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. (2.3) 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) ----------------------------- 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) -------------------------- 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) Permnently discontinue for severe dverse rections. (2.3) -------------------------DOSAGE FORMS AND STRENGTHS------------------------- Injection: 50 mg/10 ml (5 mg/ml) (3) Injection: 200 mg/40 ml (5 mg/ml) (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) Immune-medited heptitis: Evlute liver function tests before ech dose of (ipilimumb). (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) Embryo-fetl toxicity: Cn cuse fetl hrm. Advise of potentil risk to fetus nd use of effective contrception. (5.7) ------------------------------- ADVERSE REACTIONS-------------------------------- Most common dverse rections ( 5%) 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) 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 nursing during tretment with. (8.2) See 17 for PATIENT COUNSELING INFORMATION nd Mediction Guide. Revised: 10/2017 FULL PRESCRIBING INFORMATION: CONTENTS * WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS 1 INDICATIONS AND USAGE 1.1 Unresectble or Metsttic Melnom 1.2 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Unresectble or Metsttic Melnom 2.2 Recommended Dosing for 2.3 Recommended Dose Modifictions 2.4 Preprtion nd Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Medited Enterocolitis 5.2 Immune-Medited Heptitis 5.3 Immune-Medited Dermtitis 5.4 Immune-Medited Neuropthies 5.5 Immune-Medited Endocrinopthies 5.6 Other Immune-Medited Adverse Rections, Including Oculr Mnifesttions 5.7 Embryo-fetl Toxicity 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Postmrketing Experience 6.3 Immunogenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.2 Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Unresectble or Metsttic Melnom 14.2 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 WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS 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 [see Dosge nd Administrtion (2.3)]. 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 (ipilimumb) 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 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)]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing for Unresectble or Metsttic Melnom The recommended dose of is 3 mg/kg dministered intrvenously 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 The recommended dose of is 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 [see Clinicl Studies (14.2)]. In the event of toxicity, doses re omitted, not delyed. 2.3 Recommended Dose Modifictions Tble 1: Recommended Tretment Modifictions for Immune-Medited Adverse Rections of Trget/Orgn Adverse Rection (CTCAE v3) Tretment Modifiction System Endocrine Symptomtic endocrinopthy Withhold Resume in ptients with complete or prtil resolution of dverse rections ( 0 to 1) nd who re receiving less thn 7.5 mg prednisone or equivlent per dy. Symptomtic rections lsting Permnently discontinue 6 weeks or longer Inbility to reduce corticosteroid dose to 7.5 mg prednisone or equivlent per dy Ophthlmologic 2 through 4 rections not improving to 1 within 2 weeks while receiving topicl therpy or requiring systemic tretment Permnently discontinue All Other 2 Withhold Resume in ptients with complete or prtil resolution of dverse rections ( 0 to 1) nd who re receiving less thn 7.5 mg prednisone or equivlent per dy. 2 rections lsting 6 weeks or longer Inbility to reduce corticosteroid dose to 7.5 mg prednisone or equivlent per dy 3 or 4 Permnently discontinue (ipilimumb) 2.4 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. 