FDA批准银屑病治疗新药Stelara上市 近日，美国食品药品监督管理局（FDA）批准一种用于治疗中度至重度银屑病的生物制品Stelara(ustekinumab)上市。 银屑病是一种皮肤细胞快速、过度生长的免疫系统疾病，主要以皮肤炎症部位的斑块增厚、皮肤发红、伴有银色鳞屑为特征。 Stelara系由实验室制备，模拟人体自身免疫系统产生的单克隆抗体，通过阻断2种促皮肤细胞过度生长和炎症发生的蛋白活性治疗银屑病。 Stelara已有的2，266名患者参与的3项临床试验研究显示了该生物制品的安全性和有效性。 由于Stelara存在降低机体免疫能力的可能，增加了感染的风险。接受Stelara治疗的患者中，有报告患者发生由病毒、真菌或细菌引起的严重感染和入院治疗的情况。同时，该药也存在增加癌症风险可能。 FDA要求Stelara的制药商制定该药风险评估与缓解计划（REMS），其中包括制定与医护人员的交流计划和给患者的用药指南。 STELARA Manufacturer: Centocor Ortho Biotech, Inc. Pharmacological Class: Interleukin-12 and interleukin-23 antagonist Active Ingredient(s): Ustekinumab 45mg/0.5mL; soln for SC inj; preservative-free. Indication(s): Moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy. Pharmacology: Ustekinumab is a human IgG1k monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23. These cytokines are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. Ustekinumab was shown in vitro to disrupt interleukin-12 and interleukin-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor. Clinical Trials: Two double-blind, placebo-controlled studies were conducted in patients 18 years or older with plaque psoriasis who were candidates for phototherapy or systemic therapy. The patients had at least 10% body surface involvement and a Psoriasis Area and Severity Index (PASI) score of ≥12; baseline PASI scores ranged from about 17–18. Patients with guttate, erythrodermic, or pustular psoriasis were excluded. For both studies, subjects were randomized to ustekinumab 45mg, 90mg, or placebo. Those randomized to ustekinumab received 45mg or 90mg, regardless of weight, at weeks 0, 4, and 16. Those randomized to placebo received placebo at weeks 0 and 4, and were crossed over to ustekinumab 45mg or 90mg at weeks 12 and 16. The endpoints were the proportion of subjects who achieved at least a 75% reduction in the PASI score from baseline to week 12 (PASI 75) and treatment success (cleared or minimal) on the Physician's Global Assessment, which indicates the physician's overall assessment of psoriasis, focusing on thickness, induration, erythema, and scaling. Baseline PGA score was marked or severe in 44% of the 766 subjects in Study 1 and in 40% of the 1230 subjects in Study 2. In Study 1, 67% of patients achieved PASI 75 in the ustekinumab 45mg group, 66% in the 90mg, and 3% in the placebo group. In Study 2, 67% of patients given 45mg ustekinumab and 76% of patients given ustekinumab 90mg achieved PASI 75, compared to 4% for placebo. Legal Classification: Rx Adults: ≥18yrs: ≤100kg: 45mg SC once then 4wks later, then once every 12wks. >100kg: 90mg once then 4wks later, then once every 12wks. Rotate inj site. Children: <18yrs: not recommended. Warnings/Precautions: Active infections: not recommended. Increased risk of serious or fatal infections, esp. in IL-12/IL-23 genetically deficient patients (eg, mycobacteria, salmonella, BCG vaccines). Monitor for new infection; discontinue if serious infection develops. Conditions that predispose to infection. Test for and treat latent tuberculosis prior to initiating therapy. Avoid close contact with live vaccine recipients. History of malignancies. Discontinue if reversible posterior leukoencephalopathy syndrome (RPLS) occurs or is suspected. Elderly. Pregnancy (Cat.B). Nursing mothers. Interaction(s): Concomitant live vaccines, other immunosuppressants, phototherapy: not recommended. Do not give BCG vaccines during or within 1 year of starting or stopping ustekinumab. Non-live vaccines: may get suboptimal response. May affect CYP450 substrates. Adverse Reaction(s): Nasopharyngitis, upper respiratory tract infection, headache, fatigue; infections, malignancies, RPLS. How Supplied: Single use vial (0.5mL)—1 Last Updated: 11/5/2009 斑块状银屑病新型治疗药STELARA将在欧洲上市     近日，欧盟委员会批准治疗斑块型银屑病的新型生物制剂STELARA(TM) (ustekinumab)在欧洲27个国家上市销售。该药治疗成人中-重度斑块型银屑病，主要用于那些对其他全身性治疗药物（包括ciclosporin，methotrexate和PUVA等）应答不充分，有禁忌症候或耐受不好的患者。在欧洲国家，有2-3%的人深受银屑病困扰。   这次ustekinumab获准的依据是在两项大型关键III期临床实验中获取的数据，该实验属多中心随机双盲安慰剂对照实验，共招募了2000名受试患者，主要检测药物治疗中-重度斑块型银屑病的安全性和疗效。结果发现，2/3的受试者达到了主要临床终点，用药12周以后，在病变面积和病情严重指数的改善至少达到75%。   上述临床实验结果表明，患者使用ustekinumab治疗之后，能有效缓解病情，提高生活质量。而且该药每年只需注射4次，它为患者带来了全新的治疗选择。   在用药过程中，最常见的副作用为关节痛、咳嗽、头痛、注射部位出现红斑、鼻咽炎和上呼吸道感染，这些不良反应多数都比较轻微，未影响治疗。该药导致的严重副作用主要为重度感染、恶性肿瘤和心血管疾病等，但出现这些不良反应的几率极小，与预计的情况相符。 