Прадакса®

General characteristics. Structure:

Active ingredient: 86,48 mg, 126,83 mg or 172,95 mg of a dabigatran of an eteksilat of a mezilat that there correspond 75 mg, 110 mg or 150 mg of a dabigatran of an eteksilat.

Excipients. Contents of capsules: acacias gum, tartaric acid coarse-grained, tartaric acid powder, crystalline tartaric acid, gipromelloza, диметикон, talc, hypro rod (hydroxypropyl cellulose).

Structure of a capsular cover: the capsule from a gipromelloza (NRMS) with an overprint black Colorcon S-1-27797 ink. The capsule consists from: каррагинан (E407), potassium chloride, titanium dioxide (E171), indigo carmine (E132), dye a sunset yellow (E110), a gipromelloza (gidroksipropilmetil-cellulose), water cleared.

Composition of ink of black Colorcon S-1-27797: shellac, butanol, the water purified the ethanol denatured (alcohol metilirovanny), dye ferrous oxide black (E172), isopropanol, propylene glycol.

Pharmacological properties:

Pharmacodynamics. Dabigatrana этексилат is the low-molecular pro-medicine which does not have pharmacological activity. After intake it is quickly soaked up and by the hydrolysis catalyzed by esterases turns in дабигатран. Dabigatran is active, competitive, reversible direct inhibitor of thrombin and has effect generally in plasma.

As thrombin (serinovy protease) turns in the course of the coagulation cascade fibrinogen into fibrin, oppression of its activity interferes with formation of blood clot. Dabigatran inhibits free thrombin, fibrin - the connecting thrombin and the aggregation of thrombocytes caused by thrombin.

In vivo and ex vivo in researches on animals with use of various models of thrombosis is shown antitrombotichesky efficiency and anticoagulating activity of a dabigatran after intravenous use and a dabigatran of an eteksilat after intake.

Close correlation between concentration of a dabigatran in plasma and expressiveness of antykoagulyantny effect is revealed. Dabigatran extends the activated partial tromboplastinovy time (APTT).

Pharmacokinetics. After reception ПРАДАКСА® inside the pharmacokinetic profile of a dabigatran in a blood plasma of healthy volunteers is characterized by bystry increase in concentration plasma with achievement of Cmax within 0,5-2 hours.

After achievement of Cmax plasma concentration of a dabigatran decrease bieksponentsialno, the final elimination half-life averages about 14-17 hours at young people and 1.2-14 hours at elderly. The elimination half-life does not depend on a dose. The maximum concentration in a blood plasma and the area under a curve concentration time (AUC) change in proportion to a dose. Food does not influence bioavailability of a dabigatran of an eteksilat, however time of achievement of peak of plasma concentration is slowed down for 2 hours.

Absolute bioavailability of a dabigatran at reception ПРАДАКСА® inside makes about 6,5%. In a research on studying of absorption of a dabigatran of an eteksilat in 1-3 hours after operational treatment delay of absorption in comparison with healthy volunteers is shown. Smooth increase of a curve concentration time without emergence of peak of concentration in plasma is revealed. The peak of plasma concentration was observed by the 6th o'clock after reception or by 7-9 o'clock after operation. It should be noted that such factors as anesthesia, paresis of a GIT and surgery can matter in absorption delay, irrespective of a dosage form of drug. In other research it was shown that slow absorption or a delay of absorption is observed usually only in day of operation. In the next days absorption of a dabigatran happens quickly to achievement of peak of concentration in 2 hours after reception. Metabolism and excretion of a dabigatran were is studied at healthy volunteers (man) after single intravenous administration radioactive меченного a dabigatrana. Release of drug happened generally through kidneys (85%). Excretion with a stake made about 6% of the entered dose. Within 168 hours after administration of drug removal of the general radioactivity made 88-94% of size of the applied dose. After intake of a dabigatran этексилат quickly and completely turns in дабигатран, being an active form in plasma. The main way of metabolism of a dabigatran of an eteksilat is the hydrolysis catalyzed by esterases at the same time there is its transformation into an active metabolite дабигатран.