3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/10 ml (5 mg/ml) Injection: 200 mg/40 ml (5 mg/ml) 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS cn result in severe nd ftl immune-medited rections [see Boxed Wrning]. 5.1 Immune-Medited Enterocolitis 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 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 (2.3)]. Metsttic Melnom In ptients receiving 3 mg/kg in Tril 1, severe, life-thretening, or ftl (dirrhe of 7 or more stools bove bseline, fever, ileus, peritonel signs; 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; 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 3 to 5 enterocolitis ws 1.7 months (rnge: 11 dys to 3.1 months) nd for 2 enterocolitis ws 1.4 months (rnge: 2 dys to 4.3 months). Twenty-nine ptients (85%) with 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 3 to 5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to 2 severity, nd 24% did not improve. Among the 28 ptients with 2 enterocolitis, 79% experienced complete resolution, 11% improved, nd 11% did not improve. In ptients receiving 10 mg/kg in Tril 2, 3 to 5 immune-medited enterocolitis occurred in 76 ptients (16%) nd 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 3 to 4 enterocolitis ws 1.1 months (rnge: 1 dy to 33.1 months) nd for 2 enterocolitis ws 1.1 months (rnge: 1 dy to 20.6 months). Seventy-one ptients (95%) with 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 3 to 4 enterocolitis nd 15% of ptients with 2 event. Of the 75 ptients with 3 to 4 immune-medited enterocolitis, 86% experienced complete resolution, 3% experienced improvement to 1, nd 11% did not improve. Among the 68 ptients with 2 enterocolitis, 94% experienced complete resolution, 3% experienced improvement to 1, nd 3% did not improve. 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 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 2 heptotoxicity [see Dosge nd Administrtion (2.3)]. Metsttic Melnom In ptients receiving 3 mg/kg in Tril 1, 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; 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; 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. In ptients receiving 10 mg/kg in Tril 2, 3 to 4 immune-medited heptitis occurred in 51 ptients (11%) nd moderte 2 immune-medited heptitis occurred in 22 ptients (5%). Liver biopsy performed in 6 ptients with 3 to 4 heptitis showed evidence of toxic or utoimmune heptitis. The medin time to onset for 3 to 4 heptitis ws 2.0 months (rnge: 1 dy to 4.2 months) nd for 2 heptitis ws 1.4 months (rnge: 13 dys to 6.5 months). Of the 51 ptients with 3 to 4 immune-medited heptitis, 94% experienced complete resolution, 4% experienced improvement to 1, nd 2% did not improve. Of the 22 ptients with 2 immune-medited heptitis, 91% experienced complete resolution nd 9% did not improve. Forty-six ptients (90%) with 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, 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). (ipilimumb) 5.3 Immune-Medited Dermtitis 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 (2.3)]. 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. Metsttic Melnom In ptients receiving 3 mg/kg in Tril 1, severe, life-thretening, or ftl immunemedited dermtitis (e.g., Stevens-Johnson syndrome, toxic epiderml necrolysis, or rsh complicted by full thickness derml ulcertion, or necrotic, bullous, or hemorrhgic mnifesttions; 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 ( 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 ( 1) severity, nd 12 (19%) hd no reported improvement. In ptients receiving 10 mg/kg in Tril 2, 3 to 4 immune-medited dermtitis occurred in 19 ptients (4%). There were 99 ptients (21%) with moderte ( 2) dermtitis. The medin time to onset for 3 to 4 dermtitis ws 14 dys (rnge: 5 dys to 11.3 months) nd for 2 dermtitis ws 11 dys (rnge: 1 dy to 16.6 months). Sixteen ptients (84%) with 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 1. Of the 99 ptients with 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 ( 1) severity, nd 7 (7%) did not improve. 