制造商： Centocor Ortho生技公司公司 药理分类： 白细胞介素12和白细胞介素23拮抗剂 活性成分（补）： Ustekinumab 45mg/0.5mL;溶液为SC损伤;防腐剂free.Indication（补）： 中度到成年人谁是光疗或全身治疗重度斑块型银屑病的候选人。 药理作用： Ustekinumab是人类IgG1k对白细胞介素- 12和IL - 23 p40的亚基单克隆抗体。这些细胞因子参与炎症和免疫反应，如自然杀伤细胞的活化和CD4 + T细胞分化和激活。 Ustekinumab被证明在体外破坏白细胞介素12和IL - 23介导的信号，并通过破坏与共享细胞表面受体相互作用的细胞因子，这些细胞因子的级联。 临床试验： 两个双盲，安慰剂控制的研究是在18岁以上的患者牛皮癣谁属光疗或全身治疗候选人老。患者至少有10％的身体表面的参与和银屑病面积和严重程度指数（PASI），≥12分;基线的PASI分数约17-18不等。与点滴状，红皮，或脓疱性银屑病患者被排除在外。 对于这两项研究中，受试者被随机分配到ustekinumab 45mg，90毫克或安慰剂。这些随机ustekinumab收到45mg或90毫克，无论重量，周0，4和16。那些与安慰剂随机收到0和4周安慰剂，并越过ustekinumab在12周和16 45mg或90毫克。在终点为科目谁实现了从基线至少在的PASI评分减少75％至12周（PASI评分75）和治疗成功对医师的全球评估，这表明医生的牛皮癣进行全面评估（清除或很少）的比例，在厚度，硬结，红斑和缩放为重点。 PGA的得分为基准标记或在44个研究中的1 766和40％的受试者在研究1230年2％的受试者严重。 在研究一，达到67％的PASI 75的ustekinumab 45mg组中，66％的患者90毫克，3％，在安慰剂组。在研究二，67％的患者给予45mg ustekinumab达到76 PASI评分给予75％的患者ustekinumab 90毫克，而4％的安慰剂。 法律分类： 接收 成人： ≥18yrs：≤一百千克：45mg一次，然后4wks资深大律师后，再一次12wks。 >一○○千克：90毫克一次，然后4wks后，再一次12wks。旋转已经来到现场。 儿童： “18yrs：不推荐。 警告/注意事项： 主动感染：不推荐。增加对严重或致命的感染，尤其危险。在IL-12/IL-23基因缺陷患者（如，分枝杆菌，沙门氏菌，卡介苗疫苗）。新感染监控;停止，如果严重感染发展。条件，易患感染。测试和治疗潜伏肺结核开始治疗之前。避免与其密切接触活疫苗者。历史的恶性肿瘤。可逆性后部白质脑病如果停止综合征（RPLS）发生或怀疑。老人。妊娠（Cat.B）。哺乳的母亲。 互动（补）： 伴随活疫苗，其他免疫抑制剂，光疗：不推荐。不要给卡介苗期间或在1年内启动或停止ustekinumab疫苗。非活疫苗：可能会不理想的反应。可能会影响细胞色素P450基板。 不良反应（补）： 鼻咽炎，上呼吸道感染，头痛，疲劳，感染，恶性肿瘤，RPLS。 如何提供： 一次性使用瓶（0.5mL）-1 Ustekinumab and the Risk of Administration Reactions — Prescribing Information The following information regarding administration reactions represents an excerpt taken directly from the STELARA® (ustekinumab) package insert. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious allergic reactions, including angioedema and possible anaphylaxis, have been reported postmarketing. If an anaphylactic or other serious allergic reaction occurs, discontinue STELARA® and institute appropriate therapy.11997  Theoretical Risk of Immunotherapy STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergy immunotherapy and may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergy immunotherapy, particularly for anaphylaxis.11997  ADVERSE REACTIONS Clinical Studies Experience The safety data reflect exposure to STELARA® in 2266 psoriasis subjects, including 1970 exposed for at least 6 months, 1285 exposed for at least one year, and 373 exposed for at least 18 months. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The table below summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of STUDY 1 and STUDY 2.11997  Administration-Related Adverse Reactions Reported by >1% of Subjects Through Week 12 in STUDY 1 and STUDY 2 Placebo STELARA® 45 mg STELARA® 90 mg Subjects treated 665 664 666 Injection site erythema 3 (<1%) 6 (1%) 13 (2%) 11997  Administration-related adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).11997  Immunogenicity The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies, resulting in inconclusive results, due to assay interference. In STUDIES 1 and 2, antibody testing was done at time points when ustekinumab may have been present in the serum. The table below summarizes the antibody results from STUDIES 1 and 2. In STUDY 1 the last ustekinumab injection was between Weeks 28 and 48 and the last test for anti-ustekinumab antibodies was at Week 52. In STUDY 2 the last ustekinumab injection was at Week 16 and the last test for anti-ustekinumab antibodies was at Week 24.11997  Immunogenicity Antibody Results Study 1 (N=743) Study 2 (N=1198) Positive 38 (5%) 33 (3%) Negative 351 (47%) 90 (8%) Inconclusive 354 (48%) 1075 (90%) 11997  The data reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading.11997  Postmarketing Experience Adverse reactions have been reported during postapproval use with STELARA®. Because these events 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 STELARA® exposure. Immune system disorders: Serious allergic reactions (including angioedema, dyspnea and hypotension), hypersensitivity reactions (including rash and urticaria).11997  PATIENT COUNSELING INFORMATION Allergic Reactions Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions.11997  General Considerations for Administration STELARA® is intended for subcutaneous administration under the supervision of a physician. Prior to administration, STELARA® should be visually inspected for particulate matter and discoloration. STELARA® is