sialin

随着气温升高，手足口病即将进入高发季节。手足口病是由多种肠道病毒引起的5岁及以下儿童常见急性传染性疾病，4-7月为手足口病春夏季感染高峰。病原学肠道病毒属于小RNA病毒科肠道病毒属。手足口病（HFMD）由肠道病毒引起，主要致病血清型包括柯萨奇病毒(Coxsackievirus，CV)A组4～7、9、10、16型和B组1～3、5型，埃可病毒(Echovirus)的部分血清型和肠道病毒71型(Enterovirus A71，EV-A71)等，其中以CV-A16和EV-A71最为常见，其中EV-A71具有致病性强、传染性高、嗜神经等特点,可致严重甚至致命的神经系统及心肺并发症，重症及死亡病例多由EV-A71所致。流行病学1、常见亚型：亚基因型EV-A71_C4、CVA16_B1b、CVA6_D3a、CVA10_ F目前在中国占主导地位。2、传染源：患儿和隐性感染者，可通过感染者的粪便、咽喉分泌物、唾液和疱疹液等广泛传播。3、传播途径：密切接触，通过接触被病毒污染的手、毛巾、手绢、牙杯、玩具、食具、奶具以及床上用品、内衣等引起感染；呼吸道飞沫传播；饮用或食入被病毒污染的水和食物。4、易感人群：婴幼儿和儿童普遍易感，以5岁以下儿童为主。5、好发季节：该病全年都可以发病，在北方地区夏秋高发，但有逐渐提早的趋势。在南方地区以春夏为主高峰，秋冬季节为次高峰。临床表现1、潜伏期：多为2～10 d，平均3～5 d。2、出疹期：主要表现为发热，手、足、口、臀等部位出疹，可伴有咳嗽、流涕、食欲不振等症状。典型皮疹表现为斑丘疹、丘疹、疱疹。皮疹周围有炎性红晕，疱疹内液体较少，不疼不痒，皮疹恢复时不结痂、不留疤。不典型皮疹通常小、厚、硬、少，有时可见瘀点、瘀斑。某些型别肠道病毒如CV-A6和CV-A10所致皮损严重，皮疹可表现为大疱样改变，伴疼痛及痒感，且不限于手、足、口部位。此期属于手足口病普通型，绝大多数在此期痊愈。3、神经系统受累期：少数病例可出现中枢神经系统损害，多发生在病程1～5 d，表现为精神差、嗜睡、吸吮无力、易惊、头痛、呕吐、烦躁、肢体抖动、肌无力、颈项强直等。此期属于手足口病重症病例重型，大多数可痊愈。4、心肺功能衰竭前期：多发生在病程5 d内，表现为心率和呼吸增快、出冷汗、四肢末梢发凉、皮肤发花、血压升高。此期属于手足口病重症病例危重型。及时识别并正确治疗，是降低病死率的关键。5、心肺功能衰竭期：可在心肺功能衰竭前期的基础上迅速进入该期。临床表现为心动过速(个别患儿心动过缓)、呼吸急促、口唇紫绀、咳粉红色泡沫痰或血性液体、血压降低或休克。亦有病例以严重脑功能衰竭为主要表现，临床可见抽搐、严重意识障碍等。此期属于手足口病重症危重型，病死率较高。6、恢复期：此期体温逐渐恢复正常，对血管活性药物的依赖逐渐减少，神经系统受累症状和心肺功能逐渐恢复，少数可遗留神经系统后遗症。部分手足口病例(多见于CV-A6、CV-A10感染者)在病后2～4周有脱甲的症状，新甲于1～2月长出。辅助检查1、实验室检查（1）血常规及C-反应蛋白(CRP)多数病例白细胞计数正常，部分病例白细胞计数、中性粒细胞比例及CRP可升高。（2）病原学及血清学临床样本（咽拭子、粪便或肛拭子、血液等标本）肠道病毒特异性核酸检测阳性或分离到肠道病毒。急性期血清相关病毒IgM抗体阳性。恢复期血清CV-A16、EV-A71或其他可引起手足口病的肠道病毒中和抗体比急性期有4倍及以上升高。（3）血生化   部分病例丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、肌酸激酶同工酶（CK-MB）轻度升高，病情危重者肌钙蛋白、血糖、乳酸升高。（4）脑脊液神经系统受累时，脑脊液符合病毒性脑膜炎和/或脑炎改变，表现为外观清亮，压力增高，白细胞计数增多，以单核细胞为主（早期以多核细胞升高为主），蛋白正常或轻度增多，糖和氯化物正常。2、影像学检查（1）影像学：轻症患儿肺部无明显异常。重症及危重症患儿并发神经源性肺水肿时，两肺野透亮度减低，磨玻璃样改变，局限或广泛分布的斑片状、大片状阴影，进展迅速。（2）颅脑CT和/或MRI颅脑CT检查可用于鉴别颅内出血、脑疝、颅内占位等病变。神经系统受累者MRI检查可出现异常改变，合并脑干脑炎者可表现为脑桥、延髓及中脑的斑点状或斑片状长T1长T2信号。并发急性弛缓性麻痹者可显示受累节段脊髓前角区的斑点状对称或不对称的长T1长T2信号。（3）心电图可见窦性心动过速或过缓，Q-T间期延长，ST-T改变。（4）脑电图神经系统受累者可表现为弥漫性慢波，少数可出现棘(尖)慢波。（5）超声心动图重症患儿可出现心肌收缩和/或舒张功能减低，节段性室壁运动异常，射血分数降低等。诊断标准在临床诊断病例基础上，具有下列之一者即可确诊。1、肠道病毒（CV-A16、EV-A71等）特异性核酸检查阳性。2、分离出肠道病毒，并鉴定为CV-A16、EV-A71或其他可引起手足口病的肠道病毒。3、急性期血清相关病毒IgM抗体阳性。4、恢复期血清相关肠道病毒的中和抗体比急性期有4倍及以上升高。重症病例的早期识别重症病例诊疗关键在于及时准确地识别第2期和第3期，阻止发展为第4期。年龄3岁以下、病程3天以内和EV-A71感染为重症高危因素，下列指标提示患儿可能发展为重症病例危重型：1、持续高热：体温大于39℃，常规退热效果不佳；2、神经系统表现：出现精神萎靡、头痛、眼球震颤或上翻、呕吐、易惊、肢体抖动、吸吮无力、站立或坐立不稳等；3、呼吸异常：呼吸增快、减慢或节律不整，安静状态下呼吸频率超过30～40次/分；4、循环功能障碍：心率增快（＞160次/分）、出冷汗、四肢末梢发凉、皮肤发花、血压升高、毛细血管再充盈时间延长（＞2秒）5、外周血白细胞计数升高：外周血白细胞计数≥15×109/L，除外其他感染因素；6、血糖升高：出现应激性高血糖，血糖＞8.3mmol/L；7、血乳酸升高：出现循环功能障碍时，通常血乳酸≥2.0mmol/L，其升高程度可作为判断预后的参考指标。治疗目前尚无特效抗肠道病毒药物，手足口病的治疗仍以对症支持治疗为主。研究显示，干扰素α喷雾或雾化、利巴韦林静脉滴注早期使用可有一定疗效，若使用利巴韦林应关注其不良反应和生殖毒性。不应使用阿昔洛韦、更昔洛韦、单磷酸阿糖腺苷等药物治疗。1、一般治疗注意隔离，避免交叉感染；清淡饮食；做好口腔和皮肤护理。积极控制高热，体温超过38.5℃者，采用物理降温（温水擦浴、使用退热贴等）或应用退热药物治疗。惊厥病例需要及时止惊2、液体疗法重症病例可出现脑水肿、肺水肿及心功能衰竭，应控制液体入量，给予生理需要量60～80ml/（kg·d）（脱水剂不计算在内），建议匀速给予，即2.5～3.3ml/（kg·h），注意维持血压稳定。休克病例在应用血管活性药物同时，给予生理盐水5～10ml/（kg·次）进行液体复苏，15～30分钟内输入，此后酌情补液，避免短期内大量扩容。仍不能纠正者给予胶体液（如白蛋白或血浆）输注。有条件的医疗机构可依据中心静脉压（CVP）、动脉血压（ABP）等指导补液。3、降颅压常用甘露醇，严重颅内高压或低钠血症患儿可考虑联合使用高渗盐水（3%氯化钠）。有心功能障碍者，可使用利尿剂，如呋塞米1～2mg/kg静脉注射。4、血管活性药物心肺功能衰竭前期患儿血流动力学改变为高动力高阻力型，以使用扩血管药物为主。心肺功能衰竭期血压下降时，可应用正性肌力及升压药物治疗。