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The composition and form of issue:
Capsules. 1 capsule contains active substance:
etexilate of dabigatran mesylate 86.48, 126.83 or 172.95 mg
(equivalent to 75 mg, 110 mg or 150 mg of dabigatran, respectively etexilate)
capsule contents: acacia gum— 4,43/6,50/8,86 mg of coarse tartaric acid— 22,14/32,48/44,28 mg tartaric acid powder— 29,52/43,3/59,05 mg tartaric acid crystalline— 36,9/54,12/73,81 mg hypromellose— 2,23/3,27/4,46 mg Dimethicone— 0,04/0,06/0,08 mg talc— 17,16/25,16/34,31 mg hyprolose (hydroxypropyl cellulose)— 17,30/25,37/34,59 mg
shell: hypromellose (NRMS) with overprint in black ink (Colorcon S-1-27797) — 60*/70*/90* mg
NRMS: carrageenan (Е407)— 0,2/0,22/0,285 mg of potassium chloride— 0,27/0,31/0,4 mg titanium dioxide (E171)— 3,6/4,2/ 5,4 mg Indigo Carmine (Е132)— 0,036/0,042/0,054 mg dye sunset yellow (E110)— 0,002/0,003/0,004 mg hypromellose (hydroxypropyl methylcellulose)— 52,9/61,71/79,35 mg purified water — 3/3,5/4,5 mg
Colorcon S-1-27797 (wt.%): shellac is 52.5% butanol — 6,55% purified water is 1.94% denatured ethanol (methylated alcohol) — 0,65% dye iron oxide black (E172) — 33,77% isopropanol — 3,34% propylene glycol — 1,25%
*approximate weight capsules are 60, 70 or 90 mg
in blister packs with perforated aluminium foil/aluminium foil for 10 PCs in a pack a cardboard 1, 3 or 6 blisters in vials made of polypropylene, a plastic-sealed screw-caps with tamper-evident from the children and a desiccant, 60 PCs in cartons 1 a bottle.
Description pharmaceutical form:
Capsules 75 mg: oblong cap is an opaque light blue color, the body is an opaque cream color on the lid is printed the symbol of the company Boehringer Ingelheim, is on the case “R 75”.
Capsules 110 mg: oblong cap is an opaque light blue color, the body is an opaque cream color on the lid is printed the symbol of the company Boehringer Ingelheim, is on the case “R 110”.
Capsules 150 mg: oblong cap is an opaque light blue color, the body is an opaque cream color on the lid is printed the symbol of the company Boehringer Ingelheim, in the case of “R 150”.
Capsule contents: pellets yellowish color.
After oral administration of dabigatran etexilate there has been a rapid dose-dependent increase in its concentration in plasma and AUC. Cmax of dabigatran etexilate achieved within 0.5–2 hours
After reaching Cmax, the plasma concentrations of dabigatran reduced bieksponencialno, the final T1/2 is on average about 11 hrs (in the elderly). The final T1/2 after multiple dosing of the drug was approximately 12-14 h. T1/2 does not depend on the dose. However, in the case of impaired renal function T1/2 longer.
The absolute bioavailability of dabigatran after administration of dabigatran etexilate inside capsules, coated of these is about 6.5%.
Eating does not affect the bioavailability of dabigatran etexilate, however Tmax is increased by 2 hours.
When using dabigatran etexilate no special capsule shell made of these, the oral bioavailability may increase by 75% compared to the dosage form in capsules. Therefore it is necessary to preserve the integrity of the capsules made of these, given the risk of increasing the bioavailability of dabigatran etexilate, and it is not recommended to open the capsule and apply the contents to their pure form (for example, by adding to food or drinks) (see “Method of application and dosage”).
When using dabigatran etexilate after 1-3 hours in patients after surgical treatment there is a decrease in the absorption rate of the drug compared with healthy volunteers. AUC is characterized by a gradual increase of the amplitude without the appearance of high peak plasma concentrations. Cmax in plasma observed after 6 h after application of the dabigatran etexilate or through 7-9 h after surgery. It should be noted that factors such as anaesthesia, gastrointestinal paresis, and surgical procedure may be important in slowing the absorption regardless of the dosage form of the drug. The decrease in the rate of drug absorption is usually observed only on the day of surgery. On subsequent days absorption of dabigatran is fast, with the achievement of Cmax after 2 hours after its ingestion.
