Pradaksa exerts anticoagulant effect.
Dabigatran etexilate is a low molecular weight, non-pharmacological activity of the active form of dabigatran precursor. After oral administration of dabigatran etexilate is rapidly absorbed in the gastrointestinal tract (GIT) and by hydrolysis catalysed by esterases, in the liver and blood plasma is converted to dabigatran. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in blood plasma.
Since thrombin (a serine protease) in the coagulation process converts fibrinogen to fibrin, thrombin inhibition activity prevents the formation of thrombus. Dabigatran has inhibitory effects on free thrombin, thrombin associated with a fibrin clot, and thrombin-induced platelet aggregation.
In experimental studies in various thrombosis models in vivo and ex vivo antithrombotic effect and confirmed anticoagulant activity of dabigatran after intravenous administration of dabigatran etexilate and – after ingestion.
A direct correlation between dabigatran concentration in plasma and the severity of the anticoagulant effect. Dabigatran prolongs the activated partial thromboplastin time (APTT) clotting time ekarinovoe (EMU) and thrombin time (TV).
Prevention of venous thromboembolism (VTE) after total large joints
Clinical studies in patients undergoing orthopedic surgery – arthroplasty of the knee and hip joint – preserve confirmed hemostatic parameters application and equivalence of 75 mg or 110 mg of dabigatran etexilate 1-4 hours after surgery and the subsequent maintenance dose of 150 or 220 mg once a day for 6-10 days (knee surgery), and 28-35 days (on the hip joint) as compared with enoxaparin 40 mg 1 time per day, which is applied before and after surgery.
Shows equivalent antithrombotic effect of dabigatran etexilate in the application of 150 mg or 220 mg compared with enoxaparin 40 mg per day when evaluating primary endpoint, which includes all the cases of venous thromboembolism and mortality from any cause.
Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation
At long, on average, about 20 months, the application in patients with atrial fibrillation and with a moderate or high risk of stroke or systemic thromboembolic been shown to dabigatran etexilate a dosage of 110 mg, designated 2 times a day, not inferior to warfarin performance prevent stroke and systemic thromboembolism in patients with atrial fibrillation; as in the dabigatran group it was observed reduction in risk of intracranial bleeding and total bleeding rate. Application of a higher dose (150 mg 2 times daily) significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial bleeding, and total bleeding frequency compared to warfarin. A lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared to warfarin.
The net clinical benefit was assessed by determining the combined end point of incidence of stroke, systemic thromboembolism, pulmonary thromboembolism, acute myocardial infarction, cardiovascular mortality and major bleeding.
The annual incidence of these events in patients treated with dabigatran etexilate was lower than in patients treated with warfarin.
Changes in laboratory parameters of liver function in patients treated with dabigatran etexilate, were observed with comparable or lower frequency compared with patients receiving warfarin.
Following oral administration of dabigatran etexilate has been a rapid dose-dependent increase in its concentration in the blood plasma and the area under the curve “concentration-time» (AUC). Dabigatran etexilate maximum concentration (Cmax) is reached within 0.5-2 hours.
After reaching Cmax dabigatran plasma concentrations biexponential decline, terminal half-life (T1 / 2) is on average about 11 hours (in the elderly). The final T1 / 2 after repeated use of the drug was approximately 12-14 hours. The T1 / 2 is not dependent on dose. However, in case of renal dysfunction T1 / 2 longer.
The absolute bioavailability of dabigatran after receiving dabigatran etexilate inside capsules, coated from hypromellose, is about 6.5%.
Eating does not affect the bioavailability of dabigatran etexilate but the time to reach Cmax increases by 2 hours.
When using dabigatran etexilate without special capsule shell made of hypromellose, bioavailability when receiving inside can increase about 1.8 times (by 75%) compared to the dosage form in capsules. Therefore it is necessary to maintain the integrity of the capsules made from hypromellose, given the risk of increasing the bioavailability of dabigatran etexilate, and is not recommended to open the capsules, and to apply the contents in a pure form (e.g. by addition to food or drink) (see. The section “Method of administration and dose”).
In the application of dabigatran etexilate is 1-3 hours in patients after surgical treatment is decreasing the rate of absorption of the drug compared with healthy volunteers. AUC is characterized by a gradual increase in amplitude without the occurrence of high peak plasma concentrations. Cmax plasma levels observed at 6 hours after administration of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, paresis and gastrointestinal surgery may be important to slow the absorption, regardless of dosage form preparation. Reducing the rate of absorption of the drug usually is celebrated only on the day of surgery. In the days following the absorption of dabigatran is rapid, with Cmax achievement 2 hours after its intake.
After oral administration in the hydrolysis process under the influence of esterase dabigatran etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in the blood plasma. When the conjugation is formed dabigatran 4 atsilglyukuronidov pharmacologically active isomer of 1-O, 2-O, 3-O, 4-O, each of which is less than 10% of the total content of dabigatran in blood plasma. Only traces of other metabolites detected using highly sensitive analytical methods.
The volume of distribution of dabigatran of 60-70 liters and exceeds the volume of total body water, indicating a moderate distribution of dabigatran in tissues.
Dabigatran excreted unchanged, primarily by the kidneys (85%) and only 6% – in the gastrointestinal tract. It is found that after 168 hours after administration of a radioactive drug labeled with 88-94% of the dose is excreted from the body.
Dabigatran has low binding ability to plasma proteins (34-35%), it is independent of drug concentration.
Special patient groups
In the elderly the AUC higher than that of young people, by 1.4-1.6 times (40-60%) and C max – more than 1.25 times (25%).
