青蒿琥酯注射液

公司：Amivas（US），LLC

批准日期：2020年5月26日

治疗：疟疾

青蒿琥酯注射液是一种抗疟疾药物，可用于成人和小儿严重疟疾的初始治疗。 使用青蒿琥酯注射液治疗严重疟疾后应始终进行适当的口服抗疟方案的完整治疗过程。

马里兰州弗雷德里克市，2020年5月27日/美通社/-Amivas（US），LLC是罕见和被忽视的热带病（包括严重疟疾）治疗专家，今天宣布，注射用青蒿琥酯110毫克，粉末和溶液溶剂已获得美国食品和药物管理局（FDA）的市场批准。青蒿琥酯用于成人和儿童患者的严重疟疾的初始治疗。这是总部位于马里兰州弗雷德里克的Amivas将其首批获得FDA批准的产品引入其商业产品组合。

Amivas现在将制造，分销和销售青蒿琥酯注射剂，并使其商业化，并正在建立全国性的产品分销网络。在获得FDA批准之前，自2007年以来，疾病预防控制中心（CDC）通过扩大的获取研究性新药（IND）计划管理了对青蒿琥酯的研究性获取。有关Amivas生产的注射用青蒿琥酯的商业供应的更多信息，将发布到https://ivartesunate.com。疾病预防控制中心将根据CDC赞助的扩展访问IND 76,725，自2007年起根据FDA的授权，继续提供IV型青蒿琥酯的研究用药，直到未来几个月在全国范围内提供Amivas生产的注射用青蒿琥酯为止。

Amivas首席医学官医学博士Bryan Smith表示：“我们为获得注射青蒿琥酯的这一重要法规里程碑感到非常高兴。 “正如大多数医学专家所知，当重症疟疾患者到达诊所，急诊室或其他地方时，采用安全，有效，速效，可注射的治疗方法进行即时治疗对于挽救该生命绝对至关重要。鉴于今天的FDA批准，青蒿琥酯注射液以及Amivas可以为治疗罕见的热带疾病带来的深厚专业知识，我们期待为挽救严重疟疾患者的生命做出重大贡献。”

在医院获得Amivas的注射用青蒿琥酯注射液之前，寻求静脉青蒿琥酯治疗重症疟疾患者的医疗保健专业人员应联系CDC以获得经调查的静脉注射青蒿琥酯（www.cdc.gov/malaria/diagnosis_treatment/artesunate.html（770-488 -7788）周一至周五，美国东部时间上午9点至下午5点。在上述时间以外，服务提供商应致电770-488-7100。未来几个月，这种过渡将迅速进行。更新将显示在CDC和Amivas网页上。

在美国，青蒿琥酯注射剂的开发已由美国陆军医学研究与发展司令部（USAMRDC）负责。自2007年以来，在USAMRDC内，沃尔特·里德陆军研究所和美国陆军医疗物资发展活动（USAMMDA）共同为CDC提供了持续供应的IV青蒿琥酯。USAMMDA与Amivas建立了合作研发协议以使青蒿琥酯现代化在FDA生产并注册产品。

“ FDA批准注射用青蒿琥酯是美军在开发抗击疟疾的悠久历史中的另一项显著成就。由于缺乏替代的FDA批准用于治疗危及生命的严重疟疾的疗法，注射用青蒿琥酯填补了关键的缺口。 “这项艰巨的任务是通过竞标，公共/私人伙伴关系完成的，并证明了所涉团队的敬业精神和奉献精神。” USAMMDA青蒿琥酯产品经理Major Victor Zottig博士说。

医学博士布赖恩·史密斯（Bryan Smith，MD）本人是美国陆军退伍军人，他进一步评论说：“出售可能会授予阿米瓦斯的任何优先审查凭证（PRV）的收益，都已指定用于支持美国陆军提名的退伍军人慈善事业，以增加全球供应。 IV青蒿琥酯并将继续与FDA达成协议进行上市后研究。”