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 (2.3)]. Metsttic Melnom In ptients receiving 3 mg/kg in Tril 1, 1 cse of ftl Guillin-Brré syndrome nd 1 cse of severe ( 3) peripherl motor neuropthy were reported. Across the clinicl development progrm of, mystheni grvis nd dditionl cses of Guillin-Brré syndrome hve been reported. In ptients receiving 10 mg/kg in Tril 2, 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 2 immunemedited neuropthy occurred in 1 ptient (0.2%).
(ipilimumb) The time to onset cross the 9 ptients with 2 to 5 immune-medited neuropthy rnged from 1.4 to 27.4 months. All 8 ptients with 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 3 to 5 immune-medited neuropthy experienced complete resolution, 1 improved to 1, nd 3 did not improve. The single ptient with 2 immune-medited neuropthy experienced complete resolution without the use of corticosteroids. 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 (2.3)]. Metsttic Melnom In ptients receiving 3 mg/kg in Tril 1, severe to life-thretening immunemedited endocrinopthies (requiring hospitliztion, urgent medicl intervention, or interfering with ctivities of dily living; 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; 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). In ptients receiving 10 mg/kg in Tril 2, 3 to 4 immune-medited endocrinopthies occurred in 39 ptients (8%) nd 2 immune-medited endocrinopthies in 93 ptients (20%). Of the 39 ptients with 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 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 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 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 2 to 4 immunemedited endocrinopthy. Of these, 42 (34%) were ble to discontinue corticosteroids. Seventy-three ptients received thyroid hormones for tretment of 2 to 4 immunemedited hypothyroidism. Of these, 14 ptients (19%) were ble to discontinue thyroid replcement therpy. 5.6 Other Immune-Medited Adverse Rections, Including Oculr Mnifesttions 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. 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 (2.3)]. (ipilimumb) Metsttic Melnom In Tril 1, the following cliniclly significnt immune-medited dverse rections were seen in less thn 1% of -treted ptients: nephritis, pneumonitis, meningitis, pericrditis, uveitis, iritis, nd hemolytic nemi. In Tril 2, the following cliniclly significnt immune-medited dverse rections were seen in less thn 1% of -treted ptients unless specified: 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: 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, hemolytic nemi, nd nephritis. 5.7 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)]. 6 ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lbeling. Immune-medited enterocolitis [see Wrnings nd Precutions (5.1)]. Immune-medited heptitis [see Wrnings nd Precutions (5.2)]. Immune-medited dermtitis [see Wrnings nd Precutions (5.3)]. Immune-medited neuropthies [see Wrnings nd Precutions (5.4)]. Immune-medited endocrinopthies [see Wrnings nd Precutions (5.5)]. Other immune-medited dverse rections, including oculr mnifesttions [see Wrnings nd Precutions (5.6)]. In ptients receiving 3 mg/kg for unresectble or metsttic melnom in Tril 1, 15% of ptients receiving monotherpy nd 12% of ptients treted in combintion with gp100 peptide vccine experienced 3 to 5 immune-medited rections. In ptients receiving 10 mg/kg for djuvnt tretment of melnom in Tril 2, 41% experienced 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. The dt described below reflect exposure to 3 mg/kg in Tril 1, rndomized tril in ptients with unresectble or metsttic melnom nd to 10 mg/kg in Tril 2, rndomized tril in ptients with resected Stge IIIA (>1 mm nodl involvement), IIIB, nd IIIC (with no in-trnsit metstses) cutneous melnom. Cliniclly significnt dverse rections were evluted in totl of 982 ptients treted in Trils 1 nd 2 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 Tril 1, 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). Tril 1 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 Tril 1, 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 3 to 5 events.