At conjugation of a dabigatran 4 isomers pharmacological of active acylglucuronides are formed: 1-0, 2-0, 3-0, 4-0, each of which makes less than 10% of the general maintenance of a dabigatran in plasma. Traces of other metabolites are found only when using highly sensitive analytical methods. Dabigatran is allocated generally through kidneys in not changed look.

Low ability (34-35%) of linkng of a dabigatran with proteins of plasma of the person regardless of concentration of drug is established. The volume of distribution of a dabigatran makes 60-70 l and surpasses the volume of the general content of water in an organism that indicates moderate distribution of a dabigatran in fabrics.

Pharmacokinetics at special groups of patients. Renal failure: At volunteers with a moderate renal failure (clearance of creatinine of 30-50 ml/min.) AUC value of a dabigatran after intake was 2,7 times more in comparison with investigated with normal function of kidneys. At a heavy renal failure (clearance of creatinine of 10-30 ml/min.) AUC value of a dabigatrin and elimination half-life increased respectively in 6 and 2 times in comparison with persons without renal failure.

Elderly patients: In comparison with young people, at elderly AUC and Cmax value increased respectively for 40-60% and 25%. In population researches of pharmacokinetics with participation of elderly persons (to 88 years) it is established that at repeated receptions of a dabigatran its contents increased in an organism. Observed changes correlated with age decrease in clearance of creatinine.

Liver failure: At 12 patients with moderate disturbance of hepatic function (degree In on Chayld-Pyyu) changes in the maintenance of a dabigatran in comparison with control were not revealed.

Body weight: In population pharmacokinetic researches estimated pharmacokinetics parameters at patients with the body weight from 48 to 120 kg. Body weight exerted insignificant impact on plasma clearance of a dabigatran, its contents in an organism was higher at patients with low body weight. At patients with body weight higher than 120 kg are noted decrease in efficiency of drug approximately for 20%, and at the body weight of 48 kg - increase approximately for 25% in comparison with atsiyenta with average body weight.

Floor: In clinical trials 3 phases were not revealed distinctions in efficiency and safety ПРАДАКСА® at men and women. At women influence of drug was 40-50% higher, than at men, however change of a dose at the same time is not required.

Ethnic groups: At a comparative research of pharmacokinetics of a dabigatran at Europeans and Japanese after single and repeated administration of drug in the studied ethnic groups clinically significant changes were not revealed.

Pharmacokinetic researches at persons of negroid race were not conducted.

Indications to use:

- Prevention of venous thromboembolisms at patients after orthopedic operations.

- Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles.

Route of administration and doses:

It is necessary to accept capsules inside, 1 or 2 times a day, irrespective of meal time, washing down with water. It is not necessary to open the capsule.

Use for adults. Prevention of venous thromboembolisms (VTE) at patients after orthopedic operations: the recommended dose makes 220 mg of 1 times a day (2 capsules on 110 mg).

At patients with a moderate renal failure in connection with risk of bleedings, the recommended dose makes 150 mg of 1 times a day (2 capsules on 75 mg).

Prevention of VTE after endoprosthesis replacement of a knee joint: use of drug PRADAKSA should be begun in 1-4 h after completion of operation with reception of 1 capsule (110 mg) with the subsequent increase in a dose up to 2 capsules (220 mg) once in days during the next 10 days. If the hemostasis is not reached, treatment should be postponed. If treatment did not begin in day of operation, therapy should be begun with reception of 2 capsules (220 mg) once in days.

Prevention of VTE after endoprosthesis replacement of a hip joint: use of drug PRADAKSA should be begun in 1-4 h after completion of operation with reception of 1 capsule (110 mg) with the subsequent increase in a dose up to 2 capsules (220 mg) once in days during the next 28-35 days. If the hemostasis is not reached, treatment should be postponed. If treatment did not begin in day of operation, therapy should be begun with reception of 2 capsules (220 mg) once in days.

Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles:

Use of drug PRADAKSA in a daily dose of 300 mg is recommended (1 capsule on 150 mg 2 times a day). Therapy has to continue for life.

Use in special groups of patients. Use for children. At patients up to 18 years efficiency and safety of drug PRADAKSA did not study therefore use for children is not recommended (see the section "Contraindications").

