2015年10月16日，美国FDA在加速批准程序下批准Praxbind（idarucizumab），在服用抗凝药物达比加群酯患者遇到紧急情况而需要逆转达比加群酯血液稀释作用时使用。 “达比加群酯的抗凝作用对一些患者来说是重要并拯救生命的，但有些情况下逆转该药物的作用在医疗上是必要的，”FDA药物评价与研究中心血液及肿瘤产品办公室主任、医学博士Pazdur称。“对于出血不能控制的紧急或危及生命的情形，今天的批准为医学界提供了一种重要的工具，用于管理服用达比加群酯的患者。” FDA于2010年批准达比加群酯在房颤患者中用于预防中风及全身性血栓，以及用于深静脉血栓形成及肺栓塞预防。Praxbind是获批特定用于达比加群酯的首款拮抗剂，Praxbind通过与药物成分结合并中和其效果而发挥作用。Praxbind溶液通过静脉注射使用。 Praxbind的安全性有效性基于三项研究，该三项研究总共有283名服用达比加群酯的健康志愿者（如不需抗凝剂的人）参与。在被给予Praxbind的健康志愿者中，受试者血液中达比加群酯的量立迅速下降（以释放的达比加群酯血浆浓度为指标），这种下降能持续至少24小时。在这项研究中，使用Praxbind最常见的副作用是头痛。 关于Praxbind® 临床试验项目 Praxbind® 由勃林格殷格翰的科学家发现并研发。研究项目开始于2009年，即2010年泰毕全® 于美国上市之前。 公司在健康志愿者中完成了3项Praxbind® I期试验，这些数据被提交给美国食品药品监督管理局用于Praxbind® 生物制品许可申请。 勃林格殷格翰将继续在III期全球研究RE-VERSE ADTM 中评估Praxbind® ，此项研究纳入了接受泰毕全® 治疗后发生无法控制的出血或需要紧急手术的患者。这是首个在此类患者中展开的研究，于2014年5月开始，目前正在进行中，在超过35个国家中入选患者。11Praxbind® 的申请材料中还包含 RE-VERSE ADTM 的期中分析数据。 关于Praxbind® Praxbind® 是一种人源性抗体片段（Fab），设计为达比加群酯的特异性逆转剂。10Praxbind® 只与达比加群酯分子特异性结合，可中和其抗凝效应，不会干扰凝血级联。 在美国，Praxbind® 目前适用于接受泰毕全® 治疗后需要逆转达比加群酯抗凝效应的患者： 急诊手术/介入性操作 危及生命或无法控制的出血 其他国家正在进行监管机构审评和申请材料的提交。Praxbind® 是目前唯一正在进行监管机构审评的新型口服抗凝药特异性逆转剂。4勃林格殷格翰计划在达比加群酯获批的所有国家提交idarucizumab的上市申请。 Praxbind® 2.5 g/50 mL Label  NDC: 0597­0197­05 Praxbind® 2.5 g/50 mL Carton NDC: 0597­0197­05 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PRAXBIND safely and effectively. See full prescribing information for PRAXBIND. PRAXBIND ® (idarucizumab) injection, for intravenous use Initial U.S. Approval: 2015 INDICATIONS AND USAGE PRAXBIND is a humanized monoclonal antibody fragment (Fab) 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 (1) 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. (1) DOSAGE AND ADMINISTRATION For intravenous use only. The recommended dose of PRAXBIND is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab. (2.1) There is limited data to support administration of an additional 5 g of PRAXBIND. (2.1) DOSAGE FORMS AND STRENGTHS Injection: 2.5 g/50 mL solution in a single-use vial (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Thromboembolic Risk: Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Resume anticoagulant therapy as soon as medically appropriate. (2.4, 5.1) Re-elevation of Coagulation Parameters: In patients with elevated coagulation parameters and reappearance of clinically relevant bleeding or requiring a second emergency surgery/urgent procedure, an additional 5 g dose of PRAXBIND may be considered. (5.2) Hypersensitivity reactions: Discontinue administration and evaluate. (5.3) Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient: Patients with hereditary fructose intolerance may be at risk of adverse reactions. (5.4) ADVERSE REACTIONS In healthy volunteers, the most frequently reported adverse reactions in greater than or equal to 5% of subjects treated with idarucizumab was headache. (6.1) In patients, the most frequently reported adverse reactions in greater than or equal to 5% of patients treated with idarucizumab were hypokalemia, delirium, constipation, pyrexia, and pneumonia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised: 10/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 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 [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study. 2 DOSAGE AND ADMINISTRATION For intravenous use only. 2.1 Recommended Dose The recommended dose of PRAXBIND is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab (see Figure 1). There is limited data to support administration of an additional 5 g of PRAXBIND [see Warnings and Precautions (5.2)]. 2.2 Preparation Ensure aseptic handling when preparing the infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Once solution has been removed from the vial, administration should begin promptly or within 1 hour. 2.3 Administration Do not mix with other medicinal products. Use aseptic technique when administering PRAXBIND. Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g) as Two consecutive infusions (see Figure 2) or Bolus injection by injecting both vials consecutively one after another via syringe (see Figure 3). A pre-existing intravenous line may be used for administration of PRAXBIND. The line must be flushed with sterile 0.9% Sodium Chloride Injection, USP solution prior to infusion. No other infusion should be administered in parallel via the same intravenous access. PRAXBIND treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate [see Clinical Pharmacology (12.2)]. 