The observed changes were correlated with age-related decrease in creatinine clearance (CC).
Elderly women (over 65 years), the quantities AUCτ, ss and Cmax, ss were approximately 1.9 times and 1.6 times higher than in young women (18-40 years) and elderly men – 2.2 and 2.0 times higher than in young men. In a study in patients with atrial fibrillation is confirmed by the effect of age on dabigatran exposure: initial concentration of dabigatran in patients aged ≥75 years were approximately 1.3 times (31%) above and in patients aged
In volunteers with mild renal impairment (creatinine clearance – 30-50 ml / min) AUC value after ingestion of dabigatran was about 3 times greater than in those with intact renal function.
Patients with severe renal impairment (creatinine clearance – 10-30 ml / min) AUC value of dabigatran etexilate and T1 / 2 increased, respectively, in 2 and 6 times, compared with those of patients without renal dysfunction.
In patients with atrial fibrillation or moderate renal impairment (creatinine clearance of 30-50 ml / min) dabigatran concentrations before and after treatment were an average of 2.29 and 1.81 times higher than in patients without renal dysfunction.
When using hemodialysis patients without atrial fibrillation has been found that the amount of withdrawal of the drug in proportion to the blood flow velocity. The duration of dialysis with a dialysate flow rate of 700 ml / min, sotavlyaet 4 hours, and blood flow rate – 200 ml / min or 350-390 ml / min. This resulted in removal of 50% and 60% concentrations of free and total dabigatran. Anticoagulant activity of dabigatran decreased with decreasing plasma concentrations, the relationship PK and PD has not changed.
Abnormal liver function
In patients with moderate hepatic impairment (7-9 points on a scale Child-Pugh) showed no changes in dabigatran plasma concentrations as compared to patients without liver dysfunction.
In studies of basal concentration of dabigatran in patients with body weight > 100 kg were approximately 20% lower than in patients with a body weight of 50-100 kg. body weight in the majority (80.8%) patients was ≥50 – < 100 kg, within this range the obvious differences dabigatran concentrations not established. Data for patients weighing ≤50 kg restricted.
In the pivotal trials for the prevention of VTE found that exposure to the drug in female patients was approximately 1.4-1.5 times (40-50%) above. In patients with atrial fibrillation basal concentration and the concentration after treatment were an average of 1.3 (30%) above. Installed differences had no clinical significance.
In comparative pharmacokinetic study of dabigatran in Europeans and Japanese after single and repeated administration of the drug in the test ethnic groups showed no clinically significant differences. Pharmacokinetic studies in patients blacks are limited, but the available data indicate no significant differences.
Boehringer Ingelheim Austria
Adults are prescribed by a doctor
The active ingredient is:
dabigatran etexilate mesylate;
tartaric acid powder;
crystalline tartaric acid;
capsule of hypromellose (HPMC) overprinted black ink (Colorcon S-1-27797);
indigo carmine (E132);
sunset yellow dye (E110);
hypromellose (hydroxypropyl methylcellulose),
Composition of black ink Colorcon S-1-27797, (%, wt.):
Purified water 1.940%,
Denatured ethanol (methylated spirit) 0.650%,
dye black iron oxide (E172) 33.770%,
propylene glycol 1.250%
Prevention of heart attack and stroke, prevention of acute myocardial infarction, thrombosis prophylaxis
Prevention of venous thromboembolism in patients undergoing orthopedic surgery; prevention of stroke, systemic thromboembolism and reduced cardiovascular mortality in patients with atrial fibrillation.
- Known hypersensitivity to dabigatran, dabigatran etexilate or any of the excipients;
- Severe renal failure (creatinine clearance less than 30 mL / min);
- Active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacologically induced hemostasis disorders;
- The defeat of bodies as a result of clinically significant bleeding, including hemorrhagic stroke within 6 months prior to the initiation of therapy;
- Co-administration of ketoconazole for systemic use;
- Violations of the liver and liver disease, which may affect survival;
- Age 18 years (clinical data available).
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
The capsules should be ingested, 1 or 2 times a day, regardless of mealtime, with water.
Do not open the capsule.
At temperatures above 25 ° 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 Cmax 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,
AUC0-∞ and Cmax dabigatran increased 2.1 and 1.9 times (114% and 87%), respectively, and after repeated use of dronedarone 400 mg per 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 AUC0-∞ increased in 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 Cmax and AUC of dabigatran were 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 (Cmax increased by 180%, and the AUC – 150%). When using the dosage form of verapamil with sustained release, this effect is progressively reduced (Cmax increased by 90%, and AUC – 70%), as well as by using multiple doses of verapamil (Cmax increased by 60%, and AUC – 50%), which It may 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 (Cmax increased by 10%, and AUC – 20%), since after 2 hours dabigatran completely absorbed (see “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 the AUC0-∞ and Cmax 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 fold (153% and 149%), respectively. Ketoconazole did not affect the final Tmax and 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 (Cmax increased by 15%, and AUC – 19%).
Quinidine. Values AUCτ, ss and Cmax, ss dabigatran when applied 2 times a day in the case of quinidine co-administration with a dose of 200 mg every 2 hours until a total dose of 1000 mg were increased 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 AUCτ, ss and Cmax, ss dabigatran, and the parameters of blood coagulation, which are monitored to assess dabigatran effect (APTT, ekarinovoe clotting time or thrombin time (anti FIIa), and the degree of inhibition of platelet aggregation (the main figure 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 AUCt, ss and Cmax, ss dabigatran were increased by 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.
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.