Renal failure. Before therapy, in order to avoid purpose of drug to patients with heavy disturbances of a funtion of kidneys (KK less than 30 ml/min.), it is necessary to estimate clearance of creatinine previously. Due to the lack of data on use of drug for patients with heavy renal failures (KK less than 30 ml/min.) use of drug PRADAKSA is not recommended (see the section "Contraindications").

Function of kidneys has to be estimated in the course of treatment when there is a suspicion about possible decrease or deterioration in function of kidneys (for example, at a hypovolemia, dehydration, simultaneous use of certain medicines, etc.).

At use of drug PRADAKSA for the purpose of prevention of venous thromboembolisms at patients after orthopedic operations at moderate renal failures (KK of 30-50 ml/min.) the daily dose of drug has to be lowered to 150 mg (2 capsules on 75 mg once a day).

At use of drug PRADAKSA for the purpose of prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality with fibrillation of auricles at moderate renal failures (KK of 30-50 ml/min.) of dose adjustment it is not required from patients. Use of drug in a daily dose of 300 mg is recommended (on 1 capsule of 150 mg 2 times a day). Function of kidneys has to be estimated, at least, once a year.

Dabigatran is brought at a hemodialysis; however clinical experience of use for patients which carries out a hemodialysis is limited.

Use for elderly patients. Because increase in exposure of drug at elderly patients (75 years are more senior) is often caused by depression of function of kidneys, before purpose of drug it is necessary to estimate function of kidneys. Renal function has to be estimated at least once a year or more often, depending on a clinical situation. Dose adjustment of drug should be carried out depending on weight of renal failures (see. "Renal failure").

Prevention of venous thromboembolisms at elderly patients (75 years are more senior) after orthopedic operations: experience of use is limited. The recommended dose - 150 mg (2 capsules on 75 mg once).

At use of drug PRADAKSA for elderly patients 80 years for the purpose of prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles drug PRADAKSA are more senior it is necessary to accept in a daily dose 220 mg (1 capsule on 110 mg 2 times a day).

Influence of body weight. Dose adjustment depending on body weight is not required.

Simultaneous use of drug PRADAKSA with active inhibitors of a P-glycoprotein (Amiodaronum, quinidine, verapamil) for the purpose of prevention of venous thromboembolisms at patients after orthopedic operations: at simultaneous use with Amiodaronum, quinidine or verapamil, it is necessary to reduce a dose of drug PRADAKSA to 150 mg once a day (2 capsules on 75 mg) (see the section "Interaction with Other Medicines").

The patients accepting drug PRADAKSA after orthopedic operations are not recommended to begin at the same time use of verapamil and to connect it to therapy further.

Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles: dose adjustment is not required, use of drug in a daily dose of 300 mg is recommended to patients (1 capsule on 150 mg 2 times a day).

Use for patients with the increased risk of bleedings. Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles:

Presence of such factors as age of 75 years or is more senior, moderate depression of function of kidneys (KK of 30-50 ml/min.), simultaneous use of inhibitors of the R-glycoprotein, or the instruction on gastrointestinal bleeding in the anamnesis can increase risk of bleeding (see. "Special instructions"). At patients with one or more specified risk factors, at the discretion of the doctor, decrease in a daily dose of drug PRADAKSA to 220 mg is possible (reception of 1 capsule of 110 mg 2 times a day).

Transition from use of drug PRADAKSA to parenteral use of anticoagulants. Prevention of venous thromboembolisms at patients after orthopedic operations: parenteral administration of anticoagulants should be begun in 24 h after reception of the last dose of drug PRADAKSA.

Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles: parenteral use of anticoagulants should be begun in 12 h after reception of the last dose of drug PRADAKSA.

Transition from parenteral use of anticoagulants to drug PRADAKSA use. The first dose of drug PRADAKSA is appointed instead of the cancelled anticoagulant in the range of 0-2 h before the term of the next injection of alternative therapy or along with the termination of continuous infusion (for example, intravenous use of unfractionated heparin, NFG).

Transition from use of antagonists of vitamin K to drug PRADAKSA use. Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles:

Use of antagonists of vitamin K is stopped, use of drug PRADAKSA is possible at MNO <2,0. Transition from use of drug PRADAKSA to use of antagonists of vitamin K. At clearance of creatinine of ≥50 ml/min. use of antagonists of vitamin K is possible in 3 days, and at clearance of creatinine of 30-50 ml/min. - in 2 days prior to drug withdrawal of PRADAKSA.