临床研究

青蒿琥酯IV的安全性和有效性已在三项试验中进行了研究，其中包括东南亚奎宁青蒿琥酯疟疾试验（SEAQUAMAT）[i]和非洲奎宁青蒿琥酯疟疾试验（AQUAMAT）。这两项研究共检查了6,886名患者，其中包括成人，儿童和孕妇。与SEAQUMAT和AQUAMAT研究中的注射用护理药物标准相比，IV青蒿琥酯的死亡率分别降低了34.7％和22.5％。还收集了2007年1月至2010年12月间102位美国严重或复杂疟疾患者的数据，这些患者是根据CDC扩展访问协议向静脉注射青蒿琥酯的。 92名患者在0、12、24和48小时至少接受了一次药物给药。这些美国患者包括成人，儿童，孕妇和老年人。大多数是黑人或非洲裔美国人，25％是白人，9％是亚洲人。 7名患者死于严重的疟疾并发症（死亡率为6.9％）。来自参与CDC研究的患者进行数据分析的主要资金来源是美国陆军部外科医生办公室。尽管没有服务人员积极招募青蒿琥酯的任何临床试验，但根据CDC协议，为数名服务人员提供了紧急治疗。

重要安全信息

禁忌症

已知对青蒿琥酯有严重的超敏反应，例如过敏反应。

警告和注意事项

青蒿琥酯后延迟溶血：青蒿琥酯后延迟溶血的特征是血红蛋白减少，并有实验室证据表明在开始青蒿琥酯治疗后至少7天出现溶血（如触珠蛋白减少和乳酸脱氢酶增加）。据报道治疗后溶血性贫血严重到需要输血的情况。青蒿琥酯治疗后监测患者4周，以寻找溶血性贫血的证据。由于青蒿琥酯治疗后一部分溶血延迟的患者有免疫介导溶血的证据，因此请考虑进行直接抗球蛋白测试以确定是否进行治疗，例如皮质类固醇，是必须的。

过敏反应：在使用肠胃外青蒿琥酯（包括注射用青蒿琥酯）期间，已有报道对青蒿琥酯过敏，包括过敏反应。如果在注射青蒿琥酯注射期间发生低血压，呼吸困难，荨麻疹或全身性皮疹，请考虑停止注射青蒿琥酯的注射并继续使用另一种抗疟药治疗。

不良反应

在SEAQUAMAT试验中，接受静脉青蒿琥酯治疗的患者中最常见的不良反应（2％或更多）是急性肾衰竭，需要透析，血红蛋白尿和黄疸。 CDC扩展访问方案中最常见的不良反应是贫血（65％），转氨酶增加（27％），血小板减少症（18％），高胆红素血症（14％），急性肾衰竭（10％），白细胞增多（10％） ，急性呼吸窘迫综合征（8％），淋巴细胞减少症（7％），中性粒细胞减少症（5％），弥散性血管内凝血（3％），肌酐升高（3％），肺炎（3％），肺水肿（3％），和腹泻（3％）。

药物相互作用

已发表的临床报告或体外报告表明，青蒿琥酯注射液与口服利托那韦，奈韦拉平或UGT诱导剂同时使用可能会降低双氢青蒿素（DHA）AUC和Cmax，这可能会降低青蒿琥酯注射液的疗效。如果将注射用青蒿琥酯与利托那韦，奈韦拉平或强UGT诱导剂（例如利福平，卡马西平，苯妥英钠）合用，请监测注射用青蒿琥酯的抗疟药功效可能降低。

体外数据的公开报道表明，与UGT抑制剂一起注射使用青蒿琥酯注射可能会增加DHA AUC和Cmax，这可能会增加与DHA相关的不良反应。与强效UGT抑制剂（例如，阿西替尼，凡德他尼，伊马替尼，双氯芬酸）联合使用青蒿琥酯注射液时，监测不良反应。

在特定人群中使用

怀孕：怀孕期间未经治疗的严重疟疾会给母亲和胎儿带来严重风险；延迟妊娠中严重疟疾的治疗可能会导致母亲和胎儿的严重发病和死亡。静脉青蒿琥酯前瞻性监测研究报告的妊娠结局不足以确定与药物相关的重大先天缺陷，流产和/或胎儿死亡的风险。