5、静脉丙种球蛋白有脑脊髓炎和持续高热等表现者以及危重病例可酌情使用，剂量1.0g/（kg·d），连用2天。6、糖皮质激素有脑脊髓炎和持续高热等表现者以及危重病例酌情使用。7、机械通气（1）机械通气指征：出现以下表现之一者，可予气管插管机械通气：①呼吸急促、减慢或节律改变；②气道分泌物呈淡红色或血性；③短期内肺部出现湿性啰音；④胸部X线检查提示肺部明显渗出性病变；⑤脉搏血氧饱和度（SpO2）或动脉血氧分压（PaO2）下降；⑥面色苍白、紫绀、皮温低、皮肤发花、血压下降；⑦频繁抽搐或昏迷。（2）撤机指征①自主呼吸恢复正常，咳嗽反射良好；②氧合指数（PaO2/FiO2）≥200mmHg，PEEP＜10cmH2O时，开始做撤机评估；③血气分析好转，胸片肺部渗出与肺水肿好转；④意识状态好转；⑤循环稳定。预防1、一般预防措施保持良好的个人卫生习惯。勤洗手，不要让儿童喝生水，吃生冷食物。儿童玩具和常接触到的物品应当定期进行清洁消毒。避免儿童与患手足口病儿童密切接触。2、接种疫苗EV-A71型灭活疫苗可用于6月龄～5岁儿童预防EV-A71感染所致的手足口病，基础免疫程序为2剂次，间隔1个月，鼓励在12月龄前完成接种。撰文 | 梅斯医学编辑 | Swagpp● 震惊！大三甲医生惨痛教训：35岁住院医，工作6年，跟风读研后反而找不到工作了！网友：为读研而读研你太傻！学历贬值你不懂?● 柳叶刀最新：全球生育率持续下降，逼近临界值！25年后，近50%国家的自然增长率为负，中国人口将持续减少● 重磅！！国家卫健委：2024年将推进“先诊疗后付费”等新模式！依靠信用，“花呗”版看病真的来了！意味着什么？版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！

- Pivotal trial found the enfortumab vedotin plus pembrolizumab combination significantly extended overall and progression-free survival vs platinum-containing chemotherapy- - If approved, enfortumab vedotin with KEYTRUDA would be the first combination in China to offer an alternative to chemotherapy, the current standard of care in first-line locally advanced or metastatic urothelial cancer- TOKYO, March 28, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") today announced that on March 27, 2024 the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) has accepted the supplemental Biologics License Application (sBLA) for enfortumab vedotin with KEYTRUDA® (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). If approved, enfortumab vedotin with KEYTRUDA has the potential to change the treatment paradigm, becoming the first combination treatment to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC. Urothelial cancer (UC) encompasses cancers of both the lower urinary tract (bladder and urethra) and upper tract (ureter and renal pelvis), with disease that originates in the lower tract accounting for 90% to 95% of all UC cases.i,ii Globally, approximately 614,000 new cases of bladder cancer and approximately 220,000 deaths are reported annually.iii It is estimated that approximately 93,000 people in China were diagnosed with bladder cancer and approximately 41,000 deaths were reported in 2022.iv Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas "Locally advanced or metastatic urothelial cancer is a life-threatening condition in China with nearly half of those diagnosed succumbing to the disease. The CDE's acceptance of our sBLA for enfortumab vedotin and pembrolizumab brings us one step closer to delivering a much-needed, innovative new treatment option for this patient population." Professor Guo Jun, lead PI in China for the EV-302 trial, director of the Department of Melanoma and Urological Oncology at Beijing Cancer Hospital, executive board member of the Chinese Society Of Clinical Oncology (CSCO) "In China, the recommended first-line treatment for advanced urothelial cancer is platinum-based chemotherapy, and there are currently no other treatments approved in the first-line setting. Given the efficacy brought by chemotherapy, alternate treatment options are extremely needed to extend survival benefits and potentially improve the prognosis of those patients. The results of the EV-302 study demonstrated that enfortumab vedotin in combination with pembrolizumab, as the first non-platinum first-line treatment, can achieve a clinically meaningful improvement in response rate, nearly double the median progression-free survival, and significantly improve the overall survival benefit of patients with locally advanced or metastatic urothelial cancer compared to chemotherapy." The sBLA for the first-line use of this combination is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39). The study found that the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified. The NMPA is also reviewing enfortumab vedotin as a treatment for patients with locally advanced or metastatic urothelial cancer (la/mUC) who received prior treatment with a PD-1/L1 inhibitor and platinum-based chemotherapy. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency is reviewing the enfortumab vedotin in combination with pembrolizumab therapy, as well as Japan's Ministry of Health, Labour and Welfare (MHLW). The U.S. Food and Drug Administration approved the combination therapy in December 2023. About EV-302 The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety. The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) Congress 2023 in October 2023. About Bladder and Urothelial Cancer Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.v If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease.vi Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.iii Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.vii Ongoing Investigational Trials The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC). Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective. The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent/ metastatic head and neck squamous cell carcinoma. The EV-203 trial (NCT04995419) is a Phase 2, multicenter, single-arm bridging study in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the study. About Enfortumab Vedotin Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.viii Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).ix PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information BOXED WARNING: SERIOUS SKIN REACTIONS PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later. Closely monitor patients for skin reactions. Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Indication PADCEV®, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC). PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who: have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients. Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV. Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months). In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months). Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD. Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months). PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients. Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN. Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders. Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions. Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose. ADVERSE REACTIONS Most common adverse reactions, including laboratory abnormalities  (≥20%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets. Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin. EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).  Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The  most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The  most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The  most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%). EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab) Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%).  Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%).  Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%) were PN (20%) and rash (6%).  Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%) were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%).  Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%). EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%).  Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each).  Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%).  Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%).  Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each). EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy) Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%). DRUG INTERACTIONS Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors) Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors. SPECIFIC POPULATIONS Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose. Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment. For more information, please see the U.S. full Prescribing Information including BOXED WARNING for PADCEV here. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . About the Astellas, Pfizer and Merck Collaboration Astellas and Pfizer have a clinical collaboration agreement with Merck to evaluate the combination of Astellas' and Pfizer's PADCEV™ (enfortumab vedotin) and Merck's KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada). Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. i Leow JJ, Liu Z, Tan TW, Lee YM, Yeo EK, Chong YL. Optimal Management of Upper Tract Urothelial Carcinoma: Current Perspectives. Onco Targets Ther. 2020;13:1-15. ii Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1794-8. iii International Agency for Research on Cancer. Cancer Today: Bladder Globocan 2022 fact sheet (01-2024). 30-bladder-fact-sheet.pdf (who.int) iv International Agency for Research on Cancer (IARC). Bladder Fact Sheet. Lyon, France. 2022 (02-2024). Available at: 160-china-fact-sheet.pdf (who.int) v National Cancer Institute. What is bladder cancer? . vi American Society of Clinical Oncology. Bladder cancer: introduction (12-2021). . viiNational Cancer Institute. Cancer stat facts: bladder cancer. . viii Challita-Eid PM, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13. ix PADCEV [package insert]. Northbrook, IL: Astellas Pharma US, Inc. SOURCE ASTELLAS PHARMA INC.

ST. GALLEN, SWITZERLAND, March 28, 2024 /PRNewswire/ -- CSL Vifor is pleased that its partner Akebia Therapeutics, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved Vafseo (vadadustat) tablets for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Vafseo is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) developed by Akebia. "We congratulate our partner Akebia on the FDA approval, which represents an important moment in our shared efforts toward improving the lives of dialysis patients with anemia due to CKD in the U.S.," said Hervé Gisserot, General Manager of CSL Vifor. "As we continue to deliver on our promise for patients and public health, we are eager to closely collaborate with our partners to make this new oral treatment option available to patients." "Patients receiving maintenance dialysis would benefit from additional therapeutic options that can effectively increase and maintain hemoglobin concentrations within guideline-recommended target ranges," said Glenn M. Chertow, M.D., M.P.H., Professor of Medicine, Division of Nephrology at Stanford University and Co-Chair of the independent Executive Steering Committee for PRO2TECT and INNO2VATE, the global Phase 3 clinical development programs for Vafseo. The approval of Vafseo for the treatment of anemia due to CKD in adults who have been receiving dialysis for at least three months is based on efficacy and safety data from the INNO2VATE program and an assessment of post marketing safety data from Japan where Vafseo was launched in August 2020. Results from the INNO2VATE program were published in the New England Journal of Medicine: (N Engl J Med 2021; 384:1601-1612); (N Engl J Med 2021; 384:1589-1600). See the Important Safety Information section below, including BOXED WARNING regarding increased risk of death, myocardial infarction, stroke, venous thromboembolism and thrombosis of vascular access. CSL Vifor has been granted an exclusive license to sell Vafseo to Fresenius Kidney Care dialysis centers and specific other third-party dialysis organizations in the U.S., allowing us to potentially reach approximately 60% of the dialysis patients in the country. About CSL Vifor CSL Vifor is a global partner of choice for pharmaceuticals and innovative, leading therapies in iron deficiency and nephrology. We specialize in strategic global partnering, in-licensing and developing, manufacturing and marketing pharmaceutical products for precision healthcare, aiming to help patients around the world lead better, healthier lives. Headquartered in St. Gallen, Switzerland, CSL Vifor also includes the joint company Vifor Fresenius Medical Care Renal Pharma (with Fresenius Medical Care). The parent company, CSL (ASX: CSL; USOTC: CSLLY), headquartered in Melbourne, Australia, employs 32,000 people and delivers its lifesaving therapies to people in more than 100 countries. For more information about CSL Vifor, visit . About anemia due to chronic kidney disease (CKD) Anemia is a condition in which a person lacks enough healthy red blood cells to carry adequate oxygen to the body's tissues. It commonly occurs in people with CKD because their kidneys do not produce enough erythropoietin, a hormone that helps regulate production of red blood cells. Anemia due to CKD can have a profound impact on a person's quality of life1 as it can cause fatigue, dizziness, shortness of breath and cognitive dysfunction. Left untreated, anemia leads to deterioration in health and is associated with increased morbidity and mortality2 in people with CKD. Approximately 500,000 adult patients in the U.S. on dialysis suffer from anemia due to CKD3, which may be associated with many adverse clinical outcomes. The burden of managing uncontrolled anemia in CKD patients can be substantial, both in terms of healthcare costs and the impact on patients, healthcare providers and caregivers. Today, most CKD patients are treated for anemia with injectable erythropoiesis-stimulating agents mostly administered at dialysis centers. About Vafseo® (vadadustat) Vafseo tablets is a once-daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor that activates the physiologic response to hypoxia to stimulate endogenous production of erythropoietin, increasing hemoglobin and red blood cell production to manage anemia. Vafseo is approved for use in 37 countries. Indication: VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. VAFSEO is not indicated for use: As a substitute for red blood cell transfusions in patients who require immediate correction of anemia. In patients with anemia due to CKD not on dialysis. Important Safety Information about VAFSEO (vadadustat) tablets CONTRAINDICATIONS Known hypersensitivity to VAFSEO or any of its components Uncontrolled hypertension WARNINGS AND PRECAUTIONS Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access A rise in hemoglobin (Hb) levels greater than 1 g/dL over 2 weeks can increase these risks. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 month prior to starting VAFSEO. Targeting a Hb level of greater than 11g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. No specific Hb target level, dose of VASFEO, or dosing strategy has been identified to avoid these risks. Use the lowest effective dose and adhere to dosing and Hb monitoring recommendations to avoid excessive erythropoiesis. Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur. Hepatotoxicity Hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one severe case with jaundice. All events were asymptomatic and resolved after discontinuation of VAFSEO. The time to onset was generally within the first 3 months of treatment. Elevated serum ALT, AST, and bilirubin levels were observed in 1.8%, 1.8%, and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST, and bilirubin before treatment and monthly for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. Not recommended in patients with cirrhosis or active, acute liver disease. Hypertension Worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving VAFSEO and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving VAFSEO and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving VAFSEO. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. Seizures Seizures occurred in 1.6% (1.0 per 100 PY) of patients who received VAFSEO and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of VAFSEO, monitor patients closely for premonitory neurologic symptoms. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. Gastrointestinal Erosion Gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving VAFSEO and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious gastrointestinal (GI) erosions, including GI bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving VAFSEO and darbepoetin alfa, respectively. Consider the risk of GI erosion in high-risk patients, including those with a history of GI erosion, peptic ulcer disease, and tobacco or alcohol use. Advise patients of the signs and symptoms of erosions and GI bleeding and urge them to seek prompt medical care if present. Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting. In large clinical trials in adults with anemia of CKD who were not on dialysis, an increased risk of mortality, stroke, myocardial infarction, serious acute kidney injury, serious hepatic injury, and serious GI erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa. Malignancy VAFSEO has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with VAFSEO and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies. ADVERSE REACTIONS The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea. DRUG INTERACTIONS Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron. Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders. BCRP substrates: Monitor for signs of substrate adverse reactions and consider dose reduction. Statins: Monitor for statin-related adverse reactions. Limit the daily dose of simvastatin (20 mg) and rosuvastatin (5 mg). USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. Lactation: Breastfeeding not recommended until two days after the final dose. Hepatic Impairment: Not recommended for use in patients with cirrhosis or active, acute liver disease. Please note that this information is not comprehensive. Please click here for the Full Prescribing Information, including BOXED WARNING and Medication Guide. References: 1 Eriksson D, et al. BMC Nephrol. 2016;17:97; Finkelstein FO, et al. Clin J Am Soc Nephrol. 2009;4:33-38; Farag YM, et al. Clin Nephrol. 2011;75:524-533 2 Portolés J, et al. BMC Nephrol. 2013;14:2. 3. NICE. Clinical Guideline: Anaemia Management in Chronic Kidney Disease: Partial Update 2015. 4. Silverberg DS, et al. Clin Lab Haematol. 2001;23:1-6. 5. Herzog CA, et al. J Card Fail. 2004;10:467-472 3 United States Renal Data System. 2022 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2022; Dopps.org. CSL Vifor Media Contact Thomas Hutter +41 79 957 96 73 [email protected] SOURCE Vifor International AG (CSL Vifor)