Dabigatran Etexilate Capsules

Pharmacological action Dabigatran and its acetylglucuronide conjugate are competitive direct thrombin inhibitors. Since thrombin (serine protease) converts fibrinogen into fibrin in the coagulation cascade, inhibiting thrombin can prevent thrombosis, and its active group can also inhibit free thrombin, thrombin bound to blood clots, and thrombin-induced platelet aggregation. Toxicological studies Genetic toxicity: The results of Ames test, mouse lymphoma test, human lymphocyte chromosome aberration test, and rat in vivo micronucleus test were all negative. Reproductive toxicity: Rats were orally administered dabigatran etexilate 15, 70 and 200 mg/kg. Male rats were administered 29 days before mating and during the mating period to the specified end time, and female rats were administered 15 days before mating to the sixth day of pregnancy. The results showed that the 200 mg/kg group (or based on AUC comparison, 9-12 times the exposure of the most recommended human dose MRHD300 mg/day) had no significant effect on the general fertility of male and female rats. However, when female rats were dosed at 70 mg/kg (3 times the MRHD exposure based on AUC), the number of implantations decreased and pre-implantation losses increased. At maternal toxic doses (5-10 times higher than patient plasma exposure levels), rats and rabbits had decreased fetal weights and embryo-fetal viability, and increased fetal variability. In perinatal reproductive toxicity studies, increased fetal mortality was observed at maternal toxic doses (4 times higher than patient plasma exposure levels). Carcinogenicity: No significant carcinogenicity was observed when dabigatran was orally administered to mice and rats for 2 years. The maximum dose for mice and rats was 200 mg/kg/day, which is approximately 3.6 times and 6 times the MRHD exposure of 300 mg/day, respectively (based on AUC).

Dabigatran etexilate mesylate Chemical name: β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyrimidine-ethyl ester, methanesulfonate

This product is a capsule, and the contents are yellow granules.

Prevention of stroke and systemic embolism (SEE) in adults with non-valvular atrial fibrillation (NVAF) who have one or more of the following risk factors: previous stroke, transient ischemic attack, or systemic embolism Left ventricular ejection fraction <40% with symptomatic heart failure, New York Heart Association (NYHA) functional class ≥2 Age ≥75 years Age ≥65 years with any of the following conditions: diabetes, coronary artery disease, or hypertension Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related mortality. Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related mortality.