2.4 Restarting Antithrombotic Therapy Patients being treated with dabigatran therapy have underlying disease states that predispose 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. Idarucizumab is a specific reversal agent for dabigatran, with no impact on the effect of other anticoagulant or antithrombotic therapies. Pradaxa treatment can be initiated 24 hours after administration of PRAXBIND [see Clinical Pharmacology (12.2)].  3 DOSAGE FORMS AND STRENGTHS PRAXBIND is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution available as: Injection: 2.5 g/50 mL solution in a single-use vial. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Risk Patients being treated with dabigatran therapy have underlying disease states that predispose 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 [see Dosage and Administration (2.4)]. 5.2 Re-elevation of Coagulation Parameters In a limited number of patients in the clinical program, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT)) have been observed [see Dosage and Administration (2.1)]. If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed after administration of 5 g PRAXBIND, administration of an additional 5 g dose of PRAXBIND may be considered. Similarly, patients who require a second emergency surgery/urgent procedure and have elevated coagulation parameters may receive an additional 5 g dose of PRAXBIND. The safety and effectiveness of repeat treatment with PRAXBIND have not been established [see Clinical Pharmacology (12.2)]. 5.3 Hypersensitivity Reactions There is insufficient clinical experience with PRAXBIND in patients to evaluate risk of hypersensitivity to idarucizumab. In clinical studies adverse events possibly indicative of hypersensitivity reactions where a possible relationship could not be excluded were reported [see Adverse Reactions (6.1)]. The risk of using PRAXBIND in patients with known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefit of such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs, immediately discontinue administration of PRAXBIND and institute appropriate treatment. 5.4 Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient In patients with the condition of hereditary fructose intolerance who have received parenteral administration of sorbitol, serious adverse reactions, including fatal reactions, have been reported. Reactions have included hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function. The recommended dose of PRAXBIND contains 4 g sorbitol as an excipient. When prescribing PRAXBIND to patients with hereditary fructose intolerance consider the combined daily metabolic load of sorbitol/fructose from all sources, including PRAXBIND and other drugs containing sorbitol. The minimum amount of sorbitol at which serious adverse reactions may occur in these patients is not known. 6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail elsewhere in the labeling: Thromboembolic Risk [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience 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 clinical practice. Three clinical trials in healthy volunteers have been completed, in which 224 subjects were treated with idarucizumab. In these trials during the treatment period the overall frequency of adverse events was similar between idarucizumab-treated subjects (55/224, 25%) and placebo-treated subjects (26/105, 25%). Among those subjects treated with idarucizumab, adverse reactions reported in greater than or equal to 5% of subjects was headache (12/224, 5%). In the interim analysis of the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 123 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding [see Clinical Studies (14)]. Adverse reactions reported in greater than or equal to 5% of patients were: hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%), pneumonia (7/123, 6%). Of the total, 26 patients died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities. Thromboembolic Events In the interim analysis of the RE-VERSE AD trial, 5 of 123 patients reported thrombotic events, 1 patient 2 days after treatment with idarucizumab and 4 patients 7 days or more after treatment with idarucizumab. None of these patients were on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient [see Warnings and Precautions (5.1)]. Hypersensitivity Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab [see Warnings and Precautions (5.3)]. 6.2 Immunogenicity As with all proteins there is a potential for immunogenicity with idarucizumab. Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) were tested for antibodies cross-reacting with idarucizumab. Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 13% (36/283) of the subjects. The majority of pre-existing antibodies were shown to have low titers. No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed in these subjects. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (9/224) of the subjects treated with idarucizumab. The epitope specificity of antibodies to idarucizumab was characterized using probe molecules. For pre-existing antibodies, 97% (35/36) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind. For treatment emergent possibly persisting antibodies, 56% (5/9) had specificity for the C-terminus, 22% (2/9) had specificity for the variable region, 11% (1/9) had mixed specificity and 11% (1/9) was indeterminate. Detection of antibody formation is dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to idarucizumab with the incidence of antibodies to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of PRAXBIND in pregnant women to inform on associated risks. Animal reproductive and development studies have not been conducted with idarucizumab. It is also not known whether PRAXBIND can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PRAXBIND should be given to a pregnant woman only if clearly needed. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Labor or Delivery PRAXBIND has not been studied for use during labor and delivery. Safety and effectiveness of PRAXBIND during labor and delivery have not been studied in clinical trials. 8.2 Lactation Risk Summary There are no data on the effects of PRAXBIND on the breastfed child or on milk production. It is not known whether idarucizumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRAXBIND is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRAXBIND and any potential adverse effects on the breastfed child from PRAXBIND or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use A total of 111 (90%) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Renal impairment did not impact the reversal effect of idarucizumab [see Clinical Pharmacology (12.3)]. No dose adjustment is required in renally impaired patients. 8.7 Hepatic ImpairmentNo formal studies of PRAXBIND in patients with hepatic impairment have been conducted. No formal studies of PRAXBIND in patients with hepatic impairment have been conducted. 11 DESCRIPTION Idarucizumab is a humanized monoclonal antibody fragment (Fab) derived from an IgG1 isotype molecule, whose target is the direct thrombin inhibitor dabigatran. Using recombinant expression technology, idarucizumab is produced in a well characterized recombinant (mammalian) CHO cell line and is purified using standard technology. Idarucizumab is composed of a light chain of 219 amino acids and a heavy chain fragment of 225 amino acids, covalently linked together by one disulfide bond between cysteine 225 of the heavy chain fragment and cysteine 219 of the light chain, and has an estimated molecular mass of approximately 47,766 Daltons. PRAXBIND (idarucizumab) is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for intravenous administration. PRAXBIND (idarucizumab) is supplied in 2 single-use vials, each containing 2.5 g of idarucizumab in 50 mL formulated as a buffered, isotonic, solution containing acetic acid glacial (10.05 mg), polysorbate 20 (10 mg), sodium acetate trihydrate (147.35 mg), sorbitol (2004.20 mg), and water for injection with an osmolality of 270-330 mOsm/kg and a pH of 5.3-5.7. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect. 12.2 Pharmacodynamics In healthy subjects aged 45 to 64 years, the plasma concentrations of unbound dabigatran were reduced to below the lower limit of quantification immediately after the administration of 5 g idarucizumab. Subjects’ diluted thrombin time (dTT), ECT, aPTT, thrombin time (TT), and activated clotting time (ACT) parameters returned to baseline levels (see Figure 4 and Figure 5). This reduction of dabigatran plasma concentration was observed over the entire observation period of at least 24 hours. Similar findings were also observed in elderly subjects (aged 65 to 80 years) as well as subjects with mild and moderate renal impairment [see Clinical Pharmacology (12.3)]. In a limited number of patients, re-distribution of dabigatran from the periphery to plasma led to re-elevation of dTT, ECT, aPTT, and TT [see Warnings and Precautions (5.2)]. Re-dosing with 2.5 g idarucizumab in 6 healthy subjects aged 45-64 years at 2 months after first infusion revealed no differences in safety and no indication of allergic reactions [see Clinical Pharmacology (12.3)]. No changes in the pharmacokinetics or pharmacodynamics of dabigatran were noted upon re-initiation 