colorless to light yellow and may contain a few small translucent or white particles. STELARA® should not be used if it is discolored or cloudy, or if other particulate matter is present. STELARA® does not contain preservatives; therefore, any unused product remaining in the vial and/or syringe should be discarded. The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex). The needle cover should not be handled by persons sensitive to latex. It is recommended that each injection be administered at a different anatomic location (such as upper arms, gluteal regions, thighs, or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, or indurated. When using the single-use vial, a 27 gauge, ½ inch needle is recommended. STELARA® should only be administered by a healthcare provider. STELARA® should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.11997  Instructions for Administration of STELARA® Prefilled Syringes Equipped with Needle Safety Guard Refer to the diagram below for the provided instructions.11997  To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD ACTIVATION CLIPS at any time during use. Figure 3309 – Diagram of STELARA® Prefilled Syringe Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER or PLUNGER HEAD while removing the NEEDLE COVER or the PLUNGER may move. Do not use the prefilled syringe if it is dropped without the NEEDLE COVER in place. Inject STELARA® subcutaneously as recommended [see Dosage and Administration in the full Prescribing Information]. Inject all of the medication by pushing in the PLUNGER until the PLUNGER HEAD is completely between the needle guard wings. Injection of the entire prefilled syringe contents is necessary to activate the needle guard. Figure 3310 – Diagram of STELARA® Prefilled Syringe Activation After injection, maintain the pressure on the PLUNGER HEAD and remove the needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow the empty syringe to move up until the entire needle is covered by the needle guard, as shown by the illustration below: Figure 3311 – Diagram of STELARA® Prefilled Syringe After Activation Covering Needle Used syringes should be placed in a puncture-resistant container STELARA® (ustekinumab) Indications and Important Safety Information INDICATIONS AND USAGE STELARA® is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. IMPORTANT SAFETY INFORMATION Infections STELARA® (ustekinumab) may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA® should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA® in patients with a chronic infection or a history of recurrent infection. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances. Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA®. STELARA® should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA®. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA®. Malignancies STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA® in clinical studies. The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Hypersensitivity Reactions Serious allergic reactions, including angioedema and possible anaphylaxis, have been reported. Discontinue STELARA® and institute appropriate therapy if an anaphylactic or other serious allergic reaction occurs. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) One case of RPLS has been reported in a STELARA®-treated patient. If RPLS is suspected, discontinue STELARA® and administer appropriate treatment. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes. Immunizations Prior to initiating therapy with STELARA®, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA®. Exercise caution when administering live vaccines to household contacts of STELARA® patients, as shedding and subsequent transmission to STELARA® patients may occur. Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown. Theoretical Risk of Immunotherapy STELARA® may decrease the protective effect of allergy immunotherapy and may increase the risk of allergic reaction to allergen immunotherapy. Exercise caution in patients receiving or who have received allergy immunotherapy, particularly for anaphylaxis. Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in clinical trials for STELARA® 45 mg, STELARA® 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.