After ingestion by hydrolysis under the influence of esterase dabigatran etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in plasma. During conjugation, dabigatran is formed 4 isomer is pharmacologically active acylglucuronide: 1-Oh, 2-Oh, 3-Oh, 4-Oh, each of which is less than 10% of the contents of dabigatran in plasma. Traces of other metabolites detected only by using highly sensitive analytical methods.
Vd dabigatran is 60-70 l, and exceeds the volume of the total content of water in the body, which indicates a moderate distribution of dabigatran in the tissues.
Dabigatran is excreted unchanged mainly by the kidneys (85%), and only 6% through the gastrointestinal tract. It is found that after 168 h after injection of radioactive-labeled drug 88-94% of the dose is excreted from the body.
Dabigatran has a low protein binding capacity of blood plasma (34-35%), it does not depend on the concentration of the drug.
Special groups of patients
Elderly patients. The elderly, AUC and Cmax is higher than the young persons of 40-60, and 25%, respectively.
The observed changes correlated with age-related decline Cl creatinine.
In women of advanced age (over 65 years) value AUC&tau and Cmax at steady state was approximately 1.9 times and 1.6 times higher than in young women (18-40 years) and older males is 2.2 and 2 times higher than in men of young age. The study confirmed the influence of age on exposure to dabigatran: the initial concentration of dabigatran in patients aged >75 years was approximately 31% higher, and in patients aged <65 years is approximately 22% lower than in patients aged 65-75 years.
The impairment of renal function. In volunteers with moderate impairment of renal function (Cl creatinine — 30-50 ml/min) AUC of dabigatran after oral was 2.7 times higher than in patients with unchanged renal function.
Patients with severely impaired renal function (Cl creatinine — 10-30 ml/min) values of AUC of dabigatran etexilate and T1/2 increased respectively 6 and 2 times, compared to the same indicators in individuals without impaired renal function.
The liver dysfunction. In patients with moderately impaired liver (7-9 points on a scale child-Pugh) no identified changes in the concentration of dabigatran in plasma compared with patients without liver function abnormalities.
Body weight. In studies of the basal concentration of dabigatran in patients with body weight >100 kg was approximately 20% lower than that in patients weighing 50-100 kg. body Weight in the majority (80,8%) patients were &ge50–<100 kg within this range the apparent difference in concentrations of dabigatran is not established. Data for patients with body weight &le50 kg is limited.
Paul. In basic research in the prevention of development of VTE found that the effects of the drug on patients of women was approximately 40-50% higher. In patients with atrial fibrillation basal concentration and after treatment were on average 30% higher. The established differences had no clinical significance.
Ethnic groups. In the comparative study of the pharmacokinetics of dabigatran from the Europeans and Japanese after single and repeated administration of the drug in the studied ethnic groups no clinically meaningful difference. Pharmacokinetic studies in patients of Negroid race is limited, but available data show no significant differences.
Description pharmacological action:
Dabigatran etexilate is a low-molecular, non-pharmacological activity, a precursor to the active form dabigatran. After intake of dabigatran etexilate is rapidly absorbed in the gastrointestinal tract and by hydrolysis catalyzed by serum esterases in liver and blood plasma, is converted to dabigatran. Dabigatran is a potent reversible direct competitive inhibitor of thrombin and is the main active ingredient in the blood plasma.
Due to the fact that thrombin (a serine protease) in the coagulation process converts fibrinogen into fibrin, inhibition of the activity of thrombin prevents thrombus formation. Dabigatran has an inhibitory effect on free thrombin, thrombin associated with fibrin clot and thrombin-induced platelet aggregation.
In experimental studies in various models of thrombosis in vivo and confirmed ex vivo antithrombotic effect and anticoagulant activity of dabigatran after I/V administration and of dabigatran etexilate after ingestion.
There is a direct correlation between the concentration of dabigatran in plasma and the expression of anticoagulant effect. Dabigatran prolongs APTT.
