2015年10月16日，美国食品和药品监管局(FDA)授权加快批准Praxbind (idarucizumab)为正在用抗凝剂Pradaxa(达比加群[dabigatran])患者使用在紧急情况期间当需要逆转Pradaxa的血液稀释效应[blood-thinning effects]时。 FDA药品评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“Pradaxa的抗凝剂作用对有些患者是重要和挽救生命，但其中也有情况逆转药物作用是医疗上必要的，” “今天的批准为医学社会提供一个重要工具为在紧急或危及生命情况当出血不能控制时处理用Pradaxa。” 2010年FDA批准Pradaxa在有心房颤动患者中预防卒中和全身血凝，以及为深静脉血栓形成和肺栓塞治疗和预防。Praxbind是特异性地为Pradaxa批准的第一个逆转剂和通过结合至药物中和其效应作用。Praxbind溶液是为静脉注射。 在三项试验涉及共计283例健康志愿者用Pradaxa研究Praxbind的安全性和有效性(即，不需要抗凝剂人们)。在给予Praxbind健康志愿者，参加者的血液Pradaxat 量立即减低(测定非结合达比加群血浆浓度)持续共至少24小时阶段。在这项研究中，来自使用Praxbind最常见副作用是头痛。 另外试验包括123例用Pradaxa患者由于不能控制出血或因为需要紧急手术接受Praxbind。在这项正在进行试验中，根据实验室测试，在接受Praxbind四小时内89%患者中Pradaxa的抗凝剂效应被晚期逆转。在这项患者试验，最常见副作用是低钾，混乱，便秘，发热和肺炎。 Pradaxa逆转效应暴露患者来自所患疾病血栓和卒中的风险(例如心房颤动)。Praxbind说明书建议患者医疗适当时立即恢复他们的抗凝剂治疗，如他们的卫生保健提供者确定。 Praxbind是在FDA的加快批准程序下被批准，这个程序允许监管局批准对严重情况对替代指标或一个间接的临床终点的影响合理地预测对患者临床获益满足一个为满足的医疗需求。程序被设计提供患者较早得到鼓舞人有前途新药，但公司将被要求在批准后验证药物的临床获益提交另外临床信息。 Praxbind和Pradaxa都是由总部在Connecticut州Ridgefield的Boehringer Ingelheim上市。 FDA Approves Praxbind® (idarucizumab), Specific Reversal Agent for Pradaxa® (dabigatran etexilate mesylate) About Praxbind® (idarucizumab) IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Thromboembolic Risk •Dabigatran-treated patients have underlying diseases predisposing them to thromboembolic events.  Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease.  To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate. Re-elevation of Coagulation Parameters •Elevated coagulation parameters (e.g., activated partial thromboplastin time or ecarin clotting time) have been observed in a limited number of PRAXBIND-treated patients.  If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed or if patients requiring a second emergency surgery/urgent procedure have elevated coagulation parameters, an additional full dose may be considered. Hypersensitivity Reactions •There is insufficient clinical experience evaluating risk of hypersensitivity to idarucizumab, but a possible relationship could not be excluded.  Risk of hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or excipients needs to be weighed cautiously against the potential benefit.  If serious allergic reaction occurs, immediately discontinue PRAXBIND and institute appropriate treatment. Risk in Patients with Hereditary Fructose Intolerance •PRAXBIND contains 4 g sorbitol as an excipient.  When prescribing PRAXBIND in patients with hereditary fructose intolerance consider the total daily amount of sorbitol/fructose consumption from all sources as serious adverse reactions (e.g. hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure and death) may occur.  ADVERSE REACTIONS •The most frequently reported adverse reaction in ≥5% of idarucizumab-treated healthy volunteers was headache (12/224).   The most frequently reported adverse reactions in ≥5% of patients were hypokalemia (9/123), delirium (9/123), constipation (8/123), pyrexia (7/123) and pneumonia (7/123).  •As with all proteins there is a potential for immunogenicity with idarucizumab.  In treated patients, treatment-emergent antibodies with low titers were observed (9/224). USE IN SPECIFIC POPULATIONS Pregnancy and Nursing Mothers •PRAXBIND should be given to a pregnant or nursing woman only if clearly needed. INDICATIONS AND USAGE PRAXBIND is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed: •For emergency surgery/urgent procedures •In life-threatening or uncontrolled bleeding This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers.  Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study. New Drugs Online Report for idarucizumab Information Generic Name: idarucizumab   Trade Name: Praxbind  Synonym: BI 655075  Entry Type: New molecular entity   Development and Regulatory status UK: Recommended for approval (Positive opinion)  EU: Recommended for approval (Positive opinion)  US: Pre-registration (Filed)  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Sep 15: EU positive opinion for use as a specific reversal agent for dabigatran and is indicated in adults treated with Pradaxa (dabigatran etexilate) when rapid reversal of its anticoagulant effects is required: For emergency surgery/urgent procedures; and in life-threatening or uncontrolled bleeding. It is proposed that Praxbind be restricted to hospital use only [12]. 