儿科用途：青蒿琥酯注射液治疗严重疟疾的安全性和有效性已在儿科患者中确立。

老年用途：青蒿琥酯注射液的临床研究未包括足够多的65岁及65岁以上的患者来确定他们对年轻人的反应是否不同。

要报告可疑的不良反应，请通过[1-855-526-4827（1-855-5AMIVAS）]与Amivas LLC联络，或通过1-800-FDA-1088或www.fda.gov/medwatch与FDA联系。

关于疟疾和严重疟疾

疟疾是人类尤其是儿童的主要杀手之一。严重的疟疾是一种医疗急症，通常包括神经系统症状，严重的贫血，急性肾损伤，急性呼吸窘迫综合征或黄疸，因为大量患者的红细胞被疟原虫感染。单纯的恶性疟疾可以迅速发展为严重的疾病，尤其是在免疫力低或免疫力低下的人中，而严重的恶性疟疾未经治疗几乎总是致命的。必须在疟疾症状发作后的24-48小时内迅速有效地进行治疗。

疟疾是美国罕见的疾病。因此，并非总是及时地对其进行识别，诊断和治疗。在美国，几乎所有病例都发生在疟疾流行地区并在回到美国后被确诊的人中。大多数是没有获得抗疟疾免疫力的美国居民，因此有患上严重疟疾的风险。在美国，与疟疾有关的持续死亡的一个主要因素是延迟开始适当的治疗。疟疾的化学预防以及使用蚊帐和驱蚊剂有助于降低患疟疾的风险。

关于阿米瓦斯

Amivas是一家美国合资公司，致力于开发，制造和商业化用于治疗传染病的治疗产品。 Amivas总部位于马里兰州弗雷德里克（Frederick），成立于2016年，旨在将罕见和被忽视的热带病的治疗方法推向市场。

免责声明：本新闻稿中表达的观点仅为作者的观点，不一定代表美国陆军或国防部（DoD）的观点。对特定药品的讨论并不反映对那些产品的认可。

消息来源阿米瓦斯

发表于：2020年5月

Company: Amivas (US), LLC
Date of Approval: May 26, 2020
Treatment for: Malaria

Artesunate for Injection is an antimalarial indicated for the initial treatment of severe malaria in adult and pediatric patients. Treatment of severe malaria with Artesunate for Injection should always be followed by a complete treatment course of an appropriate oral antimalarial regimen.

FREDERICK, Md., May 27, 2020 /PRNewswire/ -- Amivas (US), LLC, specialists in treatments for rare and neglected tropical diseases, including severe malaria, announced today that Artesunate for Injection 110 mg, powder and solvent for solution has received marketing approval by the US Food and Drug Administration (FDA). Artesunate for Injection is indicated for the initial treatment of severe malaria in adult and pediatric patients. It is the first FDA-approved product that Amivas, headquartered in Frederick, Maryland, has introduced to their commercial portfolio.

Amivas will now manufacture, distribute, and commercialize Artesunate for Injection and is completing set-up of a nationwide product distribution network. Prior to FDA approval, access to investigational IV Artesunate had been managed by the Centers for Disease Control and Prevention (CDC) since 2007 via an expanded access investigational new drug (IND) program. Additional information regarding commercial availability of Artesunate for Injection as produced by Amivas will be posted to https://ivartesunate.com. The CDC will continue to make investigational IV artesunate available under the CDC-sponsored expanded access IND 76,725, in effect per FDA's authorization since 2007 until nationwide availability of Amivas-produced Artesunate for Injection is in place in the next few months.

"We are extremely pleased to have secured this important regulatory milestone for Artesunate for Injection," said Bryan Smith, MD, Chief Medical Officer at Amivas. "As most medical professionals know, when a patient with severe malaria arrives in the clinic, emergency room or elsewhere, immediate treatment with a safe, efficacious, fast-acting, injectable therapy is absolutely critical to saving that life. Given today's FDA approval of Artesunate for Injection and the deep expertise that Amivas can bring to the challenges of treating rare tropical diseases, we look forward to making significant ongoing contributions to saving the lives of patients with severe malaria."

