英文药名：Cyklokapron(Tranexamic Acid) 中文药名：氨甲环酸注射液/片/胶囊 给药说明 氨甲环酸片本品主要用于急性或慢性、局限性或全身性原发性纤维蛋白溶解亢进所致的各种出血。弥散性血管内凝血所致的继发性高纤溶状态，在未肝素化前，慎用本品。氨甲环酸片能直接抑制纤溶酶活力，减少纤溶酶激活补体（C1）的作用，从而达到防止遗传性血管神经性水肿的发生。 分类名称 一级分类：血液系统药物 二级分类：促凝血药 三级分类：   药品英文名 Tranexamic Acid 药品别名 反式对氨甲基环己烷羧酸、抗血纤溶环酸、凝血酸、止血环酸、血速宁、Acid Transamic、AMCHA、Amikapron、Cyklokapron、Trans-AMCA、Trans-AMCHA 药物剂型 1.片剂：0.125g，0.25g； 2.胶囊：0.25g； 3.注射剂：0.1g(2ml)，0.25g(5ml)，0.2g(2ml)，0.5g(5ml)。 药理作用 血循环中存在各种纤溶酶(原)的天然拮抗物，如抗纤溶酶等。正常情况下，血液中抗纤溶活性比纤溶活性高很多倍，所以不致发生纤溶性出血。但这些拮抗物不能阻滞已吸附在纤维蛋白网上的激活物(如尿激酶等)所激活而形成的纤溶酶。纤溶酶是一种肽链内切酶，低剂量时在中性环境中能裂解纤维蛋白(原)的精氨酸和赖氨酸肽链，形成纤维蛋白降解产物，引起凝血块溶解而出血。纤溶酶原通过其分子结构中的赖氨酸结合部位而特异地吸附在纤维蛋白上，赖氨酸则可以竞争性阻抑这种吸附作用，减少纤溶酶原的吸附率，从而减少纤溶酶的激活程度，减少出血。本药的化学结构与赖氨酸(1，5-二氨基己酸)相似，也有止血效应。本药在高剂量时尚能直接抑制纤溶酶活力，减少纤溶酶激活补体(C1)的作用，从而防止遗传性血管神经性水肿的发生。其作用较氨甲苯酸强。有报道称，与氨基己酸(氨己酸)相比，本药在组织中有更强及更持久的抗纤溶酶活性，故其止血作用要强6～10倍。但由于本药可导致局部缺血并发症的发生，因此在治疗蛛网膜下腔出血时倾向于使用氨基己酸。 药动学 本药口服后吸收较慢且不完全，吸收率为30%～50%，半衰期为2h，血药浓度达峰时间在给药后3h。按体重静脉滴注15mg/kg，1h后血药浓度可达20μg/ml；4h后血药浓度为5μg/ml。本药能透过血-脑脊液屏障，脑脊液内药物浓度可达有效药物浓度(1μg/ml)水平，可使脑脊液中纤维蛋白降解产物降低到给药前的50%左右。如按体重10mg/kg或20mg/kg静脉滴注，则血清抗纤溶活力可维持7～8h，组织内可维持17h。口服量的39%或静脉注射量的90%于24h内经肾脏排出。本药经乳汁分泌，其量约为母体血药浓度的1%。 适应证 1.本药主要用于纤维蛋白溶解亢进所致的各种出血。 2.适用于前列腺、尿道、肺、脑、子宫、肾上腺、甲状腺等富有纤溶酶原激活物的脏器外伤或手术出血。3.用作组织型纤溶酶原激活物(t-PA)、链激酶及尿激酶过量致出血的拮抗剂。 4.适用于人工流产、胎盘的过早分离(胎盘早剥)、胎死宫内(死胎)和羊水栓塞引起的纤溶性出血，以及病理性宫腔内局部纤溶性增高的月经过多。 5.中枢神经系统的轻症出血(如蛛网膜下腔出血和颅内动脉瘤出血)，应用本药止血优于其他抗纤溶药，但有并发脑水肿或脑梗死的危险。对重症有手术指征的患者，本药仅作辅助用药。 6.用于治疗遗传性血管神经性水肿，可减少其发作频率，降低其严重程度。 7.血友病患者发生活动性出血，可联合应用本药治疗。 8.用于防止或减轻凝血因子Ⅷ或凝血因子Ⅸ缺乏的血友病患者口腔手术后的出血。 9.治疗溶栓过量所致的严重出血。 禁忌证 (尚不明确) 注意事项 1.有血栓形成倾向者或有血栓栓塞病史者； 2.血友病或肾盂实质病变发生大量血尿时(本药可导致继发肾盂和输尿管凝血块阻塞)慎用。不能与溶栓剂(如苯唑西林、尿激酶)、输注血液同时使用。 3.本药需5%～25%葡萄糖注射剂或0.9%氯化钠注射剂10～20ml稀释后缓慢注射。 4.本药一般不单独用于弥散性血管内凝血所致的继发性纤溶性出血，以防血栓进一步形成，影响脏器功能，特别是引起急性肾衰竭。如有必要，应在肝素化的基础上再应用本药。 5.一般认为在凝血因子使用后8h再用本药较为妥善。 6.宫内死胎所致低纤维蛋白原血症出血，肝素治疗较本药为安全。 7.慢性肾功能不全时本药用量酌减。给药后尿液浓度常较高。治疗前列腺手术出血时，用量也应减少。 8.用药前后及用药时应当检查或监测：持续应用本药较长时间者，应做眼科检查(如视力测验、视觉、视野和眼底)。 不良反应 1.本药不良反应较氨基己酸少，可出现腹泻、恶心及呕吐，较少见的有经期不适(经期血液凝固所致)，偶有药物过量引起颅内血栓形成。 2.因本药可进入脑脊液，注射后可有视力模糊、头痛、头晕、疲乏等中枢神经系统症状，与注射速度有关，但很少见。 用法用量 1.成人常规剂量： (1)口服给药：每次0.25～0.5g，每天0.75～2g； (2)静脉滴注： ①一般用量：每次0.25～0.5g，每天0.25～2g给药，以5%～10%葡萄糖液稀释。 ②防止手术前后出血：可参考上述剂量； ③治疗原发性纤维蛋白溶解所致出血：剂量可酌情加大； (3)静脉注射：每次0.25～0.5g，每天0.25～2g给药，以25%葡萄糖液稀释后缓慢推注。 2.肾功能不全时剂量： (1)轻度肾功能不全者(血清肌酐清除率每分钟为41～60ml)，口服剂量为每次25mg/kg，每天2次；静脉注射剂量为每次10mg/kg，每天2次； (2)中度肾功能不全者(血清肌酐清除率每分钟为21～40ml)，口服剂量为每次25mg/kg，每天1次；静脉注射剂量为每次10mg/kg，每天1次； (3)重度肾功能不全者(血清肌酐清除率每分钟小于10ml)，口服剂量为每次12.5mg/kg，每天1次；静脉注射剂量为每次5mg/kg，每天1次。 药物相应作用 1.口服避孕药、苯唑西林或雌激素与本药合用，有增加血栓形成的危险。2.与其他凝血因子(如因子Ⅸ)等合用，有形成血栓可能。 专家点评 其止血机制与氨基己酸和氨甲苯酸相同，疗效比氨甲苯酸好，对创伤性出血效果尤其显著。维持时间较长。可用于急性、慢性、局限性或全身性纤溶系统亢进所致出血。对于中枢神经系统出血，如蛛网膜下腔和颅内动脉瘤出血，应用本品止血优于其他抗纤溶药。另外，弥散性血管内凝血所致的继发性高纤溶状态，在未肝素化前，慎用本品。 