WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These hihlihts do not include all the information needed to use safely and effectively. See full prescribin information for. (ipilimumab) Injection, for intravenous infusion Initial U.S. Approval: WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS See full prescribin information for complete boxed warnin. can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any oran system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (includin toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested durin treatment; however, a minority occurred weeks to months after discontinuation of. Permanently discontinue and initiate systemic hih-dose corticosteroid therapy for severe immune-mediated reactions. (.) Assess patients for sins and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries includin liver function tests and thyroid function tests at baseline and before each dose. (.,.,.3,.4,.) INDICATIONS AND USAGE is a human cytotoxic T-lymphocyte antien 4 (CTLA-4)-blockin antibody indicated for the treatment of unresectable or metastatic melanoma. () DOSAGE AND ADMINISTRATION 3 m/k administered intravenously over 9 minutes every 3 weeks for a total of 4 doses. (.) Permanently discontinue for severe adverse reactions. (.) DOSAGE FORMS AND STRENGTHS m/ ml ( m/ml) (3) m/4 ml ( m/ml) (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receivin less than 7. m prednisone or equivalent per day. Administer systemic hih-dose corticosteroids for severe, persistent, or recurrin immune-mediated reactions. (.,.,.3,.4,.) Immune-mediated hepatitis: Evaluate liver function tests before each dose of (ipilimumab). (.) Immune-mediated endocrinopathies: Monitor thyroid function tests and clinical chemistries prior to each dose. Evaluate at each visit for sins and symptoms of endocrinopathy. Institute hormone replacement therapy as needed. (.) ADVERSE REACTIONS Most common adverse reactions ( %) are fatiue, diarrhea, pruritus, rash, and colitis. (6.) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at or FDA at -8-FDA-88 or USE IN SPECIFIC POPULATIONS Prenancy: Based on animal data, may cause fetal harm. (8.) Nursin mothers: Discontinue nursin or discontinue. (8.3) See 7 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 8/ FULL PRESCRIBING INFORMATION: CONTENTS * WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION. Recommended Dosin. Recommended Dose Modifications.3 Preparation and Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Immune-mediated Enterocolitis. Immune-mediated Hepatitis.3 Immune-mediated Dermatitis.4 Immune-mediated Neuropathies. Immune-mediated Endocrinopathies.6 Other Immune-mediated Adverse Reactions, Includin Ocular Manifestations 6 ADVERSE REACTIONS 6. Clinical Trials Experience 6. Postmarketin Experience 6.3 Immunoenicity 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8. Prenancy 8.3 Nursin Mothers 8.4 Pediatric Use 8. Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechanism of Action.3 Pharmacokinetics 3 NONCLINICAL TOXICOLOGY 3. Carcinoenesis, Mutaenesis, Impairment of Fertility 3. Animal Toxicoloy and/or Pharmacoloy 4 CLINICAL STUDIES 6 HOW SUPPLIED/STORAGE AND HANDLING 7 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribin information are not listed.

2 FULL PRESCRIBING INFORMATION WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any oran system; however, the most common severe immunemediated adverse reactions are enterocolitis, hepatitis, dermatitis (includin toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested durin treatment; however, a minority occurred weeks to months after discontinuation of. Permanently discontinue and initiate systemic hih-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosae and Administration (.).] Assess patients for sins and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries includin liver function tests and thyroid function tests at baseline and before each dose. [See Warnins and Precautions (.,.,.3,.4,.).] INDICATIONS AND USAGE (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. DOSAGE AND ADMINISTRATION. Recommended Dosin The recommended dose of is 3 m/k administered intravenously over 9 minutes every 3 weeks for a total of 4 doses.. Recommended Dose Modifications Withhold scheduled dose of for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions ( ), and who are receivin less than 7. m prednisone or equivalent per day, resume at a dose of 3 m/k every 3 weeks until administration of all 4 planned doses or 6 weeks from first dose, whichever occurs earlier. Permanently discontinue for any of the followin: o Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7. m prednisone or equivalent per day. o Failure to complete full treatment course within 6 weeks from administration of first dose. o Severe or life-threatenin adverse reactions, includin any of the followin: Colitis with abdominal pain, fever, ileus, or peritoneal sins; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 4 hours, astrointestinal hemorrhae, and astrointestinal perforation Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > times the upper limit of normal or total bilirubin >3 times the upper limit of