PRADAKSA – Dabigatran etexilate is a small molecule prodrug, non-pharmacological activity. After ingestion and rapidly absorbed through hydrolysis catalysed by esterases, converted to dabigatran. Dabigatran is an active, competitive, reversible direct thrombin inhibitor and has an effect mainly in the plasma.
Since thrombin (a serine protease) in the cascade converts fibrinogen to fibrin coagulation, the inhibition of its activity prevents the formation of thrombus. Dabigatran inhibits free thrombin, fibrin-binding thrombin and thrombin-induced platelet aggregation.
In vivo and ex vivo in animal studies using various thrombosis models demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after ingestion.
The close correlation between plasma dabigatran concentration and intensity of the anticoagulant effect. Dabigatran prolongs the activated partial thromboplastin time (APTT).
Boehringer Ingelheim Austria
Adults are prescribed by a doctor
– dabigatran etexilate mesylate 172.95 mg, respectively. content dabigatran etexilate 150 mg
Acacia gum – 8.86 mg,
tartaric acid (coarse) – 44.28 mg,
tartaric acid (powder) – 59.05 mg,
tartaric acid (crystalline) – 73.81 mg
Valium – 4.46 mg,
Dimethicone – 0.08 mg
talc – 34.31 mg
giproloza (hydroxypropyl) – 34.59 mg.
Capsule shell :
Carrageenan (E407) – 0.285 mg potassium chloride – 0.4 mg, titanium dioxide (E171) – 5.4 mg, indigo carmine (E132) – 0.054 mg, colorant sunset yellow (E110) – 0.004 mg Hypromellose (hydroxypropyl) – 79.35 mg purified water – 4.5 mg.
Composition of black ink Colorcon S-1-27797: Shellac 52.5%, 6.55% butanol, denatured ethanol (alcohol methylated) 0.65%, iron oxide black dye (E172) 33.77%, 3.34% isopropanol, propylene glycol 1.25% Purified water 1.94%.
Prevention of heart attack and stroke, prevention of acute myocardial infarction, to prevent thrombosis
Prevention of venous thromboembolism in patients undergoing orthopedic surgery.
Known hypersensitivity to dabigatran or dabigatran etexilate or to one of the auxiliaries.
Patients with severe renal impairment (creatinine clearance less than 30 mL / min).
Hemorrhagic disorders, patients with hemorrhagic diathesis, patients with spontaneous or pharmacologically induced violation hemostasis.
Active clinically significant bleeding.
Dysfunction of the liver and liver disease, which can affect survival.
Simultaneous treatment with quinidine.
Organ damage as a result of clinically significant bleeding, including hemorrhagic stroke within the last 6 months prior to initiation of therapy.
The age of patients less than 18 years.
Violations by the blood and lymphatic system: anemia, thrombocytopenia.
Disorders of immune system: Hypersensitivity reactions including urticaria, rash and itching, bronchospasm.
Disorders of the nervous system: intracranial bleeding.
Violations by vessels hematoma, bleeding.
Violations by the respiratory, thoracic and mediastinal disorders: epistaxis, hemoptysis.
Violations of the gastrointestinal tract: gastrointestinal bleeding, rectal bleeding, hemorrhoids bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the gastrointestinal mucosa, gastroezofagit, gastroesophageal reflux disease, vomiting, dysphagia.
Violations by the hepatobiliary system: increased activity of “liver” transaminases, abnormal liver function, hyperbilirubinemia.
Changes in the skin and subcutaneous tissue: skin hemorrhagic syndrome.
Musculoskeletal disorders, disorders of the connective tissue and bone: hemarthrosis.
Changes in the kidney and urinary tract diseases: urogenital bleeding, hematuria.
Disturbances general and changes in location of injection: the injection site of bleeding, the bleeding from the catheter insertion site.
Damage, toxicity and complications from procedures: post-traumatic hematoma, bleeding from the site of surgical approach.
Violations by vessels: bleeding from the surgical wound.
General disorders and at the injection site: bleeding.