Cardioversion. Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles.  Carrying out planned or emergency cardioversion does not demand drug PRADAKSA therapy cancellation.

The passed dose. Prevention of venous thromboembolisms at patients after orthopedic operations. It is recommended to accept a usual daily dose of PRADAKSA in usual time next day. In case of the admission of separate doses it is not necessary to accept a double dose of drug.

Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles: the passed dose of drug PRADAKSA can be accepted if before reception of the next dose of drug there are 6 h and more; if term made less than 6 h, the passed dose should not be accepted. In case of the admission of separate doses it is not necessary to accept a double dose of drug.

Features of use:

Use at pregnancy and during breastfeeding. Data on use of a dabigatran of an eteksilat during pregnancy are absent. The potential risk at the person is unknown. In pilot studies it is not established an adverse effect on fertility or post-natal development of newborns. Women of reproductive age should apply reliable methods of contraception to exclude a possibility of approach of pregnancy at treatment by drug PRADAKSA. At pregnancy approach use of drug is not recommended, except for cases when the expected advantage exceeds possible risk. In need of use of drug during breastfeeding, due to the lack of clinical data, breastfeeding is recommended to be stopped (as a precautionary measure).

Risk of development of bleedings. Drug PRADAKSA use, also as well as other anticoagulants, is recommended with care at the states which are characterized by the increased risk of bleedings. During therapy by drug PRADAKSA development of bleedings of various localization is possible. The decrease in concentration of hemoglobin and/or a hematocrit in blood which is followed by decrease in the ABP is the basis for search of a bleeding point.

Treatment by drug PRADAKSA does not demand control of anticoagulating activity. The test should not be applied to definition of MNO as there are data on false overestimate of the MNO level.

For detection of excessive anticoagulating activity of a dabigatran it is necessary to use tests for definition of thrombin or ekarinovy time of coagulation. In case these tests are not available, it is necessary to use the test for definition of AChTV.

In a research at patsent with fibrillation of auricles exceeding of the AChTV level of norm 2-3 times higher than border before reception of the next dose of drug was associated with the increased risk of bleeding.

In pharmacokinetic researches PRADAKSA it is shown that at patients with reduced function of kidneys (including at elderly patients), increase in exposure of drug is observed. Use of drug PRADAKSA is contraindicated in case of the expressed renal failures (KK <30 ml/min.).

In case of development of an acute renal failure drug PRADAKSA should be cancelled.

In plasma can lead the following factors to increase in concentration of a dagibatran: depression of function of kidneys (KK of 30-50 ml/min.), age of ≥75 years, simultaneous use of inhibitor of the R-glycoprotein. Existence of one or several such factors can increase risk of bleeding (see the section "Route of Administration and Doses").

It was not studied, but simultaneous use of drug PRADAKSA with the following drugs can increase risk of bleedings: unfractionated heparin (except for the doses which are required for maintenance of passability of a venous or arterial catheter) and heparin derivatives, low-molecular heparins (NMG), фондапаринукс sodium, thrombolytic drugs, blockers of glycoprotein GP IIb/IIIa of receptors of thrombocytes, тиклопидин, a dextran, ривароксабан, ticagrelor, antagonists of vitamin K and inhibitors of the R-glycoprotein (итраконазол, такролимус, cyclosporine, ритонавир, нелфинавир and саквинавир). The risk of bleedings increases at the patients who are at the same time accepting selective serotonin reuptake inhibitors. Also the risk of bleedings can increase at simultaneous use of antiagregant and other anticoagulants.

Combined use of a dronedaron and dabigatran is not recommended (see the section "Vzamodeystviye with Other Medicines").

At increase in risk of bleedings (for example, at recently carried out biopsy or the postponed extensive injury, a bacterial endocarditis) control of a condition of the patient for the purpose of timely detection of symptoms of bleeding is required.