Prevention of venous thromboembolism (VTE) after replacement of large joints
The results of clinical trials in patients undergoing orthopaedic operations — knee and hip joints, confirmed the preservation of parameters of hemostasis and equivalence applications of 75 or 110 mg of dabigatran etexilate through 1-4 h after surgery and subsequent maintenance doses of 150 or 220 mg 1 time per day for 6-10 days (surgery on knee) and 28-35 days (hip) compared to enoxaparin at a dose of 40 mg 1 time per day, which was used before and after surgery.
Shown the equivalence of the antithrombotic effect of dabigatran etexilate when using 150 or 220 mg compared to enoxaparin at a dose of 40 mg/day in the evaluation of the primary endpoint, which includes all cases of venous thromboembolism and death from any cause.
The prevention of stroke and systemic embolism in patients with atrial fibrillation
At long, averaging about 20 months, used in patients with atrial fibrillation and moderate or high risk of stroke or systemic embolism, it was shown that dabigatran etexilate at a dose of 110 mg appointed 2 times a day was not inferior to warfarin for the effective prevention of stroke and systemic embolism in patients with atrial fibrillation also in the group of dabigatran, there was a reduction in the risk of intracranial hemorrhage and total bleeding frequency. Application of higher dose (150 mg 2 times daily) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial hemorrhage and total frequency of bleeding compared with warfarin. Smaller dose of dabigatran was characterized by a significantly lower risk of large bleeding compared to warfarin.
The net clinical effect was evaluated by determining the combined endpoint, which included stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, cardiovascular mortality, and large bleeding.
The annual frequency of these events in patients receiving dabigatran etexilate, was lower than in patients receiving warfarin. Changes in laboratory parameters of liver function in patients receiving dabigatran etexilate was also noted at comparable or lower incidence compared to patients treated with warfarin.
Application of pregnancy and breast-feeding:
Data on the use of dabigatran etexilate during pregnancy. The potential risk in humans is unknown.
In experimental studies have not found adverse effects on fertility or postnatal development of the newborn.
Women of reproductive age should use reliable methods of contraception in order to exclude the possibility of pregnancy in drug treatment Pradaxa. If pregnancy the drug is not recommended, except when the expected benefit outweighs the potential risk. If necessary, the use of drugs in breastfeeding, in the absence of clinical data, breast-feeding should stop as a safety precaution.
Below are the side effects identified with use of the drug for prevention of VTE after orthopedic surgery and for prevention of stroke and systemic embolism in patients with atrial fibrillation.
From the hematopoietic and lymphatic systems: anemia, thrombocytopenia.
The immune system: hypersensitivity reactions, including hives, rash and itching, bronchospasm.
From the nervous system: intracranial hemorrhage.
From the vessel: hematoma, bleeding.
Side respiratory, thoracic and mediastinal: epistaxis, hemoptysis.
Gastrointestinal: gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the mucous membrane of the gastrointestinal tract, gastroesophageal, gastroesophageal reflux disease, vomiting, dysphagia.
Hepatobiliary system: elevated liver transaminases, abnormal liver function, hyperbilirubinemia.
The skin and subcutaneous tissue: skin hemorrhagic syndrome.
From the side of musculoskeletal system and connective tissue: hemarthrosis.
The kidneys and urinary tracts: urogenital haemorrhage, haematuria.
Violations of a General nature and changes in the location of injections: bleeding from the injection site, bleeding from the insertion site of the catheter.
Injury, poisoning and complications from procedures: post-traumatic hematoma, bleeding from the designated operational access.
Additional specific side effects identified in the prevention of venous thromboembolism in patients who underwent orthopedic surgery.
From vessels: bleeding from the surgical wound.
General disorders injection site: bleeding.
Damage, toxicity and complications of treatment postoperative: hematoma after treatment of the wound, the bleeding after treatment of wounds, anemia in the postoperative period, discharge from the wound after the procedures, the secretion from the wound.
Surgical and medical procedures: wound drainage, drainage after treatment of the wound.
The combined use of the drug Pradaxa with drugs that affect hemostasis or coagulation, including vitamin K antagonists, can significantly increase the risk of bleeding.