25/09/2015 12:54:18  Apr 15: FDA grants priority review for idarucizumab. Idarucizumab will be reviewed under the FDA´s Accelerated Approval process [7].  24/04/2015 08:47:29  Mar 15: Boehringer Ingelheim files idarucizumab for approval in the US, EU and Canada for use in patients requiring an antidote to dabigatran. The submissions also include first interim data from the ongoing PIII RE-VERSE ADTM study, assessing idarucizumab in patients treated with dabagatran who are in need of emergency intervention, or experience an uncontrolled or life-threatening bleeding event [6]. 04/03/2015 11:28:04  Jun 14: US FDA grants breakthrough therapy designation to idarucizumab [2]. 27/06/2014 11:51:39  Trial or other data It is the first NOAC reversal agent to be reviewed. Currently, no NOACs have an approved reversal agent [7]. An editorial Published in the NEJM, discusses the potential place in therapy of the targeted anti-anticoagulants" [11].  28/09/2015 14:41:35 Jun 15: Boehringer Ingelheim announced positive results from PIII RE-VERSE AD (NCT02104947) clinical trial. The study shows that 5g of idarucizumab almost immediately reversed the anticoagulant effect of dabigatran in pts who needed it under emergency situations. Study results were also published in The New England Journal of Medicine and authors concluded that “Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.” The study was designed to look at different pts and real-world emergency situations. This interim analysis included 90 pts who received idarucizumab (51 patients in group A and 39 in group B). Pts in gp A had uncontrolled or life-threatening bleeding complications (e.g. intracranial haemorrhage or severe trauma) and pts in gp B needed emergency surgery or an invasive procedure. Based on laboratory analysis of dilute thrombin time, the median maximum % reversal of the anticoagulant effect within 4 hours was 100% (95% confidence interval, 100 to 100). One thrombotic event occurred within 72hrs after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated [9,10]. 23/06/2015 09:53:23 Jun 15: Results of PI trial NCT01688830 published in The Lancet [8]. 19/06/2015 15:34:23 Dec 14: PI data reported showing administration of idarucizumab in healthy volunteers who were middle-aged (45 to 64 years) or elderly (65 to 80 years), or volunteers with mild or moderate kidney impairment (n=46) resulted in immediate, complete and sustained reversal of the anticoagulation effects of dabigatran. Anticoagulation was restored when volunteers were re-dosed with dabigatran 24 hours after idarucizumab was administered [5]. 15/12/2014 10:55:37 Nov 14: New data on idarucizumab show it can reverse the effect of dabigatran etexilate on both blood coagulation and the blood clotting mechanism in a PI study in 35 healthy volunteers [4]. 20/11/2014 11:41:06 Apr 14: NCT02104947 is a PIII case series study of the reversal of the anticoagulant effects of dabigatran over 4 hours by 5g idarucizumab IV in 250 patients treated with dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures. The study starts Apr 14 and is due to complete Jul17 [1] 15/04/2014 10:34:38 Evidence Based Evaluations NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/idarucizumab-for-the-reversal-of-anticoagulation-d/  References   Available only to registered users  Category BNF Category: Anticoagulants and protamine (02.08) Pharmacology: Fully humanised monoclonal antibody fragment which has a highly specific binding affinity with dabigatran therefore reversing any anticoagulant activity of dabigatran and its metabolites.   Epidemiology: Across several trials assessing the use of dabigatran against enoxaparin, warfarin or placebo for various indications in relation to venous thromboembolism, the percentage of patients experiencing any bleeding event ranged from 10.5% to 19.4% and included minor bleeding events in the range of 13.2% to 14.9% and major bleeding events in the range 0.3% to 3.3% [3].   Indication: Anticoagulation reversal  Additional Details: in patients taking dabigatran – required for life-threatening or uncontrolled haemorrhage, or emergency surgery/procedures; first line. Method(s) of Administration   Intravenous  Company Information Name: Boehringer Ingelheim  US Name: Boehringer Ingelheim  Further Information Anticipated commissioning route (England) CCG  High cost drug list? Awaiting Update Tariff Likely HRG included Implications Available only to registered users