Cyklokapron Generic Name: tranexamic acid Dosage Form: injection, solution Cyklokapron® tranexamic acid injection Antifibrinolytic agent Cyklokapron Description Each mL of the sterile solution for intravenous injection contains 100 mg tranexamic acid and Water for Injection to 1 mL FORMULATION Chemical Name: trans-4-(aminomethyl)cyclohexanecarboxylic acid Structural Formula: Tranexamic acid is a white crystalline powder. The aqueous solution for injection has a pH of 6.5 to 8.0. Cyklokapron - Clinical Pharmacology Tranexamic acid is a competitive inhibitor of plasminogen activation, and at much higher concentrations, a noncompetitive inhibitor of plasmin, i.e., actions similar to aminocaproic acid. Tranexamic acid is about 10 times more potent in vitro than aminocaproic acid. Tranexamic acid binds more strongly than aminocaproic acid to both the strong and weak receptor sites of the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. Tranexamic acid in a concentration of 1 mg per mL does not aggregate platelets in vitro. Tranexamic acid in concentrations up to 10 mg per mL blood has no influence on the platelet count, the coagulation time, or various coagulation factors in whole blood or citrated blood from normal subjects. On the other hand, tranexamic acid in concentrations of 10 mg and 1 mg per mL blood prolongs the thrombin time. The plasma protein binding of tranexamic acid is about 3% at therapeutic plasma levels and seems to be fully accounted for by its binding to plasminogen. Tranexamic acid does not bind to serum albumin. After an intravenous dose of 1 g, the plasma concentration time curve shows a triexponential decay with a half-life of about 2 hours for the terminal elimination phase. The initial volume of distribution is about 9 to 12 liters. Urinary excretion is the main route of elimination via glomerular filtration. Overall renal clearance is equal to overall plasma clearance (110 to 116 mL/min), and more than 95% of the dose is excreted in the urine as unchanged drug. Excretion of tranexamic acid is about 90% at 24 hours after intravenous administration of 10 mg per kg body weight. An antifibrinolytic concentration of tranexamic acid remains in different tissues for about 17 hours, and in the serum, up to seven or eight hours. Tranexamic acid passes through the placenta. The concentration in cord blood after an intravenous injection of 10 mg per kg to pregnant women is about 30 mg per liter, as high as in the maternal blood. Tranexamic acid diffuses rapidly into joint fluid and the synovial membrane. In the joint fluid, the same concentration is obtained as in the serum. The biological half-life of tranexamic acid in the joint fluid is about three hours. The concentration of tranexamic acid in a number of other tissues is lower than in blood. In breast milk, the concentration is about one hundredth of the serum peak concentration. Tranexamic acid concentration in cerebrospinal fluid is about one tenth of that of the plasma. The drug passes into the aqueous humor, the concentration being about one tenth of the plasma concentration. Tranexamic acid has been detected in semen where it inhibits fibrinolytic activity but does not influence sperm migration. Indications and Usage for Cyklokapron Cyklokapron Injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. Contraindications Cyklokapron Injection is contraindicated: In patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see WARNINGS). In patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by Cyklokapron in such patients. In patients with active intravascular clotting. In patients with hypersensitivity to tranexamic acid or any of the ingredients. Warnings Focal areas of retinal degeneration have developed in cats, dogs, and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground, and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment. Precautions General The dose of Cyklokapron Injection should be reduced in patients with renal insufficiency because of the risk of accumulation. (See DOSAGE AND ADMINISTRATION.) Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with Cyklokapron. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with Cyklokapron. In addition, cases of central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. Cyklokapron should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with Cyklokapron, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. Drug Interactions No studies of interactions between Cyklokapron and other drugs have been conducted. Carcinogenesis, Mutagenesis, Impairment of Fertility An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic / neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitro and in vivo test systems. There are no clinical or nonclinical data to assess the effects of tranexamic acid on fertility. Pregnancy (Category B) Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery See above under Pregnancy. Nursing Mothers Tranexamic acid is present in the mother's milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when Cyklokapron is administered to a nursing woman. Pediatric Use The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing Cyklokapron therapy. Geriatric Use Clinical studies of Cyklokapron did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Adverse Reactions Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined. Overdosage Cases of overdosage of Cyklokapron have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; visual impairment; convulsions, mental status changes; myoclonus, and rash. Cyklokapron Dosage and Administration Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of Cyklokapron intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days. Note: For patients with moderate to severe impaired renal function, the following dosages are recommended: Serum Creatinine (µmol/L) Tranexamic Acid I.V. Dosage 120 to 250 (1.36 to 2.83 mg/dL) 10 mg/kg BID 250 to 500 (2.83 to 5.66 mg/dL) 10 mg/kg daily >500 (>5.66 mg/dL) 10 mg/kg every 48 hours or 5 mg/kg every 24 hours For intravenous infusion, Cyklokapron Injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to Cyklokapron Injection. Cyklokapron Injection should NOT be mixed with blood. The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin. How is Cyklokapron Supplied Cyklokapron Injection 100 mg/mL NDC 0013-1114-10 10 × 10 mL ampules STORAGE Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature].