Dabigatran эteksilat
When ATH:
B01AE07
Pharmacological action
Anticoagulants. The direct thrombin inhibitor. Dabigatran etexilate is a small molecule prodrug, do not possess pharmacological activity. After intake of rapidly absorbed and by hydrolysis, catalysed by esterases, converted into dabigatran.
Dabigatran is an active, competitive, reversible direct thrombin inhibitor and has an effect mainly in plasma.
Tak how thrombin (serinovaya protease) It turns in the coagulation cascade, fibrinogen into fibrin, the inhibition of its activity prevents the formation of a blood clot. Dabigatran ingibiruet svobodnыy thrombin, fibrinsvyazыvayushtiy thrombin and vыznannuyu trombinom agregatsiyu trombotsitov.
In vivo and ex vivo in animal studies using a variety of thrombosis demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after the I / O applications and of dabigatran etexilate after oral administration.
The close correlation between the concentration of dabigatran in plasma and the severity of the anticoagulant effect. Dabigatran udlinyaet aktivirovannoe partiality tromboplastinovoe Vremya (ACHTV).
Pharmacokinetics
Absorption
After taking the drug pharmacokinetic profile of dabigatran in blood plasma of healthy volunteers characterized by a rapid increase in the plasma concentration Cmax within achievement 0.5-2 no.
After reaching a Cmax plasma concentrations of dabigatran reduced biexponential manner, the final T1 / 2 is about average 14-17 h in young people and 12-14 hours in the elderly. T1 / 2 was not dose-dependent. Cmax and AUC values vary in proportion to the dose. Food does not affect the bioavailability of dabigatran etexilate, but slowed down to Tmax 2 no.
The absolute bioavailability of dabigatran is about 6.5%.
The research for the study of absorption of dabigatran etexilate over 1-3 hours after surgery demonstrated depot compared with healthy volunteers. Revealed a smooth increase without the appearance of AUC in plasma Cmax. Cmax was observed for 6 hours after administration or 7-9 hours after surgery. It should be noted, Such factors, as anesthesia, gastrointestinal paresis, and surgical operation, may have a value in the depot, regardless of dosage forms of the drug. In another study, it was shown, that slow the absorption or delay absorption is usually observed only in the day of surgery. In subsequent days absorption of dabigatran is rapid with the achievement of Cmax by 2 h after administration.
Distribution
Slow capacity (34-35%) binding of dabigatran to human plasma proteins, regardless of the concentration of the drug. Dabigatran is Vd 60-70 L and greater than the volume of total body water, indicating moderate tissue distribution of dabigatran.
Metabolism and excretion
After oral administration, dabigatran etexilate is rapidly and completely converted to dabigatran, It is the active form in plasma. The main route of metabolism of dabigatran etexilate is the hydrolysis, catalysed by esterases, this is accompanied by its conversion to the active metabolite of dabigatran.
When dabigatran conjugation forms 4 isomers pharmacologically aktivnыh atsilglyukuronidov: 1-ABOUT, 2-ABOUT, 3-ABOUT, 4-ABOUT, each of which is less than 10% the total content of dabigatran plasma. Traces of other metabolites were found only by using highly sensitive analytical methods.
Metabolism and excretion of dabigatran were studied in healthy volunteers (men) After odnokpatnogo / in the radioactively-labeled dabigatran. Withdrawal occurred mainly through the kidneys (85%) in unchanged form. Excretion in the feces was about 6% From the administered dose. During 168 h after administration of the drug excretion of total radioactivity was 88-94% the magnitude of the applied dose.
Pharmacokinetics in special clinical situations
In volunteers with mild renal impairment (CC 30-50 ml / min) the AUC of dabigatran after the oral administration was 2.7 fold increase compared with the test with normal renal function. In renal failure, severe (CC 10-30 ml / min) the AUC of dabigatran and T1 / 2 increases, respectively, 6 and 2 times compared with patients without renal failure.
Compared with young people, elderly patients, and the AUC Cmax increased respectively 40-60% and 25%. In the population pharmacokinetic studies with elderly patients to 88 s found, that the repeated receptions dabigatran increased its content and body. The observed changes were correlated with age-related decrease in creatinine clearance.