(ipilimumb) Tble 2: Selected Adverse Rections in Tril 1 System Orgn Clss/ Preferred Term 3 mg/kg n=131 Any Percentge (%) of Ptients 3 to 5 3 mg/kg+gp100 n=380 Any 3 to 5 Any gp100 n=132 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 Tril 1. Tble 3: Severe to Ftl Immune-Medited Adverse Rections in Tril 1 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 Other Pneumonitis 0 <1 Meningitis 0 <1 Nephritis 1 0 Eosinophili c 1 0 Pericrditis,c 0 <1 Including ftl outcome. b Including intestinl perfortion. c Underlying etiology not estblished. The sfety of ws evluted in Tril 2, rndomized (1:1), double-blind, plcebo-controlled tril in which 945 ptients with resected Stge IIIA (>1 mm nodl involvement), IIIB, nd IIIC (with no in-trnsit metstses) cutneous melnom received 10 mg/kg (n=471) or plcebo (n=474) dministered s n intrvenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning t Week 24 up to mximum of 3 yers [see Clinicl Studies (14.2)]. In this tril, 36% of ptients received for longer thn 6 months nd 26% of ptients received for longer thn 1 yer. -treted ptients in the tril received medin of 4 doses (rnge: 1 to 16). Tril 2 excluded ptients with prior systemic therpy for melnom, utoimmune disese, condition requiring systemic immunosuppression, or positive test for heptitis B, heptitis C, or HIV. The tril popultion chrcteristics were: medin ge 51 yers (rnge: 18 to 84 yers), 62% mle, 99% white, nd bseline ECOG performnce sttus 0 (94%). ws discontinued for dverse rections in 52% of ptients. Tble 4 presents selected dverse rections from Tril 2 which occurred in t lest 5% of -treted ptients nd with t lest 5% incresed incidence over the plcebo group for ll-grde events. (ipilimumb) Tble 4: Selected Adverse Rections in Tril 2 Percentge (%) of Ptients System Orgn Clss/ Preferred Term Any 10 mg/kg n=471 3 to 5 Any Plcebo n=474 3 to 5 Skin nd Subcutneous Tissue Disorders Rsh 50 2.1 20 0 Pruritus 45 2.3 15 0 Gstrointestinl Disorders Dirrhe 49 10 30 2.1 Nuse 25 0.2 18 0 Colitis b 16 8 1.5 0.4 Vomiting 13 0.4 6 0.2 Investigtions Weight Decresed 32 0.2 9 0.4 Generl Disorders nd Administrtion-Site Conditions Ftigue 46 2.3 38 1.5 Pyrexi 18 1.1 4.9 0.2 Nervous System Disorders Hedche 33 0.8 18 0.2 Metbolism nd Nutrition Disorders Decresed Appetite 14 0.2 3.4 0.2 Psychitric Disorders Insomni 10 0 4.4 0 Incidences presented in this tble re bsed on reports of dverse events regrdless of cuslity. b Includes 1 deth. Tble 5 presents selected lbortory bnormlities from Tril 2 which occurred in t lest 10% of -treted ptients t higher incidence compred to plcebo. Tble 5: Test Lbortory Abnormlities Worsening from Bseline Occurring in 10% of -Treted Ptients (Tril 2) All s Percentge of Ptients with Worsening Lbortory Test from Bseline 3 to 4 All s Plcebo 3 to 4 Chemistry Incresed ALT 46 10 16 0 Incresed AST 38 9 14 0.2 Incresed lipse b 26 9 17 4.5 Incresed mylse b 17 2.0 7 0.6 Incresed lkline phosphtse 17 0.6 6 0.2 Incresed bilirubin 11 1.5 9 0 Incresed cretinine 10 0.2 6 0 Hemtology Decresed hemoglobin 25 0.2 14 0 Ech test incidence is bsed on the number of ptients who hd both bseline nd t lest one on-study lbortory mesurement vilble. Excluding lipse nd mylse, group (rnge: 466 to 470 ptients) nd plcebo group (rnge: 472 to 474 ptients). b For lipse nd mylse, group (rnge: 447 to 448 ptients) nd plcebo group (rnge: 462 to 464 ptients). Tble 6 presents the per-ptient incidence of severe, life-thretening, or ftl immunemedited dverse rections from Tril 2.