normal Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhaic manifestations Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia ravis Severe immune-mediated reactions involvin any oran system (e, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.3 Preparation and Administration Do not shake product. Inspect parenteral dru products visually for particulate matter and discoloration prior to administration. Discard vial if solution is cloudy, there is pronounced discoloration (solution may have pale-yellow color), or there is forein particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution Allow the vials to stand at room temperature for approximately minutes prior to preparation of infusion. Withdraw the required volume of and transfer into an intravenous ba. Dilute with.9% Sodium Chloride Injection, USP or % Dextrose Injection, USP to prepare a diluted solution with a final concentration ranin from m/ml to m/ml. Mix diluted solution by entle inversion. Store the diluted solution for no more than 4 hours under refrieration ( C to 8 C, 36 F to 46 F) or at room temperature ( C to C, 68 F to 77 F). Discard partially used vials or empty vials of. Administration Instructions (ipilimumab) Do not mix with, or administer as an infusion with, other medicinal products. Flush the intravenous line with.9% Sodium Chloride Injection, USP or % Dextrose Injection, USP after each dose. Administer diluted solution over 9 minutes throuh an intravenous line containin a sterile, non-pyroenic, low-protein-bindin in-line filter. 3 DOSAGE FORMS AND STRENGTHS m/ ml ( m/ml) m/4 ml ( m/ml) 4 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warnin.]. Immune-mediated Enterocolitis In Study, severe, life-threatenin, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal sins; 3 ) immune-mediated enterocolitis occurred in 34 (7%) -treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; ) enterocolitis occurred in 8 (%) -treated patients. Across all -treated patients (n=), (%) patients developed intestinal perforation, 4 (.8%) patients died as a result of complications, and 6 (%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (rane:.6 3.4) and 6.3 weeks (rane:.3 8.9) after the initiation of for patients with 3 enterocolitis and with enterocolitis, respectively. Twenty-nine patients (8%) with 3 enterocolitis were treated with hih-dose ( 4 m prednisone equivalent per day) corticosteroids, with a median dose of 8 m/day of prednisone or equivalent; the median duration of treatment was.3 weeks (ranin up to 3.9 weeks) followed by corticosteroid taper. Of the 8 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 9% were treated with <4 m prednisone or equivalent per day for a median duration of. weeks, and % were treated with hih-dose corticosteroids for a median duration of days prior to corticosteroid taper. Infliximab was administered to of the 6 patients (8%) with moderate, severe, or life-threatenin immune-mediated enterocolitis followin inadequate response to corticosteroids. Of the 34 patients with 3 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to severity, and 4% did not improve. Amon the 8 patients with enterocolitis, 79% experienced complete resolution, % improved, and % did not improve. Monitor patients for sins and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal sins and ileus). In symptomatic patients, rule out infectious etioloies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of to m/k/day of prednisone or equivalent. Upon improvement to or less, initiate corticosteroid taper and continue to taper over at least month. In clinical trials, rapid corticosteroid taperin resulted in recurrence or worsenin symptoms of enterocolitis in some patients. Withhold dosin for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than week, initiate systemic corticosteroids at a dose of. m/k/day prednisone or equivalent. [See Dosae and Administration (.).]. Immune-mediated Hepatitis In Study, severe, life-threatenin, or fatal hepatotoxicity (AST or ALT elevations of more than times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; 3 ) occurred in 8 (%) -treated patients, with fatal hepatic failure in.% and hospitalization in.4% of treated patients. An additional 3 (.%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than. times but not more than times the upper limit of normal or total bilirubin elevation of more than. times but not more than 3 times the upper limit of normal; ). The underlyin patholoy was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event. Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for sins and symptoms of hepatotoxicity before each dose of. In patients with hepatotoxicity, rule out infectious or malinant causes and increase frequency of liver function test monitorin until resolution. Permanently discontinue in patients with 3 hepatotoxicity and administer systemic corticosteroids at a dose of to m/k/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid taperin and continue to taper over month. Across the clinical development proram for, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite hih-dose corticosteroids. Withhold in patients with hepatotoxicity. [See Dosae and Administration (.).]