24 hours after the administration of idarucizumab [see Dosage and Administration (2.4)]. Thrombin Generation Parameters Idarucizumab alone has shown no procoagulant effect measured as endogenous thrombin potential (ETP). Cardiac Electrophysiology Clinical trials with idarucizumab in healthy subjects measured heart rate and electrocardiogram (ECG) parameters (waveform morphology, P wave duration, and PR, QRS, QT, and QTc intervals). There were no clinically relevant abnormal findings related to ECG. Drug Interactions In vitro Assessment of Drug Interactions In vitro data suggest that the inhibition of dabigatran by idarucizumab is not affected by coagulation factor concentrates [3- or 4-factor prothrombin complex concentrates (PCCs), activated PCC, or recombinant Factor VIIa]. Assessment of Drug Interactions in Animal Studies The potential effect of the binding of idarucizumab to dabigatran in the presence of volume replacement agents (e.g., crystalloids, colloids, and retransfusion of washed red blood cells) was investigated in swine. The results of this study suggest that neutralization of dabigatran anticoagulant activity is not influenced by 50% hemodilution with routinely used volume replacement strategies. 12.3 Pharmacokinetics There were no obvious differences in the idarucizumab plasma concentration time profiles when idarucizumab was administered alone or after pretreatment with dabigatran. A dose-dependent increase in the fraction of unchanged idarucizumab excreted in urine was observed. Distribution Idarucizumab exhibited multiphasic disposition kinetics and limited extravascular distribution. Following the intravenous infusion of a 5 g dose, the geometric mean volume of distribution at steady state (Vss) was 8.9 L (geometric coefficient of variation (gCV 24.8%)). Elimination Idarucizumab was rapidly eliminated with a total clearance of 47.0 mL/min (gCV 18.4%), an initial half-life of 47 minutes (gCV 11.4%), and a terminal half-life of 10.3 h (gCV 18.9%). After intravenous administration of 5 g idarucizumab, 32.1% (gCV 60.0%) of the dose was recovered in urine within a collection period of 6 hours and less than 1% in the following 18 hours. The remaining part of the dose is assumed to be eliminated via protein catabolism, mainly in the kidney. Metabolism Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve biodegradation of the antibody to smaller molecules, i.e., small peptides or amino acids which are then reabsorbed and incorporated in the general protein synthesis. Specific Populations Age, Sex, Race and Body Weight Age, sex, race (Caucasian vs Asian) and body weight had no clinically important effect on systemic exposure of idarucizumab based on population pharmacokinetic analyses in a healthy volunteer cohort of 201 males and 19 females. Renal Impairment Idarucizumab has been studied in 12 subjects with mild renal impairment (creatinine clearance ≥60 to <90 mL/min, by Cockcroft-Gault equation) and 6 subjects with moderate impairment (creatinine clearance ≥30 to <60 mL/min). Compared to healthy subjects, the total clearance was reduced, leading to an increase in idarucizumab’s area under the curve (AUC) by 43.5% and 83.5% in mild and moderate renal impairment, respectively [see Use in Specific Populations (8.6)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or genotoxicity studies have been conducted with idarucizumab. No animal studies have been performed to evaluate the potential effects of idarucizumab on fertility in males or females or on reproduction and development. 14 CLINICAL STUDIES The safety and effectiveness of PRAXBIND has been investigated in pharmacokinetic/pharmacodynamic trials with healthy volunteers and in an ongoing single cohort case series trial with dabigatran-treated patients who have life-threatening or uncontrolled bleeding, or who require emergency surgery or urgent procedure (RE-VERSE AD). Healthy Volunteers Three randomized, placebo-controlled trials in a total of 283 subjects assessed the safety, dose-response, and effect of idarucizumab on reducing unbound dabigatran and coagulation parameters. Of the 283 subjects, 224 received at least one dose of idarucizumab. These trials included 19 females and 30 subjects aged 65 years or older (median age 36 years). The tables below summarize the idarucizumab effect on coagulation parameters dTT, aPTT, ECT, TT, and ACT over time for 14 subjects treated in one of the healthy volunteer trials. Fourteen subjects received dabigatran 220 mg orally twice daily for three days and an additional single 220 mg dose of dabigatran