Oral administration: swallow the whole tablet with water, either during or after meals. If gastrointestinal symptoms occur, it is recommended to take this product with meals and/or take a proton pump inhibitor, such as pantoprazole. Do not open the capsule. Prevention of stroke and SEE (SPAF) in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors: The recommended dose for adults is 300 mg orally daily, i.e. 1 150 mg capsule twice a day. Long-term treatment should be maintained. Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related mortality: The recommended dose for adults is 300 mg orally daily, i.e. 1 150 mg capsule twice a day. It should be started after receiving at least 5 days of parenteral anticoagulant therapy. Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related mortality: The recommended dose for adults is 300 mg orally daily, i.e. 1 150 mg capsule twice a day. Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE), prevention of related mortality, prevention of recurrent DVT and/or PE and related mortality: Duration of treatment should be determined on an individual basis after careful assessment of the benefit of treatment versus the risk of bleeding. Short-term treatment (at least 3 months) should be used based on transient risk factors (e.g., recent surgery, trauma, immobilization), and long-term treatment should be used based on permanent risk factors or idiopathic DVT or PE. Dose adjustment for SPAF, DVT/PE patients: The recommended dose of 220 mg of valproate is one 110 mg capsule twice daily orally for the following patients: • Patients 80 years of age and older • Patients receiving concomitant verapamil For the following patient groups, the daily dose of 300 mg or 220 mg of valproate should be selected based on individual assessment of the patient's thromboembolic risk and bleeding risk. • Patients aged 75-80 years • Patients with moderate renal impairment • Patients with gastritis, esophagitis or gastroesophageal reflux • Other patients at increased risk of bleeding For DVT/PE, the recommended dose of 220 mg per day, one 110 mg capsule twice daily, is based on pharmacokinetic and pharmacodynamic analyses and has not been studied in a clinical setting. See below for details. Elderly (SPAF, DVT/PE) For patients aged 75-80 years, a dose of 300 mg per day, one 150 mg capsule twice daily, should be used. When the risk of thromboembolism is low and the risk of bleeding is high, a dose of 220 mg per day, one 110 mg capsule twice daily, may be considered at the discretion of the physician. For patients aged 80 years and older, due to their increased risk of bleeding, a dose of 220 mg per day, one 110 mg capsule twice daily should be used. Because renal impairment is common in the elderly (>75 years old), renal function should be assessed by calculating creatinine clearance (CrCL) before starting treatment with this product, and patients with severe renal impairment (i.e., CrCL <30 mL/min) should be excluded. For patients treated with this product, renal function should be assessed at least once a year during treatment when there are clinical conditions that may cause a decrease or worsening of renal function (such as hypovolemia, dehydration, and some specific concomitant medications). Patients with increased bleeding risk (SPAF, DVT/PE) Patients with increased bleeding risk should be closely monitored clinically (for signs of bleeding or anemia). After evaluating the potential benefits and risks for individual patients, the physician may decide whether to adjust the dose at his or her discretion. Coagulation tests may help determine whether the patient's increased bleeding risk is caused by excessive exposure to dabigatran. When patients with high bleeding risk are determined to be exposed to dabigatran excessively, a daily dose of 220 mg is recommended, that is, one 110 mg capsule twice a day. Renal impairment (SPAF, DVT/PE) Before starting treatment with this product, renal function should be assessed by calculating creatinine clearance and patients with severe renal impairment (i.e., CrCL <30 mL/min) should be excluded. There are no data to support the use of the drug in patients with severe renal impairment (CrCL <30 mL/min); treatment with this product is not recommended in these populations (see [Contraindications]). During treatment, renal function should be assessed when there are clinical conditions that may cause a decrease or worsening of renal function (such as hypovolemia, dehydration, and some specific concomitant medications). Dabigatran can be removed by dialysis, and there is limited experience in the application of this method in clinical trials. For patients with mild renal impairment (CrCL50-≤80 mL/min), no dose adjustment is required. For patients with moderate renal impairment (CrCL30~50 mL/min), the recommended dose of this product is 300 mg, that is, one 150 mg capsule twice a day. However, for patients at high risk of bleeding, a dose reduction of 220 mg should be considered, i.e. one 110 mg capsule twice daily. Close clinical monitoring is recommended for patients with impaired renal function. Weight (SPAF, DVT/PE) Based on available clinical and kinetic data, no dose adjustment is required, but close clinical monitoring is recommended for patients weighing <50 kg. Gender (SPAF, DVT/PE) Based on available clinical and kinetic data, no dose adjustment is required. Conversion of other drugs from tadalafil to parenteral anticoagulant therapy Conversion from tadalafil to parenteral anticoagulant therapy should be performed 12 hours after the last dose of tadalafil. Conversion from parenteral anticoagulant therapy to tadalafil should be taken within 2 hours before the next treatment time, and if the patient is receiving maintenance therapy (such as intravenous unfractionated heparin), tadalafil should be taken at the time of discontinuation. Conversion from vitamin K antagonists to tadalafil therapy should discontinue the vitamin K antagonist. When the INR (international normalized ratio of prothrombin) is <2.0, tadalafil can be given immediately. Switching from tamoxifen to vitamin K antagonist therapy The decision on when to start vitamin K antagonist (VKA) therapy should be based on the patient's creatinine clearance: • When CrCL ≥ 50 ml/min, start VKA therapy 3 days before stopping tamoxifen; • When 30 ml/min ≤ CrCL < 50 ml/min, start VKA therapy 2 days before stopping tamoxifen. Other Cardioversion: tamoxifen therapy can be maintained during cardioversion. Catheter ablation for the treatment of atrial fibrillation Catheter ablation can be performed in patients with atrial fibrillation who are treated with tamoxifen 150 mg twice daily. There is no need to interrupt treatment with tamoxifen. Missed medication: If the next dose is more than 6 hours away, the missed dose of tamoxifen can still be taken. If the next dose is less than 6 hours away, the missed dose should be ignored. Do not use a double dose of medication to make up for a missed dose. Instructions for use/handling: When removing hard capsules from blisters, please observe the following instructions: • Tear off a blister from the blister card along the perforation line • Tear off the backing foil and remove the capsule • Do not remove the capsule through the outside of the blister foil.