3 (ipilimumab) Concurrent Administration with Vemurafenib In a dose-findin trial, 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of patients who received concurrent (3 m/k) and vemurafenib (96 m BID or 7 m BID)..3 Immune-mediated Dermatitis In Study, severe, life-threatenin, or fatal immune-mediated dermatitis (e, Stevens- Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhaic manifestations; 3 ) occurred in 3 (.%) -treated patients. One (.%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (%) patients with moderate ( ) dermatitis. The median time to onset of moderate, severe, or life-threatenin immune-mediated dermatitis was 3. weeks and raned up to 7.3 weeks from the initiation of. Seven (4%) -treated patients with severe dermatitis received hih-dose corticosteroids (median dose 6 m prednisone/day or equivalent) for up to 4.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution raned up to.6 weeks. Of the 63 patients with moderate dermatitis, (4%) were treated with systemic corticosteroids (median of 6 m/day of prednisone or equivalent) for a median of. weeks, 7 (%) were treated with only topical corticosteroids, and 3 (49%) did not receive systemic or topical corticosteroids. Forty-four (7%) patients with moderate dermatitis were reported to have complete resolution, 7 (%) improved to mild ( ) severity, and (9%) had no reported improvement. Monitor patients for sins and symptoms of dermatitis such as rash and pruritus. Unless an alternate etioloy has been identified, sins or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhaic manifestations. Administer systemic corticosteroids at a dose of to m/k/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid taperin should occur over a period of at least month. Withhold dosin in patients with moderate to severe sins and symptoms. [See Dosae and Administration (.).] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within week..4 Immune-mediated Neuropathies In Study, case of fatal Guillain-Barré syndrome and case of severe ( 3) peripheral motor neuropathy were reported. Across the clinical development proram of, myasthenia ravis and additional cases of Guillain-Barré syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue in patients with severe neuropathy (interferin with daily activities) such as Guillain- Barré-like syndromes. Institute medical intervention as appropriate for manaement of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of to m/k/day prednisone or equivalent for severe neuropathies. Withhold dosin in patients with moderate neuropathy (not interferin with daily activities). [See Dosae and Administration (.).]. Immune-mediated Endocrinopathies In Study, severe to life-threatenin immune-mediated endocrinopathies (requirin hospitalization, urent medical intervention, or interferin with activities of daily livin; 3 4) occurred in 9 (.8%) -treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypoonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requirin hormone replacement or medical intervention; ) occurred in (.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and case each of hyperthyroidism and Cushin s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was weeks and raned up to 9.3 weeks after the initiation of. Of the patients with moderate to life-threatenin endocrinopathy, 7 patients required lon-term hormone replacement therapy includin, most commonly, adrenal hormones (n=) and thyroid hormones (n=3). Monitor patients for clinical sins and symptoms of hypophysitis, adrenal insufficiency (includin adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatiue, headache, mental status chanes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlyin disease. Unless an alternate etioloy has been identified, sins or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was dianosed by imain studies throuh enlarement of the pituitary land. Withhold dosin in symptomatic patients. Initiate systemic corticosteroids at a dose of to m/k/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosae and Administration (.).] (ipilimumab).6 Other Immune-mediated Adverse Reactions, Includin Ocular Manifestations The followin clinically sinificant immune-mediated adverse reactions were seen in less than % of -treated patients in Study : nephritis, pneumonitis, meninitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development proram for, the followin likely immunemediated adverse reactions were also reported with less than % incidence: myocarditis, aniopathy, temporal arteritis, vasculitis, polymyalia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, autoimmune thyroiditis, sarcoidosis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and ocular myositis. Permanently discontinue for clinically sinificant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of to m/k/day prednisone or equivalent for severe immune-mediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosae and Administration (.).] 6 ADVERSE REACTIONS The followin adverse reactions are discussed in reater detail in other sections of the labelin. Immune-mediated enterocolitis [see Warnins and Precautions (.)]. Immune-mediated hepatitis [see Warnins and Precautions (.)]. Immune-mediated dermatitis [see Warnins and Precautions (.3)]. Immune-mediated neuropathies [see Warnins and Precautions (.4)]. Immune-mediated endocrinopathies [see Warnins and Precautions (.)]. Other immune-mediated adverse reactions, includin ocular manifestations [see Warnins and Precautions (.6)]. 6. Clinical Trials Experience Because clinical trials are conducted under widely varyin conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice. The clinical development proram excluded patients with active autoimmune disease or those receivin systemic immunosuppression for oran transplantation. Exposure to 3 m/k for 4 doses iven by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study ). [See Clinical Studies (4).] One hundred thirty-one patients (median ae 7 years, 6% male) received as a sinle aent, 38 patients (median ae 6 years, 6% male) received with an investiational p peptide vaccine (p), and 3 patients (median ae 7 years, 4% male) received p peptide vaccine alone. Patients in the study received a median of 4 doses (rane: 4 doses). was discontinued for adverse reactions in % of patients. The most common adverse reactions ( %) in patients who received at 3 m/k were fatiue, diarrhea, pruritus, rash, and colitis. Table presents selected adverse reactions from Study, which occurred in at least % of patients in the -containin arms and with at least % increased incidence over the control p arm for all-rade events and at least % incidence over the control roup for 3 events. Table : Selected Adverse Reactions in Study Percentae (%) of Patients a System Oran Class/ Preferred Term Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatiue 3 m/k n=3 Any m/k+p n=38 Any < p n=3 Any a Incidences presented in this table are based on reports of adverse events reardless of causality. Table presents the per-patient incidence of severe, life-threatenin, or fatal immune-mediated adverse reactions from Study. 3

4 (ipilimumab) Table : Severe to Fatal Immune-mediated Adverse Reactions in Study Any Immune-mediated Adverse Reaction Enterocolitis a,b Hepatotoxicity a Dermatitis a Neuropathy a Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meninitis Nephritis Eosinophilia c Pericarditis a,c a Includin fatal outcome. b Includin intestinal perforation. c Underlyin etioloy not established. Percentae (%) of Patients 3 m/k n= m/k+p n= < Across clinical studies that utilized doses ranin from.3 to m/k, the followin adverse reactions were also reported (incidence less than % unless otherwise noted): urticaria (%), lare intestinal ulcer, esophaitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical proram for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent. 6. Postmarketin Experience The followin adverse reactions have been identified durin postapproval use of. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to dru exposure. Skin and Subcutaneous Tissue Disorders: Dru reaction with eosinophilia and systemic symptoms (DRESS syndrome) 6.3 Immunoenicity In clinical studies,.% of 4 evaluable patients tested positive for bindin antibodies aainst ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detectin anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these patients nor were neutralizin antibodies aainst ipilimumab detected. Because trouh levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trouh levels. In this analysis, 6.9% of 8 evaluable patients, who were treated with.3 m/k dose, tested positive for bindin antibodies aainst ipilimumab. Immunoenicity assay results are hihly dependent on several factors includin assay sensitivity and specificity, assay methodoloy, sample handlin, timin of sample collection, concomitant medications, and underlyin disease. For these reasons, comparison of incidence of antibodies to with the incidences of antibodies to other products may be misleadin. 