on day four, two hours before receiving idarucizumab. Idarucizumab was administered as one 5 g intravenous infusion over five minutes. Table 1 shows the results of the idarucizumab treatment group and Table 2 shows the results of the placebo treatment group. Table 1 Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects Treated with 5 g Idarucizumab  Clotting Assay (Mean and Standard Deviation) Pre-Idarucizumab (N=14) End of infusion of Idarucizumab (N=14) 24 hours after Idarucizumab (N=14) dTT [s] 66.6 (12.0) 32.1 (1.38) 33.0 (1.69) aPTT [s] 67.8 (14.5) 29.2 (4.74) 31.9 (5.71) ECT [s] 122 (42.2) 34.7 (1.92) 38.8 (2.86) TT [s] 127 (62.6) 12.5 (0.786) 19.3 (5.14) ACT [s] 236 (47.6) 116 (7.71) 140 (10.1) Table 2 Change in Coagulation Parameters in 14 Dabigatran-exposed Subjects Treated with Placebo Clotting Assay (Mean and Standard Deviation) Pre-Placebo (N=14) End of infusion of Placebo (N=14) 24 hours after Placebo (N=14) dTT [s] 64.7 (9.82) 65.3 (12.1) 36.1 (2.48) aPTT [s] 65.2 (14.0) 66.5 (13.2) 37.0 (7.10) ECT [s] 117 (29.8) 122 (32.9) 44.7 (5.39) TT [s] 132 (35.4) 147 (46.7) 39.5 (11.8) ACT [s] 219 (44.7) 216 (50.5) 148 (15.1) The effect of idarucizumab on reducing unbound dabigatran in healthy volunteers is summarized in section 12.2, Pharmacodynamics. RE-VERSE AD Patient Experience In an ongoing single cohort case series trial, 5 g idarucizumab was administered to patients treated with dabigatran who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint was the maximum percentage reversal of the pharmacodynamic anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT. An interim analysis of the ongoing single cohort case series trial included data for 123 patients: 66 patients with serious bleeding (Group A) and 57 requiring an urgent procedure (Group B). Approximately half of the patients in each group were male. The median age was 77 years and the median creatinine clearance was 55 mL/min. Approximately 67% of patients in Group A and 63% of patients in Group B had been treated with dabigatran 110 mg BID. Results of central laboratory evaluations were available for a subset of 90 patients (51 in Group A, 39 in Group B). Among the 90 patients with available data, the median maximum reversal of the pharmacodynamic anticoagulant effect of dabigatran as measured by ECT or dTT in the first 4 hours after administration of 5 g idarucizumab was 100%, with most patients (>89%) achieving complete reversal. Reversal of the pharmacodynamics effects was evident immediately after administration. Results for Groups A and B were similar. In a limited number of patients, between 12 and 24 hours after administration of 5 g idarucizumab, elevated coagulation parameters (e.g., aPTT or ECT) have been observed. ECT measures over the 24-hour observation time are shown in Figure 6. Activated partial thromboplastin time (aPTT) showed similar results to ECT (see Figure 7). 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PRAXBIND is a sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution supplied as 2 single-use vials each containing 2.5 g/50 mL of idarucizumab. NDC number 0597-0197-05: Carton containing two 2.5 g/50 mL vials. 16.2 Storage and Handling Store PRAXBIND vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Do not shake. Prior to use, the unopened vial may be kept at room temperature 25°C (77°F) for up to 48 hours, if stored in the original package in order to protect from light, or up to 6 hours when exposed to light. 17 PATIENT COUNSELING INFORMATION Thromboembolic Risk Inform patients that reversing dabigatran therapy exposes them to the thromboembolic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as the patient is sufficiently stable [see Warnings and Precautions (5.1)]. Recurrence of Bleeding Inform patients to get immediate medical attention for any signs or symptoms of bleeding [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions Inform patients of signs and symptoms of allergic hypersensitivity reactions such as anaphylactoid reactions that may be experienced during or after injection of PRAXBIND [see Warnings and Precautions (5.3)]. Risk of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient Inform patients with hereditary fructose intolerance (HFI) that PRAXBIND contains sorbitol. Parenteral administration of sorbitol in patients who have HFI has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death and may occur during or after injection of PRAXBIND [see Warnings and Precautions (5.4)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7400f8a-dcf4-a6df-6d07-983081b1bf34