英文药名：PRADAXA(dabigatran etexilate mesylate) 中文药名：甲磺酸达比加群酯 生产厂家：Boehringer Ingelheim 药品说明 2013年8月29日,勃林格殷格翰（Boehringer Ingelheim）8月28日宣布，FDA已接受审查Pradaxa（dabigatran，达比加群酯）用于深静脉血栓（DVT）和肺栓塞（PE）患者治疗的补充新药申请（sNDA）。 深静脉血栓（DVT）和肺栓塞（PE）统称为静脉血栓栓塞（VTE），是继冠状动脉疾病、中风之后的第3种最常见心血管疾病。在美国，每年约有90万例VTE事件，其中约1/3患者死于PE。此外，大约有1/3的VTE患者会在10年内复发。目前，急性VTE患者的标准护理是抗凝治疗。 Pradaxa补充新药申请的提交，是基于4项全球性III期临床研究（RE-COVER I,RE-COVER II,RE-MEDY,RE-SONATE），评价了Pradaxa治疗VTE的疗效和安全性。 目前，Pradaxa已获FDA批准，用于非瓣膜性心房颤动（NVAF）患者减少中风和全身性栓塞风险，该药是过去50多年来，获FDA批准用于该适应症的首个口服抗凝血剂。 关于Pradaxa （dabigatran，达比加群酯） 达比加群酯（Dabigatran）是德国勃林格殷格翰公司开发的新型抗凝血药物。该药于2008年4月首先在德国和英国上市，商品名为Pradaxa。这是继华法林之后50年来首个上市的抗凝血口服新药，是抗凝血治疗领域和潜在致死性血栓预防领域的又一个里程碑。 达比加群酯具有口服、强效、无需特殊用药监测、药物相互作用少等特点。体外、体内试验和临床各项研究均提示本品具有良好的疗效及药动学特性，临床应用前景乐观，对预防深静脉血栓和肺动脉栓塞有较好的作用。其成功上市是抗凝血药物研究领域的一项重大突破。 2008年，欧洲和加拿大已批准达比加群酯用于防治急性静脉血栓（VTE）。目前，达比加群酯适应证还包括关节置换术后血栓形成的预防及房颤患者预防中风。全球每年约300万人罹患房颤相关性卒中，这一情况日趋严重，并且患者的致残率明显上升，其中约半数患者在一年内死亡。研究表明，达比加群酯不但可以提供良好的卒中预防作用，而且出血风险较少并且无需常规监测。 Pradaxa的竞争对手包括拜耳和强生公司的拜瑞妥（Xarelto）及施贵宝公司和辉瑞公司的Eliquis。 PRADAXA®(甲磺酸达比加群酯,dabigatran etexilate mesylate)胶囊为口服药 适应证和用途 PRADAXA是一种直接凝血酶抑制剂适用于有非瓣膜性心房颤动患者中减低中风和全身栓塞的风险 剂量和给药方法 （1）对有CrCl>30 mL/min患者：150mg口服，每天2次 （2）对有CrCl 15-30 mL/min患者：75mg口服，每天2次 （3）指导患者不要咀嚼，弄碎，或打开胶囊 （4）复习对转换至或从其它口服或非肠道抗凝剂的建议 （5）当可能时在损伤性或手术操作前暂时停止PRADAXA，然后立即在开始 剂型和规格 胶囊：75mg和150mg 禁忌证 （1）活动病理性出血 （2）对PRADAXA严重超敏性反应史 警告和注意事项 出血的风险：PRADAXA可能引起严重和，有时，致命出血。及时评价失血的征象和症状暂时停止：避免治疗中过失以缩小中风的风险 P-gp诱导剂和抑制剂：避免利福平[rifampin]与PRADAXA同时给药因为对达比加群暴露的影响 不良反应 最常见不良反应(>15%)是胃炎-样症状和出血 在特殊人群中的使用 老年人使用：出血的风险随年龄增加 Pradaxa 110 mg hard capsules 1. Name of the medicinal product Pradaxa 110 mg hard capsules 2. Qualitative and quantitative composition Each hard capsule contains 110 mg of dabigatran etexilate (as mesilate). Excipient(s) with known effect: Each hard capsule contains 3 micrograms of sunset yellow (E110). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Hard capsule Capsules with light blue, opaque cap and cream-coloured, opaque body of size 1 filled with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with “R110”. 4. Clinical particulars 4.1 Therapeutic indications Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age ≥ 75 years; heart failure (NYHA Class ≥ II); diabetes mellitus; hypertension. 4.2 Posology and method of administration Posology Prevention of Venous Thromboembolism (VTE) Patients following elective knee replacement surgery The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1-4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days. Patients following elective hip replacement surgery The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1-4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days. For the following groups the recommended daily dose of Pradaxa is 150 mg taken once daily as 2 capsules of 75 mg: • Patients with moderate renal impairment (creatinine clearance (CrCL) 30-50 mL/min) [see Renal impairment (prevention of VTE)] • Patients who receive concomitant verapamil, amiodarone, quinidine [see Concomitant use of Pradaxa with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil (prevention of VTE)] • Patients aged 75 or above [see Elderly (prevention of VTE)] For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily. Assessment of renal function (prevention of VTE): In all patients: • Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2). Pradaxa is contraindicated in patients with severe renal impairment • Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products) The method used to estimate renal function (CrCL in mL/min) during the clinical development of Pradaxa was the Cockgroft-Gault method.The formula is as follows: This method is recommended when assessing patients' CrCL prior to and during Pradaxa treatment. Special populations Renal impairment (prevention of VTE) Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see section 4.3). In patients with moderate renal impairment (CrCL 30-50 mL/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1). Concomitant use of Pradaxa with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil (prevention of VTE) Dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa in patients who receive concomitantly dabigatran etexilate and amiodarone, quinidine or verapamil (see sections 4.4 and 4.5). In this situation Pradaxa and these medicinal products should be taken at the same time. In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5). Elderly (prevention of VTE) In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1). As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the CrCL prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min). While on treatment the renal function should also be assessed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc) (see sections 4.3, 4.4 and 5.2). Hepatic impairment (prevention of VTE) Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3). Weight (prevention of VTE) There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4). Gender (prevention of VTE) Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2). Switching (prevention of VTE) Pradaxa treatment to parenteral anticoagulant It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral anticoagulant (see section 4.5). Parenteral anticoagulants to Pradaxa Discontinue the parenteral anticoagulant and start dabigatran etexilate 0 2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5). Paediatric population (prevention of VTE) There is no relevant use of Pradaxa in the paediatric population in the indication: primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Missed dose (prevention of VTE) It is recommended to continue with the remaining daily doses of dabigatran etexilate at the same time of the next day. No double dose should be taken to make up for missed individual doses. Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors (SPAF) The recommended daily dose of Pradaxa is 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term. For the following two groups the recommended daily dose of Pradaxa is 220 mg taken as one 110 mg capsule twice daily: • Patients aged 80 years or above • Patients who receive concomitant verapamil For the following groups, the daily dose of Pradaxa of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and the risk of bleeding: • Patients between 75-80 years • Patients with moderate renal impairment • Patients with gastritis, esophagitis or gastroesophageal reflux • Other patients at increased risk of bleeding See further down and sections 4.4, 4.5, 5.1 and 5.2. In case of intolerability to dabigatran, patients should be instructed to immediately consult their treating physician in order to be switched to alternate acceptable treatment options for prevention of stroke and SEE associated with atrial fibrillation. Elderly (SPAF) Patients between 75-80 years should be treated with a daily dose of 300 mg taken as one 150 mg capsule twice daily. A dose of 220 mg taken as one 110 mg capsule twice daily can be individually considered, at the discretion of the physician, when the thromboembolic risk is low and the bleeding risk is high (see section 4.4). Patients aged 80 years or above should be treated with a daily dose of 220 mg taken as one 110 mg capsule twice daily due to the increased risk of bleeding in this population. As renal impairment may be frequent in the elderly (>75 years), renal function should be assessed by calculating the CrCL prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min ). The renal function should also be assessed at least once a year in patients treated with Pradaxa or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (such as hypovolemia, dehydration, and with certain comedications, etc) (see sections 4.3, 4.4 and 5.2). Patients at risk of bleeding (SPAF) Patients with an increased bleeding risk (see sections 4.4, 4.5, 5.1 and 5.2) should be closely monitored clinically (looking for signs of bleeding or anaemia). Dose adjustment should be decided at the discretion of the physician, following assessment of the potential benefit and risk to an individual patient. A coagulation test (see section 4.4) may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure. When excessive dabigatran exposure is identified in patients at high risk of bleeding, a dose of 220 mg taken as one 110 mg capsule twice daily is recommended. When clinically relevant bleeding occurs, treatment should be interrupted. For subjects with gastritis, esophagitis, or gastroesophageal reflux, the dose of 220 mg taken as one 110 mg capsule twice daily may be considered due to the elevated risk of major gastro-intestinal bleeding (see section 4.4). Assessment of renal function (SPAF): In all patients: • Renal function should be assessed by calculating the creatinine clearance (CrCL) prior to initiation of treatment with Pradaxa to exclude patients with severe renal impairment (i.e. CrCL < 30 mL/min) (see sections 4.3, 4.4 and 5.2). Pradaxa is contraindicated in patients with severe renal impairment • Renal function should also be assessed when a decline in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products) Additional requirements in patients with mild to moderate renal impairment and in patients aged over 75 years: • Renal function should be assessed during treatment with Pradaxa at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products) The method used to estimate renal function (CrCL in mL/min) during the clinical development of Pradaxa was the Cockgroft-Gault method. The formula is as follows: This method is recommended when assessing patients' CrCL prior to and during Pradaxa treatment. Renal impairment (SPAF) Treatment with Pradaxa in patients with severe renal impairment (CrCL < 30 mL/min) is contraindicated (see section 4.3). No dose adjustment is necessary in patients with mild renal impairment (CrCL 50- ≤ 80 mL/min). For patients with moderate renal impairment (CrCL 30-50 mL/min) the recommended dose of Pradaxa is also 300 mg taken as one 150 mg capsule twice daily. However, for patients with high risk of bleeding, a dose reduction of Pradaxa to 220 mg taken as one 110 mg capsule twice daily should be considered (see sections 4.4 and 5.2). Close clinical surveillance is recommended in patients with renal impairment. Concomitant use of Pradaxa with mild to moderate P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil (SPAF) No dose adjustment is necessary for concomitant use of amiodarone or quinidine (see sections 4.4, 4.5 and 5.2). Dosing should be reduced to 220 mg taken as one 110 mg capsule twice daily in patients who receive concomitantly dabigatran etexilate and verapamil (see sections 4.4 and 4.5). In this situation Pradaxa and verapamil should be taken at the same time. Weight (SPAF) Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2), but close clinical surveillance is recommended in patients with a body weight < 50 kg (see section 4.4). Gender (SPAF) Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2). Hepatic impairment (SPAF) Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2). Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3). Switching (SPAF) Pradaxa treatment to parenteral anticoagulant It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant (see section 4.5). Parenteral anticoagulants to Pradaxa Discontinue the parenteral anticoagulant and start dabigatran etexilate 0 2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5). Pradaxa treatment to Vitamin K antagonists (VKA) Adjust the starting time of the VKA based on CrCL as follows: • CrCL ≥ 50 mL/min, start VKA 3 days before discontinuing dabigatran etexilate • CrCL ≥ 30-< 50 mL/min, start VKA 2 days before discontinuing dabigatran etexilate Because Pradaxa can contribute to an elevated INR, INR testing should not be performed until Pradaxa has been stopped for at least 2 days. VKA to Pradaxa The VKA should be stopped. Dabigatran etexilate can be given as soon as the International Normalized Ratio (INR) is < 2.0. Cardioversion (SPAF) Patients can stay on dabigatran etexilate while being cardioverted. Paediatric population (SPAF) There is no relevant use of Pradaxa in the paediatric population in the indication: prevention of stroke and systemic embolism in patients with NVAF. Missed dose (SPAF) A forgotten dabigatran etexilate dose may still be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next scheduled dose on, the missed dose should be omitted. No double dose should be taken to make up for missed individual doses. Method of administration (prevention of VTE and SPAF) Pradaxa can be taken with or without food. Pradaxa should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach. Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see sections 5.2 and 6.6). 4.3 Contraindications  • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • Patients with severe renal impairment (CrCL < 30 mL/min) (see section 4.2) • Active clinically significant bleeding • Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities • Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5) • Hepatic impairment or liver disease expected to have any impact on survival • Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.5) • Prosthetic heart valves requiring anticoagulant treatment (see section 5.1). 4.4 Special warnings and precautions for use  Hepatic impairment Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials investigating the VTE prevention following elective hip or knee replacement surgery as well as in the study investigating the prevention of stroke and SEE associated with atrial fibrillation. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population. Haemorrhagic risk Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding and in situations with concomitant use of drugs affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy with dabigatran etexilate. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site. Factors, such as decreased renal function (30-50 mL/min CrCL), age ≥ 75 years, low body weight < 50 kg, or mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, quinidine or verapamil) are associated with increased dabigatran plasma levels (see sections 4.2, 4.5 and 5.2). The concomitant use of ticagrelor increases the exposure to dabigatran and may show pharmacodynamic interaction, which may result in an increased risk of bleeding (see section 4.5). In a study of prevention of stroke and SEE in adult patients with NVAF, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding which was statistically significant for dabigatran etexilate 150 mg twice daily. This increased risk was seen in the elderly (≥ 75 years). Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux increase the risk of GI bleeding. In these atrial fibrillation patients a dosage of 220 mg dabigatran given as 110 mg capsule twice daily should be considered and posology recommendations in section 4.2 be followed. The administration of a PPI can be considered to prevent GI bleeding. Bleeding risk may be increased in patients concomitantly treated with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) (see section 4.5). Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined (see section 5.1). Table 1 summarises factors which may increase the haemorrhagic risk. Please also refer to contraindications in section 4.3. Pharmacodynamic and kinetic factors Age ≥ 75 years Factors increasing dabigatran plasma levels Major: • Moderate renal impairment (30-50 mL/min CrCL) • P-gp inhibitor co-medication (some P-gp inhibitors are contraindicated, see section 4.3 and 4.5) Minor: Low body weight (< 50 kg) Pharmacodynamic interactions • ASA • NSAID • Clopidogrel • SSRIs or SNRIs • Other drugs which may impair haemostasis Diseases / procedures with special haemorrhagic risks • Congenital or acquired coagulation disorders • Thrombocytopenia or functional platelet defects • Recent biopsy, major trauma • Bacterial endocarditis • Esophagitis, gastritis and gastroesophageal reflux The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see section 4.5), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Pradaxa should only be given if the benefit outweighs bleeding risks. Pradaxa does not in general require routine anticoagulant monitoring. However, the measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. The INR test is unreliable in patients on Pradaxa and false positive INR elevations have been reported. Therefore INR tests should not be performed. Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but the tests are not standardised, and results should be interpreted with caution (see section 5.1). Table 2 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see section 5.1) Test (trough value) Indication   Prevention of VTE Prevention of stroke and SEE dTT [ng/mL] > 67 > 200 ECT [x-fold upper limit of normal] No data > 3 aPTT [x-fold upper limit of normal] > 1.3 > 2 INR Should not be performed Should not be performed Patients who develop acute renal failure must discontinue Pradaxa (see section 4.3). Limited data is available in patients < 50 kg (see section 5.2). When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see section 4.9). Medicinal products that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5). Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the ULN according to the local reference range. Interaction with P-gp inducers Concomitant administration of P-gp inducers (such as rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2). Surgery and interventions Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate. Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired. Preoperative phase Table 3 summarises discontinuation rules before invasive or surgical procedures. Renal function (CrCL in mL/min) Estimated half-life (hours) Stop dabigatran before elective surgery High risk of bleeding or major surgery Standard risk ≥ 80 ~ 13 2 days before 24 hours before ≥ 50-< 80 ~ 15 2-3 days before 1-2 days before ≥ 30-< 50 ~ 18 4 days before 2-3 days before (> 48 hours) If an acute intervention is required, dabigatran etexilate should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention (for cardioversion see section 4.2). Spinal anaesthesia/epidural anaesthesia/lumbar puncture Procedures such as spinal anaesthesia may require complete haemostatic function. The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma. Postoperative phase Dabigatran etexilate should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see sections 4.4 and 5.1). Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution. Hip fracture surgery There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not recommended. Myocardial Infarction In the phase III study RE-LY (see section 5.1.) the overall rate of myocardial infarction (MI) was 0.82, 0.81, and 0.64 % / year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29 % and 27 % compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥ 65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction < 40 %, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone. Colorants Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction Anticoagulants and antiplatelet aggregation medicinal products There is no or only limited experience with the following treatments which may increase the risk of bleeding when used concomitantly with Pradaxa: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section 4.3), and plateletet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section 4.4). From the limited data collected in the phase III study RE LY in patients with atrial fibrillation it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see section 4.3). UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see section 4.3). Clopidogrel and ASA: From the data collected in the phase III study RE-LY (see section 5.1) it was observed that the concomitant use of antiplatelets, ASA or clopidogrel approximately doubles major bleeding rates with both dabigatran etexilate and warfarin (see section 4.4). Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUC,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUC,ss and Cmax,ss were increased by about 30-40 % (see section 4.4) (see also subsection on ASA below). ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4). NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in the RE-LY study, NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran etexilate and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of bleeding is recommended (see section 4.4). LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin. Interactions linked to dabigatran etexilate and dabigatran metabolic profile Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran. Transporter interactions P-gp inhibitors Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin and ticagrelor) is expected to result in increased dabigatran plasma concentrations. If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1). The following strong P-gp inhibitors are contraindicated: systemic ketoconazole, cyclosporine, itraconazole and dronedarone (see section 4.3). Concomitant treatment with tacrolimus is not recommended. Caution should be exercised with mild to moderate P-gp inhibitors (e.g. amiodarone, posaconazole, quinidine, verapamil and ticagrelor) (see sections 4.2 and 4.4). Ketoconazole: Ketoconazole increased total dabigatran AUC0-∞ and Cmax values by 138 % and 135 %, respectively, after a single oral dose of 400 mg, and 153 % and 149 %, respectively, after multiple oral dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3). Dronedarone: When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold (+136 % and 125 %), respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold (+114 % and 87 %), respectively, after a single dose of 400 mg. The terminal half-life and renal clearance of dabigatran were not affected by dronedarone. When single and multiple doses of dronedarone were given 2 h after dabigatran etexilate, the increases in dabigatran AUC0-∞ were 1.3-fold and 1.6-fold, respectively. Concomitant treatment with dronedarone is contraindicated. Amiodarone: When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4). Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and amiodarone (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment. Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUC,ss and Cmax,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4). Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and quinidine (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment. Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4). The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of Cmax by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increased of Cmax by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increased of Cmax by about 60 % and AUC by about 50 %). Therefore, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with verapamil. In patients with normal renal function after hip or knee replacement surgery, receiving dabigatran etexilate and verapamil concomitantly, the dose of Pradaxa should be reduced to 150 mg taken once daily as 2 capsules of 75 mg. In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.2 and 4.4). For patients with NVAF treated for prevention of stroke and SEE, concomitantly receiving dabigatran etexilate and verapamil, the dose of Pradaxa should be reduced to 220 mg taken as one 110 mg capsule twice daily (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment. There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increased of Cmax by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours (see section 4.4). Clarithromycin: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 19 % and Cmax by about 15 % was observed without any clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment. Ticagrelor: When a single dose of 75mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmaxwere increased by 1.73-fold and 1.95-fold (+73% and 95 %), respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold (+56% and 46%) for Cmax and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUC,ss and Cmax,ss by 1.49-fold and 1.65-fold (+49% and 65%), respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mgticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUC,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold (+27% and 23%), respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose. Concomitant administration of 90 mg ticagrelor BID (maintenance dose) with 110 mg dabigatran etexilate increased the adjusted dabigatran AUC,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone. The following potent P-gp inhibitors have not been clinically studied but from in vitro results a similar effect as with ketoconazole may be expected: Itraconazole and cyclosporine, which are contra-indicated (see section 4.3). Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. Based on these data concomitant treatment with tacrolimus is not recommended. Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when Pradaxa is co-administered with posaconazole. P-gp inducers Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided (see sections 4.4 and 5.2). Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days. Other medicinal products affecting P-gp Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Pradaxa. P-gp substrate Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed. Co-medication with selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) SSRIs and SNRIs increased the risk of bleeding in RE-LY in all treatment groups. Gastric pH Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa. Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran. 4.6 Fertility, pregnancy and lactation Women of childbearing potential / Contraception in males and females Women of childbearing potential should avoid pregnancy during treatment with dabigatran etexilate. Pregnancy There are limited amount of data from the use of dabigatran etexilate in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pradaxa should not be used during pregnancy unless clearly necessary. Breast-feeding There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa. Fertility No human data available. In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients). 4.7 Effects on ability to drive and use machines Pradaxa has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile A total of 10,795 patients were treated in 6 actively controlled VTE prevention trials with at least one dose of the medicinal product. Of these 6,684 were treated with 150 mg or 220 mg daily of Pradaxa. In the pivotal study investigating the prevention of stroke and SEE in patients with atrial fibrillation, a total of 12,042 patients were treated with dabigatran etexilate. Of these 6,059 were treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily. In total, about 9 % of patients treated for elective hip or knee surgery (short-term treatment for up to 42 days) and 22 % of patient with atrial fibrillation treated for the prevention of stroke and SEE (long-term treatment for up to 3 years) experienced adverse reactions. The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of patients treated short-term for elective hip or knee replacement surgery, and 16,5 % in patients with atrial fibrillation treated for the prevention of stroke and SEE. Since the patient populations treated in the 2 indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and given in tables 5 and 6 below. Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes. Tabulated list of adverse reactions Table 4 shows the adverse reactions identified from the primary VTE prevention studies after hip or knee replacement surgery and the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation program ranked under headings of SOC and frequency using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). SOC / Preferred term. Primary VTE prevention after hip or knee replacement surgery Stroke and SEE prevention in patients with atrial fibrillation Blood and lymphatic system disorders Anaemia Uncommon Common Haemoglobin decreased Common Uncommon Thrombocytopenia Rare Uncommon Haematocrit decreased Uncommon Rare Immune system disorder Drug hypersensitivity Uncommon Uncommon Rash Rare Uncommon Pruritus Rare Uncommon Anaphylactic reaction Rare Rare Angioedema Rare Rare Urticaria Rare Rare Bronchospasm Not known Not known Nervous system disorders Intracranial haemorrhage Rare Uncommon Vascular disorders Haematoma Uncommon Uncommon Haemorrhage Rare Uncommon Wound haemorrhage Uncommon - Respiratory, thoracic and mediastinal disorders Epistaxis Uncommon Common Haemoptysis Rare Uncommon Gastrointestinal disorders Gastrointestinal haemorrhage Uncommon Common Abdominal pain Rare Common Diarrhoea Uncommon Common Dyspepsia Rare Common Nausea Uncommon Common Rectal haemorrhage Uncommon Uncommon Haemorrhoidal haemorrhage Uncommon Uncommon Gastrointestinal ulcer, including oesophageal ulcer Rare Uncommon Gastroesophagitis Rare Uncommon Gastroesophageal reflux disease Rare Uncommon Vomiting Uncommon Uncommon Dysphagia Rare Uncommon Hepatobiliary disorders Hepatic function abnormal/ Liver function Test abnormal Common Uncommon Alanine aminotransferase increased Uncommon Uncommon Aspartate aminotransferase increased Uncommon Uncommon Hepatic enzyme increased Uncommon Rare Hyperbilirubinaemia Uncommon Rare Skin and subcutaneous tissue disorder Skin haemorrhage Uncommon Common Musculoskeletal and connective tissue disorders Haemarthrosis Uncommon Rare Renal and urinary disorders Genitourological haemorrhage, including haematuria Uncommon Common General disorders and administration site conditions Injection site haemorrhage Rare Rare Catheter site haemorrhage Rare Rare Bloody discharge Rare - Injury, poisoning and procedural complications Traumatic haemorrhage Uncommon Rare Incision site haemorrhage Rare Rare Post procedural haematoma Uncommon - Post procedural haemorrhage Uncommon - Anaemia postoperative Rare - Post procedural discharge Uncommon - Wound secretion Uncommon - Surgical and medical procedures Wound drainage Rare - Post procedural drainage Rare - Prevention of VTE Bleeding The table 5 shows the number (%) of patients experiencing the adverse reaction bleeding during the treatment period in the VTE prevention in the two pivotal clinical trials, according to dose. Dabigatran etexilate 150 mg once daily N (%) Dabigatran etexilate 220 mg once daily N (%) Enoxaparin N (%) Treated 1,866 (100.0) 1,825 (100.0) 1,848 (100.0) Major bleeding 24 (1.3) 33 (1.8) 27 (1.5) Any bleeding 258 (13.8) 251 (13.8) 247 (13.4) The definition of the adverse reaction major bleeding in the RE-NOVATE and RE-MODEL studies were as follows: • fatal bleeding • clinically overt bleeding in excess of what was expected and associated with ≥ 20 g/L (corresponds to 1.24 mmol/L) fall in haemoglobin in excess of what was expected • clinically overt bleeding in excess of what was expected and leading to transfusion of ≥ 2 units packed cells or whole blood in excess of what was expected • symptomatic retroperitoneal, intracranial, intraocular or intraspinal bleeding • bleeding requiring treatment cessation • bleeding leading to re-operation Objective testing was required for a retroperitoneal bleed (ultrasound or Computer Tomography (CT) scan) and for an intracranial and intraspinal bleed (CT scan or Magnetic Resonance Imaging). Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors Bleeding The table 6 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and SEE in patients with atrial fibrillation. Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomized 6,015 6,076 6,022 Major bleeding 342 (2.87 %) 399 (3.32 %) 421 (3.57 %) Intracranial bleeding 27 (0.23 %) 38 (0.32 %) 90 (0.76 %) GI bleeding 134 (1.14 %) 186 (1.57 %) 125 (1.07 %) Fatal bleeding 23 (0.19 %) 28 (0.23 %) 39 (0.33 %) Minor bleeding 1,566 (13.16 %) 1,787 (14.85 %) 1,931 (16.37 %) Any bleeding 1,754 (14.74 %) 1,993 (16.56 %) 2,166 (18.37 %) Major bleeding was defined to fulfil one or more of the following criteria: Bleeding associated with a reduction in haemoglobin of at least 20 g/L or leading to a transfusion of at least 2 units of blood or packed cells. Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding. Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria: Fatal bleed; symptomatic intracranial bleed; reduction in haemoglobin of at least 50 g/L; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic medicinal products; a bleed that necessitated surgical intervention. Subjects randomized to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p < 0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomized to dabigatran etexilate 110 mg twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.80 [p=0.0026]). Subjects randomized to dabigatran etexilate 150 mg twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.47 [p=0.0008]. This effect was seen primarily in patients ≥ 75 years. The clinical benefit of dabigatran with regard to stroke and SEE prevention and decreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renal impairment, age, concomitant medication use such as anti-platelets or P-gp inhibitors. While certain patient subgroups are at an increased risk of major bleeding when treated with an anticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within the first 3-6 months following initiation of dabigatran etexilate therapy. Myocardial infarction In the RE-LY study, in comparison to warfarin the annual myocardial infarction rate for dabigatran etexilate was increased from 0.64 % (warfarin) to 0.82 % (dabigatran etexilate 110 mg twice daily) / 0.81 % (dabigatran etexilate 150 mg twice daily) (see section 5.1). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt 4.9 Overdose Doses of dabigatran etexilate beyond those recommended, expose the patient to increased risk of bleeding. In case of an overdose suspicion, coagulation tests can help to determine a bleeding risk (see sections 4.4 and 5.1). A calibrated quantitative dTT test or repetitive dTT measurements allow prediction of the time by when certain dabigatran levels will be reached (see section 5.1), also in case additional measures e.g. dialysis have been initiated. Excessive anticoagulation may require interruption of Pradaxa treatment. There is no specific antidote to dabigatran. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route adequate diuresis must be maintained. Appropriate supportive treatment, such as surgical haemostasis and blood volume replacement, should be undertaken at the prescribers discretion. Activated prothrombin complex concentrates (e.g., FEIBA) or recombinant Factor VIIa or concentrates of coagulation factors II, IX and X, may be considered. There is some experimental evidence to support the role of these medicinal products in reversing the anticoagulant effect of dabigatran, but data on their usefulness in clinical settings and also on the possible risk of rebound thromboembolism is very limited. Coagulation tests may become unreliable following administration of suggested reversing medicinal products. Caution should be exercised when interpreting these tests. Consideration should also be given to administration of platelet concentrates in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used. All symptomatic treatment should be given according to the physician's judgement. Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings. As protein binding is low, dabigatran can be dialysed; there is limited clinical experience to demonstrate the utility of this approach in clinical studies (see section 5.2). 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antithrombotic, direct thrombine inhibitors, ATC code: B01AE07. Mechanism of action Dabigatran etexilate is a small molecule prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation. Pharmacodynamic effects In-vivo and ex-vivo animal studies have demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration in various animal models of thrombosis. There is a clear correlation between plasma dabigatran concentration and degree of anticoagulant effect based on phase II studies. Dabigatran prolongs the thrombin time (TT), ECT, and aPTT. The calibrated diluted TT (dTT) test provides an estimation of dabigatran plasma concentration that can be compared to the expected dabigatran plasma concentrations. The ECT can provide a direct measure of the activity of direct thrombin inhibitors. The aPTT test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution. In general, it can be assumed that these measures of anti-coagulant activity may reflect dabigatran levels and can provide guidance for the assessment of bleeding risk, i.e. exceeding the 90th percentile of dabigatran trough levels or a coagulation assay such as aPTT measured at trough is considered to be associated with an increased risk of bleeding. Prevention of VTE Steady state (after day 3) geometric mean dabigatran peak plasma concentration, measured around 2 hours after 220 mg dabigatran etexilate administration, was 70.8 ng/mL, with a range of 35.2-162 ng/mL (25th–75th percentile range).The dabigatran geometric mean trough concentration, measured at the end of the dosing interval (i.e. 24 hours after a 220 mg dabigatran dose), was on average 22.0 ng/mL, with a range of 13.0-35.7 ng/mL (25th–75th percentile range). In patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily, • the 90th percentile of dabigatran plasma concentrations was 67 ng/mL, measured at trough (20-28 hours after the previous dose) (see section 4.4 and 4.9), • the 90th percentile of aPTT at trough (20-28 hours after the previous dose) was 51 seconds, which would be 1.3-fold upper limit of normal. The ECT was not measured in patients treated for prevention of VTEs after hip or knee replacement surgery with 220 mg dabigatran etexilate once daily. Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors Steady state geometric mean dabigatran peak plasma concentration, measured around 2 hours after 150 mg dabigatran etexilate administration twice daily, was 175 ng/mL, with a range of 117-275 ng/mL (25th–75th percentile range). The dabigatran geometric mean trough concentration, measured at trough in the morning, at the end of the dosing interval (i.e. 12 hours after the 150 mg dabigatran evening dose), was on average 91.0 ng/mL, with a range of 61.0-143 ng/mL (25th–75th percentile range). For patients with NVAF treated for prevention of stroke and SEE with 150 mg dabigatran etexilate twice daily, • the 90th percentile of dabigatran plasma concentrations measured at trough (10-16 hours after the previous dose) was about 200 ng/mL, • an ECT at trough (10-16 hours after the previous dose), elevated approximately 3-fold upper limit of normal refers to the observed 90th percentile of ECT prolongation of 103 seconds, • an aPTT ratio greater than 2-fold upper limit of normal (aPTT prolongation of about 80 seconds), at trough (10-16 hours after the previous dose) reflects the 90th percentile of observations. Clinical efficacy and safety Ethnic origin No clinically relevant ethnic differences among Caucasians, African-American, Hispanic, Japanese or Chinese patients were observed. Clinical trials in Venous Thromboembolism (VTE) prophylaxis following major joint replacement surgery In 2 large randomized, parallel group, double-blind, dose–confirmatory trials, patients undergoing elective major orthopaedic surgery (one for knee replacement surgery and one for hip replacement surgery) received Pradaxa 75 mg or 110 mg within 1-4 hours of surgery followed by 150 mg or 220 mg once daily thereafter, haemostasis having been secured, or enoxaparin 40 mg on the day prior to surgery and daily thereafter. In the RE-MODEL trial (knee replacement) treatment was for 6-10 days and in the RE-NOVATE trial (hip replacement) for 28-35 days. Totals of 2,076 patients (knee) and 3,494 (hip) were treated respectively. Composite of total VTE (including PE, proximal and distal DVT, whatever symptomatic or asymptomatic detected by routine venography) and all-cause mortality constituted the primary end-point for both studies. Composite of major VTE (including PE and proximal DVT, whatever symptomatic or asymptomatic detected by routine venography) and VTE-related mortality constituted a secondary end-point and is considered of better clinical relevance. Results of both studies showed that the antithrombotic effect of Pradaxa 220 mg and 150 mg were statistically non-inferior to that of enoxaparin on total VTE and all-cause mortality. The point estimate for incidence of Major VTE and VTE related mortality for the 150 mg dose was slightly worse than enoxaparin (table 7). Better results were seen with the 220 mg dose where the point estimate of Major VTE was slightly better than enoxaparin (table 7). The clinical studies have been conducted in a patient population with a mean age > 65 years. There were no differences in the phase 3 clinical studies for efficacy and safety data between men and women. In the studied patient population of RE-MODEL and RE-NOVATE (5,539 patients treated), 51 % suffered from concomitant hypertension, 9 % from concomitant diabetes, 9 % from concomitant coronary artery disease and 20 % had a history of venous insufficiency. None of these diseases showed an impact on the effects of dabigatran on VTE-prevention or bleeding rates. Data for the major VTE and VTE-related mortality endpoint were homogeneous with regards to the primary efficacy endpoint and are shown in table 7. Data for the total VTE and all cause mortality endpoint are shown in table 8. Data for adjudicated major bleeding endpoints are shown in table 9 below. Table 7: Analysis of major VTE and VTE-related mortality during the treatment period in the RE-MODEL and the RE-NOVATE orthopaedic surgery studies. Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) N 909 888 917 Incidences (%) 28 (3.1) 38 (4.3) 36 (3.9) Risk ratio over enoxaparin 0.78 1.09   95 % CI 0.48, 1.27 0.70, 1.70   RE-MODEL (knee) N 506 527 511 Incidences (%) 13 (2.6) 20 (3.8) 18 (3.5) Risk ratio over enoxaparin 0.73 1.08   95 % CI 0.36, 1.47 0.58, 2.01 Table 8: Analysis of total VTE and all cause mortality during the treatment period in the RE-NOVATE and the RE-MODEL orthopaedic surgery studies. Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) N 880 874 897 Incidences (%) 53 (6.0) 75 (8.6) 60 (6.7) Risk ratio over enoxaparin 0.9 1.28   95 % CI (0.63, 1.29) (0.93, 1.78)   RE-MODEL (knee) N 503 526 512 Incidences (%) 183 (36.4) 213 (40.5) 193 (37.7) Risk ratio over enoxaparin 0.97 1.07   95 % CI (0.82, 1.13) (0.92, 1.25) Table 9: Major bleeding events by treatment in the individual RE-MODEL and the RE-NOVATE studies. Trial Dabigatran etexilate 220 mg once daily Dabigatran etexilate 150 mg once daily Enoxaparin 40 mg RE-NOVATE (hip) Treated patients N 1,146 1,163 1,154 Number of MBE N(%) 23 (2.0) 15 (1.3) 18 (1.6) RE-MODEL (knee) Treated patients N 679 703 694 Number of MBE N(%) 10 (1.5) 9 (1.3) 9 (1.3) Prevention of stroke and SEE in adult patients with NVAF with one or more risk factors The clinical evidence for the efficacy of dabigatran etexilate is derived from the RE-LY study (Randomized Evaluation of Long–term anticoagulant therapy) a multi-centre, multi-national, randomized parallel group study of two blinded doses of dabigatran etexilate (110 mg and 150 mg twice daily) compared to open-label warfarin in patients with atrial fibrillation at moderate to high risk of stroke and SEE. The primary objective in this study was to determine if dabigatran etexilate was non-inferior to warfarin in reducing the occurrence of the composite endpoint stroke and SEE. Statistical superiority was also analyzed. In the RE-LY study, a total of 18,113 patients were randomized, with a mean age of 71.5 years and a mean CHADS2 score of 2.1. The patient population was 64 % male, 70 % Caucasian and 16 % Asian. For patients randomized to warfarin, the mean percentage of time in therapeutic range (TTR) (INR 2-3) was 64.4 % (median TTR 67 %). The RE-LY study demonstrated that dabigatran etexilate, at a dose of 110 mg twice daily, is non-inferior to warfarin in the prevention of stroke and SEE in subjects with atrial fibrillation, with a reduced risk of ICH, total bleeding and major bleeding. The dose of 150 mg twice daily reduces significantly the risk of ischemic and haemorrhagic stroke, vascular death, ICH and total bleeding compared to warfarin. Major bleeding rates with this dose were comparable to warfarin. Myocardial infarction rates were slightly increased with dabigatran etexilate 110 mg twice daily and 150 mg twice daily compared to warfarin (hazard ratio 1.29; p=0.0929 and hazard ratio 1.27; p=0.1240, respectively). With improving monitoring of INR the observed benefits of dabigatran etexilate compared to warfarin diminish. Tables 10-12 display details of key results in the overall population: Table 10: Analysis of first occurrence of stroke or SEE (primary endpoint) during the study period in RE-LY. Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomized 6,015 6,076 6,022 Stroke and/or SEE       Incidences (%) 183 (1.54) 134 (1.11) 202 (1.71) Hazard ratio over warfarin (95 % CI) 0.90 (0.74, 1.10) 0.65 (0.52, 0.81)   p value superiority p=0.2943 p=0.0001 % refers to yearly event rate Table 11: Analysis of first occurrence of ischemic or haemorrhagic strokes during the study period in RE-LY. Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomized 6,015 6,076 6,022 Stroke       Incidences (%) 171 (1.44) 122 (1.01) 186 (1.58) Hazard ratio vs. warfarin (95 % CI) 0.91 (0.74, 1.12) 0.64 (0.51, 0.81)   p-value 0.3828 0.0001   SEE       Incidences (%) 15 (0.13) 13 (0.11) 21 (0.18) Hazard ratio vs. warfarin (95 % CI) 0.71 (0.37, 1.38) 0.61 (0.30, 1.21)   p-value 0.3099 0.1582   Ischemic stroke       Incidences (%) 152 (1.28) 103 (0.86) 134 (1.14) Hazard ratio vs. warfarin (95 % CI) 1.13 (0.89, 1.42) 0.75 (0.58, 0.97)   p-value 0.3139 0.0296   Haemorrhagic stroke       Incidences (%) 14 (0.12) 12 (0.10) 45 (0.38) Hazard ratio vs. warfarin (95 % CI) 0.31 (0.17, 0.56) 0.26 (0.14, 0.49)   p-value < 0.001 < 0.001 % refers to yearly event rate Table 12: Analysis of all cause and cardiovascular survival during the study period in RE-LY. Dabigatran etexilate 110 mg twice daily Dabigatran etexilate 150 mg twice daily Warfarin Subjects randomized 6,015 6,076 6,022 All-cause mortality       Incidences (%) 446 (3.75) 438 (3.64) 487 (4.13) Hazard ratio vs. warfarin (95 % CI) 0.91 (0.80, 1.03) 0.88 (0.77, 1.00)   p-value 0.1308 0.0517   Vascular mortality       Incidences (%) 289 (2.43) 274 (2.28) 317 (2.69) Hazard ratio vs. warfarin (95 % CI) 0.90 (0.77, 1.06) 0.85 (0.72, 0.99)   p-value 0.2081 0.0430 % refers to yearly event rate Tables 13-14 display results of the primary efficacy and safety endpoint in relevant sub-populations: For the primary endpoint, stroke and SEE, no subgroups (i.e., age, weight, gender, renal function, ethnicity, etc.) were identified with a different risk ratio compared to warfarin. Table 13: Hazard Ratio and 95 % CI for stroke/SEE by subgroups Endpoint Dabigatran etexilate 110 mg twice daily vs. warfarin Dabigatran etexilate 150 mg twice daily vs. warfarin Age (years)     < 65 1.10 (0.64, 1.87) 0.51 (0.26, 0.98) 65 ≤ and < 75 0.87 (0.62, 1.20) 0.68 (0.47, 0.96) ≥ 75 0.88 (0.66, 1.17) 0.67 (0.49, 0.90) ≥ 80 0.68 (0.44, 1.05) 0.65 (0.43, 1.00) CrCL (mL/min)     30 ≤ and < 50 0.89 (0.61, 1.31) 0.47 (0.30, 0.74) 50 ≤ and < 80 0.91 (0.68, 1.20) 0.65 (0.47, 0.88) ≥ 80 0.83 (0.52, 1.32) 0.71 (0.44, 1.15) For the primary safety endpoint of major bleeding there was an interaction of treatment effect and age. The relative risk of bleeding with dabigatran compared to warfarin increased with age. Relative risk was highest in patients ≥ 75 years. The concomitant use of antiplatelets ASA or clopidogrel approximately doubles MBE rates with both dabigatran etexilate and warfarin. There was no significant interaction of treatment effects with the subgroups of renal function and CHADS2 score. Table 14: Hazard Ratio and 95 % CI for major bleeds by subgroups Endpoint Dabigatran etexilate 110 mg twice daily vs. warfarin Dabigatran etexilate 150 mg twice daily vs. warfarin Age (years)     < 65 0.33 (0.19, 0.59) 0.36 (0.21, 0.62) 65 ≤ and < 75 0.70 (0.56, 0.89) 0.80 (0.64, 1.00) ≥ 75 1.01 (0.83, 1.23) 1.18 (0.98, 1.43) ≥ 80 1.12 (0.84, 1.49) 1.35 (1.03, 1.77) CrCL (mL/min)     30 ≤ and < 50 1.00 (0.77, 1.29) 0.94 (0.72, 1.21) 50 ≤ and < 80 0.76 (0.61, 0.93) 0.89 (0.73, 1.08) ≥ 80 0.59 (0.43, 0.82) 0.84 (0.62, 1.13) ASA use 0.85 (0.68, 1.05) 0.92 (0.75, 1.14) Clopidogrel use 0.88 (0.56, 1.37) 0.95 (0.62, 1.46) Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Pradaxa in all subsets of the paediatric population in prevention of thromboembolic events in the granted indication (see section 4.2 for information on paediatric use). Clinical trials for the prevention of thromboembolism in patients with prosthetic heart valves A phase II study examined dabigatran etexilate and warfarin in a total of 252 patients with recent mechanical valve replacement surgery (i.e. within the current hospital stay) and in patients who received a mechanical heart valve replacement more than three months ago. More thromboembolic events (mainly strokes and symptomatic/asymptomatic prosthetic valve thrombosis) and more bleeding events were observed with dabigatran etexilate than with warfarin. In the early post-operative patients, major bleeding manifested predominantly as haemorrhagic pericardial effusions, specifically in patients who started dabigatran etexilate early (i.e. on Day 3) after heart valve replacement surgery (see section 4.3). 5.2 Pharmacokinetic properties  After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, which is the active form in plasma. The cleavage of the prodrug dabigatran etexilate by esterase-catalysed hydrolysis to the active principle dabigatran is the predominant metabolic reaction. The absolute bioavailability of dabigatran following oral administration of Pradaxa was approximately 6.5 %. After oral administration of Pradaxa in healthy volunteers, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in plasma concentrations with Cmax attained within 0.5 and 2.0 hours post administration. Absorption A study evaluating post-operative absorption of dabigatran etexilate, 1-3 hours following surgery, demonstrated relatively slow absorption compared with that in healthy volunteers, showing a smooth plasma concentration-time profile without high peak plasma concentrations. Peak plasma concentrations are reached at 6 hours following administration in a postoperative period due to contributing factors such as anaesthesia, gastrointestinal paresis, and surgical effects independent of the oral medicinal product formulation. It was demonstrated in a further study that slow and delayed absorption is usually only present on the day of surgery. On subsequent days absorption of dabigatran is rapid with peak plasma concentrations attained 2 hours after medicinal product administration. Food does not affect the bioavailability of dabigatran etexilate but delays the time to peak plasma concentrations by 2 hours. The oral bioavailability may be increased by 75 % compared to the reference capsule formulation when the pellets are taken without the Hydroxypropylmethylcellulose (HPMC) capsule shell. Hence, the integrity of the HPMC capsules should always be preserved in clinical use to avoid unintentionally increased bioavailability of dabigatran etexilate. Therefore, patients should be advised not to open the capsules and taking the pellets alone (e.g. sprinkled over food or into beverages) (see section 4.2). Distribution Low (34-35 %) concentration independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran of 60–70 L exceeded the volume of total body water indicating moderate tissue distribution of dabigatran. Cmax and the area under the plasma concentration-time curve were dose proportional. Plasma concentrations of dabigatran showed a biexponential decline with a mean terminal half-life of 11 hours in healthy elderly subjects. After multiple doses a terminal half-life of about 12-14 hours was observed. The half-life was independent of dose. Half-life is prolonged if renal function is impaired as shown in table 15. Biotransformation Metabolism and excretion of dabigatran were studied following a single intravenous dose of radiolabeled dabigatran in healthy male subjects. After an intravenous dose, the dabigatran-derived radioactivity was eliminated primarily in the urine (85 %). Faecal excretion accounted for 6 % of the administered dose. Recovery of the total radioactivity ranged from 88-94 % of the administered dose by 168 hours post dose. Dabigatran is subject to conjugation forming pharmacologically active acylglucuronides. Four positional isomers, 1-O, 2-O, 3-O, 4-O-acylglucuronide exist, each accounts for less than 10 % of total dabigatran in plasma. Traces of other metabolites were only detectable with highly sensitive analytical methods. Dabigatran is eliminated primarily in the unchanged form in the urine, at a rate of approximately 100 mL/min corresponding to the glomerular filtration rate. Special populations Renal insufficiency In phase I studies the exposure (AUC) of dabigatran after the oral administration of Pradaxa is approximately 2.7-fold higher in volunteers with moderate renal insufficiency (CrCL between 30-50 mL/min) than in those without renal insufficiency. In a small number of volunteers with severe renal insufficiency (CrCL 10-30 mL/min), the exposure (AUC) to dabigatran was approximately 6 times higher and the half-life approximately 2 times longer than that observed in a population without renal insufficiency (see sections 4.2, 4.3 and 4.4). Table 15: Half-life of total dabigatran in healthy subjects and subjects with impaired renal function. glomerular filtration rate (CrCL,) [mL/min] gMean (gCV %; range) half-life [h] ≥ 80 13.4 (25.7 %; 11.0-21.6) ≥ 50-< 80 15.3 (42.7 %;11.7-34.1) ≥ 30-< 50 18.4 (18.5 %;13.3-23.0) < 30 27.2(15.3 %; 21.6-35.0) Clearance of dabigatran by haemodialysis was investigated in 7 patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was conducted with 700 mL/min dialysate flow rate, four hour duration and a blood flow rate of either 200 mL/min or 350-390 mL/min. This resulted in a removal of 50 % to 60 % of dabigatran concentrations, respectively. The amount of drug cleared by dialysis is proportional to the blood flow rate up to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure. The median CrCL in RE-LY was 68.4 mL/min. Almost half (45.8 %) of the RE-LY patients had a CrCL > 50-< 80 mL/min. Patients with moderate renal impairment (CrCL between 30-50 mL/min) had on average 2.29-fold and 1.81-fold higher pre- and post-dose dabigatran plasma concentrations, respectively, when compared with patients without renal impairment (CrCL ≥ 80 mL/min). Elderly patients Specific pharmacokinetic phase I studies with elderly subjects showed an increase of 40 to 60 % in the AUC and of more than 25 % in Cmax compared to young subjects. The effect by age on exposure to dabigatran was confirmed in the RE-LY study with an about 31 % higher trough concentration for subjects ≥ 75 years and by about 22 % lower trough level for subjects < 65 years compared to subjects between 65 and 75 years (see sections 4.2 and 4.4). Hepatic impairment No change in dabigatran exposure was seen in 12 subjects with moderate hepatic insufficiency (Child Pugh B) compared to 12 controls (see sections 4.2 and 4.4). Body weight The dabigatran trough concentrations were about 20 % lower in patients with a body weight > 100 kg compared with 50-100 kg. The majority (80.8 %) of the subjects were in the ≥ 50 kg and < 100 kg category with no clear difference detected (see sections 4.2 and 4.4). Limited clinical data in patients < 50 kg are available. Gender Active substance exposure in the primary VTE prevention studies was about 40 % to 50 % higher in female patients and no dose adjustment is recommended. In atrial fibrillation patients females had on average 30 % higher trough and post-dose concentrations. No dose adjustment is required (see section 4.2). Ethnic origin No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding dabigatran pharmacokinetics and pharmacodynamics. Pharmacokinetic interactions The pro-drug dabigatran etexilate but not dabigatran is a substrate of the efflux transporter P-gp. Therefore concomitant use of P-gp transporter inhibitors (amiodarone, verapamil, clarithromycin, quinidine, dronedarone, ticagrelor and ketoconazole) and inducers (rifampicin) had been investigated (see sections 4.2, 4.4 and 4.5). In vitro interaction studies did not show any inhibition or induction of the principal isoenzymes of cytochrome P450. This has been confirmed by in vivo studies with healthy volunteers, who did not show any interaction between this treatment and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction) and diclofenac (CYP2C9). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Effects observed in the repeat-dose toxicity studies were due to the exaggerated pharmacodynamic effect of dabigatran. An effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (5-fold the plasma exposure level in patients). At doses that were toxic to the mothers (5- to 10-fold the plasma exposure level in patients), a decrease in foetal body weight and viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients). In lifetime toxicology studies in rats and mice, there was no evidence for a tumorigenic potential of dabigatran up to maximum doses of 200 mg/kg. 6. Pharmaceutical particulars 6.1 List of excipients Capsule fill • Tartaric acid • Acacia • Hypromellose • Dimeticone 350 • Talc • Hydroxypropylcellulose Capsule shell • Carrageenan • Potassium chloride • Titanium dioxide • Indigo carmine (E132) • Sunset yellow (E110) • Hypromellose • Water purified Black printing ink • Shellac • N-Butyl alcohol • Isopropyl alcohol • Industrial methylated spirit • Iron oxide black (E172) • Purified water • Propylene glycol 6.2 Incompatibilities Not applicable. 6.3 Shelf life Blister and bottle: 3 years Once the bottle is opened, the medicinal product must be used within 4 months. 6.4 Special precautions for storage Blister Store in the original package in order to protect from moisture. Bottle Store in the original package in order to protect from moisture. Keep the bottle tightly closed. 6.5 Nature and contents of container Cartons containing 10 x 1, 30 x 1 or 60 x 1 hard capsules a multipack containing 3 packs of 60 x 1 hard capsules (180 hard capsules) and a multipack containing 2 packs of 50 x 1 hard capsules (100 hard capsules) in perforated aluminium unit dose blisters. Furthermore, cartons containing 6 blister strips (60 x 1) in perforated aluminium unit dose white blisters. The blister consists of an aluminium lidding foil coated with polyvinylchloride-polyvinylacetate copolymer-acrylate (PVCAC acrylate) in contact with the product and an aluminium bottom foil with polyvinylchloride (PVC) in contact with the product. Polypropylene bottle with a screw cap containing 60 hard capsules. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling When taking Pradaxa capsules out of the blister pack, the following instructions should be followed: • The hard capsules should be taken out of the blister card by peeling off the backing foil. • The hard capsules should not be pushed through the blister foil. • The blister foil should only be peeled off, when a hard capsule is required. When taking a hard capsule out of the bottle, please observe the following instructions: • The cap opens by pushing and turning. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Boehringer Ingelheim International GmbH Binger Str. 173 D-55216 Ingelheim am Rhein Germany 8. Marketing authorisation number(s) EU/1/08/442/005 EU/1/08/442/006 EU/1/08/442/007 EU/1/08/442/008 EU/1/08/442/014 EU/1/08/442/015 EU/1/08/442/018 9. Date of first authorisation/renewal of the authorisation  Date of first authorisation: 18 March 2008 Date of latest renewal: 17 January 2013 10. Date of revision of the text 05/2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/. --------------------------------------------------------------- 注：以下产品不同规格和不同价格，购买以咨询为准！ --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 750mg KAPS 56.33mg/cap 10caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 75毫克胶囊剂 56.33毫克/胶囊 10胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 750mg KAPS 56.33mg/cap 30caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 75毫克胶囊剂 56.33毫克/胶囊 30胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 110mg KAPS 82.63mg/cap 10caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 110毫克胶囊剂  82.63毫克/胶囊 10胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 110mg KAPS  82.63mg/cap 30caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 110毫克胶囊剂 82.63毫克/胶囊 30胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 75mg KAPS 82.63mg/cap 10caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 75毫克胶囊剂 82.63毫克/胶囊 10胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 150mg KAPS 112.666mg/cap 60caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 150毫克胶囊剂 112.666毫克/胶囊 60胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 150mg KAPS 112.666mg/cap 30caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 150毫克胶囊剂 112.666毫克/胶囊 30胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A --------------------------------------------------------------- 产地国家: 欧洲共同体国家 原产地英文商品名: PRADAXA 150mg KAPS 112.666mg/cap 10caps/box 原产地英文药品名: DABIGATRAN ETEXILATE 原产地英文化合物名称: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl] amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate 中文参考商品译名: PRADAXA 150毫克胶囊剂 112.666毫克/胶囊 10胶囊/盒 中文参考药品译名: 达比加群酯 生产厂家中文参考译名: 勃林格殷格翰 生产厂家英文名: BOEHRINGER INGELHEIM ESPA&Ntilde;A