——易普利姆玛Ipilimumab，商品名为Yervoy 2011年3月25日，美国食品与药物管理局（FDA）发布公告，批准Yervoy（活性成分：ipilimumab）用于治疗晚期（转移性）黑色素瘤。 黑色素瘤是最危险的皮肤癌类型。经Yervoy治疗后，黑色素瘤患者生存时间将延长。 Yervoy是一种单克隆抗体，已知可阻断细胞毒性T淋巴细胞抗原或CTLA-4等分子。CTLA-4可能在减缓或关闭人体免疫系统中发挥作用，影响免疫系统攻击癌细胞的能力。Yervoy可能通过让机体免疫系统识别、瞄准、攻击黑色素瘤细胞发挥作用。该药物通过经静脉给药。 通过一项纳入676例黑色素瘤患者的国际研究，确立了Yervoy的安全性和有效性。这些患者的疾病已扩散或者无法手术切除。这项研究旨在衡量总生存，从该治疗开始直到患者死亡的时间。经随机分组的患者接受Yervoy加上一种被称为gp100的试验性肿瘤疫苗治疗，或是只接受Yervoy治疗，或是只接受疫苗治疗。那些接受了Yervoy与疫苗组合治疗或者单独使用Yervoy治疗的患者，平均生存时间约10个月，而那些只接受试验性疫苗的患者平均生存时间为6.5个月。 与使用Yervoy相关的自身免疫反应所导致的常见副作用包括疲乏、腹泻、皮疹、内分泌不足（腺体或激素）和肠炎（结肠炎）。严重的、甚至是致命的自身免疫反应可见于12.9%经Yervoy治疗的患者。当发生严重副作用时，应停用Yervoy，并开始皮质类固醇治疗。并非所有患者都对这种治疗产生反应。在某些情况下，有些产生反应的患者在几周时间内也并没有看到任何改善。 由于存在与Yervoy相关的罕见和严重的副作用，该疗法被“风险评估和减低策略”（Risk Evaluation and Mitigation Strategy）批准，以告知医疗专业人员这些严重的风险。药物治疗指南也将同时提供给患者，以告知他们治疗的潜在副作用。 “晚期黑色素瘤是毁灭性的，只有极少的治疗方案可提供给患者，而且以前，这些方案中没有一个能延长患者的生命”，FDA药物评价和研究中心肿瘤药品办公室主任Pazdur博士说。“Yervoy是第一个被FDA批准、并能清楚显示转移性黑色素瘤患者用药后可延长生存时间的治疗方法。” 黑色素瘤是皮肤疾病导致死亡的首要原因。根据美国国家癌症研究所的数据，2010年，在美国，估计有68130例新诊断的黑色素瘤病例，约8700人死于这种疾病。 批准日期：2011年3月25日；公司：百时美施贵宝Bristol-Myers Squibb YERVOY  - ipilimumab injection E.R. Squibb & Sons, L.L.C. ---------- HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use YERVOY safely and effectively. See full prescribing information for YERVOY. YERVOYTM (ipilimumab) Injection, for intravenous infusion Initial U.S. Approval: 2011 INDICATIONS AND USAGE YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for the treatment of unresectable or metastatic melanoma. (1)   DOSAGE AND ADMINISTRATION YERVOY 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses. (2.1) Permanently discontinue for severe adverse reactions. (2.2) DOSAGE FORMS AND STRENGTHS 50 mg/10 mL (5 mg/mL) (3) 200 mg/40 mL (5 mg/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 receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions. (5.1, 5.2, 5.3, 5.4, 5.5) Immune-mediated hepatitis: Evaluate liver function tests before each dose of YERVOY. Immune-mediated endocrinopathies: Monitor thyroid function tests and clinical chemistries prior to each dose. Evaluate at each visit for signs and symptoms of endocrinopathy. Institute hormone replacement therapy as needed. ADVERSE REACTIONS Most common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, YERVOY may cause fetal harm. (8.1) Nursing mothers: Discontinue nursing or discontinue YERVOY. (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide  Revised: 03/2011  FULL PRESCRIBING INFORMATION 1    INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. 2    DOSAGE AND ADMINISTRATION 2.1   Recommended Dosing The recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of four doses. 2.2   Recommended Dose Modifications Withhold scheduled dose of YERVOY for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy. For patients with complete or partial resolution of adverse reactions (Grade 0–1), and who are receiving less than 7.5 mg prednisone or equivalent per day, resume YERVOY at a dose of 3 mg/kg every 3 weeks until administration of all 4 planned doses or 16 weeks from first dose, whichever occurs earlier. Permanently discontinue YERVOY for any of the following: Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day. Failure to complete full treatment course within 16 weeks from administration of first dose. Severe or life-threatening adverse reactions, including any of the following: Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 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 hemorrhagic manifestations Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis Severe immune-mediated reactions involving any organ system (eg, nephritis, pneumonitis, pancreatitis, non-infectious myocarditis) Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy 2.3   Preparation and Administration Do not shake product. Inspect parenteral drug 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 foreign particulate matter other than translucent-to-white, amorphous particles. Preparation of Solution Allow the vials to stand at room temperature for approximately 5 minutes prior to preparation of infusion. Withdraw the required volume of YERVOY and transfer into an intravenous bag. Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. Mix diluted solution by gentle inversion. Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F). Discard partially used vials or empty vials of YERVOY. Administration Instructions Do not mix YERVOY with, or administer as an infusion with, other medicinal products. Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP after each dose. Administer diluted solution over 90 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding in-line filter. 3    DOSAGE FORMS AND STRENGTHS 50 mg/10 mL (5 mg/mL). 200 mg/40 mL (5 mg/mL). 4    CONTRAINDICATIONS None. 5    WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] 5.1   Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs 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 signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2)] 5.2   Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology 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 signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution. Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2)] 5.3   Immune-mediated Dermatitis In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis. The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY. Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2)] 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 1 week. 5.4   Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis 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 YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2)] 5.5   Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4); occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormonal replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. 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. Unless an alternate etiology has been identified, signs 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 diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2)] 5.6   Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2)] 6    ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. Immune-mediated enterocolitis [see Warnings and Precautions (5.1)]. Immune-mediated hepatitis [see Warnings and Precautions (5.2)]. Immune-mediated dermatitis [see Warnings and Precautions (5.3)]. Immune-mediated neuropathies [see Warnings and Precautions (5.4)]. Immune-mediated endocrinopathies [see Warnings and Precautions (5.5)]. Other immune-mediated adverse reactions, including ocular manifestations [see Warnings and Precautions (5.6)]. 6.1   Clinical Trials Experience Because clinical trials are conducted under widely varying 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 program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14)] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events. Table 1: Selected Adverse Reactions in Study 1 a Incidences presented in this table are based on reports of adverse events regardless of causality. Percentage (%) of Patientsa   YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 gp100 n=132 System Organ Class/ Preferred Term Any Grade Grade 3–5 Any Grade Grade 3–5 Any Grade Grade 3–5 Gastrointestinal Disorders     Diarrhea 32 5 37 4 20 1     Colitis 8 5 5 3 2 0 Skin and Subcutaneous Tissue Disorders     Pruritus 31 0 21 <1 11 0     Rash 29 2 25 2 8 0 General Disorders and Administration Site Conditions     Fatigue 41 7 34 5 31 3 Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1 a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Percentage (%) of Patients YERVOY 3 mg/kg n=131 YERVOY 3 mg/kg+gp100 n=380 Any Immune-mediated Adverse Reaction 15 12 Enterocolitisa,b 7 7 Hepatotoxicitya 1 2 Dermatitisa 2 3 Neuropathya 1 <1 Endocrinopathy 4 1     Hypopituitarism 4 1     Adrenal insufficiency 0 1 Other     Pneumonitis 0 <1     Meningitis 0 <1     Nephritis 1 0     Eosinophiliac 1 0     Pericarditisa,c 0 <1 Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent. 6.2   Immunogenicity In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected. Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading. 7    DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with YERVOY. 8    USE IN SPECIFIC POPULATIONS 8.1   Pregnancy Pregnancy Category C There are no adequate 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. In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2)] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. 8.3   Nursing Mothers It is not known whether ipilimumab is secreted in human milk. Because 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, taking into account the importance of YERVOY to the mother. 8.4   Pediatric Use Safety and effectiveness of YERVOY have not been established in pediatric patients. 8.5   Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). 8.6   Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3)] 8.7   Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3)] 10   OVERDOSAGE There is no information on overdosage with YERVOY. 11   DESCRIPTION YERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture. YERVOY is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous infusion, which may contain a small amount of visible translucent-to-white, amorphous ipilimumab particulates. It is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7. 12   CLINICAL PHARMACOLOGY 12.1  Mechanism of Action CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses. 12.3  Pharmacokinetics The pharmacokinetics of ipilimumab was studied in 499 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg administered once every 3 weeks for four doses. Peak concentration (Cmax), trough concentration (Cmin), and area under the curve (AUC) of ipilimumab were found to be dose proportional within the dose range examined. Upon repeated dosing of YERVOY administered every 3 weeks, ipilimumab clearance was found to be time-invariant, and minimal systemic accumulation was observed as evident by an accumulation index of 1.5-fold or less. Ipilimumab steady-state concentration was reached by the third dose. The following mean (percent coefficient of variation) parameters were generated through population pharmacokinetic analysis: terminal half-life of 14.7 days (30.1%); systemic clearance (CL) of 15.3 mL/h (38.5%); and volume of distribution at steady-state (Vss) of 7.21 L (10.5%). The mean (±SD) ipilimumab Cmin achieved at steady-state with the 3-mg/kg regimen was 21.8 mcg/mL (±11.2). Specific Populations: Cross-study analyses were performed on data from patients with a variety of conditions, including 420 patients with melanoma who received single or multiple infusions of YERVOY at doses of 0.3, 3, or 10 mg/kg. The effects of various covariates on ipilimumab pharmacokinetics were assessed in population pharmacokinetic analyses. Ipilimumab CL increased with increasing body weight; however, no dose adjustment of YERVOY is required for body weight after administration on a mg/kg basis. The following factors had no clinically meaningful effect on the CL of ipilimumab: age (range 26 to 86 years), gender, concomitant use of budesonide, performance status, HLA-A2*0201 status, positive anti-ipilimumab antibody status, prior use of systemic anticancer therapy, or baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined as there were insufficient numbers of patients in non-Caucasian ethnic groups. Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect on ipilimumab pharmacokinetics in patients with calculated creatinine clearance values of 29 mL/min or greater. Hepatic Impairment: Baseline AST, total bilirubin, and ALT levels did not have a clinically important effect on ipilimumab pharmacokinetics in patients with various degrees of hepatic impairment. 13   NONCLINICAL TOXICOLOGY 13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies. Mutagenesis The genotoxic potential of ipilimumab has not been evaluated. Impairment of Fertility Fertility studies have not been performed with ipilimumab. 13.2  Animal Toxicology and/or Pharmacology The effects of ipilimumab on prenatal and postnatal development in monkeys have not been fully investigated. Preliminary results are available from an ongoing study in cynomolgus monkeys. Pregnant monkeys received ipilimumab every 21 days from the onset of organogenesis in the first trimester through delivery, at dose levels either 2.6 or 7.2 times higher than the clinical dose of 3 mg/kg of ipilimumab (by AUC). No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, the ipilimumab groups experienced higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner compared to controls. Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction. 14   CLINICAL STUDIES The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund’s adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. YERVOY/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for four doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for four doses. Assessment of tumor response was conducted at week 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively. The major efficacy outcome measure was overall survival (OS) in the YERVOY+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY+gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response. Of the randomized patients, 61%, 59%, and 54% in the YERVOY+gp100, YERVOY, and gp100 arms, respectively, were men. Twenty-nine percent were ≥65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin and 38% had elevated LDH level. Sixty-one percent of patients randomized to either YERVOY-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months. Table 3: Overall Survival Results a Not adjusted for multiple comparisons. YERVOY n=137 YERVOY+gp100 n=403 gp100 n=136 Hazard Ratio (vs. gp100) 0.66 0.68     (95% CI) (0.51, 0.87) (0.55, 0.85)     p-value p=0.0026a p=0.0004 Hazard Ratio (vs. YERVOY) 1.04     (95% CI) (0.83, 1.30) Median (months) 10 10 6     (95% CI) (8.0, 13.8) (8.5, 11.5) (5.5, 8.7)   The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the YERVOY+gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the YERVOY arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 months in the YERVOY+gp100 arm and has not been reached in the YERVOY or gp100 arm. 16   HOW SUPPLIED/STORAGE AND HANDLING YERVOY is available as follows: Carton Contents NDC One 50 mg vial (5 mg/mL), single-use vial NDC 0003-2327-11 One 200 mg vial (5 mg/mL), single-use vial NDC 0003-2328-22 Store YERVOY under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials from light. -------------------------------------------------- 产地国家: 美国 原产地英文商品名: YERVOY 50mg/10ml/vial 原产地英文药品名: IPILIMUMAB 中文参考商品译名: YERVOY 50毫克/10毫升/瓶 中文参考药品译名: 伊匹单抗 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB -------------------------------------------------- 产地国家: 美国 原产地英文商品名: YERVOY 50mg/10ml/vial 原产地英文药品名: IPILIMUMAB 中文参考商品译名: YERVOY 50毫克/10毫升/瓶 中文参考药品译名: 伊匹单抗 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB -------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: YERVOY 50mg/10ml/vial 原产地英文药品名: IPILIMUMAB 中文参考商品译名: YERVOY 50毫克/10毫升/瓶 中文参考药品译名: 伊匹单抗 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB -------------------------------------------------- 产地国家: 瑞士 原产地英文商品名: YERVOY 50mg/10ml/vial 原产地英文药品名: IPILIMUMAB 中文参考商品译名: YERVOY 50毫克/10毫升/瓶 中文参考药品译名: 伊匹单抗 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: BRISTOL MYERS SQUIBB