(ipilimumb) Tble 6: Severe to Ftl Immune-Medited Adverse Rections in Tril 2 Percentge (%) of Ptients 10 mg/kg n=471 Any Immune-Medited Adverse Rection 41 Enterocolitis,b 16 Heptitis 11 Dermtitis 4.0 Neuropthy 1.7 Endocrinopthy 8 Hypopituitrism 7 Primry hypothyroidism 0.2 Hyperthyroidism 0.6 Other Myocrditis 0.2 Meningitis 0.4 Pericrditis c 0.2 Pneumonitis 0.2 Uveitis 0.2 Including ftl outcome. b Including intestinl perfortion. c Underlying etiology not estblished. Other Clinicl Experience Across clinicl studies tht utilized doses rnging from 0.3 to 10 mg/kg, the following dverse rections were lso reported (incidence less thn 1% unless otherwise noted): urticri (2%), lrge intestinl ulcer, esophgitis, cute respirtory distress syndrome, renl filure, nd infusion rection. 6.2 Postmrketing Experience The following dverse rections hve been identified during postpprovl use of. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. Skin nd Subcutneous Tissue Disorders: Drug rection with eosinophili nd systemic symptoms (DRESS syndrome) 6.3 Immunogenicity As with ll therpeutic proteins, there is potentil for immunogenicity. Eleven (1.1%) of 1024 evluble ptients with unresectble or metsttic melnom tested positive for tretment-emergent binding ntibodies ginst ipilimumb (TE-ADAs) in n electrochemiluminescent (ECL) bsed ssy. This ssy hd substntil limittions in detecting nti-ipilimumb ntibodies in the presence of ipilimumb. Seven (4.9%) of 144 ptients receiving ipilimumb nd 7 (4.5%) of 156 ptients receiving plcebo for the djuvnt tretment of melnom tested positive for TE-ADAs using n ECL ssy with improved drug tolernce. No ptients tested positive for neutrlizing ntibodies. No infusion-relted rections occurred in ptients who tested positive for TE-ADAs. Immunogenicity ssy results re highly dependent on severl fctors including ssy sensitivity nd specificity, ssy methodology, smple hndling, timing of smple collection, concomitnt medictions, nd underlying disese. For these resons, comprison of incidence of ntibodies to ipilimumb with the incidences of ntibodies to other products my be misleding. 7 DRUG INTERACTIONS No forml phrmcokinetic drug interction studies hve been conducted with. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Risk Summry Bsed on dt from niml studies nd its mechnism of ction, cn cuse fetl hrm when dministered to pregnnt womn [see Clinicl Phrmcology (12.1)]. 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 (see Dt). The effects of ipilimumb re likely to be greter during the second nd third trimesters of pregnncy. Humn IgG1 is known to cross the plcentl brrier nd ipilimumb is n IgG1; therefore, ipilimumb hs the potentil to be trnsmitted from the mother to the developing fetus. There is insufficient humn dt for exposure in pregnnt women. Advise pregnnt women of the potentil risk to fetus. (ipilimumb) In the U.S. generl popultion, the estimted bckground risk of mjor birth defects nd miscrrige in cliniclly recognized pregnncies is 2% to 4% nd 15% to 20%, respectively. A Pregnncy Sfety Surveillnce Study hs been estblished to collect informtion bout pregnncies in women who hve received. Helthcre providers re encourged to enroll ptients or hve their ptients enroll directly by clling 1-844-593-7869. Dt Animl Dt In combined study of embryo-fetl nd peri-postntl development, pregnnt cynomolgus monkeys received ipilimumb every 3 weeks from the onset of orgnogenesis in the first trimester through prturition. No tretment-relted dverse effects on reproduction were detected during the first two trimesters of pregnncy. Beginning in the third trimester, dministrtion of ipilimumb t doses resulting in exposures pproximtely 2.6 to 7.2 times the humn exposure t dose of 3 mg/kg resulted in dose-relted increses in bortion, stillbirth, premture delivery (with corresponding lower birth weight), nd n incresed