Damage, toxicity and complications posleperatsionnoy processing hematoma after the treatment of wounds, bleeding after the treatment of wounds, anemia in the postoperative period, discharge from the wound after the procedure, the secretion from the wound.
Surgical and therapeutic procedures: wound drainage, drainage of wound after processing.
How to accept, acceptance rate and dosage
Inside. During meals or on an empty stomach with water.
Cautions when removing the capsules from blister
Remove capsule from a blister, otslaivaya foil. Do not squeeze the capsule through the foil. Remove the foil so that it was convenient to take out the capsule.
Prevention of venous thromboembolism (VT) in patients undergoing orthopedic surgery
The recommended dose is 220 mg once a day (2 capsules of 110 mg).
Stored in a dry place at a temperature no higher than 25º C.
Combined use PRADAKSA formulation with drugs affecting hemostasis or coagulation system, including vitamin K antagonists, can significantly increase the risk of bleeding.
In studies conducted in vitro, not found inducing or inhibitory effect on dabigatran cytochrome P450. In studies in vivo in healthy volunteers not observed interaction between dabigatran etexilate and atorvastatin (substrate CYP3A4) and diclofenac (substrate CYP2C9).
Interaction with inhibitors / inducers of P-glycoprotein:
The substrate for a transporter molecule P-glycoprotein is dabigatran etexilate. Simultaneous use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, ketoconazole for systemic use or clarithromycin) leads to an increase in dabigatran plasma concentrations.
The simultaneous use of P-glycoprotein inhibitors:
Selection of doses in the case of the above P-glycoprotein inhibitors for the prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation is not required.
In the case of use in the prophylaxis of venous thromboembolic events in patients undergoing orthopedic surgery – see sections “Dosage and Administration” and “interaction with other drugs.”.
Amiodarone. With simultaneous application of dabigatran etexilate with a single dose of amiodarone (600 mg), taken orally, the extent and rate of absorption of amiodarone and its active metabolite, dezetilamiodarona not changed. The values of AUC and C max dabigatran increased approximately 1.6 and 1.5 times (by 60% and 50%), respectively.
In a study in patients with atrial fibrillation, dabigatran concentration increased by not more than 14%, increase the risk of bleeding was not recorded.
Dronedarone. After the simultaneous application of dabigatran etexilate and dronedarone 400 mg once,
AUC 0-∞ and C max dabigatran increased 2.1 and 1.9 times (114% and 87%), respectively, and after repeated use of dronedarone at a dose of 400 mg day – 2.4 and 2.3 (136% and 125%), respectively. After single and multiple use of dronedarone through 2 hours after administration of dabigatran etexilate AUC 0-∞ was increased to 1.3 and 1.6 times respectively. Dronedarone had no effect on the final T1 / 2 and the renal clearance of dabigatran.
Verapamil. With simultaneous application of dabigatran etexilate with verapamil, is administered orally, the values of C max and AUC dabigatran increased depending on the time of application and the dosage form of verapamil.
The greatest increase in dabigatran effect observed with the first dose of verapamil in the dosage form immediate release, which was applied for 1 hr before receiving dabigatran etexilate (C max increased by 180%, and the AUC – 150%). When using the dosage form of verapamil with sustained release, this effect is progressively decreased (C max increased by 90%, and AUC – 70%), as well as by using multiple doses of verapamil (C max increased by 60%, and AUC – 50%), which could be explained by induction of P-glycoprotein in the gastrointestinal tract of verapamil with prolonged use.
When using verapamil after 2 h after administration of dabigatran etexilate clinically significant interactions were observed (C max was increased by 10%, and AUC – 20%), since after 2 hours dabigatran completely absorbed (see section “. Dosing and dose “).
In a study in patients with atrial fibrillation, dabigatran concentration increased by not more than 21%, increase the risk of bleeding was not recorded.
Data on the interaction of dabigatran etexilate and verapamil, parenteral administration, are not available; clinically significant interaction is expected.
