[Approval Date
Dabigatranate Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: (A) Early discontinuation of dabigatranate increases the risk of thrombotic events
(B) Spinal/epidural hematoma
(A) Increased risk of thrombotic events with early discontinuation of dabigatranate: Early discontinuation of any oral anticoagulant, including dabigatranate, increases the risk of thrombotic events. To reduce this risk, another anticoagulant should be considered if dabigatranate is discontinued for reasons other than pathologic bleeding or completion of a course of therapy.
(B) Spinal/Epidural Hematomas: Patients treated with dabigatranate who receive intrathecal anesthesia or undergo spinal puncture may develop epidural or spinal hematomas. These hematomas may result in long-term or permanent paralysis. Patients should be monitored frequently for signs and symptoms of neurological impairment and treated immediately if any of these signs and symptoms are observed. For patients receiving or requiring anticoagulant therapy, the benefits and risks should be considered before performing intralesional interventions.
Drug Name]
Generic name: Dabigatranate Capsules
English name: Dabigatran Etexilate Capsules
Hanyu Pinyin: Dabijiaqunzhi Jiaonang
【Composition】 The active ingredient of this product is 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.
Chemical structure formula.
Molecular formula: C34H41N7O5-CH4O3S
Molecular weight: 723.86 (methanesulfonate)
627.75 (free)
【Properties】.
This product is a capsule, the contents of which are off-white to yellow granules.
Indications】
Prevention of stroke and body circulation embolism (SEE) in adults with non-valvular atrial fibrillation (NVAF) in the presence of one or more of the following risk factors.
Prior stroke, transient ischemic attack, or embolism of the body circulation
Left ventricular ejection fraction<40%
Symptomatic heart failure with New York Heart Association (NYHA) cardiac function 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 deaths.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related deaths.
Specification
(1) 75mg (as dabigatranate); (2) 110mg (as dabigatranate).
Dosage and Administration
Take orally, swallow whole with water, either with or after meals. If gastrointestinal symptoms occur, it is recommended to take this product with a meal and/or a proton pump inhibitor, such as pantoprazole. Do not open the capsule.
Prevention of stroke and SEE (SPAF) in adults with non-valvular atrial fibrillation (NVAF) in the presence of one or more risk factors.
The recommended dose for adults is 300 mg orally twice daily, i.e., 150 mg per dose (2 75 mg capsules). Long-term treatment should be maintained.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related deaths.
The recommended dose for adults is 300 mg orally twice daily, i.e., 150 mg per dose (2 75 mg capsules). It should be initiated after receiving at least 5 days of parenteral anticoagulant therapy.
Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related deaths.
The recommended dose for adults is 300 mg orally twice daily, i.e., 150 mg per dose (2 75 mg capsules).
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE), prevention of associated death, prevention of recurrent DVT and/or pulmonary embolism (PE) and associated death: The duration of treatment should be determined on an individual basis after careful assessment of treatment benefit versus bleeding risk. Short-term treatment (at least 3 months) should be given based on transient risk factors (e.g., recent surgery, trauma, braking) and long-term treatment based on permanent risk factors or idiopathic DVT or PE.
SPAF, Dose adjustment for patients with DVT/PE.
The recommended dose of this product is 220 mg orally twice daily in one 110 mg capsule for the following patients.
Patients aged 80 years and older
Patients receiving concomitant treatment with verapamil
For the following patient groups, the dose of 300 mg or 220 mg of this product daily should be selected based on individual assessment of the patient’s thromboembolic risk and bleeding risk.
Patients between the ages of 75 and 80 years
Patients with moderately impaired renal function
Patients with gastritis, esophagitis, or gastroesophageal reflux
Other patients with increased risk of bleeding
For DVT/PE, the recommended dose is 220 mg orally per day in one 110 mg capsule twice daily, which is based on pharmacokinetic and pharmacodynamic analysis and has not been studied in a clinical setting.
See below for more details.
Elderly (SPAF, DVT/PE)
A daily dose of 300 mg, i.e., 150 mg per dose (2 75 mg capsules) twice daily, should be used for patients between the ages of 75 and 80 years. When the risk of thromboembolism is low and the risk of bleeding is high, a dose of 220 mg daily, i.e., one 110 mg capsule twice daily, may be considered, at the discretion of the physician.
For patients aged 80 years and older, a dose of 220 mg daily, one 110 mg capsule twice daily, should be used due to their increased risk of bleeding.
Because impaired renal function is more common in the elderly (>75 years of age), renal function should be assessed by calculating creatinine clearance (CrCL) before initiating treatment with this product, and this should be used to exclude patients with severe renal impairment (i.e., CrCL<30 mL/min). In patients treated with this product, renal function should be evaluated at least annually during the course of therapy when clinical conditions exist in which renal function may decline or deteriorate (e.g., hypovolemia, dehydration, and with some specific combination of medications).
Patients with bleeding risk (SPAF, DVT/PE)
Patients at increased risk of bleeding should be closely monitored clinically (for signs of bleeding or anemia). Dose adjustments may be made at the discretion of the physician following an assessment of the potential benefit and risk to the individual patient. Coagulation testing may be helpful in determining whether a patient’s increased risk of bleeding is the result of excessive dabigatran exposure. When dabigatran overexposure is identified in patients with a high risk of bleeding, a dose of 220 mg per day, one 110 mg capsule twice daily, is recommended. Treatment should be interrupted if clinically relevant bleeding occurs.
In patients with gastritis, esophagitis, or gastroesophageal reflux who are at increased risk for major gastrointestinal bleeding, a dose of 220 mg daily, one 110 mg capsule twice daily, should be considered.
Impaired renal function (SPAF, DVT/PE)
Renal function should be assessed by calculating creatinine clearance prior to initiation of therapy with this product, and this should be used to exclude patients with severe renal impairment (i.e., CrCL < 30 mL/min). There are no data to support administration in patients with severe renal impairment (CrCL < 30 mL/min); administration of this product in these populations is not recommended (see [Contraindications]).
Renal function should be evaluated during therapy when clinical conditions exist in which renal function may decline or worsen (e.g., hypovolemia, dehydration, and with some specific combinations of medications).
Dabigatran can be cleared by dialysis; there is limited experience with the clinical application of this method in clinical trials.
In patients with mild renal impairment (CrCL 50-≤80 mL/min), no dose adjustment is required. For patients with moderate renal impairment (CrCL 30-50 mL/min), the recommended dose of this product is 300 mg, i.e., 150 mg per dose (2 capsules of 75 mg) twice daily. However, for patients at high risk of bleeding, a dose reduction to 220 mg, i.e., one 110 mg capsule twice daily, should be considered. Close clinical monitoring is recommended for patients with impaired renal function.
Body weight (SPAF, DVT/PE)
Based on available clinical and kinetic data, no dose adjustment is necessary, 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.