incidence of infnt mortlity. In ddition, developmentl bnormlities were identified in the urogenitl system of 2 infnt monkeys exposed in utero to 30 mg/kg of ipilimumb (7.2 times the AUC in humns t the 3 mg/kg dose). One femle infnt monkey hd unilterl renl genesis of the left kidney nd ureter, nd 1 mle infnt monkey hd n imperforte urethr with ssocited urinry obstruction nd subcutneous scrotl edem. Geneticlly engineered mice heterozygous for CTLA-4 (CTLA-4+/ ), the trget for ipilimumb, ppered helthy nd gve birth to helthy CTLA-4+/ heterozygous offspring. Mted CTLA-4+/ heterozygous mice lso produced offspring deficient in CTLA-4 (homozygous negtive, CTLA-4 / ). The CTLA-4 / homozygous negtive offspring ppered helthy t birth, exhibited signs of multiorgn lymphoprolifertive disese by 2 weeks of ge, nd ll died by 3 to 4 weeks of ge with mssive lymphoprolifertion nd multiorgn tissue destruction. 8.2 Lcttion Risk Summry It is not known whether is present in humn milk. In monkeys, ipilimumb ws present in milk (see Dt). There re no dt to ssess the effects of on milk production. Advise women to discontinue nursing during tretment with nd for 3 months following the finl dose. Dt In monkeys treted t dose levels resulting in exposures 2.6 nd 7.2 times higher thn those in humns t 3 mg/kg dose, ipilimumb ws present in milk t concentrtions of 0.1 mcg/ml nd 0.4 mcg/ml, representing rtio of up to 0.3% of the stedy-stte serum concentrtion of the drug. 8.3 Femles nd Mles of Reproductive Potentil Contrception Bsed on its mechnism of ction, cn cuse fetl hrm when dministered to pregnnt womn [see Use in Specific Popultions (8.1)]. Advise femles of reproductive potentil to use effective contrception during tretment with nd for 3 months following the lst dose of. 8.4 Peditric Use The sfety nd effectiveness of hve been estblished in peditric ptients 12 yers nd older. Use of in this ge group is supported by evidence from dequte nd well-controlled studies of in dults nd popultion phrmcokinetic dt demonstrting tht the exposure t dose of 3 mg/kg in the peditric nd dult popultions is comprble. In ddition, the tumor biology nd course of dvnced melnom is sufficiently similr in dults nd peditric ptients 12 yers nd older to llow extrpoltion of dt from dults to peditric ptients. The sfety nd effectiveness for peditric ptients less thn 12 yers of ge hs not been estblished [see Dosge nd Administrtion (2.1), Clinicl Phrmcology (12.3), nd Clinicl Studies (14)]. ws evluted in totl of 45 peditric ptients cross two clinicl trils. In dose-finding tril, 33 peditric ptients with relpsed or refrctory solid tumors were evluted. The medin ge ws 13 yers (rnge 2 to 21 yers), nd 20 ptients were 12 yers old. ws dministered t doses of 1, 3, 5, nd 10 mg/kg intrvenously over 90 minutes every 3 weeks for 4 doses nd then every 12 weeks therefter until progression or tretment discontinution. ws lso evluted in n open-lbel, single-rm, tril in 12 peditric ptients 12 yers old (rnge 12 to 16 yers) with previously treted or untreted, unresectble Stge 3 or 4 mlignnt melnom. Ptients received 3 mg/kg (4 ptients) or 10 mg/kg (8 ptients) intrvenously over 90 minutes every 3 weeks for 4 doses. Of the 17 ptients 12 yers of ge with melnom treted with cross both studies, two ptients experienced objective responses including one prtil response tht ws sustined for 16 months. There were no responses in ptients with nonmelnom solid tumors. The overll sfety profile of in children nd dolescents ws consistent with the sfety profile in dults. Peditric Phrmcokinetics (PK) Bsed on popultion PK nlysis using vilble pooled dt from 565 ptients from 4 phse 2 dult studies (N=521) nd 2 peditric studies (N=44), body weight normlized clernce of ipilimumb is comprble between dult nd peditric ptients.