Prevention of venous thromboembolisms at patients after orthopedic operations. It is established that use of NPVP for short-term anesthesia at surgical interventions along with drug PRADAKSA is not followed by the increased risk of bleedings. There are limited data on regular use of NPVP (having T1/2 less than 12 h) against the background of treatment by drug PRADAKSA, data on increase in risk of bleedings is not obtained.

Prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality at patients with fibrillation of auricles. Simultaneous use of drug PRADAKSA, antiagregant (including ASK also klopidogret) and NPVP increases risk of bleeding.

Use of fibrinolitic drugs can be considered only if indicators of TV, EVS or AChTV at the patient do not exceed the upper bound of norm of local referensny range.

Interaction with P-glycoprotein inductors. Use inside together with PRADAKSA of the inductor of the R-glycoprotein of rifampicin reduced concentration of a dabigatran in plasma. It is supposed that other inductors of the R-glycoprotein, such as St. John's Wort made a hole or carbamazepine, can also reduce concentration of a dabigatran in a blood plasma and have to be applied with care (see the section "Interaction with Other Medicines").

Surgeries and interventions. At the patients using drug PRADAKSA when carrying out surgeries or invasive procedures the risk of bleedings increases. Therefore when carrying out surgical interventions it is necessary to cancel drug PRADAKSA (see also section "Pharmacokinetics").

Preoperative period. Before holding invasive procedures or surgeries drug PRADAKSA is cancelled, at least, for 24 h before their carrying out. At patients with the increased risk of bleedings or before carrying out the extensive operations demanding a full hemostasis it is necessary to stop use of drug PRADAKSA in 2-4 days prior to operation. At patients with a renal failure the clearance of a dabigatran can be extended.

At drug withdrawal it is necessary to consider the following information:

KK (ml/min.)	T1/2	The termination of administration of drug before planned surgery
		High risk of bleeding or carrying out big operation	Standard risk
≥ 80	~ 13	In 2 days	For 24 h
≥50-<80	~ 15	In 2-3 days	In 1-2 days
≥30-<50	~ 18	In 4 days	In 2-3 days (> 48 h)

It should be taken into account before holding any procedures (see also section "Pharmacokinetics").

Drug PRADAKSA is contraindicated to patients with heavy renal failures (KK <30 ml/min.), but if drug is used nevertheless, should cancel it not less than in 5 days prior to operation.

In case of need carrying out the emergency surgical intervention administration of drug of PRADAKSA need to be stopped temporarily. In the presence of such opportunity, it is reasonable to carry out surgical intervention not earlier than in 12 h after the last reception of PRADAKSA. If operation cannot be postponed, the risk of bleeding can increase (in case of cardioversion see. "Route of administration and doses"). In that case it is necessary to estimate a ratio of risk of bleeding and need of the emergency carrying out intervention.

Spinal anesthesia / epidural anesthesia / lumbar puncture. Such procedures as spinal anesthesia, can demand a complete recovery of a hemostasis.

In case of a traumatic or repeated spinal puncture and long use of an epidural catheter the risk of development of spinal bleeding or epidural hematoma can increase. The first dose of drug PRADAKSA should be accepted not earlier than in 2 h after removal of a catheter. Control of a condition of patients is necessary for an exception of neurologic symptoms which can be caused by spinal bleeding or an epidural hematoma.

The period after holding a procedure. To continue use of drug ПРАДАКСАможно on reaching a full hemostasis.

Influence on ability to control of vehicles and mechanisms. Influence of drug PRADAKSA on ability to manage vehicles and to be engaged in other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions was not studied, but, considering that use of drug ПРАДАКСАможет to be followed by the increased risk of bleedings, it is necessary to be careful when performing such types of activity.

Side effects:

The side effects revealed at use of drug for the purpose of prevention of VTE after orthopedic operations and for prevention of a stroke and system thromboembolisms at patients with fibrillation of auricles.

Disturbances from hemopoietic and lymphatic system: anemia, thrombocytopenia.

Disturbances from immune system: hypersensitivity reactions, including urticaria, rash and an itch, a bronchospasm.

Disturbances from a nervous system: intracranial bleeding.

Disturbances from vessels: hematoma, bleeding.

Disturbances from respiratory organs, a thorax and a mediastinum: nasal bleeding, pneumorrhagia.