In studies conducted in vitro, not installed or inducing an inhibitory effect of dabigatran on cytochrome P450. In vivo studies in healthy volunteers not observed interaction between etexilate dabigatran and atorvastatin (substrate of CYP3A4) and diclofenac (CYP2C9 substrate).
Interaction with inhibitors/inducers of P-glycoprotein
A substrate for the transport molecule P-glycoprotein is dabigatran etexilate, but not dabigatran. In this regard, was conducted to study the simultaneous use of dabigatran etexilate with inhibitors and inducers of P-glycoprotein.
The simultaneous administration of inhibitors of P-glycoprotein
Amiodarone. While the use of dabigatran etexilate with a single dose of amiodarone (600 mg) taken inside, the extent and rate of absorption of amiodarone and its active metabolite, desethylamiodarone not changed. The values of Cmax and AUC of dabigatran were increased respectively by approximately 60 and 50%.
Dronedarone. The concentration of dabigatran in plasma is increased when used together with dronedarone.
Verapamil While the use of dabigatran etexilate with verapamil, prescribed orally, the values of Cmax and AUC of dabigatran were increased depending on the time of application and dosage forms of verapamil. The greatest increase in the effect of dabigatran was observed when using the 1st dose of verapamil in pharmaceutical form with immediate release, which was applied for 1 h prior to receiving dabigatran for etexilate (Cmax increased by 180, a AUC by 150%). When using dosage forms of verapamil sustained release this effect progressively decreased (Cmax increased by 90, a AUC 70%) as well as by using multiple doses of verapamil (increased of Cmax by 60, a AUC — 50%), which may be due to induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil.
When using verapamil 2 hours after dabigatran ingestion of etexilate clinically significant interactions were observed (Cmax increased by 10, a AUC by 20%), since after 2 h dabigatran completely absorbed (see “Method of application and dosage”).
Data on the interaction of dabigatran etexilate with verapamil, introduced parenterally, there are no clinically significant interactions are not expected.
Ketoconazole. Ketoconazole after single administration in a dose of 400 mg increases the AUC0-&infin and Cmax of dabigatran, respectively, at 138 and 135%, and after repeated use of ketoconazole in the dose 400 mg per day — 153 and 149%, respectively. Ketoconazole did not affect the Tmax and the final T1/2.
Clarithromycin. While the use of clarithromycin in a dose of 500 mg 2 times a day with dabigatran etexilate a clinically significant pharmacokinetic interaction was observed (Cmax increased by 15, a AUC by 19%).
Quinidine. Values of AUC&tau and Cmax of dabigatran at steady state when applied 2 times daily in the case of co-administration with quinidine at a dose of 200 mg every 2 h until reaching a total dose of 1000 mg increased on average respectively by 53 and 56%.
Concurrent use of substrates for P-glycoprotein
Digoxin. While the use of dabigatran etexilate digoxin is a substrate of P-glycoprotein pharmacokinetic interaction was observed. Neither dabigatran nor the prodrug dabigatran etexilate are not clinically significant inhibitors of P-glycoprotein.
The simultaneous use with inducers of P-glycoprotein
The use of the drug Pradaxa and inducers of P-glycoprotein it is possible with care (see “precautions”).
Rifampicin. Preliminary use of the test inducer rifampicin at a dose of 600 mg per day for 7 days led to a decrease in exposure to dabigatran. After the abolition of rifampicin, this inductive effect was decreased on the 7th day the effect of dabigatran was similar to the original state. Over the next 7 days to further increase the bioavailability of dabigatran was observed.
Interaction with inducers of P-glycoprotein
It is assumed that other inducers of P-glycoprotein, such as St. John’s wort or carbamazepine, may also reduce the concentration of dabigatran in plasma and should be used with caution.
