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Solid Tumors When compared with baseline values during an additional phase 1/2 trial of abiraterone in chemotherapy-naĂŻve patients, 67% of the patients achieved a decline in prostate-specific antigen (PSA) â‰Ľ50% and the median time to PSA progression (TTPP) on abiraterone alone for all phase 2 patients was 225 days.11 Toxicities observed were
attributed to changes in mineralocorticoid, which were manageable with lowdose corticosteroids.11,12 The pivotal trial for abiraterone was conducted in the postchemotherapy setting for men with CRPC. In COUAA-301, a large randomized, doubleblind, placebo-controlled phase 3 study, chemotherapy-refractory meta-
static patients were treated with either abiraterone plus low-dose prednisone (n = 797) or prednisone plus placebo (n = 398). The median overall survival, the primary end point for this study, was 15.8 months and 11.2 months, respectively, after 775 events (hazard ratio, 0.740; 95% confidence interval, 0.638-0.859), and the benefit
was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received. Other trial end points, including PSA change, TTPP, and radiographic progression-free survival (PFS), also resulted in superior outcomes. Patients on abiraterone achieved a PSA decline of
Important Safety Information (continued) Recommended Dose Modifications:
Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: t1FSTJTUFOUNPEFSBUFBEWFSTFSFBDUJPOTPSJOBCJMJUZUPSFEVDF corticosteroid dose to 7.5 mg prednisone or equivalent per day. t'BJMVSFUPDPNQMFUFGVMMUSFBUNFOUDPVSTFXJUIJOXFFLTGSPN administration of first dose. t4FWFSFPSMJGFUISFBUFOJOHBEWFSTFSFBDUJPOT
t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF to life-threatening immune-mediated endocrinopathies (requiring IPTQJUBMJ[BUJPO VSHFOUNFEJDBMJOUFSWFOUJPO PSJOUFSGFSJOHXJUIBDUJWJUJFT of daily living; Grade 3-4) occurred in 9 (1.8%). â€“ All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. o PGUIFQBUJFOUTXFSFIPTQJUBMJ[FEGPSTFWFSFFOEPDSJOPQBUIJFT t.PEFSBUFFOEPDSJOPQBUIZ SFRVJSJOHIPSNPOFSFQMBDFNFOUPSNFEJDBM intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1Â case each of hyperthyroidism and Cushingâ€™s syndrome. t.FEJBOUJNFUPPOTFUPGNPEFSBUFUPTFWFSFJNNVOFNFEJBUFE endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. t.POJUPSQBUJFOUTGPSDMJOJDBMTJHOTBOETZNQUPNTPGIZQPQIZTJUJT adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. â€“ Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. â€“ Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. â€“ Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. o *OBMJNJUFEOVNCFSPGQBUJFOUT IZQPQIZTJUJTXBTEJBHOPTFECZ imaging studies through enlargement of the pituitary gland.
Immune-mediated Enterocolitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF MJGF threatening or fatal (diarrhea of â‰Ľ7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred JO BOENPEFSBUF EJBSSIFBXJUIVQUPTUPPMTBCPWFCBTFMJOF abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients. t"DSPTTBMM:&370:USFBUFEQBUJFOUT O EFWFMPQFE intestinal perforation, 4 (0.8%) died as a result of complications, and XFSFIPTQJUBMJ[FEGPSTFWFSFFOUFSPDPMJUJT t.POJUPSQBUJFOUTGPSTJHOTBOETZNQUPNTPGFOUFSPDPMJUJT TVDIBT diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). o *OTZNQUPNBUJDQBUJFOUT SVMFPVUJOGFDUJPVTFUJPMPHJFTBOEDPOTJEFS endoscopic evaluation for persistent or severe symptoms.
Immune-mediated Hepatitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF MJGF threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3â€“5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and IPTQJUBMJ[BUJPOJO t BEEJUJPOBM:&370:USFBUFEQBUJFOUTFYQFSJFODFENPEFSBUF IFQBUPUPYJDJUZNBOJGFTUFECZ-'5BCOPSNBMJUJFT "45PS"-5FMFWBUJPOT >2.5X but â‰¤5X the ULN or total bilirubin elevation >1.5X but â‰¤3X the ULN; Grade 2). t.POJUPS-'5T IFQBUJDUSBOTBNJOBTFBOECJMJSVCJOMFWFMT BOEBTTFTT patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. o *OQBUJFOUTXJUIIFQBUPUPYJDJUZ SVMFPVUJOGFDUJPVTPSNBMJHOBOU DBVTFTBOEJODSFBTFGSFRVFODZPG-'5NPOJUPSJOHVOUJMSFTPMVUJPO
Immune-mediated Dermatitis: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT TFWFSF life-threatening or fatal immune-mediated dermatitis (e.g., StevensJohnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â€“5) occurred in 13 (2.5%) patients. â€“ 1 (0.2%) patient died as a result of toxic epidermal necrolysis. o BEEJUJPOBMQBUJFOUSFRVJSFEIPTQJUBMJ[BUJPOGPSTFWFSFEFSNBUJUJT t5IFSFXFSF :&370:USFBUFEQBUJFOUTXJUINPEFSBUF (SBEF dermatitis. t.POJUPSQBUJFOUTGPSTJHOTBOETZNQUPNTPGEFSNBUJUJTTVDIBTSBTI and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Immune-mediated Neuropathies: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT DBTFPGGBUBM Guillain-BarrĂŠ syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. t"DSPTTUIFDMJOJDBMEFWFMPQNFOUQSPHSBNPG:&370: NZBTUIFOJBHSBWJT and additional cases of Guillain-BarrĂŠ syndrome have been reported. t.POJUPSGPSTZNQUPNTPGNPUPSPSTFOTPSZOFVSPQBUIZTVDIBT unilateral or bilateral weakness, sensory alterations, or paresthesia.
Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t*OUIFQJWPUBM1IBTFTUVEZJO:&370:USFBUFEQBUJFOUT DMJOJDBMMZ significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. t"DSPTTUIFDMJOJDBMEFWFMPQNFOUQSPHSBNGPS:&370: JNNVOF mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.
Pregnancy & Nursing: t:&370:JTDMBTTJGJFEBTQSFHOBODZDBUFHPSZ$5IFSFBSFOPBEFRVBUF and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus. t)VNBO*H(JTLOPXOUPDSPTTUIFQMBDFOUBMCBSSJFSBOE:&370:JTBO *H(UIFSFGPSF :&370:IBTUIFQPUFOUJBMUPCFUSBOTNJUUFEGSPNUIF mother to the developing fetus. t*UJTOPULOPXOXIFUIFS:&370:JTTFDSFUFEJOIVNBONJML#FDBVTF many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY.
Common Adverse Reactions: tThe most common adverse reactions (â‰Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).
1MFBTFTFF#SJFG4VNNBSZPG'VMM1SFTDSJCJOH*OGPSNBUJPO JODMVEJOHBoxed WARNING regarding immune-mediated adverse reactions, on following pages.
For additional information, please visit ÂŠ2011 Bristol-Myers Squibb, Princeton, NJ 08543 731US11AB08002 YERVOY is a trademark of Bristol-Myers Squibb. All rights reserved.
Printed in USA
May 2011 I VOL 4, NO 3