Disturbances from a GIT: gastrointestinal bleedings, rectal bleedings, hemorrhoidal bleedings, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of a mucous membrane of a GIT, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagy.

Disturbances from gepatobiliarny system: increase in activity of "hepatic" transaminases, abnormal liver function, hyperbilirubinemia.

Changes from skin and hypodermic fabrics: skin hemorrhagic syndrome.

Skeletal and muscular disturbances, disturbances from connecting fabric and bones: hemarthrosis.

Changes from kidneys and urinary tract: urogenital bleedings, hamaturia.

Disturbances of the general character and change in the venue of injections: bleedings from the place of an injection, bleeding from a catheter injection site.

Damages, toxicity and complications from procedures: a posttraumatic hematoma, bleedings from the place of operational access.

The additional specific side effects revealed at prevention of venous thromboembolisms at patients to whom orthopedic operations are performed. Disturbances from vessels: bleeding from an operational wound.

The general frustration and disturbances in an injection site: bloody allocations.

Damages, toxicity and complications of posleperatsionny processing: a hematoma after carrying out processing of a wound, bleeding after carrying out processing of a wound, anemia in the postoperative period, allocations from a wound after holding procedures, secretion from a wound.

Surgical and therapeutic procedures: a wound drainage, a drainage after processing of a wound.

Interaction with other medicines:

Combined use of drug PRADAKSA with the medicines influencing a hemostasis or system of coagulation, including antagonists of vitamin K, can significantly increase risk of development of bleedings.

Pharmacokinetic interactions. In the researches conducted by in vitro it is not established the inducing or inhibiting influence of a dabigatran on P450 cytochrome. In the researches in vivo at healthy volunteers interaction between a dabigatran eteksilaty and atorvastatiny (CYP3A4 substrate) and diclofenac is noted (CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inductors. Substrate for a transport molecule of a P-glycoprotein is the dabigatrana этексилат. Simultaneous use of inhibitors of the R-glycoprotein (Amiodaronum, verapamil, quinidine, a ketokonazol for system use or a klaritromitsin) leads to increase in concentration of a dabigatran in a blood plasma.

Simultaneous use with P-glycoprotein inhibitors. Selection of a dose in case of use of the listed R-glycoprotein inhibitors for prevention of a stroke, system thromboembolisms and decrease in cardiovascular mortality with fibrillation of auricles is not required from patients.

In case of use for the purpose of prevention of venous thromboembolisms for patients after orthopedic operations - see the sections "Route of Administration and Doses" and "Interaction with Other Medicines".

Amiodaronum. At simultaneous use of a dabigatran of an eteksilat with a single dose of Amiodaronum (600 mg) which was accepted inside, degree and speed of absorption of Amiodaronum and its active metabolite, dezetilamiodaron, did not change. AUC and Cmax values of a dabigatran increased approximately in 1,6 and 1,5 times (by 60% and 50%) respectively.

In a research at patients with fibrillation of auricles concentration of a dabigatran increased no more than by 14%, increase in risk of bleedings was not registered.

Dronedaron. After simultaneous use of a dabigatran of an eteksilat and a dronedaron in a dose of 400 mg once, AUC0-∞ and Cmax of a dabigatran increase in 2,1 and 1.9 times (by 114% and 87%) respectively, and after repeated use of a dronedaron in a dose of 400 mg a day – in 2.4 and 2.3 (for 136% and 125%) respectively. After single and repeated use of a dronedaron in 2 hours after reception of a dabigatran of an eteksilat of AUC0-∞ increased in 1.3 and 1.6 times respectively. Dronedaron did not influence final T1/2 and renal clearance of a dabigatran.

Verapamil. At simultaneous use of a dabigatran of an eteksilat with the verapamil appointed orally Cmax and AUC values of a dabigatran increased depending on time of use and a dosage form of verapamil.

The greatest increase in effect of a dabigatran was observed when using the first dose of verapamil in a dosage form with immediate release which was applied for 1 h before reception of a dabigatran of an eteksilat (Cmax increased by 180%, and AUC – for 150%). When using a dosage form of verapamil with the slowed-down release this effect progressively decreased (Cmax increased by 90%, and AUC – for 70%), also as when using repeated doses of verapamil (Cmax increased by 60%, and AUC – for 50%) that can speak induction of the R-glycoprotein in a GIT at prolonged use of verapamil.