Ketoconazole. Ketoconazole for systemic use after a single destination in a dose of 400 mg increases AUC 0-∞ and C max dabigatran approximately 2.4 times (138% and 135%), respectively, and after multiple destination ketoconazole at a dose of 400 mg per day – about 2.5 times (153% and 149%), respectively. Ketoconazole did not affect T max and the final T1 / 2. Simultaneous use of the drug PRADAKSA and ketoconazole contraindicated for systemic use.
Clarithromycin. With simultaneous application of clarithromycin 500 mg 2 times a day with dabigatran etexilate clinically relevant pharmacokinetic interaction was observed (C max increased by 15%, and AUC – 19%).
Quinidine. Values of AUC τ, ss and C max, ss dabigatran when applied 2 times a day in the case of co-administration with quinidine in the dosage of 200 mg every 2 hours until a total dose of 1000 mg rose on average, respectively, 53% and 56%.
The simultaneous use of substrates for P-glycoprotein:
Digoxin. With simultaneous application of dabigatran etexilate with digoxin, which is P-glycoprotein substrate, pharmacokinetic interactions were observed. Neither dabigatran nor the prodrug dabigatran etexilate are not clinically significant inhibitors of P-glycoprotein.
Simultaneous use of inducers P-glycoprotein:
Avoid simultaneous administration of the drug PRADAKSA and inducers of P-glycoprotein, since the combined use leads to mitigation of dabigatran (cm. “Special instructions” section).
Rifampicin. Pretreatment with test inducer rifampicin at a dose of 600 mg daily for 7 days led to a decrease in impact dabigatran. After the cancellation of the inductive effect of rifampicin decreased on day 7 the effect of dabigatran was close to the initial level. Over the next 7 days to further increase the bioavailability of dabigatran was observed.
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 blood plasma and should be used with caution.
The simultaneous use of antiplatelet
Acetylsalicylic acid (ASA). When studying the simultaneous application of dabigatran etexilate 150 mg 2 times a day and acetylsalicylic acid (ASA) in patients with atrial fibrillation found that the risk of bleeding can be increased from 12% to 18% (using ASA dose 81 mg) and 24 % (using ASA 325 mg). It is shown that ASA or clopidogrel, applied simultaneously with dabigatran etexilate a dosage of 110 mg or 150 mg 2 times daily, may increase the risk of major bleeding. Bleeding occur more frequently as well, while the use of warfarin or clopidogrel with ASA.
NSAIDs. Applied NSAIDs (nonsteroidal antiinflammatory drugs) for short analgesia after operations do not increase the risk of bleeding when used simultaneously with dabigatran etexilate. Previous long-term use of NSAIDs, T1 / 2 is less than 12 hours, with dabigatran etexilate is limited, there is no data on the additional increased risk of bleeding.
Clopidogrel. It is found that the simultaneous application of dabigatran etexilate and clopidogrel does not lead to an additional increase in capillary bleeding time in comparison with monotherapy with clopidogrel. Furthermore, it is shown that the values of AUC τ, ss and C max, ss dabigatran, and the parameters of blood coagulation, which are monitored to assess the effect of dabigatran (APTT, ekarinovoe clotting time or thrombin time (anti FIIa), and the degree of inhibition of platelet aggregation (the main component of clopidogrel effect) during combination therapy did not change compared with the corresponding figures in monotherapy. When using the “loading” dose of clopidogrel (300 or 600 mg), the values of AUC t, ss and C max, ss dabigatra and rose to 30-40%.
Concomitant use with drugs that increase the pH of gastric contents
Pantoprazole. When the joint application of dabigatran etexilate and pantoprazole observed decrease in AUC of dabigatran is 30%. Pantoprazole and other proton pump inhibitors used in conjunction with dabigatran etexilate in clinical studies, the effect on the risk of bleeding or efficacy were observed.
Ranitidine. Ranitidine when applied simultaneously with dabigatran etexilate, had no significant effect on the extent of absorption of dabigatran.