Until Amivas' Artesunate for Injection is available in hospitals, healthcare professionals seeking IV artesunate for treatment of patients with severe malaria should contact the CDC for obtaining investigational IV artesunate (www.cdc.gov/malaria/diagnosis_treatment/artesunate.html (770-488-7788) Monday–Friday, 9 am–5 pm EST. Outside these hours, providers should call 770-488-7100). This transition will progress rapidly in coming months. Updates will appear on CDC and Amivas webpages.

Development of Artesunate for Injection in the US has been under US Army Medical Research and Development Command (USAMRDC). Within USAMRDC, the Walter Reed Army Institute of Research and the US Army Medical Materiel Development Activity (USAMMDA) joint collaborative work has provided the CDC a constant supply of IV artesunate since 2007. USAMMDA established a cooperative research and development agreement with Amivas to modernize Artesunate manufacture and register the product with the FDA.

"FDA approval of Artesunate for Injection is another notable achievement for the US Army in its long history of developing therapies for combating malaria. With a lack of alternate FDA approved therapies to treat life-threatening severe malaria, Artesunate for Injection fills a critical gap for the military and US population. This difficult undertaking was accomplished through a competitively bid, public/private partnership and is testament to the professionalism and dedication of the team involved," said Major Victor Zottig, PhD, Artesunate Product Manager for USAMMDA.

Bryan Smith, MD, himself a US Army Veteran, further commented, "Proceeds from the sale of any Priority Review Voucher (PRV) that may be awarded to Amivas have been earmarked to support a US Army nominated Veteran charity, to augment global supply of IV Artesunate and to continue post-marketing studies agreed with FDA."

For more information about Artesunate for Injection, including the US prescribing information, visit https://ivartesunate.com.

Clinical Studies
The safety and efficacy of IV Artesunate was studied in three trials including the South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT)[i] and the African Quinine Artesunate Malaria Trial (AQUAMAT). These two studies examined a total of 6,886 patients and included adults, children and pregnant women. IV Artesunate reduced mortality by 34.7 percent and 22.5 percent compared with the injectable standard of care drug in the SEAQUMAT and AQUAMAT studies respectively. Data were also collected between January 2007 and December 2010 on 102 US patients with severe or complicated malaria who were supplied IV Artesunate under the CDC expanded access protocol. Ninety two patients received at least one administration of drug at 0, 12, 24 and 48 hours. These US patients included adults, children, pregnant women and older adults. Most were Black or African American, 25 percent were White, 9 percent were Asian. Seven patients died from complications of severe malaria (mortality rate, 6.9 percent). Primary funding source for the data analysis from patients enrolled in the CDC study was the Office of the Surgeon General, Department of the US Army. While no service personnel were actively recruited into any of the clinical trials of IV Artesunate, several service members were offered emergency treatment under the CDC protocol.

Important Safety Information
Contraindications
Known serious hypersensitivity to artesunate, such as anaphylaxis.

Warnings and Precautions
Post Artesunate Delayed Hemolysis: Post-artesunate delayed hemolysis is characterized by decreased hemoglobin with laboratory evidence of hemolysis (such as decreased haptoglobin and increased lactate dehydrogenase) occurring at least 7 days after initiating artesunate treatment. Cases of post-treatment hemolytic anemia severe enough to require transfusion have been reported. Monitor patients for 4 weeks after artesunate treatment for evidence of hemolytic anemia. Since a subset of patients with delayed hemolysis after artesunate therapy have evidence of immune-mediated hemolysis, consider performing a direct antiglobulin test to determine if therapy, e.g. corticosteroids, is necessary.

Hypersensitivity reactions: Hypersensitivity to artesunate including cases of anaphylaxis have been reported during the use of parenteral artesunate (including Artesunate for Injection). If hypotension, dyspnea, urticaria, or generalized rash occur during administration of Artesunate for Injection, consider discontinuing Artesunate for Injection administration and continuing therapy with another antimalarial drug.