Switching therapy from other drugs
Conversion from this product to parenteral anticoagulation
Conversion from this product to parenteral anticoagulation therapy should be made 12 hours after the last dose of this product.
Conversion from parenteral anticoagulation therapy to this drug
This product should be administered within 2 hours prior to the next treatment time or, if the patient is receiving maintenance therapy (e.g., regular heparin given intravenously), at the time of discontinuation.
Switching from vitamin K antagonist to this treatment
Vitamin K antagonists should be discontinued. When the INR (International Normalized Ratio of prothrombin) < 2.0, this product may be given immediately.
Switching from this product 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 discontinuation of this product.
When 30 ml/min ≤ CrCL < 50 ml/min, VKA therapy should be given 2 days prior to discontinuation of this product.
Other
Cardioversion
Treatment with this drug may be maintained during cardioversion.
Catheter ablation for the treatment of atrial fibrillation
Catheter ablation may be performed in patients with atrial fibrillation treated with 150 mg (2 75 mg capsules) of this drug twice daily. There is no need to suspend treatment with this product.
Missed Doses
If it is more than 6 hours before the next dose, the missed dose of this product 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 to make up for a missed dose.
Instructions for use/operation
After the bottle is opened, the desiccant should be placed in the original bottle, please do not throw it away.
[Adverse Reactions].
Safety summary
The overall safety of dabigatranate capsules has been evaluated in 11 clinical trials with a total of 38,141 patients; 23,393 of these dabigatranate capsules patients were investigated.
In the pivotal study looking at the effect of dabigatranate capsules on stroke and SEE prevention in patients with atrial fibrillation, a total of 12,042 patients were treated with dabigatranate capsules. Of these, 6,059 patients received dabigatranate capsules at 150 mg twice daily and 5,983 patients received dabigatranate capsules at 110 mg twice daily.
A total of 2,553 patients were included in the safety analysis of dabigatranate capsules in the trials for the treatment of acute deep vein thrombosis/pulmonary embolism (RE-COVER, RE-COVER II). All patients received dabigatranate capsules at 150 mg twice daily.
In the trials for the prevention of recurrent deep vein thrombosis/pulmonary embolism (RE-MEDY, RE-SONATE), a total of 2,114 patients received dabigatranate capsules; 552 of these patients were converted from the RE-COVER trial (treatment of acute deep vein thrombosis/pulmonary embolism) to the RE-MEDY trial and were counted in the total number of acute and recurrent patients. All patients received dabigatranate capsules 150 mg each time twice daily.
A total of 22% of patients with atrial fibrillation receiving stroke or SEE prophylaxis (maximum treatment duration of 3 years); 14% of patients treated for acute DVT/pulmonary embolism (maximum treatment duration of 6 months); and 15% of patients receiving recurrent DVT/pulmonary embolism prophylaxis (maximum treatment duration of 36 months) experienced adverse reactions.
The most frequently reported adverse reaction was bleeding, which occurred to varying degrees in approximately 16.6% of patients with atrial fibrillation treated with stroke and SEE prophylaxis and 14.4% of patients treated with acute DVT/pulmonary embolism. In the recurrent DVT/pulmonary embolism trials RE-MEDY and RE-SONATE, bleeding was found in 19.4% and 10.5% of patients, respectively.
Although the frequency of occurrence in clinical trials is low, major or severe bleeding can still occur, and bleeding at any site may result in disability, life-threatening or fatal outcomes.
Adverse effects
Table 1 Adverse reactions observed in thromboembolic stroke prevention and SEE studies in patients with atrial fibrillation and in the treatment of acute deep vein thrombosis (DVT)-formation/pulmonary embolism (PE) and prevention of recurrent DVT/PE, listed according to the System Organ Classification (SOC) and classified using the following customary frequency definitions: very common (≥1/10); common (≥1/100,< 1/10); occasional (≥1/1,000,<1/100); rare (≥1/10,000,<1/1,000); very rare (<1/10,000); and unclear (cannot be estimated from the available data).
Table 1 Adverse effects observed in thromboembolic stroke prevention and SEE studies in patients with atrial fibrillation and in the treatment of acute deep vein thrombosis (DVT)-formation/pulmonary embolism (PE) and prevention of recurrent DVT/PE
Stroke and SEE prevention in patients with atrial fibrillation DVT/PE treatment and DVT/PE prevention SOC/preferred terms Frequency of occurrence Frequency of occurrence Blood and lymphatic system abnormalities Anemia common uncommon Hemoglobinopenia uncommon unknown Thrombocytopenia uncommon rare Red blood cell pressure reduction rare unspecified Immune system abnormalities Drug allergy uncommon uncommon Rash uncommon uncommon pruritus uncommon uncommon rapid onset Allergic reaction rare rare angioedema rare rare urticaria rare rare bronchospasm unknown unspecified neurologic abnormality intracranial hemorrhage uncommon uncommon vascular abnormality hematoma uncommon uncommon bleeding uncommon uncommon respiratory, thoracic and mediastinal abnormalities nasal bleeding common common hemoptysis uncommon uncommon gastrointestinal abnormality gastrointestinal bleeding common common abdominal pain common uncommon diarrhea common uncommon dyspepsia Common Common Nausea Common Uncommon Rectal bleeding Uncommon Common Hemorrhoid bleeding Uncommon Uncommon Uncommon Gastrointestinal ulcers, including esophageal ulcers Uncommon Uncommon Gastroesophagitis Uncommon Uncommon Gastroesophageal reflux disease Uncommon Uncommon Vomiting Uncommon Uncommon Dysphagia Uncommon Rare Abnormalities of the hepatobiliary system Abnormal liver function/abnormal liver function tests Uncommon Uncommon Elevated alanine aminotransferase Uncommon Uncommon Elevated aspartate aminotransferase uncommon uncommon elevated liver enzymes rare uncommon hyperbilirubinemia rare unspecified Skin and subcutaneous tissue abnormalities Skin bleeding common common musculoskeletal and connective tissue abnormalities Joint effusion rare uncommon Renal and urinary system abnormalities Genitourinary bleeding, including hematuria common common common systemic and drug administration site abnormalities Injection site bleeding rare rare catheter site bleeding rare rare Injury, poisoning, and surgical complications Traumatic bleeding rare uncommon Incision site bleeding rare rare
Hemorrhage
Table 2 lists the bleeding events classified as major bleeding and any bleeding in the pivotal studies of thromboembolic stroke and SEE prevention in patients with atrial fibrillation.
Table 2 Number of bleeding events and annualized event rate (%) in the RE-LY trial
Dabigatranate 110 mg twice daily Dabigatranate 150 mg twice daily Warfarin Number of subjects randomized 6,0156,0766,022 Major bleeding 347 (2.92%) 409 (3.40%) 426 (3.61%) Intracranial bleeding 27 (0.23%) 39 (0.32%) 91 (0.77%) Gastrointestinal bleeding 134 ( 1.13%)192 (1.60%)128 (1.09%)Fatal bleeding26 (0.22%)30 (0.25%)42 (0.36%)Minor bleeding1,566 (13.16%)1,787 (14.85%)1,931 (16.37%)Any bleeding1,759 (14.78%)1,997 (16.60% ) 2,169 (18.39%)
One or more of the following criteria were met to qualify as major bleeding.