In 12 patients with moderate liver function violation (Class B for Child-Pugh) There were no changes in the content of dabigatran compared to control.
In the population pharmacokinetic studies, pharmacokinetic parameters were evaluated in patients with a body weight of 48 to 120 kg. Body weight has little effect on the plasma clearance of dabigatran. Its content in the body was higher in patients with low body weight. In patients weighing more than 120 kg decreased efficacy about 20%, and body weight 48 kg increase approximately 25% compared to patients with a mean body weight.
In clinical studies, 3 phase, there was no difference in the efficacy and safety of dabigatran etexilate in men and women. In women, the impact of the drug was on the 40-50% higher, than men, however, dose modification is not required.
A comparative study of the pharmacokinetics of dabigatran in Europeans and the Japanese after single and repeated administration of the drug in the studied ethnic groups showed no clinically significant changes. Pharmacokinetic studies in patients blacks were not carried out.
Testimony
Prevention of venous thromboembolism in patients undergoing orthopedic surgery.
Dosage regimen
The drug is prescribed inside.
Adults for the prevention of venous thromboembolism (VT) in patients undergoing orthopedic surgery The recommended dose is 220 mg / once.
In patients with moderate renal impairment are at increased risk of bleeding, the recommended dose is 150 mg dose.
To prevent BT after knee replacement treatment should be started by 1-4 hours after dosing operations 110 mg followed by increasing doses up to 220 mg / once a day for the next 10 days. If hemostasis was not achieved, Treatment should be delayed. If treatment is not started on the day of surgery, therapy should be initiated with a dose 220 mg dose.
To prevent BT after hip replacement surgery treatment should be started by 1-4 hours after dosing operations 110 mg followed by increasing doses up to 220 mg / once a day for the next 28-35 days. If hemostasis was not achieved, Treatment should be delayed. If treatment is not started on the day of surgery, therapy should be initiated with a dose 220 mg dose.
Patients with severe hepatic impairment (Class B and C Child-Pugh) or liver disease, may have an impact on survival, or increase over 2 times ULN liver enzymes were excluded from clinical trials. Concerning, dabigatran etexilate use in these patients is not recommended.
After the on / in the 85% dabigatran eliminated via the kidneys. In patients with moderate renal impairment (CC 30-50 ml / min) there is a high risk of bleeding. In such patients, the dose should be reduced to 150 mg /
Creatinine clearance is determined by Cockcroft:
For men
CC (ml / min)=(140-age) X weight (kg)/72 x serum creatinine (mg / dL)
For women 0.85 QC's values for men.
No data on the use of the drug in patients with severely impaired renal function (CC less than 30 ml / min). Use of the drug dabigatran etexilate in these patients is not recommended.
Dabigatran vыvoditsya Dialysis. Clinical studies in these patients has not been.
Experience with elderly patients aged 75 years limited. The recommended dose is 150 mg / once. When conducting pharmacokinetic studies in elderly patients, which with age there is a decrease in renal function, It was found elevated levels of drug in the body. The dose should be calculated as, as well as for patients with impaired renal function.
The transition from the treatment of dabigatran etexilate to a parenteral administration of anticoagulants should be carried out 24 h after the last dose of dabigatran etexilate.
Transition from parenteral anticoagulants dabigatran etexilate on: no data, it is not recommended to start therapy dabigatran etexilate before the planned introduction of the next dose of parenteral anticoagulant.
Side effect
In controlled trials of the drug for patients receiving 150-220 mg /, part – less 150 mg /, part – more 220 mg.
There may be bleeding at any site. Extensive bleeding is rare. The development of adverse reactions was similar to the reaction in the case of enoxaparin sodium.
From the hematopoietic system: anemia, thrombocytopenia.
From the blood coagulation: hematoma, bleeding wounds, nosebleed, Gastrointestinal bleeding, bleeding from the rectum, hemorrhoidal bleeding, cutaneous hemorrhagic syndrome, gemartroz, hematuria.
From the digestive system: abnormal liver function, increase in liver transaminases, giperʙiliruʙinemija.
From the laboratory parameters: reduction of hemoglobin and hematocrit
Local reactions: bleeding from the injection site, bleeding from the catheter site.
Complications, related to the procedures and surgeries: bloody discharge from the wounds, bruising after the procedure, bleeding after the procedure, posleoperatsionnaya anemia, post-traumatic hematoma, bloody discharge after the procedure, bleeding from the incision site, drainage after the procedure, wound drainage.
The frequency of observed adverse reactions when taking dabigatran etexilate did not exceed the range of the frequency of adverse reactions, Developing using sodium enoksiparina.
Contraindications
Severe renal insufficiency (CC less than 30 ml / min);
Hemorrhagic disorders, gyemorragichyeskii diatyez, spontaneous or pharmacologically induced hemostasis disorders;
Active clinically significant bleeding;
Abnormal liver function and liver disease, which may affect survival;
Simultaneous treatment with quinidine;
The defeat of the organs as a result of clinically significant bleeding, including hemorrhagic stroke within the previous 6 months before treatment;
Age less 18 years;
Known hypersensitivity to dabigatran or dabigatran etexilate or any of the excipients.
Pregnancy and lactation
In animal studies reproductive toxicity has been identified. Clinical data on the use of dabigatran etexilate in pregnancy is not available. The potential risk for humans is not known.
Women of childbearing age should avoid pregnancy during treatment of dabigatran etexilate. In pregnancy, the use of dabigatran etexilate is not recommended, except, when the expected benefits outweigh the potential risks.
In the case of dabigatran etexilate breast-feeding should be discontinued. Clinical data on the use of the drug during breast-feeding is not available.
Application for violations of liver function
Patients with severe hepatic impairment (Class B and C Child-Pugh) or liver disease, may have an impact on survival, or increase over 2 times ULN liver enzymes were excluded from clinical trials. Concerning, dabigatran etexilate use in these patients is not recommended.
Application for violations of renal function
After the on / in the 85% dabigatran eliminated via the kidneys in patients with moderate renal impairment (CC 30-50 ml / min) there is a high risk of bleeding. In such patients, the dose should be reduced to 150 mg /
Creatinine clearance may be determined using the Cockcroft-Gault:
140 – age (in Years)) x body weight (kg)
Creatinine clearance (ml / min)
Men 72 x creatinine sыvorotochnыy (mg / 100ml)
0.85 x (140 – age (in Years)) x body weight (kg)
Creatinine clearance (ml / min)
Women 72 x creatinine sыvorotochnыy (mg / 100ml).
No data on the use of the drug in patients with severely impaired renal function (CC less than 30 ml / min). Use of the drug dabigatran etexilate in these patients is not recommended.
Dabigatran vыvoditsya Dialysis. Clinical studies in these patients has not been.
Cautions
Unfractionated heparin may be employed to maintain the functioning central venous or arterial catheter.
It should not be used simultaneously with the drug dabigatran etexilate unfractionated heparin or its derivatives, nizkokomolekulyarnye heparins, fondaparinux sodium, desirudin, thrombolytic agents, receptor antagonists, GPIIb / IIIa, Clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists.
The combined use of dabigatran etexilate in recommended for the treatment of deep vein thrombosis and the dose of acetylsalicylic acid in doses 75-320 mg increases the risk of bleeding. Data, evidence of an increased risk of bleeding, associated with dabigatran etexilate Dabigatran when taking the recommended dose, sick, get a small dose of aspirin to prevent cardiovascular disease, no. But, Available information is limited, so the joint application of acetylsalicylic acid at a low dose of dabigatran etexilate and necessary to monitor the patient for the purpose of timely diagnosis of bleeding.
Careful observation (for signs of bleeding or anemia) should be performed in cases, where possible increased risk of bleeding complications:
recent biopsy or trauma;
the use of drugs, increase the risk of bleeding complications;
dabigatran etexilate with the combination of drugs, that affect hemostasis or coagulation processes;
bacterial endocarditis.
Appointment for a short time NSAIDs when combined with dabigatran etexilate chain analgesia after surgery does not increase the risk of bleeding. Limited data are available regarding systemic administration of NSAIDs T1 / 2 is less than 12 h in conjunction with dabigatran etexilate, confirm an increased risk of bleeding are absent.
When conducting pharmacokinetic studies have shown, In patients with reduced renal function, incl. age-related, It noted an increase in drug efficacy. In patients with moderately decreased kidney function (CC 30-50 ml / min) it is recommended to reduce the daily dose 150 mg / dabigatran etexilate is contraindicated in patients with severe renal impairment (CC <30 ml / min). With the development of acute renal failure the drug should be discontinued.
In the case of traumatic or repeated lumbar puncture and prolonged use of epidural catheter may increase the risk of spinal or epidural hematoma bleeding. The first dose of dabigatran etexilate should be taken no earlier than 2 hours after removal of the catheter. Such patients should be monitored for possible detection of neurological symptoms.
Effects on ability to drive vehicles and management mechanisms
The effects of dabigatran etexilate on the ability to drive and use machines has not been studied.
Overdose
There is no antidote to dabigatran etexilate or dabigatran.
Using doses, than recommended, It leads to an increased risk of bleeding. In case of bleeding, treatment should be stopped to ascertain the causes of bleeding. Given the primary route of elimination of dabigatran through the kidneys, It is recommended to ensure adequate urine output. If necessary, possible surgical hemostasis or transfusion of fresh frozen plasma.
Dabigatran udalyaetsya Dialysis, However, clinical experience with this method, there is no.
Drug Interactions
The combined use of drugs, affecting hemostasis or coagulation processes, vitamin K antagonists including, can significantly increase the risk of bleeding.
Dabigatran эteksilat and dabigatran are not metaboliziruyutsya with uchastiem sistemы cytochrome P450 and vliyayut of in vitro cytochrome P450 in fermentы per person. Therefore, when combined with the use of dabigatran etexilate drug interactions are not expected.
When combined with atorvastatin interaction is not observed.
In a joint application pharmacokinetics of dabigatran etexilate and diclofenac did not change, indicating little interaction. Application over a short time NSAIDs for pain relief after surgery did not increase the risk of bleeding.
There is limited experience with the use of dabigatran etexilate in conjunction with a systematic long-term NSAID, and therefore it requires careful monitoring of patients.
Pharmacokinetic interaction with digoxin is not revealed.
In clinical studies did not reveal the effect of the combination of pantoprazole or other proton pump inhibitors and dabigatran etexilate for the development of bleeding or pharmacological effects.
In a joint application with ranitidine extent of absorption of dabigatran is not changed.
In a joint application of dabigatran etexilate and amiodarone rate and extent of absorption of the latter and formation of its active metabolite dezetilamiodarona unchanged. AUC and Cmax increased by 60% and 50% respectively. In a joint application of dabigatran etexilate and amiodarone is necessary to reduce the dose of dabigatran etexilate to 150 mg / Because of the long T1 / 2 of amiodarone the potential drug interactions may persist for several weeks after discontinuation of amiodarone.
Caution should be exercised when dabigatran etexilate a joint application with the active inhibitors of P-glycoprotein (verapamil, clarithromycin).
Repeated administration of verapamil for several days led to an increase in the concentration of dabigatran 50-60%. This effect can be reduced by assigning at least dabigatran 2 hours before drug verapamil.
Simultaneous administration of dabigatran etexilate with quinidine is contraindicated.
Potential inducers, such as rifampicin and hypericum extract of the herb, may reduce the effect of dabigatran. Caution should be exercised when used in conjunction with such drugs dabigatran.
In a joint application with antacids and dabigatran means, depressing gastric secretion, changing the dose of dabigatran is not required.
There were no interactions with dabigatran opioid analgesics, Diuretics, paracetamol, NSAIDs (incl. COX-2 inhibitors), inhibitors MMC-CoA reductase, preparations, lowering cholesterol / triglyceride (unrelated to statins), angiotensin II receptor blockers, ACE inhibitors, beta-blockers, calcium channel blockers, prokinetiki, benzodiazepines.
