multicenter, non-rndomized multiple prllel cohort tril in ptients with previously treted, MSI-H or dmmr metsttic colorectl cncer. Cliniclly significnt dverse rections were evluted in totl of 982 ptients treted in MDX010-20 nd CA184-029 nd in 21 dose-rnging trils (n=2478) dministering t doses of 0.1 to 20 mg/kg [see Wrnings nd Precutions (5.6)]. Unresectble or Metsttic Melnom The sfety of ws evluted in MDX010-20, rndomized, double-blind clinicl tril in which 643 previously treted ptients with unresectble or metsttic melnom received 3 mg/kg for 4 doses given by intrvenous infusion s single gent (n=131), with n investigtionl gp100 peptide vccine (gp100) (n=380), or gp100 peptide vccine s single gent (n=132) [see Clinicl Studies (14.1)]. Ptients in the tril received medin of 4 doses (rnge: 1 to 4 doses). MDX010-20 excluded ptients with ctive utoimmune disese or those receiving systemic immunosuppression for orgn trnsplnttion. The tril popultion chrcteristics were: medin ge 57 yers (rnge: 19 to 90), 59% mle, 94% white, nd bseline ECOG performnce sttus 0 (56%). ws discontinued for dverse rections in 10% of ptients. Tble 2 presents selected dverse rections from MDX010-20, which occurred in t lest 5% of ptients in the -contining rms nd with t lest 5% incresed incidence over the control gp100 rm for ll-grde events nd t lest 1% incidence over the control group for Grde 3 to 5 events. Tble 2: System Orgn Clss/ Preferred Term Selected Adverse Rections in MDX010-20 Percentge (%) of Ptients 3 mg/kg n=131 Any Grde Grde 3 to 5 3 mg/kg+gp100 n=380 Any Grde Grde 3 to 5 Any Grde gp100 n=132 Grde 3 to 5 Generl Disorders nd Administrtion-Site Conditions Ftigue 41 7 34 5 31 3 Gstrointestinl Disorders Dirrhe 32 5 37 4 20 1 Colitis 8 5 5 3 2 0 Skin nd Subcutneous Tissue Disorders Pruritus 31 0 21 <1 11 0 Rsh 29 2 25 2 8 0 Incidences presented in this tble re bsed on reports of dverse events regrdless of cuslity. Tble 3 presents the per-ptient incidence of severe, life-thretening, or ftl immunemedited dverse rections from MDX010-20. Tble 3: Severe to Ftl Immune-Medited Adverse Rections in MDX010-20 Percentge (%) of Ptients 3 mg/kg n=131 3 mg/kg+gp100 n=380 Any Immune-Medited Adverse Rection 15 12 Enterocolitis,b 7 7 Heptotoxicity 1 2 Dermtitis 2 3 Neuropthy 1 <1 Endocrinopthy 4 1 Hypopituitrism 4 1 Adrenl insufficiency 0 1 (Continued)