Concurrent use with antiplatelet agents
Acetylsalicylic acid (ASA). When studying the simultaneous application of etexilate dabigatran at a dose of 50 mg 2 times a day and ask for patients with atrial fibrillation found that the risk of bleeding may be increased from 12 to 18% (when using an ASA dose of 81 mg) to 24% (with the use of ASA in a dose of 325 mg). It is shown that ASA or clopidogrel, is used simultaneously with etexilate dabigatran dose of 110 mg or 150 mg 2 times a day, can increase the risk of large bleeding. Bleeding is also often observed when coadministration of warfarin with ASA or clopidrogrel.
NSAIDs. Used NSAIDs for short-term analgesia after surgery does not increase the risk of bleeding during concomitant use of dabigatran with etexilate. Experience prolonged use of NSAIDs, T1/2 which is less than 12 hours, with dabigatran etexilate limited, there are no data about further increase the risk of bleeding.
Clopidogrel. It is established that the simultaneous use of etexilate dabigatran and clopidogrel does not result in additional increase of time of capillary bleeding compared with monotherapy clopidogrelum. In addition it is shown that the values of AUC&tau and Cmax of dabigatran at steady state and the parameters of blood coagulation, which were controlled to assess the effect of dabigatran (APTT, karinova time or thrombin time, and the degree of inhibition of platelet aggregation (the main indicator of the effect of clopidogrel) during combination therapy was not changed in comparison with those in monotherapy. When using a loading dose of clopidogrel (300 or 600 mg) values of AUC&tau and Cmax of dabigatran at steady state was increased by 30-40%.
Concurrent use with drugs that increase pH of stomach contents
Pantoprazole. In a joint application etexilate of dabigatran and pantoprazole was observed a decrease in AUC of dabigatran by about 30%. Pantoprazole and other proton pump inhibitors used in conjunction with dabigatran etexilate in clinical studies impact on the risk of bleeding or efficacy were observed.
Ranitidine. Ranitidine should be consumed in conjunction with etexilate dabigatran had a significant impact on the extent of absorption of dabigatran.
Identified in the population analysis of the changes of pharmacokinetic parameters of dabigatran under the influence of proton pump inhibitors and antacids were clinically insignificant, because the severity of these changes was small (decrease of bioavailability was not significant for antacids and proton pump inhibitors 14.6%). It is established that the simultaneous use of proton pump inhibitors is not accompanied by a decrease in the concentration of dabigatran and, on average, only slightly reduces the concentration of drug in plasma (11%). Therefore, the simultaneous use of proton pump inhibitors apparently does not increase the frequency of stroke or systemic embolism, especially in comparison with warfarin, and hence, reduced bioavailability of dabigatran caused by concurrent use of pantoprazole, probably, has no clinical significance.
Method of application and dose:
Capsules should be taken 1 or 2 times a day, regardless of mealtime with water. You should not open the capsule.
Prevention of venous thromboembolism (VTE) in patients after orthopedic surgery
The recommended dose is 220 mg 1 time per day (2 caps. at 110 mg).
Patients with moderate impairment of renal function. In connection with the risk of bleeding, the recommended dose is 150 mg 1 time per day (2 caps. for 75 mg).
Prevention of VTE after knee arthroplasty. The use of the drug Pradaxa should start 1-4 h after completion of the operation of the reception 1 capsule. (110 mg), followed by increasing the dose to 2 caps. (220 mg) once a day for the next 10 days. If hemostasis is not achieved, treatment should be postponed. If treatment is not started on the day of surgery, therapy should begin with an intake of 2 caps. (220 mg) once per day.
Prevention of VTE after hip replacement. The use of the drug Pradaxa should start 1-4 h after completion of the operation of the reception 1 capsule. (110 mg), followed by increasing the dose to 2 caps. (220 mg) once a day for the next 28-35 days. If hemostasis is not achieved, treatment should be postponed. If treatment is not started on the day of surgery, therapy should begin with an intake of 2 caps. (220 mg) once per day.
Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation
The preparation should be used Pradaxa in a daily dose of 300 mg (1 caps. 150 mg 2 times a day). Therapy should continue for life.
Special groups of patients
The impairment of renal function. In the absence of data on the use of the drug in patients with severe renal impairment (Cl creatinine <30 ml/min) of the drug Pradaxa is not recommended (see “Contraindications”).