Safety Summary The safety of this product has been comprehensively evaluated through 11 clinical trials with a total of 38,141 patients: 23,393 patients with this product were investigated. In the key study observing the effect of this product in preventing stroke and SEE in patients with atrial fibrillation, a total of 12,042 patients were treated with this product. Among them, 6,059 patients received this product at a dose of 150 mg twice a day, and 5,983 patients received this product at a dose of 110 mg twice a day. In the trial for the treatment of acute deep vein thrombosis/pulmonary embolism (RE-COVER, RE-COVERⅡ), a total of 2,553 patients were included in the safety analysis of this product. All patients received this product at a dose of 150 mg twice a day. In the trials for the prevention of recurrent deep vein thrombosis/pulmonary embolism (RE-MEDY, RE-SONATE), a total of 2,114 patients were treated with this product; 552 patients were switched from the RE-COVER trial (acute deep vein thrombosis/pulmonary embolism treatment) to the RE-MEDY trial and were included in the total number of acute and recurrent patients. All patients received 150 mg of this product twice daily. A total of 22% of patients with atrial fibrillation receiving stroke or SEE prevention (maximum treatment duration of 3 years); 14% of patients receiving acute deep vein thrombosis/pulmonary embolism treatment (maximum treatment duration of 6 months); and 15% of patients receiving recurrent deep vein thrombosis/pulmonary embolism prevention (maximum treatment duration of 36 months) experienced adverse reactions. The most commonly reported adverse reaction was bleeding, with approximately 16.6% of patients with atrial fibrillation receiving stroke and SEE prevention treatment and 14.4% of patients receiving acute deep vein thrombosis/pulmonary embolism treatment experiencing varying degrees of bleeding. In the RE-MEDY and RE-SONATE trials for recurrent DVT/PE, bleeding was observed in 19.4% and 10.5% of patients, respectively. Although the frequency of occurrence in clinical trials is very low, major or severe bleeding can occur, and bleeding at any site may result in disabling, life-threatening, or fatal outcomes. Adverse Reactions Table 1 shows the adverse reactions observed in the Prevention of Thromboembolic Stroke and SEE studies in patients with atrial fibrillation, as well as in the treatment of acute deep vein thrombosis (DVT)/pulmonary embolism (PE) and prevention of recurrent DVT/PE, listed by system organ class (SOC) and classified using the following customary frequency definitions: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1000, <1/100); Rare (≥1/10000, <1/1000); Very rare (<1/10000); Unknown (cannot be estimated from available data). Major bleeding is defined as bleeding that meets one or more of the following criteria: bleeding accompanied by a drop in hemoglobin level of at least 20 g/L, or bleeding that requires transfusion of at least 2 units of blood or blood cells. Symptomatic bleeding in critical sites or organs: intraocular, intracranial, intraspinal, or intramuscular bleeding with compartment syndrome, retroperitoneal bleeding, intraarticular bleeding, or pericardial bleeding. Major bleeding that meets one or more of the following criteria is defined as life-threatening bleeding: fatal bleeding, symptomatic intracranial bleeding; bleeding accompanied by a drop in hemoglobin of at least 50 g/L; bleeding that requires transfusion of at least 4 units of blood cells, bleeding accompanied by hypotension requiring intravenous vasopressors; bleeding that requires surgical intervention. Compared with those receiving warfarin, patients randomized to dabigatran etexilate 110 mg twice daily and 150 mg twice daily had a significantly reduced risk of overall bleeding, life-threatening bleeding, and intracranial bleeding (p < 0.05). The risk of major bleeding was significantly reduced in subjects randomized to dabigatran 110 mg twice daily compared with warfarin (hazard ratio 0.81, [p=0.0027]). The risk of major gastrointestinal bleeding was significantly increased in subjects randomized to dabigatran 150 mg twice daily compared with warfarin (hazard ratio 1.47, [p=0.0008]), mainly in patients ≥75 years of age. The benefits of dabigatran compared with warfarin in preventing stroke and SEE, as well as the reduction in the risk of intracranial hemorrhage (ICH), were consistent across subgroups (eg, renal impairment, age, and concomitant medications such as antiplatelet agents or P-gp inhibitors). In specific subgroups of patients at increased risk of major bleeding while on anticoagulant therapy, the excess bleeding risk with dabigatran was driven by gastrointestinal bleeding, which generally occurred within the first 3 to 6 months after the start of dabigatran therapy. Major bleeding events (MBE) were defined according to the recommendations of the International Society on Thrombosis and Haemostasis. Bleeding events were classified as MBEs if they met one or more of the following criteria: • Fatal bleeding • Symptomatic bleeding at a critical site or organ: intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or muscle (with compartment syndrome). Bleeding at a critical site or organ must have symptomatic clinical presentation to be classified as an MBE. • Bleeding that resulted in a fall in hemoglobin level greater than 20 g/L (1.24 mmol/L) or resulted in the transfusion of 2 or more units of whole blood or red blood cells. Myocardial infarction In the RE-LY study, the annualized event rate of myocardial infarction was 0.82% (110 mg of 110 mg twice daily) and 0.81% (150 mg of 110 mg twice daily) in the tamoxifen group and 0.64% in the warfarin group (see [Clinical Trials]).