Adverse Reactions
The most common adverse reactions (2 percent or greater) occurring more frequently in patients receiving intravenous artesunate in the SEAQUAMAT trial were acute renal failure requiring dialysis, hemoglobinuria, and jaundice. The most common adverse reactions in the CDC expanded access protocol were anemia (65 percent), transaminase increase (27 percent), thrombocytopenia (18 percent), hyperbilirubinemia (14 percent), acute renal failure (10 percent), leukocytosis (10 percent), acute respiratory distress syndrome (8 percent), lymphopenia (7 percent), neutropenia (5 percent), disseminated intravascular coagulation (3 percent), elevated creatinine (3 percent), pneumonia (3 percent), pulmonary edema (3 percent), and diarrhea (3 percent).

Drug Interactions
Published clinical reports or in vitro reports indicate that concomitant use of Artesunate for Injection with oral ritonavir, nevirapine, or UGT inducers may decrease dihydroartemisinin (DHA) AUC and Cmax, which may reduce the efficacy of Artesunate for Injection. If Artesunate for Injection is co-administered with ritonavir, nevirapine or strong UGT inducers (e.g., rifampin, carbamazepine, phenytoin), monitor for possible reduced antimalarial efficacy of Artesunate for Injection.

Published reports of in vitro data indicate that concomitant use of Artesunate for Injection with UGT inhibitors may increase DHA AUC and Cmax, which may increase DHA associated adverse reactions. Monitor for adverse reactions when co-administering Artesunate for Injection with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac).

Use in Specific Populations
Pregnancy: There are serious risks to the mother and fetus associated with untreated severe malaria during pregnancy; delaying treatment of severe malaria in pregnancy may result in serious morbidity and mortality to the mother and fetus. Pregnancy outcomes reported from a prospective surveillance study with intravenous artesunate are insufficient to identify a drug-associated risk of major birth defects, miscarriage, and or fetal death.

Pediatric Use: The safety and effectiveness of Artesunate for Injection for the treatment of severe malaria have been established in pediatric patients.

Geriatric Use: Clinical studies of Artesunate for Injection did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger subjects.

To report SUSPECTED ADVERSE REACTIONS, contact Amivas LLC at [1-855-526-4827 (1-855-5AMIVAS)] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 

About Malaria and Severe Malaria
Malaria is one of the world's leading killers of people, especially children. Severe malaria, a medical emergency, typically includes neurologic symptoms, severe anemia, acute renal injury, acute respiratory distress syndrome, or jaundice, as a large number of the patient's red blood cells become infected by a malaria parasite. Uncomplicated falciparum malaria can progress rapidly to severe forms of the disease, especially in people with no or low immunity, and severe falciparum malaria is almost always fatal without treatment. Prompt, effective treatment within 24-48 hours of the onset of malaria symptoms is necessary. 

Malaria is a rare disease in the US. Therefore, it is not always recognized, diagnosed and treated in timely fashion. Nearly all cases in the US occur in persons who acquire the infection while in a malaria endemic area and who are diagnosed after returning to the US. Most are US residents with no acquired immunity to malaria and who are, therefore, at risk of developing severe malaria. A major contributing factor to continued malaria-associated mortality in the US is delay in initiation of appropriate treatment. Malaria chemoprophylaxis and the use of bed nets and insect repellants help reduce the risk of contracting malaria. 

About Amivas
Amivas is a US joint venture focused on the development, manufacture and commercialization of therapeutic products for the treatment of infectious diseases. Headquartered in Frederick, Maryland, Amivas was formed in 2016 expressly for the purpose of bringing treatments to market for rare and neglected tropical diseases.

Disclaimer: The views expressed in this release are those of the author and do not necessarily represent the views of the US Army or the Department of Defense (DoD). Discussion of specific pharmaceutical products does not reflect an endorsement of those products.

SOURCE Amivas

Posted: May 2020