7 DRUG INTERACTIONS No formal pharmacokinetic dru interaction studies have been conducted with. 8 USE IN SPECIFIC POPULATIONS 8. Prenancy Prenancy Cateory C There are no adequate and well-controlled studies of in prenant women. Use durin prenancy only if the potential benefit justifies the potential risk to the fetus. In a combined study of embryo-fetal and peri-postnatal development, prenant cynomolus monkeys received ipilimumab every 3 weeks from the onset of oranoenesis in the first trimester throuh parturition, at exposure levels either.6 or 7. times hiher by AUC than the exposures at the clinical dose of 3 m/k of ipilimumab. No treatment-related adverse effects on reproduction were detected durin the first two trimesters of prenancy. Beinnin in the third trimester, the ipilimumab-treated roups experienced hiher incidences of severe toxicities includin abortion, stillbirth, premature delivery (with correspondin lower birth weiht), and hiher incidences of infant mortality in a dose-related manner compared to controls. [See Nonclinical Toxicoloy (3.).] Human IG is known to cross the placental barrier and ipilimumab is an IG; therefore, ipilimumab has the potential to be transmitted from the mother to the developin fetus. < < < (ipilimumab) 8.3 Nursin Mothers It is not known whether ipilimumab is secreted in human milk. In monkeys treated at dose levels resultin in exposures.6 and 7. times hiher than those in humans at the recommended dose, ipilimumab was present in milk at concentrations of. and.4 mc/ml, representin a ratio of up to.3% of the serum concentration of the dru. Because many drus are secreted in human milk and because of the potential for serious adverse reactions in nursin infants from, a decision should be made whether to discontinue nursin or to discontinue, takin into account the importance of to the mother. 8.4 Pediatric Use The safety and effectiveness of have not been established in pediatric patients. 8. Geriatric Use Of the patients treated with at 3 m/k, 8% were 6 years and over. No overall differences in safety or efficacy were reported between the elderly patients (6 years and over) and youner patients (less than 6 years). 8.6 Renal Impairment No dose adjustment is needed for patients with renal impairment. [See Clinical Pharmacoloy (.3).] 8.7 Hepatic Impairment No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >. to. the upper limit of normal [ULN] or AST >ULN). has not been studied in patients with moderate (TB >. to 3. ULN and any AST) or severe (TB >3 ULN and any AST) hepatic impairment. [See Clinical Pharmacoloy (.3).] OVERDOSAGE There is no information on overdosae with. DESCRIPTION (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antien 4 (CTLA-4). Ipilimumab is an IG kappa immunolobulin with an approximate molecular weiht of 48 kda. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. is a sterile, preservative-free, clear to slihtly opalescent, colorless to paleyellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in sinle-use vials of m/ ml and m/4 ml. Each milliliter contains m of ipilimumab and the followin inactive inredients: diethylene triamine pentaacetic acid (DTPA) (.4 m), mannitol ( m), polysorbate 8 (veetable oriin) (. m), sodium chloride (.8 m), tris hydrochloride (3. m), and Water for Injection, USP at a ph of 7. CLINICAL PHARMACOLOGY. Mechanism of Action CTLA-4 is a neative reulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its liands, CD8/CD86. Blockade of CTLA-4 has been shown to aument T-cell activation and proliferation, includin the activation and proliferation of tumor infiltratin T-effector cells. Inhibition of CTLA-4 sinalin can also reduce T-reulatory cell function, which may contribute to a eneral increase in T cell responsiveness, includin the anti-tumor immune response..3 Pharmacokinetics The pharmacokinetics of ipilimumab were studied in 78 patients with unresectable or metastatic melanoma who received doses of.3, 3, or m/k once every 3 weeks for 4 doses. Peak concentration (C max ), trouh concentration (C min ), and area under the plasma concentration versus time curve (AUC) of ipilimumab increased dose proportionally within the dose rane examined. Upon repeated dosin every 3 weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was.-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean C min at steady-state was 9.4 mc/ml followin repeated doses of 3 m/k. The mean value (% coefficient of variation) enerated throuh population pharmacokinetic analysis for the terminal half-life (t / ) was.4 days (34%) and for CL was 6.8 ml/h (38%). Specific Populations: The effects of various covariates on the pharmacokinetics of ipilimumab were assessed in population pharmacokinetic analyses. The CL of ipilimumab increased with increasin body weiht; however, no dose adjustment is recommended for body weiht after administration on a m/k basis. The followin factors had no clinically important effect on the CL of ipilimumab: ae (rane: 3 88 years), ender, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydroenase (LDH) levels. The effect of race was not examined due to limited data available in non-caucasian ethnic roups. Renal Impairment: The effect of renal impairment on the CL of ipilimumab was evaluated in patients with mild (GFR <9 and 6 ml/min/.73 m ; n=349), moderate (GFR <6 and 3 ml/min/.73 m ; n=8), or severe (GFR <3 and ml/min/.73 m ; n=4) renal impairment compared to patients with normal renal function (GFR 9 ml/min/.73 m ; n=3) in population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function. [See Use in Specific Populations (8.6).]