In applying the drug Pradaxa for prevention of venous thromboembolism in patients after orthopedic surgery with moderate renal impairment (Cl creatinine 30-50 ml/min) daily dose should be reduced to 150 mg (2 caps. 75 mg 1 time per day).
In applying the drug Pradaxa for prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation dose adjustment is not required, we recommend the use of the drug in a daily dose of 300 mg (1 caps. 150 mg 2 rasav day).
Dabigatran is excreted in the renal dialysis, however clinical experience of use in patients receiving dialysis is limited.
Use in elderly patients. Due to the fact that the increase in drug exposure in older patients is often due to reduced renal function, dosage adjustment should be performed depending on the severity of the renal impairment (See. “Impaired renal function”).
Elderly patients (over 75 years): experience of use in this group of patients is limited, the recommended dose is 150 mg (2 caps. at 75 mg once).
In applying the drug in elderly patients to prevent stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation dose adjustment is not required, the drug Pradaxa should be taken in a daily dose of 300 mg (1 caps. 150 mg 2 times a day).
The influence of body weight. Is not required correction doses depending on body mass.
The simultaneous use of the drug Pradaxa active inhibitors of P-glycoprotein (amiodarone, quinidine, verapamil) prevention of venous thromboembolism in patients after orthopedic surgery
While the use of amiodarone, quinidine or verapamil the dose of the drug Pradaxa should be reduced to 150 mg 1 time per day (2 caps. 75 mg) (see “Interaction”).
Patients taking the drug Pradaxa after orthopedic operations do not simultaneously start administration of verapamil and connect it to your treatment in the future.
Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation. Dose adjustment is not required, patients are recommended the use of the drug in a daily dose of 300 mg (1 caps. 150 mg 2 times a day).
Use in patients with increased bleeding risk
Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation. In patients with potentially high high risk of bleeding (age &ge75 years, index >3 on a scale assessing stroke risk CHADS2 and moderate decrease of renal function, creatinine Cl 30-50 ml/min, with simultaneous use of inhibitors of P-glycoprotein, or the indication of gastrointestinal bleeding in anamnesis) may reduce the daily dose of the drug Pradaxa to 220 mg (1 caps. 110 mg 2 times a day).
The transition from the use of the drug Pradaxa for parenteral use of anticoagulants. Prevention of venous thromboembolism in patients after orthopedic surgery: parenteral anticoagulants should be started 24 hours after the last dose of the drug Pradaxa.
Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the use of parenteral anticoagulants should be started 12 hours after the last dose of the drug Pradaxa.
Transition from parenteral anticoagulants to the drug Pradaxa. The first dose Pradaxa is assigned in the range of 0-2 hours before the next injection is an alternative therapy or simultaneously with the cessation of the constant infusion (e.g. in/with the use of fractionated heparin).
The transition from the use of vitamin K antagonists to the drug Pradaxa. Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation: application of vitamin K antagonists stop the drug Pradaxa possible with MHO <2.
The cardioversion. Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation: planned or emergency cardioversion do not require discontinuation of drug therapy Pradaxa.
The missed dose. Prevention of venous thromboembolism in patients after orthopedic surgery: the recommended usual daily dose Pradaxa at the usual time the next day. In the case of missing individual doses should not take a double dose of the drug.
Prevention of stroke, systemic embolism and reduction of cardiovascular mortality in patients with atrial fibrillation: the missed dose of the drug Pradaxa can be taken in the event that if, before taking the next dose of the drug remains 6 hours or more if the period was less than 6 hours, the missed dose should not be accepted. In the case of missing individual doses should not take a double dose of the drug.
Symptoms: overdose when using the drug Pradaxa may be accompanied by haemorrhagic complications due to its pharmacodynamic characteristics of the drug. If you experience bleeding stop drug use.
Treatment: treatment is symptomatic no specific antidote.
Given the main route of viagenie dabigatran (kidney), it is recommended to ensure adequate diuresis. Carry out surgical hemostasis, and fill the BCC. It is possible to use fresh whole blood or the transfusion of fresh frozen plasma. Since dabigatran has a low ability to bind with blood plasma proteins, the drug may also be displayed when gemod
|The purpose of the medication||Anti-coagulants|