When using verapamil in 2 h after reception of a dabigatran of an eteksilat of clinically significant interactions it was not observed (Cmax increased by 10%, and AUC – for 20%) as in 2 h дабигатран it is completely soaked up (see the section "Route of Administration and Doses").

In a research at patients with fibrillation of auricles concentration of a dabigatran increased no more than by 21%, increase in risk of bleedings was not registered.

Data on interaction of a dabigatran of an eteksilat with the verapamil entered parenterally are absent; clinically significant interaction is not expected.

Ketokonazol. Ketokonazol for system use after single appointment in a dose of 400 mg increases AUC0-∞ and Cmax of a dabigatran approximately by 2,4 times (by 138% and 135%) respectively, and after repeated purpose of a ketokonazol in a dose of 400 mg a day – approximately by 2,5 times (for 153% and 149%) respectively. Ketokonazol did not influence Tmax and final T1/2. Simultaneous use of drug PRADAKSA and a ketokonazol for system use is contraindicated.

Klaritromitsin. At simultaneous use of a klaritromitsin in a dose of 500 mg 2 times a day from a dabigatran eteksilaty clinically significant pharmacokinetic interaction was not observed (Cmax increased by 15%, and AUC – for 19%).

Quinidine. AUCτ, ss and Cmax, ss values of a dabigatran at use 2 times a day in case of co-administration with quinidine in a dose of 200 mg each 2 h before achievement of a total dose of 1000 mg increased on average, respectively, by 53% and for 56%.

Simultaneous use with substrates for a P-glycoprotein. Digoxin. At simultaneous use of a dabigatran of an eteksilat with the digoxin which is substrate of a P-glycoprotein, pharmacokinetic interaction was not observed. дабигатран, pro-medicine of a dabigatran этексилат are not clinically significant inhibitors of a P-glycoprotein.

Simultaneous use with P-glycoprotein inductors. It is necessary to avoid co-administration of drug PRADAKSA and inductors of the R-glycoprotein as combined use leads to decrease in influence of a dabigatran (see the section "Special Instructions").

Rifampicin. Preliminary use of the test inductor of rifampicin in a dose of 600 mg a day within 7 days led to decrease in influence of a dabigatran. After rifampicin cancellation this inductive effect decreased, for the 7th day the effect of a dabigatran was close to initial level. During the next 7 days of further increase in bioavailability of a dabigatran it was not observed.

It is supposed that other inductors of the R-glycoprotein, such as St. John's Wort made a hole or carbamazepine, can also reduce concentration of a dabigatran in a blood plasma and have to be applied with care.

Simultaneous use with antiagregant. Acetylsalicylic acid (ASK). When studying simultaneous use of a dabigatran of an eteksilat in a dose of 150 mg 2 times a day and acetylsalicylic acid (ASK) at patients with fibrillation of auricles are established that the risk of bleedings can increase from 12% to 18% (when using ASK in a dose of 81 mg) and to 24% (when using ASK in a dose of 325 mg). It is shown that ASK or klopidogret, applied along with a dabigatran eteksilaty in a dose of 110 mg or 150 mg 2 times a day, can increase risk of big bleedings. Bleedings are observed more often also at simultaneous use of warfarin with ASK or klopidogrely.

NPVP. The applied NPVP (non-steroidal anti-inflammatory drugs) for a short-term analgesia after operations did not increase risk of bleedings at simultaneous use from a dabigatran eteksilaty. Which experience of prolonged use of NPVP, T1/2 makes less than 12 h, from a dabigatran eteksilaty is limited, there are no data on additional increase in risk of bleedings.

Klopidogrel. It is established that simultaneous use of a dabigatran of an eteksilat and a klopidogrel does not lead to additional increase in time of capillary bleeding in comparison with monotherapy klopidogrely. Besides, it is shown that AUCτ, ss and Cmax, ss values of a dabigatran, and also blood coagulation parameters which were controlled for assessment of effect of a dabigatran (AChTV, ekarinovy time of coagulation or thrombin time (anti-FIIa), and also degree of inhibition of aggregation of thrombocytes (the main indicator of effect of a klopidogrel) during a combination therapy did not change in comparison with the corresponding indicators in monotherapy. When using a "load" dose of a klopidogrel (300 or 600 mg), AUCt, ss and Cmax, ss values of a dabigatran increased by 30-40%.