Identified during the analysis of changes in the population pharmacokinetic parameters dabigatran influenced by proton pump inhibitors and antacid preparations proved clinically insignificant, since the degree of these changes was small (reduction of the bioavailability was not significant for antacids, and was 14.6% for the proton pump inhibitors). It is found that the simultaneous use of proton pump inhibitors is not accompanied by a reduction of dabigatran concentrations and on average only slightly reduces the concentration of drug in blood plasma (11%). Therefore, the simultaneous use of proton pump inhibitors, apparently, does not lead to an increase in stroke or systemic thromboembolic events, especially in comparison with warfarin, and therefore decrease the bioavailability of dabigatran caused by simultaneous application of pantoprazole probably has no clinical significance.
The risk of haemorrhage: Unfractionated heparin can be applied in order to maintain the functioning central venous or arterial catheter.
Should not be used simultaneously with the preparation PRADAKSA®:
unfractionated heparins or its derivatives, low molecular weight heparins, fondaparinux sodium, dezirudin, thrombolytic agents, receptor antagonists, GPIIb / IIIa, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists
Combined use PRADAKSA® at recommended for the treatment of deep vein thrombosis and doses of aspirin at doses of 75-320 mg increases the risk of bleeding. Evidence of an increase in the risk of bleeding associated with dabigatran PRADAKSA® when receiving the recommended dose of patients receiving low-dose aspirin to prevent cardiovascular disease, no. However, the information available is limited, however, when used together with acetylsalicylic acid at a low dose and PRADAKSA® must monitor the status of patients for
timely diagnosis of bleeding.
Careful observation (for symptoms of bleeding or anemia) should be performed in cases where the possible increased risk of bleeding complications:
– A recent biopsy or trauma
– The use of drugs that increase the risk of bleeding complications. PRADAKSA® combination with drugs that affect hemostasis or coagulation processes.
– Bacterial endocarditis
Appointment for a short time NSAIDs when combined with PRADAKSA® the purpose of analgesia after surgery does not increase the risk of bleeding. There is limited data on systemic administration of NSAIDs with half-life of less than 12 hours in a combination with PRADAKSA®, confirmation of no increase bleeding risks.
Renal impairment: in conducting pharmacokinetic studies have shown that patients with reduced kidney function, including those related to age, there was an increase efficacy. Patients with moderately reduced renal function (creatinine clearance of 50-30 ml / min) it is recommended to reduce the daily dose to about 150 mg per day. PRADAKSA® contraindicated in patients with severe renal impairment (creatinine clearance Spinal anesthesia / epidural / Lumbar puncture:. In the case of traumatic spinal puncture or repeated and prolonged use of an epidural catheter can increase the risk of bleeding spinal or epidural hematoma should take no first dose PRADAKSA® sooner than 2 hours after removal of the catheter. These patients should be monitored for possible detection of neurological symptoms.
Effects on ability to operate machinery
The effect of dabigatran etexilate on the ability to drive vehicles and management mechanisms have not been studied.
Overdosing the application PRADAKSA preparation may be accompanied by hemorrhagic complications due pharmacodynamic characteristics of the drug. When bleeding occurs, the use of drug is stopped. Displaying symptomatic treatment. No specific antidote.
Considering the main route of elimination of dabigatran (kidney), it is recommended to ensure adequate diuresis. Carry surgical haemostasis and replenishing the circulating blood volume (CBV). Perhaps the use of fresh whole blood or fresh frozen plasma transfusions. Since dabigatran has low binding affinity to plasma proteins, the drug can be displayed in hemodialysis, but clinical experience in the use of dialysis in these situations is limited (see. The section “Pharmacokinetics”).
If overdose PRADAKSA possible to use an activated prothrombin complex concentrate or recombinant factor VIIa or concentrates II, IX or X clotting factors. There is experimental evidence supporting the effectiveness of these tools in opposition to the anticoagulant effect of dabigatran, but specific clinical studies have been conducted.
In the case of thrombocytopenia, or in the application of long-acting antiplatelet agents, can be considered the use of platelets.