5 (ipilimumab) Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (TB. to. ULN or AST >ULN as defined usin the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ULN; n=78) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. has not been studied in patients with moderate (TB >. to 3 ULN and any AST) or severe hepatic impairment (TB >3 ULN and any AST). [See Use in Specific Populations (8.7).] 3 NONCLINICAL TOXICOLOGY 3. Carcinoenesis, Mutaenesis, Impairment of Fertility Carcinoenesis The carcinoenic potential of ipilimumab has not been evaluated in lon-term animal studies. Mutaenesis The enotoxic potential of ipilimumab has not been evaluated. Impairment of Fertility Fertility studies have not been performed with ipilimumab. 3. Animal Toxicoloy and/or Pharmacoloy In addition to the severe findins of abortion, stillbirths, and postnatal deaths observed in prenant cynomolus monkeys that received ipilimumab every 3 weeks from the onset of oranoenesis in the first trimester throuh parturition [see Use in Specific Populations (8.)], developmental abnormalities were identified in the uroenital system of infant monkeys exposed in utero to 3 m/k of ipilimumab (7. times the AUC in humans at the clinically recommended dose). One female infant monkey had unilateral renal aenesis of the left kidney and ureter, and male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema. Genetically enineered mice heterozyous for CTLA-4 (CTLA-4+/ ), the taret for ipilimumab, appeared healthy and ave birth to healthy CTLA-4+/ heterozyous offsprin. Mated CTLA-4+/ heterozyous mice also produced offsprin deficient in CTLA-4 (homozyous neative, CTLA-4 / ). The CTLA-4 / homozyous neative offsprin appeared healthy at birth, exhibited sins of multioran lymphoproliferative disease by weeks of ae, and all died by 3 4 weeks of ae with massive lymphoproliferation and multioran tissue destruction. 4 CLINICAL STUDIES The safety and efficacy of were investiated in a randomized (3::), double-blind, double-dummy study (Study ) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the followin: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 43 were randomized to receive at 3 m/k in combination with an investiational peptide vaccine with incomplete Freund s adjuvant (p), 37 were randomized to receive at 3 m/k, and 36 were randomized to receive p alone. The study enrolled only patients with HLA-A* enotype; this HLA enotype facilitates the immune presentation of the investiational peptide vaccine. The study excluded patients with active autoimmune disease or those receivin systemic immunosuppression for oran transplantation. /placebo was administered at 3 m/k as an intravenous infusion every 3 weeks for 4 doses. Gp/placebo was administered at a dose of m peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of tumor response was conducted at weeks and 4, and every 3 months thereafter. Patients with evidence of objective tumor response at or 4 weeks had assessment for confirmation of durability of response at 6 or 8 weeks, respectively. The major efficacy outcome measure was overall survival (OS) in the +p arm compared to that in the p arm. Secondary efficacy outcome measures were OS in the +p arm compared to the arm, OS in the arm compared to the p arm, best overall response rate (BORR) at week 4 between each of the study arms, and duration of response. Of the randomized patients, 6%, 9%, and 4% in the +p,, and p arms, respectively, were men. Twenty-nine percent were 6 years of ae, the median ae was 7 years, 7% had Mc stae, % had a history of previously treated brain metastasis, 98% had ECOG performance status of and, 3% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either -containin arm received all 4 planned doses. The median duration of follow-up was 8.9 months. The OS results are shown in Table 3 and Fiure. Table 3: Overall Survival Results n=37 Hazard Ratio (vs. p) (9% CI) p-value Hazard Ratio (vs. ) (9% CI) Median (months) (9% CI) a Not adjusted for multiple comparisons. Fiure : Overall Survival.66 (.,.87) p=.6 a (8., 3.8) (ipilimumab) +p n=43.68 (.,.8) p=.4.4 (.83,.3) (8.,.) p n=36 6 (., 8.7) MONTHS SUBJECTS AT RISK Ipi+ p Ipi p PROPORTION ALIVE Ipi+p CENSORED Ipi CENSORED p CENSORED The best overall response rate (BORR) as assessed by the investiator was.7% (9% CI: 3.7%, 8.4%) in the +p arm,.9% (9% CI: 6.3%, 7.4%) in the arm, and.% (9% CI:.%,.%) in the p arm. The median duration of response was. months in the +p arm and has not been reached in the or p arm. 6 HOW SUPPLIED/STORAGE AND HANDLING is available as follows: Carton Contents NDC One m vial ( m/ml), sinle-use vial NDC One m vial ( m/ml), sinle-use vial NDC Store under refrieration at C to 8 C (36 F to 46 F). Do not freeze. Protect vials from liht. 7 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labelin (Medication Guide). Inform patients of the potential risk of immune-mediated adverse reactions. Advise patients to read the Medication Guide before each infusion. Advise women that may cause fetal harm. Advise nursin mothers not to breastfeed while takin. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 843 USA U.S. License No A Rev Auust