Bleeding accompanied by a decrease in hemoglobin level of at least 20 g/L or resulting in the need for blood transfusion or bleeding of at least 2 units of blood cells
Symptomatic bleeding at a critical site or organ: intraocular, intracranial, intraspinal or intramuscular bleeding with osteofascial compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding.
A hemorrhage is said to be life-threatening if it meets one or more of the following criteria.
Fatal bleeding, symptomatic intracranial hemorrhage; bleeding accompanied by a drop in hemoglobin of at least 50 g/L; bleeding requiring blood transfusion or blood cells of at least 4 units, bleeding accompanied by hypotension requiring intravenous antihypertensive drugs; bleeding that must be treated surgically.
Patients randomized to receive dabigatranate capsules 110 mg twice daily and 150 mg twice daily showed a significantly reduced risk of overall bleeding, life-threatening bleeding and intracranial hemorrhage compared to those receiving warfarin (p<0.05). Subjects randomized to receive dabigatranate capsules at 110 mg twice daily had a significantly lower risk of major bleeding compared to warfarin (hazard ratio 0.81, [p=0.0027]). Subjects randomized to receive dabigatranate capsules 150 mg each twice daily had a significantly increased risk of major gastrointestinal bleeding compared to warfarin (hazard ratio 1.47, [p=0.0008]), which was predominantly seen in patients ≥75 years of age.
All subgroups (e.g., renal impairment, age, combination of antiplatelet agents or P-gp inhibitors) demonstrated benefits of dabigatran compared with warfarin in stroke and SEE prevention, as well as a decreased risk of intracranial hemorrhage (ICH). In the specific subgroup of patients at increased risk of major bleeding with anticoagulant therapy, the excess bleeding risk with dabigatran was due to gastrointestinal bleeding and generally occurred in the first 3 to 6 months after initiation of dabigatranate capsule therapy.
The definition of a major bleeding event (MBE) follows the recommendations of the International Society for Thrombosis and Haemostasis. A bleeding event is classified as an MBE if it meets 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 muscular (with osteofascial compartment syndrome) bleeding. Bleeding from a critical site or organ must have symptomatic clinical manifestations to be classified as MBE.
Bleeding that results in a decrease in hemoglobin level of more than 20 g/L (1.24 mmol/L) or results in 2 or more units of whole blood or red blood cell transfusions.
Myocardial infarction
In the RE-LY study, the annualized event rate of myocardial infarction was 0.82% (dabigatranate capsules 110 mg twice daily) and 0.81% (dabigatranate capsules 150 mg twice daily) in the dabigatranate capsules group and 0.64% in the warfarin group.
[Contraindication].
Known hypersensitivity to the active ingredient or any of the excipients of this product.
Patients with severe renal impairment (CrCL <30ml/min) (see [Dosage and Administration]).
Clinically significant active bleeding.
Lesions or conditions with significant risk of major bleeding, such as current or recent peptic ulcers, malignant bullae 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 intra-spinal or intracerebral vascular abnormalities.
Combine any other anticoagulant such as normal heparin (UFH), low molecular heparin (enoxaparin, dalteparin, etc.), heparin derivatives (sulforaphane sodium, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except when switching from such therapy to this product or vice versa (see [DOSAGE AND ADMINISTRATION]), and at doses necessary to maintain patency of central venous or arterial placement with UFH (see [DOSAGE AND ADMINISTRATION]). See [Drug Interactions]) in these cases.
Have hepatic impairment or liver disease that is expected to affect survival time.
Combine cyclosporine, systemic ketoconazole, itraconazole, and dronedarone (see [Drug Interactions]).
Prosthetic heart valves requiring anticoagulation therapy (see [Precautions]).
[Precautions].
Impaired liver function
Patients with elevated liver enzymes >2 ULN (upper limit of normal) were excluded from clinical trials of atrial fibrillation-associated stroke and SEE prevention. There is no treatment experience with this patient subgroup, so this product is not recommended for this population.
Risk of Bleeding
As with all other anticoagulants, this product should be used with caution when there is an increased risk of bleeding. Bleeding can occur at any site during treatment with this product. If unexplained decreases in hemoglobin and/or red blood cell pressure or blood pressure occur, look for the site of bleeding.
If life-threatening or uncontrollable bleeding occurs, specific reversal medications (etanercept Injection) may be used when rapid reversal of the anticoagulant effect of dabigatran is required (see “Surgery and Operations”, “Before Surgery” and [Drug Overdose].)
The following factors are associated with increased dabigatran blood levels: decreased renal function (CrCL 30-50 mL/min), age ≥ 75 years, low body weight <50 kg, or co-administration of potent P-gp inhibitors (e.g., amiodarone, quinidine, or verapamil) (see [Dosage], [Drug Interactions], and [Pharmacokinetics]).
Co-administration of tegretol increases dabigatran exposure and may exhibit pharmacodynamic interactions that result in an increased risk of bleeding (see [Drug Interactions]).
In a stroke and SEE prevention study in adult patients with non-valvular atrial fibrillation, dabigatran was associated with a higher incidence of gastrointestinal (GI) major bleeding, and a statistically significant increase in the incidence of major bleeding was seen following twice-daily administration of 150 mg of this product, and this increased risk was seen in older patients (≥75 years). The use of acetylsalicylic acid (ASA), clopidogrel, or nonsteroidal anti-inflammatory drugs (NSAID) and the presence of esophagitis, gastritis, or gastroesophageal reflux requiring treatment with a proton pump inhibitor (PPI) or histamine 2 (H2)-blocker increases the risk of gastrointestinal bleeding. In these patients with atrial fibrillation, a dose of 220 mg daily of this product should be considered, i.e., one 110 mg capsule taken twice daily (see [Dosage]). A PPI may be considered for the prevention of GI bleeding.
The risk of bleeding may be increased in patients on combination selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) or selective 5-hydroxytryptamine noradrenaline reuptake inhibitors (SNRIs) (see [Drug Interactions]).
Close clinical monitoring (monitoring for signs of bleeding or anemia) throughout the treatment period is recommended, especially when combined risk factors are present (see [Pharmacologic Toxicology]).
Factors that may increase the risk of bleeding are summarized in Table 3. Please also see contraindications in [Contraindications].
Table 3 Factors that may increase the risk of bleeding
Pharmacodynamic and Kinetic Factors Age ≥ 75 years Factors that increase dabigatran blood levels are mainly.
Moderate renal impairment (30 to 50 ml/min CrCL)
Combined use of P-gp inhibitors (some P-gp inhibitors are contraindicated, see [Contraindications] and [Drug Interactions])
Secondary.
Low body weight (<50 kg) Pharmacodynamic interactions ASA
NSAID
Clopidogrel
SSRIs or SNRIs
Other drugs that may diminish hemostasis Diseases with specific bleeding risks/operations Congenital or acquired coagulation abnormalities
Thrombocytopenia or functional platelet defects
Recent biopsy or major trauma
Bacterial endocarditis
Esophagitis, gastritis, or gastroesophageal reflux A careful risk-benefit assessment is required when lesions, conditions, operations, and/or drug treatments (e.g., NSAIDs, antiplatelet agents, SSRIs, and SNRIs, see [Drug Interactions]) that significantly increase the risk of bleeding are present. This product should only be used when the benefit outweighs the risk of bleeding.
This product does not require routine anticoagulation monitoring. However, dabigatran-related anticoagulation testing may be useful to avoid overexposure to dabigatran in the presence of other risk factors. INR testing in patients taking this product is unreliable and false positive reports of elevated INR may occur. Therefore, INR testing should not be performed. Dilute prothrombin time (dTT), serrapeptin clotting time (ECT), and activated partial thromboplastin time (aPTT) may provide valid information, but these tests are not standardized and results should be interpreted with caution (see [Pharmacology and Toxicology]). The anticoagulant effect associated with dabigatran can be evaluated by ECT or TT. If ECT or TT cannot be tested, the anticoagulant activity of the product can be broadly assessed using aPTT.
Table 4 shows the lower limits of anticoagulation assays that may indicate an increased risk of bleeding.
Table 4 Lower limits of anticoagulation assays that may indicate an increased risk of bleeding
Assay (lower limit value) dTT [ng/ml]>200ECT [x times the upper limit of normal]>3aPTT [x times the upper limit of normal]>2INR should not be performed (see [Pharmacology and Toxicology])
This product should be discontinued in patients who have experienced acute renal failure (see [Contraindications]).
Limited data in patients weighing <50 Kg (see [Pharmacokinetics])
If severe bleeding occurs, treatment should be discontinued and the source of the bleeding investigated (see [Drug Overdose]).
Drugs that may cause an increased risk of bleeding should not be given in combination with this product or should be given with caution (see [Drug Interactions]).
Use of thrombolytic drugs in the treatment of acute ischaemic stroke
Thrombolytic drugs may be considered in the treatment of acute ischaemic stroke if the patient’s dTT, ECT or aPTT does not exceed the upper limit of normal for local reference values.
Interaction with P-gp inducers
It is expected that the combination of this product with P-gp inducers (e.g., rifampicin, Kanbacil (goldenseal), carbamazepine, or phenytoin) will decrease dabigatran blood levels and should be avoided (see [Drug Interactions] and [Pharmacokinetics]).
Surgery and Operations
Surgery or invasive procedures can increase the risk of bleeding in patients using this product. Therefore, temporary discontinuation of this product may be required when undergoing surgical procedures.
Patients may continue to receive this product during cardioversion. In patients undergoing catheter ablation for atrial fibrillation, maintenance therapy (150 mg twice daily) is available (see Dosage and Administration).
If an emergency procedure or urgent operation is performed, a specific reversal agent (etanercept Injection) of dabigatranate capsules may be used when rapid reversal of the anticoagulant effect is required.
Reversal of the effects of dabigatran therapy may expose patients to the risk of thrombosis due to the underlying disease. If the patient is clinically stable and adequate hemostasis has been achieved, dabigatranate capsule therapy may be resumed 24 hours after administration of edasalizumab injection.
Caution should be exercised when temporarily discontinuing treatment with this product due to manipulation, and anticoagulation monitoring should be performed. Dabigatran clearance may take longer in patients with renal impairment (see [Pharmacokinetics]). This must be taken into account prior to any manipulation. In such cases, coagulation tests (see [Precautions] and [Pharmacology and Toxicology]) may be useful to determine whether hemostasis remains impaired.
Before surgery
Table 5 summarizes the criteria for discontinuation of medication prior to invasive or surgical procedures.
Table 5 Criteria for discontinuation prior to invasive or surgical procedures
Renal function (CrCL, ml/min) Half-life estimate (hours) Discontinuation before elective surgery High risk of bleeding or major surgery Standard risk ≥ 80 to 132 days before 24 hours before >50 to <80 to 152 to 3 days before 1 to 2 days before >30 to <50 to 184 days before 2 to 3 days before (>48 hours) Emergency surgery/ Operation
Emergency surgery or urgent operations.
When rapid reversal of the anticoagulant effect is required, the specific reversal agent (etanercept Injection) may be used with dabigatranate capsules (see “Surgery and Operations”).
This product should be temporarily discontinued. If possible, emergency surgery/operation should be delayed until at least 12 hours after the last dose. If surgery cannot be delayed, there may be an increased risk of bleeding (see [Dosage] for cardioversion).
Endotracheal anesthesia/epidural anesthesia/lumbar puncture
Epidural or spinal hematomas may occur in patients treated with this product who receive endotracheal anesthesia or have a spinal puncture. These hematomas may result in long-term or permanent paralysis. Patients should be monitored frequently for signs and symptoms of neurological impairment and treated immediately if any of these signs and symptoms are observed. For patients receiving or requiring anticoagulant therapy, the benefits and risks should be considered prior to intravesical intervention. The optimal timing of dabigatranate administration with intralesional manipulation is not known.
Operations such as endovascular anesthesia may require complete hemostasis.
Trauma or repeated punctures and prolonged epidural catheter use may increase the risk of vertebral or epidural hematoma. The first dose of this product should be given at least 2 hours after removal of the catheter. Close monitoring of these patients for neurologic signs and symptoms of spinal or epidural hematoma is required.
Post-surgical patients at increased risk of bleeding
Patients at risk of bleeding or at risk of overexposure, especially in patients with moderate renal impairment (CrCL 30-50 ml/min), should be treated with caution (see [Precautions] and [Pharmacology and Toxicology]). Treatment should be restarted after complete hemostasis.
Patients at high risk of surgical death and with inherent risk factors for thromboembolic events
There are limited data on the efficacy and safety of dabigatran in these patients; therefore, they should use caution with this product.
Myocardial infarction
In the Phase III study RE-LY, the overall annualized event rates for myocardial infarction (MI) were 0.82%, 0.81%, and 0.64% for dabigatranate capsules 110 mg twice daily, dabigatranate capsules 150 mg twice daily, and warfarin, respectively. The absolute risk of myocardial infarction was highest in the following subgroups, independent of the treatment drug, and the relative risk was similar across subgroups: patients with prior myocardial infarction, patients aged ≥65 years with diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal impairment. In addition, a higher risk of myocardial infarction was observed in patients taking ASA + clopidogrel in combination or clopidogrel alone.
Effects on the ability to drive and operate machinery
This product has no or negligible effect on the ability to drive and operate machinery.
Pregnant women and nursing mothers
Contraception for women of childbearing age/men and women
Pregnancy should be avoided in women of childbearing age who are 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]). The existence of a potential risk to humans is unknown.
Pregnant females should not be treated with this product unless truly necessary.
Lactation
There are no clinical data on the effects of dabigatran on nursing infants. Breastfeeding should be discontinued during treatment with this product.
Fertility
No human trial data are available.
In animal studies, effects on fertility in females were manifested by a decrease in the number of engagements and an increase in prearrival losses at 70 mg/kg (a level 5 times higher than the patient’s plasma exposure level). No other effects on fertility were observed in females. There were no effects on fertility in males. At maternally toxic doses (levels 5 to 10 times higher than patient plasma exposure levels), decreased fetal litter weight and embryonic fetal viability and increased fetal variability were observed in rats and rabbits. In prenatal and postnatal studies, increased fetal mortality was observed at maternally toxic dose levels (4-fold higher than patient plasma exposure levels).
[Pediatric Dosage].
Prevention of stroke and somatic embolism (SEE) in adult patients with non-valvular atrial fibrillation (NVAF) in the presence of one or more risk factors: Dabigatranate capsules are not recommended for use in patients under 18 years of age due to the lack of safety and efficacy data on the use of dabigatranate capsules in patients under 18 years of age.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death, prevention of recurrent DVT and/or pulmonary embolism (PE) and related death: The safety and efficacy of dabigatranate capsules for use in children has not been established, so dabigatranate capsules are not recommended for use in patients under 18 years of age.
[Geriatric Use].
Prevention of stroke and body circulation embolism (SEE) in adults with non-valvular atrial fibrillation (NVAF) in the presence of one or more risk factors.
Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death, Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related death.
The therapeutic dose for patients 80 years of age and older is 220 mg per day, i.e., one 110 mg capsule twice daily.
See Special Populations under Dosage and Administration.
[Drug Interactions].
Anticoagulants and anti-platelet aggregating agents
There is no or limited experience with the following treatments that may increase the risk of bleeding when used in combination with this product: anticoagulants such as normal heparin (UFH), low molecular heparin (LMWH), heparin derivatives (sodium fondaparinux, deciludine), thrombolytic agents, vitamin K antagonists, rivaroxaban, or other oral anticoagulants (see [Contraindications]), and antiplatelet aggregation agents such as GPIIb/ IIIa receptor antagonists, ticlopidine, prasugrel, tegretol, dextran, and sulfopiridone (see [Precautions]).
The limited data collected from the Phase III study RE-LY in patients with atrial fibrillation observed that the combination of other oral or injectable anticoagulants, whether dabigatranate capsules or warfarin, increased the incidence of major bleeding by approximately 2.5-fold, primarily in the setting of switching from one anticoagulant to another (see [Contraindications] and [Precautions]).
Doses of UFH required to maintain central venous or arterial catheter patency may be used (see [Contraindications]).
Data from patients with atrial fibrillation collected in the phase III study RE-LY observed that the combination of the antiplatelet agents ASA or clopidogrel, whether dabigatranate capsules or warfarin, resulted in a doubling of the incidence of major bleeding (see [Precautions]).
Clopidogrel: In a clinical phase I study that included healthy young male volunteers, the combination of dabigatranate capsules and clopidogrel did not result in a further prolongation of capillary bleeding time compared with clopidogrel monotherapy. In addition, the dabigatran AUCτ,ss and Cmax,ss, the coagulation markers used to assess the effect of dabigatran, or the platelet aggregation inhibition marker used to assess the effect of clopidogrel remained essentially unchanged when the combination was administered compared to monotherapy with both. A 30% to 40% increase in dabigatran AUCτ,ss and Cmax,ss was observed with 300 mg or 600 mg clopidogrel loading doses (see [Precautions]) (see ASA paragraph below).
Aspirin (ASA): A phase II clinical study was conducted in patients with atrial fibrillation to examine the effect of the combination of dabigatranate capsules and ASA on the risk of bleeding in patients randomized to the combination of ASA. Based on logistic regression analysis, the combination of 81 mg or 325 mg ASA and dabigatranate capsules 150 mg twice daily may increase the risk of bleeding from 12% to 18% and 24%, respectively (see [Caution]).
Data obtained from the phase III clinical study RE-LY observed that the combination of ASA or clopidogrel with 110 or 150 mg dabigatranate capsules twice daily may increase the risk of major bleeding. However, an increased incidence of bleeding was also observed when ASA or clopidogrel was combined with warfarin.
NSAIDs: NSAIDs for short-term analgesic treatment during the perioperative period have been shown not to be associated with an increased risk of bleeding when co-administered with dabigatranate capsules. In the RE-LY study, long-term use of NSAIDs increased the risk of bleeding with dabigatranate capsules and warfarin by approximately 50%. Therefore, close observation for signs of bleeding is recommended due to the risk of bleeding, especially with NSAIDs that have an elimination half-life >12 hours. There is limited evidence for routine use of NSAIDs (half-life less than 12 hours) during dabigatranate capsule therapy and no indication of additional bleeding risks (see [Caution]).
LMWH: The combination of LMWH (e.g., enoxaparin) and dabigatranate capsules has not been studied specifically. Switching from once-daily 40 mg enoxaparin subcutaneous administration for 3 days to dabigatranate capsules, dabigatran exposure 24 hours after the last administration of enoxaparin was slightly lower than after dabigatranate capsules alone (single dose of 220 mg). Higher anti-FXa/FIIa activity was observed after enoxaparin pretreatment followed by administration of dabigatranate capsules than after dabigatranate capsules alone. This may be due to the after-effects of enoxaparin treatment and is considered to be of no clinical relevance. Enoxaparin pretreatment did not result in significant changes in other dabigatran-related anticoagulation tests.
Dabigatranate Capsules and Dabigatran Metabolic Properties-Related Interactions
Dabigatranate capsules and dabigatran are not metabolized by the cytochrome P450 system and have no in vitro effect on human cytochrome P450 enzymes. Therefore, no dabigatran-related drug interactions are expected to occur.
Transporter protein interactions
P-gp Inhibitors
Dabigatranate capsules are substrates of the efflux transporter P-gp. Combinations with potent P-gp inhibitors (e.g., amiodarone, verapamil, quinidine, ketoconazole, dronedarone, clarithromycin, and tegretol) are expected to result in elevated dabigatran blood levels.
If not otherwise specifically described, close clinical monitoring (monitoring for signs of bleeding or anemia) is required when dabigatran is used in combination with potent P-gp inhibitors.
Coagulation testing may help identify patients at increased risk of bleeding due to increased dabigatran exposure (see [Dosage], [Precautions], and [Pharmacologic Toxicology]).
Cyclosporine, systemic ketoconazole, itraconazole, and dronedarone are contraindicated (see [Contraindications]). Combination with tacrolimus is not recommended. Caution should be exercised when used in combination with other potent P-gp inhibitors (e.g., amiodarone, quinidine, verapamil, and tegretol) (see [Dosage] and [Precautions]).
Ketoconazole: A single 400 mg dose of ketoconazole increased the overall AUC0-∞ and Cmax of dabigatran by up to 138% and 135%, respectively, and continuous dosing of ketoconazole 400 mg once daily increased the overall AUC0-∞ and Cmax of dabigatran by up to 153% and 149%, respectively. Ketoconazole did not affect the time to peak, terminal half-life, or mean residence time of dabigatranate capsules (see [Precautions]). The combination of dabigatranate capsules with systemic ketoconazole is prohibited (see [Contraindications]).
Dronedarone: When dabigatranate capsules and dronedarone were administered concomitantly, dronedarone 400 mg administered twice daily increased the overall AUC0-∞ and Cmax of dabigatran by 2.4-fold and 2.3-fold (+136 % and 125 %), respectively, and dronedarone 400 mg administered as a single dose increased the overall AUC0-∞ and Cmax of dabigatran by 2.1-fold and 1.9-fold (+114 % and 87 %), respectively. (+114 % and 87 %). The terminal half-life and renal clearance of dabigatran were unaffected by dronedarone. Dabigatran AUC0-∞ increased 1.3-fold and 1.6-fold when dabigatran was given as a single dose and multiple doses after 2 hours of dabigatran administration, respectively. Combination of dabigatranate capsules with dronedarone is contraindicated.
Amiodarone: When dabigatranate capsules are combined with a single dose of 600 mg of amiodarone orally, the extent and rate of absorption of amiodarone and its active metabolite DEA remain essentially unchanged. The AUC and Cmax of dabigatran, on the other hand, were increased by approximately 60% and 50%, respectively. The mechanism of the interaction has not been fully elucidated. Given the long half-life of amiodarone, the potential for drug interactions also exists several weeks after amiodarone is discontinued (see [Precautions]). Close clinical monitoring is recommended when dabigatranate capsules are used in combination with amiodarone, especially in the event of bleeding, and is particularly indicated in patients with mild to moderate renal impairment.
Quinidine: Quinidine 200 mg administered every two hours to a total dose of 1000 mg, dabigatranate capsules twice daily for more than three consecutive days, in combination with or without quinidine on the third day. The above combination of quinidine resulted in an average increase in dabigatran AUCτ,ss and Cmax,ss of 53% and 56%, respectively (see [Precautions]). When dabigatranate capsules are used in combination with quinidine, close clinical monitoring is recommended, particularly in patients with mild to moderate renal impairment, especially in the event of bleeding.
Verapamil: When dabigatranate capsules (150 mg) are combined with oral verapamil, the Cmax and AUC of dabigatran are increased, but the magnitude of the change varies depending on the timing of verapamil administration and dosage form (see [Precautions]).
The largest increase in dabigatran exposure (approximately 180% increase in Cmax and 150% increase in AUC) occurred when the first dose of the immediate-release form of verapamil was given orally one hour prior to dabigatran ester capsule administration. This effect declined sequentially with administration of the extended-release form (~90% increase in Cmax and ~70% increase in AUC) or multiple doses of verapamil (~60% increase in Cmax and ~50% increase in AUC).
Close clinical monitoring is recommended when dabigatranate capsules are used in combination with verapamil, especially in the event of bleeding, and is particularly necessary in patients with mild to moderate renal impairment.
No meaningful interaction was observed when verapamil was given two hours after dabigatranate capsules (Cmax increased by approximately 10% and AUC by approximately 20%). This can be explained by the fact that dabigatran was completely absorbed two hours after administration (see [Precautions]).
Clarithromycin: When clarithromycin 500 mg twice daily was combined with dabigatran ester capsules in healthy volunteers, an increase in AUC of approximately 19% and an increase in Cmax of approximately 15% was observed without any clinical safety concerns. However, clinically relevant interactions cannot be excluded when dabigatran is combined with clarithromycin in patients taking dabigatran. Therefore, close monitoring should be performed when dabigatranate capsules are used in combination with clarithromycin, especially in the event of bleeding, and is particularly necessary in patients with mild to moderate renal impairment.
Tegretol: When a single 75 mg dose of dabigatranate capsules is administered concomitantly with a loading dose of 180 mg of tegretol, the AUC and Cmax of dabigatran increase to 1.73 and 1.95 times (+73% and 95%), respectively. Following administration of multiple doses of tegretol at 90 mg twice daily, dabigatran exposure Cmax and AUC then increased to 1.56-fold and 1.46-fold (+56% and 46%), respectively.
The AUCτ,ss and Cmax of dabigatran increased 1.49-fold and 1.65-fold (+ 49% and 65%) after concomitant administration of a loading dose of 180 mg of tegretol with 110 mg of dabigatranate capsules (steady state) compared with dabigatranate capsules alone. Compared to dabigatranate capsules alone, the increase in AUCτ,ss and Cmax for dabigatran was reduced to 1.27-fold and 1.23-fold (+ 27% and 23%) for a loading dose of 180 mg of tegretol administered 2 hours after 110 mg of dabigatranate capsules (steady-state).
Concomitant administration of 90 mg of tegretol BID (maintenance dose) with 110 mg of dabigatranate capsules resulted in a 1.26-fold and 1.29-fold increase in AUCτ,ss and Cmax for dabigatran compared with dabigatranate capsules alone.
Clinical studies have not been conducted with the following potent P-gp inhibitors, but similar effects to ketoconazole are expected based on the results of in vitro studies.
Itraconazole and cyclosporine, which are contraindicated for concomitant use with dabigatranate capsules (see [Contraindications]).
In vitro studies have found that tacrolimus inhibits P-gp at levels similar to itraconazole and cyclosporine. The combination of dabigatranate capsules with tacrolimus has not been studied in the clinical setting. However, limited clinical data on another P-gp substrate (everolimus) suggest that tacrolimus has a weaker inhibitory effect on P-gp than potent P-gp inhibitors. Based on these data, concomitant use of tacrolimus is not recommended.
Posaconazole also inhibits P-gp to some extent, but has not been studied in the clinic. Caution should be exercised with the combination of dabigatranate capsules and posaconazole.
P-gp inducers
It is expected that the combination with P-gp inducers (e.g., rifampicin, Kanbabrium (goldenseal), carbamazepine, or phenytoin) will decrease dabigatran blood levels and should be avoided (see [Precautions] and [Pharmacokinetics]).
Rifampin: Administration of the induction agent rifampin 600 mg once daily for seven days prior to dabigatran ester capsule administration reduced peak dabigatran exposure and total exposure by 65.5% and 67%, respectively. On the seventh day after rifampicin discontinuation, the induction effect was reduced, resulting in a dabigatran exposure close to the reference value. After a further seven days, no further increase in bioavailability was observed.