(ipilimumb) In peditric ptients with dosing regimen of 3 mg/kg every 3 weeks, the model simulted geometric men (CV%) stedy-stte serum pek nd trough concentrtions of ipilimumb were 65.8 (17.6%) nd 20.7 (33.1%) mcg/ml (for 2 to 6 yers old), 70.1 (19.6%) nd 19.6 (42.9%) mcg/ml (for 6 to <12 yers old), nd 73.3 (20.6%) nd 17.8 (50.8%) mcg/ml (for 12 yers nd older), which re comprble to those in dult ptients. 8.5 Geritric Use Of the 511 ptients treted with in Tril 1, 28% were 65 yers nd over. No overll differences in sfety or efficcy were reported between the elderly ptients (65 yers nd over) nd younger ptients (less thn 65 yers). Tril 2 did not include sufficient numbers of ptients ged 65 yers nd older to determine whether they respond differently from younger ptients. 8.6 Renl Impirment No dose djustment is needed for ptients with renl impirment [see Clinicl Phrmcology (12.3)]. 8.7 Heptic Impirment No dose djustment is needed for ptients with mild heptic impirment (totl bilirubin [TB] >1.0 to 1.5 times the upper limit of norml [ULN] or AST >ULN). hs not been studied in ptients with moderte (TB >1.5 to 3.0 times ULN nd ny AST) or severe (TB >3 times ULN nd ny AST) heptic impirment [see Clinicl Phrmcology (12.3)]. 10 OVERDOSAGE There is no informtion on overdosge with. 11 DESCRIPTION (ipilimumb) is recombinnt, humn monoclonl ntibody tht binds to the cytotoxic T-lymphocyte-ssocited ntigen 4 (CTLA-4). Ipilimumb is n IgG1 kpp immunoglobulin with n pproximte moleculr weight of 148 kd. Ipilimumb is produced in mmmlin (Chinese hmster ovry) cell culture. is sterile, preservtive-free, cler to slightly oplescent, colorless to pleyellow solution for intrvenous infusion, which my contin smll mount of visible trnslucent-to-white, morphous ipilimumb prticultes. It is supplied in single-use vils of 50 mg/10 ml nd 200 mg/40 ml. Ech milliliter contins 5 mg of ipilimumb nd the following inctive ingredients: diethylene trimine pentcetic cid (DTPA) (0.04 mg), mnnitol (10 mg), polysorbte 80 (vegetble origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), nd Wter for Injection, USP t ph of 7. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action CTLA-4 is negtive regultor of T-cell ctivity. Ipilimumb is monoclonl ntibody tht binds to CTLA-4 nd blocks the interction of CTLA-4 with its lignds, CD80/CD86. Blockde of CTLA-4 hs been shown to ugment T-cell ctivtion nd prolifertion, including the ctivtion nd prolifertion of tumor infiltrting T-effector cells. Inhibition of CTLA-4 signling cn lso reduce T-regultory cell function, which my contribute to generl increse in T cell responsiveness, including the nti-tumor immune response. 12.3 Phrmcokinetics The phrmcokinetics (PK) of ipilimumb ws studied in 785 ptients with unresectble or metsttic melnom who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumb is liner in the dose rnge of 0.3 to 10 mg/kg. Following dministrtion of every 3 weeks, the systemic ccumultion ws 1.5-fold or less. Stedy-stte concentrtions of ipilimumb were reched by the third dose; the men C min t stedy stte ws 19.4 mcg/ml t 3 mg/kg nd 58.1 mcg/ml t 10 mg/kg every 3 weeks. The men vlue (percent coefficient of vrition) bsed on popultion PK nlysis for the terminl hlf-life (t 1/2) ws 15.4 dys (34%) nd for clernce (CL) ws 16.8 ml/h (38%). Specific Popultions The effects of vrious covrites on the PK of ipilimumb were ssessed in popultion PK nlyses. The CL of ipilimumb incresed with incresing body weight supporting the recommended body weight (mg/kg) bsed dosing. The following fctors hd no cliniclly importnt effect on the CL of ipilimumb: ge (rnge: 23 to 88 yers), sex, performnce sttus, renl impirment, mild heptic impirment, previous cncer therpy, nd bseline lctte dehydrogense (LDH) levels. The effect of rce ws not exmined due to limited dt vilble in non-cucsin ethnic groups. Renl Impirment: The effect of renl impirment on the CL of ipilimumb ws evluted in ptients with mild (GFR <90 nd 60 ml/min/1.73 m 2 ; n=349), moderte (GFR <60 nd 