6 (ipilimumab) MEDICATION GUIDE (yur-voi) (ipilimumab) Read this Medication Guide before you start receivin and before each infusion. There may be new information. This Medication Guide does not take the place of talkin with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about? can cause serious side effects in many parts of your body which can lead to death. These side effects are most likely to bein durin treatment; however, side effects can show up months after your last infusion. These side effects may include:. Inflammation of the intestines (colitis) that can cause tears or holes (perforation) in the intestines. Sins and symptoms of colitis may include: diarrhea (loose stools) or more bowel movements than usual blood in your stools or dark, tarry, sticky stools stomach pain (abdominal pain) or tenderness. Inflammation of the liver (hepatitis) that can lead to liver failure. Sins and symptoms of hepatitis may include: yellowin of your skin or the whites of your eyes dark urine (tea colored) nausea or vomitin pain on the riht side of your stomach bleedin or bruise more easily than normal 3. Inflammation of the skin that can lead to severe skin reaction (toxic epidermal necrolysis). Sins and symptoms of severe skin reactions may include: skin rash with or without itchin sores in your mouth your skin blisters and/or peels (ipilimumab) 4. Inflammation of the nerves that can lead to paralysis. Symptoms of nerve problems may include: unusual weakness of les, arms, or face numbness or tinlin in hands or feet. Inflammation of hormone lands (especially the pituitary, adrenal, and thyroid lands) that may affect how these lands work. Sins and symptoms that your lands are not workin properly may include: persistent or unusual headaches unusual sluishness, feelin cold all the time, or weiht ain chanes in mood or behavior such as decreased sex drive, irritability, or foretfulness dizziness or faintin 6. Inflammation of the eyes. Symptoms may include: blurry vision, double vision, or other vision problems eye pain or redness Call your healthcare provider if you have any of these sins or symptoms or they et worse. Do not try to treat symptoms yourself. Gettin medical treatment riht away may keep the problem from becomin more serious. Your oncoloist may decide to delay or stop. What is? is a prescription medicine used in adults to treat melanoma (a kind of skin cancer) that has spread or cannot be removed by surery. It is not known if is safe and effective in children less than 8 years of ae. What should I tell my healthcare provider before ettin? Before you are iven, tell your healthcare provider about all your health problems if you: have an active condition where your immune system attacks your body (autoimmune disease), such as ulcerative colitis, Crohn s disease, lupus, or sarcoidosis

7 (ipilimumab) had an oran transplant, such as a kidney transplant have liver damae from diseases or drus have any other medical conditions are prenant or plan to become prenant. may cause stillbirth, premature delivery, and/or death of your unborn baby are breastfeedin Tell your healthcare provider about all the medicines you take, includin all prescription and non-prescription medicines, steroids or other medicines that lower your immune response, vitamins, and herbal supplements. Know the medicines you take. Keep a list to show your doctors and pharmacists each time you et a new medicine. You should not start a new medicine before you talk with the healthcare provider who prescribes you. How will I receive? You will et throuh an intravenous line in your vein (infusion). It takes about 9 minutes to et a full dose. is usually iven every 3 weeks for up to 4 doses. Your healthcare provider may chane how often you receive or how lon the infusion may take. Your healthcare provider should perform blood tests before startin and durin treatment with. It is important for you to keep all appointments with your healthcare provider. Call your healthcare provider if you miss an appointment. There may be special instructions for you. What are the possible side effects of? can cause serious side effects. See What is the most important information I should know about? The most common side effects of include: tiredness diarrhea itchin rash (ipilimumab) These are not all of the possible side effects of. For more information, ask your healthcare provider. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at -8-FDA-88. You may also report side effects to Bristol-Myers Squibb at General information about the safe and effective use of. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about that is written for healthcare professionals. For more information, call What are the inredients of? Active inredient: ipilimumab Inactive inredients: diethylene triamine pentaacetic acid (DTPA), mannitol, polysorbate 8, sodium chloride, tris hydrochloride, and Water for Injection, USP This Medication Guide has been approved by the U.S. Food and Dru Administration. Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 843 USA U.S. License No A 3744A Rev December 3 73US778--