Other drugs that affect P-gp
Protease inhibitors (including ritonavir and its combinations with other protease inhibitors) affect P-gp (as inhibitors or inducers). They have not been studied and therefore are not recommended for use in combination with dabigatranate capsules.
P-gp substrates
Digoxin: In a study including 24 healthy subjects, no effect on digoxin was observed when dabigatranate capsules were combined with digoxin, and no clinically relevant changes in dabigatran exposure were observed.
Combination of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) or selective 5-hydroxytryptamine noradrenaline reuptake inhibitors (SNRIs)
Both SSRIs and SNRIs increased the risk of bleeding in all treatment groups of RE-LY.
Intragastric pH.
Pantoprazole: When dabigatranate capsules were used in combination with pantoprazole, an approximately 30% decrease in the area under the time curve of dabigatran blood concentrations was once observed. Pantoprazole and other proton pump inhibitors (PPIs) have been used in combination with dabigatranate capsules in clinical studies and no effect on the efficacy of dabigatranate capsules has been observed.
Ranitidine: The combination of ranitidine and dabigatranate capsules did not have a clinically relevant effect on the extent of dabigatran absorption.
[Drug Overdose].
Exceeding the recommended dose of this product can increase the risk of bleeding in patients.
In cases of suspected overdose, coagulation tests are useful to determine the risk of bleeding (see [Precautions] and [Pharmacology and Toxicology]). A calibrated quantitative (dTT) test or a repeat dTT test may predict the time to reach a specific dabigatran level (see [Pharmacologic Toxicology]), even if other measures (e.g., dialysis) have been initiated.
If excessive anticoagulation occurs, it may be necessary to interrupt treatment with this product. There is no specific antidote for dabigatran. If bleeding complications occur, treatment must be discontinued and the source of bleeding must be identified. Because dabigatran is excreted primarily by the renal route, moderate diuresis must be maintained. Appropriate supportive therapy, such as surgical hemostasis and blood volume replacement, should be administered under the direction of a physician.
When rapid reversal is required, a specific reversal drug (etanercept injection) that antagonizes the pharmacodynamic effects of dabigatranate capsules may be used. See also
[Precautions], “Surgery and Operations”, “Pre-surgery”.
Activated prothrombin complex concentrates (e.g., FEIBA) or recombinant factor VIIa, or coagulation factor II, IX, or X concentrates may be considered. There is some experimental evidence to support the role of these agents in reversing the anticoagulant effect of dabigatran, but data on their effectiveness in clinical practice and the potential risk of rebound leading to thromboembolism are limited. Anticoagulation assays may be unreliable after administration of these reversal agents, so caution should be exercised when performing these assays. Administration of platelet concentrates should be considered in cases where thrombocytopenia is present or where long-acting antiplatelet agents are already in use. All symptomatic treatment should be given according to the physician’s judgment.
If available, a consultation with an anticoagulation specialist should be considered when major bleeding occurs.
Because of its low protein binding rate, dabigatran can be cleared by dialysis, but clinical experience with dialysis treatment in this setting is limited (see [Pharmacokinetics]).
Pharmacology and Toxicology
Pharmacological effects
Dabigatran and its acetylglucuronide conjugate product are competitive direct thrombin inhibitors. Since thrombin (serine protease) converts fibrinogen to fibrin in the coagulation cascade reaction, inhibition of thrombin prevents thrombosis, and its active group also inhibits free thrombin, clot-bound thrombin, and thrombin-induced platelet aggregation.
Toxicological studies
Genotoxicity.
Ames test, mouse lymphoma test, human lymphocyte chromosomal aberration test, and in vivo micronucleus test results in rats were all negative.
Reproductive toxicity.
Oral administration of dabigatranate 15, 70 and 200 mg/kg to rats for 29 days prior to mating and during the mating period to the prescribed end time in males and 15 days prior to mating to day 6 of gestation in females showed that the 200 mg/kg group (or 9-12 times the most recommended human dose of MRHD 300 mg/day exposure based on AUC comparisons), did not significant effects on general fertility in male and female rats. However, female rats administered at a dose of 70 mg/kg (3 times the MRHD exposure based on AUC comparisons) showed a decrease in the number of engendered beds and an increase in pre-germinal loss. At maternal animal toxicity doses (5 to 10 times higher than patient plasma exposure levels), decreased litter weight and embryo-fetal viability and increased litter variability were seen in rats and rabbits. In perinatal reproductive toxicity studies, increased fetal mortality was seen at maternal toxicity doses (4-fold higher than patient plasma exposure levels).
Carcinogenicity.
No significant carcinogenicity was seen in mice and rats given dabigatran orally for 2 years. The maximum administered dose of 200 mg/kg/day in mice and rats was approximately 3.6 and 6 times the MRHD 300 mg/day exposure, respectively (based on AUC).
Pharmacokinetics]
After oral administration, dabigatranate capsules are rapidly and completely converted to dabigatran, which is the active component of dabigatranate capsules in plasma. The formation of the active ingredient dabigatran by esterase-catalyzed hydrolysis of the precursor drug dabigatran ester capsules is the main metabolic reaction. The absolute bioavailability of dabigatran after oral administration of dabigatran ester capsules is approximately 6.5%. The pharmacokinetics of dabigatran in plasma after oral administration of dabigatran ester capsules in healthy volunteers is characterized by a rapid increase in blood concentration, with peak concentration (Cmax) reached 0.5 to 2.0 hours after dosing.
Absorption
A study evaluating the postoperative absorption of dabigatranate capsules showed a relatively slow absorption rate, a flat plasma concentration-time curve, and no significant peak plasma concentrations occurring 1 to 3 hours after surgery compared to healthy volunteers. In the post-surgical phase, peak plasma concentrations were reached 6 hours after dosing due to influences such as anesthesia, gastrointestinal paralysis, and surgical effects unrelated to the oral drug formulation. Further findings show that slowed and delayed absorption usually occurs only on the day of surgery. After this time, dabigatran is rapidly absorbed, reaching peak plasma levels 2 hours after dosing.
Eating did not affect the bioavailability of dabigatranate capsules, but delayed the time to peak blood levels by 2 hours.
An increase in oral bioavailability of up to 75% may occur when the hydroxypropylmethylcellulose (HPMC) capsule shell is removed and the pellets are taken directly from it compared to the reference capsule form. Therefore, care should always be taken to maintain the integrity of the HPMC capsule during clinical use to avoid unintentional increases in the bioavailability of dabigatranate capsules. Therefore, patients should be advised not to open the capsule and to take the pellets alone (e.g., dispersed in food or in a beverage).
Dispersion
A non-concentration-dependent lower (34-35%) human plasma protein binding rate of dabigatran has been observed. The volume of distribution of dabigatran was 60-70 L, the latter exceeding the total body fluid volume, suggesting a moderate tissue distribution profile for dabigatran.