30 ml/min/1.73 m 2 ; n=82), or severe (GFR <30 nd 15 ml/min/1.73 m 2 ; n=4) renl impirment compred to ptients with norml renl function (GFR 90 ml/min/1.73 m 2 ; n=350) in popultion PK nlyses. No cliniclly importnt differences in the CL of ipilimumb were found between ptients with renl impirment nd ptients with norml renl function [see Use in Specific Popultions (8.6)]. Heptic Impirment: The effect of heptic impirment on the CL of ipilimumb ws evluted in ptients with mild heptic impirment (n=76) compred to ptients with norml heptic function (n=708) in the popultion PK nlyses, nd no cliniclly importnt differences in the CL of ipilimumb were found. hs not been studied in ptients with moderte or severe heptic impirment [see Use in Specific Popultions (8.7)]. Peditric Popultion: [see Use in Specific Popultions (8.4)]. 13 NONCLINICAL TOXICOLOGY (ipilimumb) 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility The crcinogenic potentil of ipilimumb hs not been evluted in long-term niml studies, nd the genotoxic potentil of ipilimumb hs not been evluted. Fertility studies hve not been performed with ipilimumb. 14 CLINICAL STUDIES 14.1 Unresectble or Metsttic Melnom The sfety nd efficcy of were investigted in rndomized (3:1:1), double-blind, double-dummy tril (Tril 1) tht included 676 rndomized ptients with unresectble or metsttic melnom previously treted with one or more of the following: ldesleukin, dcrbzine, temozolomide, fotemustine, or crbopltin. Of these 676 ptients, 403 were rndomized to receive t 3 mg/kg in combintion with n investigtionl peptide vccine with incomplete Freund s djuvnt (gp100), 137 were rndomized to receive t 3 mg/kg, nd 136 were rndomized to receive gp100 s single gent. The tril enrolled only ptients with HLA-A2*0201 genotype; this HLA genotype fcilittes the immune presenttion of the investigtionl peptide vccine. The tril excluded ptients with ctive utoimmune disese or those receiving systemic immunosuppression for orgn trnsplnttion. /plcebo ws dministered t 3 mg/kg s n intrvenous infusion every 3 weeks for 4 doses. Gp100/plcebo ws dministered t dose of 2 mg peptide by deep subcutneous injection every 3 weeks for 4 doses. Assessment of tumor response ws conducted t weeks 12 nd 24, nd every 3 months therefter. Ptients with evidence of objective tumor response t 12 or 24 weeks hd ssessment for confirmtion of durbility of response t 16 or 28 weeks, respectively. The mjor efficcy outcome mesure ws overll survivl (OS) in the plus gp100 rm compred to tht in the single-gent gp100 rm. Secondry efficcy outcome mesures were OS in the plus gp100 rm compred to the rm, OS in the rm compred to the gp100 rm, best overll response rte (BORR) t week 24 between ech of the tril rms, nd durtion of response. Of the rndomized ptients, 61%, 59%, nd 54% in the plus gp100,, nd gp100 rms, respectively, were men. Twenty-nine percent were 65 yers of ge, the medin ge ws 57 yers, 71% hd M1c stge, 12% hd history of previously treted brin metstsis, 98% hd ECOG performnce sttus of 0 nd 1, 23% hd received ldesleukin, nd 38% hd elevted LDH level. Sixty-one percent of ptients rndomized to either -contining rm received ll 4 plnned doses. The medin durtion of follow-up ws 8.9 months. The OS results re shown in Tble 7 nd Figure 1. Tble 7: Overll Survivl Results n=137 +gp100 n=403 gp100 n=136 Hzrd Rtio (vs. gp100) 0.66 0.68 (95% CI) (0.51, 0.87) (0.55, 0.85) p-vlue p=0.0026 p=0.0004 Hzrd Rtio (vs. ) 1.04 (95% CI) (0.83, 1.30) Medin (months) 10 10 6 (95% CI) (8.0, 13.8) (8.5, 11.5) (5.5, 8.7) Not djusted for multiple comprisons. Figure 1: Overll Survivl 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 MONTHS SUBJECTS AT RISK Ipi+ gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0 Ipi 137 106 79 56 38 30 24 18 13 13 8 5 2 1 0 gp100 136 93 58 32 23 17 16 7 5 5 3 1 0 0 0 PROPORTION ALIVE Ipi+gp100 CENSORED Ipi CENSORED gp100 CENSORED