Simultaneous use with the drugs raising stomach contents pH. Pantoprazol. At combined use of a dabigatran of an eteksilat and pantoprazol decrease in AUC of a dabigatran by 30% was observed. Pantoprazol and other inhibitors of a proton pomp were applied together with a dabigatran eteksilaty in clinical trials, influence on risk of bleeding or efficiency was not observed.

Ranitidine. Ranitidine at use along with a dabigatran eteksilaty, did not exert significant impact on extent of absorption of a dabigatran. The changes of pharmacokinetic parameters of a dabigatran revealed during the population analysis under the influence of inhibitors of a proton pomp and antiacid drugs were clinically insignificant as degree of manifestation of these changes was small (decrease in bioavailability was not significant for antacids, and for inhibitors of a proton pomp made 14,6%). It is established that simultaneous use of inhibitors of a proton pomp is not followed by decrease in concentration of a dabigatran and on average, only slightly reduces concentration of drug in a blood plasma (by 11%). Therefore simultaneous use of inhibitors of a proton pomp, apparently, does not lead to increase in frequency of a stroke or system thromboembolisms, especially in comparison with warfarin, and, therefore, the decrease in bioavailability of a dabigatran caused by simultaneous use of a pantoprazol probably has no clinical importance.

Contraindications:

- The known hypersensitivity to a dabigatran, a dabigatrana to an eteksilat or to any of excipients;
- Heavy degree of a renal failure (KK less than 30 ml/min.);
- Active clinically significant bleeding, hemorrhagic diathesis, spontaneous or pharmacological the induced disturbance of a hemostasis;
- Defeat of bodies as a result of clinically significant bleeding, including a hemorrhagic stroke within 6 months prior to therapy;
- Co-administration of a ketokonazol for system use;
- Abnormal liver functions and diseases of a liver which can affect survival;
- Age up to 18 years (clinical data are absent).

Overdose:

The overdose at use of drug PRADAKSA can be followed by hemorrhagic complications that is caused by pharmakodinamichesky features of drug. When developing bleeding use of drug is stopped. The symptomatic treatment is shown. There is no specific antidote.

Considering the main way of removal of a dabigatran (kidneys), it is recommended to provide an adequate diuresis. Carry out a surgical hemostasis and completion of the volume of the circulating blood (VCB). Perhaps use is fresher than whole blood or transfusion of freshly frozen plasma. As дабигатран has low ability to linkng with proteins of a blood plasma, drug can be removed at a hemodialysis, however clinical experiment on use of dialysis in these situations is limited (see the section "Pharmacokinetics").

At overdose of drug PRADAKSA use of concentrates of the activated prothrombin complex or a recombinant factor of VIIa or concentrates II, IX or X factors of coagulation is possible. There are experimental data confirming efficiency of these means in counteraction to anticoagulating effect of a dabigatran, however special clinical trials were not conducted.

In case of development of thrombocytopenia, or at use of antiagregant of long action, the question of use of a platelet concentrate can be considered.

Storage conditions:

Bottle: at a temperature not above 25 °C. To store a bottle densely corked, for protection against moisture. For 75 mg, 110 mg: after opening of a bottle to use drug within 30 days. For 150 mg: after opening of a bottle to use drug within 4 months. Blisters: in the dry place, at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to use after expiry date.

Issue conditions:

According to the recipe

Packaging:

Capsules of 75 mg, 110 mg and 150 mg. On 10 capsules in the blister with perforation from foil Al/Al. 1, 3, 6 blisters in a pack cardboard with the application instruction.

On 60 capsules in the bottle from polypropylene corked by the plastic screwing-up cover with control of opening from children with a moisture absorber. One bottle in a pack cardboard with the application instruction.

Packaging for hospitals (for a dosage of 150 mg): on 10 capsules in the blister with perforation from Al/Al. 6 blisters in a pack cardboard with the application instruction. On 3 packs cardboard in a film from polypropylene.