• Those with known hypersensitivity to the active ingredient or any of the excipients of this product. • Patients with severe renal insufficiency (CrCl < 30 ml/min) (see [Dosage and Administration]). • Clinically significant active bleeding. • Lesions or conditions with a significant risk of major bleeding, such as current or recent peptic ulcers, malignant neoplasms with high bleeding risk, recent brain or spinal cord injury, recent brain, spinal cord or eye surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. • Use any other anticoagulant drugs in combination, such as unfractionated heparin (UFH), low molecular weight heparin (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux sodium, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except in the case of switching from such treatment to this product or vice versa (see [Dosage and Administration]), and the necessary dose of UFH for maintaining the patency of central venous or arterial catheters (see [Drug Interactions]). • Hepatic impairment or liver disease that could be expected to affect survival. • Concomitant use of cyclosporine, systemic ketoconazole, itraconazole, and dronedarone (see [Drug Interactions]). • Prosthetic heart valves requiring anticoagulation (see [Precautions]).

Precautions for children: Prevention of stroke and systemic embolism (SEE) in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors: Due to the lack of safety and efficacy data for the use of this product in patients under 18 years of age, this product is not recommended for use in patients under 18 years of age. Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related deaths, prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related deaths: The safety and efficacy of pediatric use have not yet been established, so this product is not recommended for use in patients under 18 years of age. Pregnancy and lactation precautions: Contraception for women of childbearing age/men and women Women of childbearing age should avoid pregnancy while receiving this product. Pregnancy There are no adequate data on the exposure of pregnant women to this product. Animal studies have shown reproductive toxicity (see Toxicology Studies in [Pharmacology and Toxicology]). Whether there is a potential risk to humans is unknown. Pregnant women should not be treated with this product unless absolutely necessary. Lactation There are no clinical data on the effects of dabigatran on breastfeeding infants. Breastfeeding should be discontinued during treatment with this product. There are no human test data for reproduction. In animal studies, the effect on female animal fertility was manifested as a decrease in the number of implantations and an increase in pre-implantation losses at 70 mg/kg (a level 5 times higher than the patient's plasma exposure level). No other effects on female animal fertility were observed. There was no effect on male animal fertility. At doses toxic to the mother (5 to 10 times higher than the patient's plasma exposure level), decreased fetal weight and embryo-fetal survival were observed in rats and rabbits, and increased fetal variability. In prenatal and postnatal studies, increased fetal mortality was observed at dose levels toxic to the mother (4 times higher than the patient's plasma exposure level). Elderly precautions: Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related deaths, prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related deaths: The therapeutic dose for patients aged 80 years and above is 220 mg per day, i.e. 1 110 mg capsule each time, twice a day. See Special Populations under Dosage and Administration.

Not yet clear

Seal and store in a dry place below 25℃

110 mg x 10 capsules x 3 plates

24 months

Chengdu Easton Bio Pharmaceuticals Co., Ltd.

• Founded in:

  2009-06-01

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  No. 8, Xiyuan Avenue, Chengdu Hi-tech Zone

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