Cmax and area under the blood concentration time curve were dose dependent. Dabigatran plasma concentrations decreased in a double power, with a mean terminal half-life of approximately 11 hours in healthy older adults. The terminal half-life observed after multiple doses was approximately 12 to 14 hours. The half-life is independent of the dose administered. However, as shown in Table 11 below, the half-life is prolonged in the presence of renal impairment.
Biotransformation
The metabolism and excretion of radiolabeled dabigatran after a single dose of intravenous administration was evaluated in a trial in healthy men. Following intravenous administration, dabigatran-associated radioactivity was excreted primarily in the urine (85%). Fecal excretion accounted for 6% of the administered dose. The overall radioactivity recovery reached 88-94% of the administered dose at 168 hours post-dose. Dabigatran forms pharmacologically active acetylglucuronide conjugates via conjugation reactions. There are four positional isomers, 1-O, 2-O, 3-O, and 4-O-acetylglucuronide, and each component accounts for less than 10% of the total dabigatran in plasma. The presence of only trace amounts of other metabolites can be measured by high-sensitivity assays. Dabigatran is mainly cleared in its original form via urine at a clearance rate consistent with the glomerular filtration rate of approximately 100 ml/min.
Special Populations
Renal impairment
In a phase I clinical study, dabigatran exposure (AUC) was increased approximately 2.7-fold after oral administration of dabigatranate capsules in volunteers with moderate renal impairment (CrCL: 30-50 ml/min) compared to volunteers without renal impairment.
In a small number of volunteers with severe renal impairment (CrCL 10-30 ml/min), dabigatran exposure (AUC) was increased approximately 6-fold and the half-life was prolonged approximately 2-fold compared to those without renal impairment (see [Dosage], [Contraindications] and [Precautions]).
Table 6 Total dabigatran half-life profile in healthy subjects and those with impaired renal function
Glomerular filtration rate
(CrCL)
[ml/min]g Mean value (gCV%; range)
Half-life
[h] ≥ 8013.4 (25.7 %; 11.0 to 21.6) ≥ 50 to <8015.3 (42.7 %; 11.7 to 34.1) ≥ 30 to <5018.4 (18.5 %; 13.3 to 23.0) <3027.2 (15.3 %; 21.6 to 35.0) Dialysis clearance of dabigatran has been demonstrated in 7 cases of patients with end-stage renal disease (ESRD) and without atrial fibrillation. The dialysis rate was 700 ml/min for 4 h with a blood flow rate of 200 ml/min or 350-390 ml/min. The result was that 50 to 60% of the dabigatran concentration was cleared, respectively. When the blood flow rate was increased to 300 ml/min, the amount of drug cleared by dialysis was in equal proportion to the blood flow rate. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, while the PK/PD relationship was not affected by manipulation.
The median CrCL in the RE-LY study was 68.4 ml/min. nearly half (45.8%) of the RE-LY patients had a CrCL between 50 and 80 ml/min. Compared to patients without renal impairment (CrCL ≥ 80 ml/min), patients with moderate renal impairment (CrCL between 30 and 50 ml/min) had mean pre- and post-dose dabigatran blood concentrations that were 2.29-fold and 1.81-fold higher, respectively.
The median CrCL in the RE-COVER study was 100.4 mL/min. 21.7% of patients had mild renal impairment (CrCL > 50 to < 80 mL/min) and 4.5% of patients had moderate renal impairment (CrCL between 30 and 50 mL/min). Compared to patients with CrCL > 80 mL / min, steady-state dabigatran trough concentrations were on average 1.8-fold and 3.6-fold higher in patients with mild and moderate renal impairment, respectively, than before dosing. similar CrCL values were observed in the RE-COVER II study results.
The median CrCL was 99.0 mL/min and 99.7 mL/min in the RE-MEDY and RE-SONATE studies, respectively. 22.9% and 22.5% of patients in the RE-MEDY and RE-SONATE studies, respectively, had a CrCL >50 ~ <80 mL/min, and 4.1% and 4.8% of patients had a CrCL ranged from 30 to 50 mL/min.
Older adults
Pharmacokinetic studies in the elderly in phase I studies showed a 40% to 60% increase in AUC and a more than 25% increase in Cmax compared to younger adults.
The effect of age on dabigatran exposure was also demonstrated in the RE-LY study, which showed an approximately 31% increase in trough blood concentrations in subjects aged ≥75 years and an approximately 22% decrease in trough blood concentrations in those aged <65 years compared to subjects aged between 65 and 75 years (see [Dosage] and [Precautions]).
Liver Function Impairment
Dabigatran exposure was unchanged in 12 patients with moderate hepatic impairment (Child Pugh B) compared to 12 controls (see [Precautions]).
Body weight
Patients weighing between 50 and 100 kg had approximately 20% lower trough dabigatran blood levels compared to those weighing between 50 and 100 kg. The majority of subjects (80.8%) weighed between 50 and 100 kg and no significant differences were found (see [Precautions]). Data on patients weighing less than 50 kg are limited.
Gender
In patients with atrial fibrillation, trough and post-dose concentrations were on average 30% higher in women. No dose adjustment was required.
Ethnicity
No clinically relevant racial differences in dabigatran pharmacokinetics or pharmacodynamics were observed among Caucasians, African Americans, Hispanics, Japanese, or Chinese.
Pharmacokinetic Interactions
The precursor drug dabigatranate capsules is a substrate for the efflux transporter P-gp, whereas dabigatran is not a substrate for it. Therefore, coadministration with P-gp transporter protein inhibitors (amiodarone, verapamil, clarithromycin, quinidine, dronedarone, tegretol, and ketoconazole) and inducers (rifampin) has been studied (see [Precautions] and [Drug Interactions]).
In vitro interaction studies did not reveal any inhibition or induction of the major cytochrome P450 isoenzymes. This was also confirmed by in vivo studies in healthy volunteers, where no interaction was found between dabigatranate capsule treatment and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter protein interaction) and diclofenac (CYP2C9).
Storage】 Seal and store in dry below 25℃.
Package】 Oral solid medicine in HDPE bottle (built-in desiccant). 10 capsules/bottle; 30 capsules/bottle.
After the bottle is opened, desiccant should be put in the original bottle, please do not throw away.
Expiration date】 24 months, should be taken within 4 months after the cap is opened. Execution standard】【Approval number】【Manufacturer
Company Name: Zhengda Tianqing Pharmaceutical Group Co.
Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Postal code: 22006
Telephone number: 0518-85804002
Fax number: 0518-85806524
Web address: http://www.cttq.com
Health Consultation Hotline：400-788-5028
[Marketing license holder
Company name: Zhengda Tianqing Pharmaceutical Group Co.
Address: No. 369, Yuzhou South Road, Lianyungang City, Jiangsu Province
Telephone number: 0518-85804002
Fax number: 0518-85806524