Pradaxa, 75 mg capsules 30 pcs

Pradaxa has an anticoagulant effect.

Pharmacodynamics

Dabigatran etexilate is a low molecular weight, nonpharmacologically active precursor form of dabigatran. After oral administration, dabigatran etexilate is rapidly absorbed in the gastrointestinal (GI) tract and, by esterase-catalyzed hydrolysis, is converted to dabigatran in the liver and blood plasma. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in blood plasma.

Because thrombin (a serine protease) converts fibrinogen into fibrin during coagulation, inhibition of thrombin activity prevents thrombus formation. Dabigatran has an inhibitory effect on free thrombin, thrombin associated with fibrin clot, and thrombin-induced platelet aggregation.

The antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate after oral administration have been confirmed in experimental studies in various models of thrombosis in vivo and ex vivo.

The direct correlation between the plasma concentration of dabigatran and the severity of the anticoagulant effect has been established. Dabigatran prolongs activated partial thromboplastin time (APTT), ekarin clotting time (EVT), and thrombin time (TT).

Prevention of venous thromboembolism (VTE) after arthroplasty of major joints

. Results of clinical studies in patients, orthopaedic surgery – knee and hip arthroplasty – have confirmed the preservation of hemostasis parameters and the equivalence of dabigatran etexilate 75 mg or 110 mg 1-4 hours after surgery and a subsequent maintenance dose of 150 or 220 mg once daily for 6-10 days (for knee surgery) and 28-35 days (for hip surgery) compared to enoxaparin at a dose of 40 mg once daily, which was used the day before and after surgery.

The equivalence of the antithrombotic effect of dabigatran etexilate at 150 mg or 220 mg compared with enoxaparin at a dose of 40 mg daily was shown when assessing the primary endpoint, which included all venous thromboembolic events and all-cause mortality.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

. In long-term use, averaging about 20 months in patients with atrial fibrillation and at moderate to high risk of stroke or systemic thromboembolism, dabigatran etexilate at a dose of 110 mg twice daily was shown to be as effective as warfarin in preventing stroke and systemic thromboembolism in patients with atrial fibrillation; as in the dabigatran group, a decrease in the risk of intracranial bleeding and overall bleeding rate was also noted. Administration of higher dose of drug (150 mg 2 times per day) significantly reduced the risk of ischemic and hemorrhagic strokes, cardiovascular death, intracranial bleeding and overall bleeding rate compared to warfarin. The lower dose of dabigatran was characterized by a significantly lower risk of major bleeding compared with warfarin.

The net clinical effect was assessed by determining a combined endpoint that included the incidence of stroke, systemic thromboembolism, pulmonary embolism, acute myocardial infarction, cardiovascular mortality and major bleeding.

The annual incidence of these events was lower in patients receiving dabigatran etexilate than in patients receiving warfarin.

Changes in laboratory measures of liver function in patients receiving dabigatran etexilat were of comparable or lower frequency compared with patients receiving warfarin.

Pharmacokinetics

After oral administration of dabigatran etexilate there is a rapid dose-dependent increase in its plasma concentration and area under the concentration-time curve (AUC). Maximum concentration of dabigatran etexilate (C_max) is reached within 0.5-2 hours.

After reaching C_max plasma concentrations of dabigatran decrease biexponentially, the final elimination half-life (T1/2) averages about 11 h (in the elderly). The final T1/2 after multiple administration of the drug was about 12-14 h. T1/2 is independent of the dose. However, in case of impaired renal function the T1/2 is prolonged.

The absolute bioavailability of dabigatran after oral dabigatran etexilate in hypromellose capsules is approximately 6.5%.

Eating does not affect the bioavailability of dabigatran etexilate, but the time to reach C_max increases by 2 h.

When dabigatran etexilate is used without the special capsule shell made of hypromellose, the bioavailability when taken orally may increase by approximately 1.8 times (75%) compared to the capsule dosage form. Therefore, the integrity of hypromellose capsules should be maintained, given the risk of increased bioavailability of dabigatran etexilate, and it is not recommended to open the capsules and use their contents in their pure form (e.g. by adding to food or drinks) (see section “Dosage and administration”).

When dabigatran etexilate is administered 1-3 h in patients after surgical treatment, a decrease in the rate of absorption of the drug compared to healthy volunteers is noted. AUC is characterized by a gradual increase in amplitude without the appearance of a high peak plasma concentration. C_max in plasma is noted 6 h after dabigatran etexilate administration or 7-9 h after surgery. It should be noted that factors such as anesthesia, gastrointestinal paresis and surgery may be important in slowing absorption, regardless of the dosage form of the drug. A decrease in the rate of drug absorption is usually noted only on the day of surgery. On subsequent days, absorption of dabigatran is rapid, with C_max reaching 2 h after oral administration.

Metabolism

After oral administration during hydrolysis under the influence of dabigatran esterase, etexilate is rapidly and completely converted to dabigatran, which is the main active metabolite in blood plasma. Conjugation of dabigatran produces 4 isomers of pharmacologically active acylglucuronides: 1-O, 2-O, 3-O, 4-O, each of which is less than 10% of the total dabigatran in blood plasma. Traces of other metabolites are detectable only with highly sensitive analytical methods.

Distribution

The volume of distribution of dabigatran is 60-70 liters and exceeds the volume of total body water, indicating a moderate distribution of dabigatran in tissues.

Excretion

Dabigatran is excreted unchanged, mainly by the kidneys (85%), and only 6% through the gastrointestinal tract. It has been found that 88-94% of the labeled radioactive drug dose is eliminated from the body 168 h after administration.

Dabigatran has a low capacity of binding to plasma proteins (34-35%); it does not depend on the concentration of the drug.

Particular groups of patients

Elderly patients

. In elderly persons, the AUC value is 1.4-1.6 times higher than in younger persons (by 40-60%) and the C_max is more than 1.25 times higher (by 25%).

The observed changes correlated with an age-related decrease in creatinine clearance (CC).

In elderly women (over 65 years of age), the AUC_τ,ss and C_max,ss were approximately 1.9-fold and 1.6-fold higher than in younger women (18-40 years old), and 2.2-fold and 2.0-fold higher in older men than in younger men. In a study in patients with atrial fibrillation, the effect of age on dabigatran exposure was confirmed: Dabigatran baseline concentrations were approximately 1.3-fold (31%) higher in patients aged ≥75 years, and in patients aged

Disordered renal function

In volunteers with moderate renal function impairment (CK – 30-50 mL/min), the AUC of dabigatran after oral administration was approximately 3-fold higher than in those with unchanged renal function.

In patients with severe renal impairment (CK – 10-30 ml/min) the AUC values of dabigatran etexilate and T1/2 increased by 6 and 2 times, respectively, compared to the same values in persons without renal impairment.

In patients with atrial fibrillation and moderate renal impairment (CK 30-50 ml/min), dabigatran concentrations before and after drug administration were on average 2.29 and 1.81 times higher than in patients without renal impairment.

When hemodialysis was used in patients without atrial fibrillation, it was found that the amount of drug excreted was proportional to the blood flow rate. The duration of dialysis, with a dialysate flow rate of 700 mL/min, was 4 hours and the blood flow rate was 200 mL/min or 350-390 mL/min. This resulted in removal of 50% and 60% of free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased as plasma concentrations decreased; the relationship of FC and FD did not change.

Hepatic impairment

There were no changes in plasma concentrations of dabigatran in patients with moderate hepatic impairment (Child-Pugh score 7-9) compared to patients without hepatic impairment.

Body weight

In studies, basal concentrations of dabigatran in patients with a body weight of >100 kg were approximately 20% lower than in patients with a body weight of 50-100 kg. The majority (80.8%) of patients had a body weight of ≥50 to <100 kg; no clear differences in dabigatran concentrations were found within this range. Data are limited for patients with a body weight ≤50 kg.

Per sex

In major studies on the prevention of VTE, exposure to the drug was found to be approximately 1.4-1.5 times (40-50%) higher in female patients. In patients with atrial fibrillation, basal concentrations and concentrations after drug administration were on average 1.3 (by 30%) higher. The established differences had no clinical significance.

Ethnic Groups

In a comparative study of the pharmacokinetics of dabigatran in Europeans and Japanese after a single and repeated administration of the drug, no clinically significant differences were found in the ethnic groups studied. Pharmacokinetic studies in patients of the Negro race are limited, but available data indicate no significant differences.

Indications

Prevention of venous thromboembolism in patients after orthopedic surgery;

prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation.

Pharmacological effect

Pradaxa has an anticoagulant effect.

Pharmacodynamics

Dabigatran etexilate is a low molecular weight, non-pharmacologically active precursor to the active form of dabigatran. After oral administration, dabigatran etexilate is rapidly absorbed from the gastrointestinal tract (GIT) and, by hydrolysis catalyzed by esterases, is converted to dabigatran in the liver and blood plasma. Dabigatran is a potent competitive reversible direct thrombin inhibitor and the main active substance in blood plasma.

Since thrombin (serine protease) converts fibrinogen into fibrin during coagulation, inhibition of thrombin activity prevents thrombus formation. Dabigatran has inhibitory effects on free thrombin, fibrin clot-bound thrombin, and thrombin-induced platelet aggregation.

Experimental studies on various models of thrombosis in vivo and ex vivo confirmed the antithrombotic effect and anticoagulant activity of dabigatran after intravenous administration and dabigatran etexilate after oral administration.

A direct correlation has been established between the concentration of dabigatran in the blood plasma and the severity of the anticoagulant effect. Dabigatran prolongs the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and thrombin time (TT).

Prevention of venous thromboembolism (VTE) after large joint replacement

The results of clinical studies in patients who underwent orthopedic surgery – knee and hip joint replacement – confirmed the preservation of hemostasis parameters and the equivalence of the use of 75 mg or 110 mg of dabigatran etexilate 1-4 hours after surgery and a subsequent maintenance dose of 150 or 220 mg once a day for 6-10 days (for knee surgery) and 28-35 days (for hip joint) compared with enoxaparin at a dose of 40 mg 1 time per day, which was used before and after surgery.

The antithrombotic effect of dabigatran etexilate at 150 mg or 220 mg was shown to be equivalent to enoxaparin at a dose of 40 mg per day when assessing the primary endpoint, which included all cases of venous thromboembolism and mortality from any cause.

Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation

During long-term use, averaging approximately 20 months, in patients with atrial fibrillation and at moderate to high risk of stroke or systemic thromboembolism, dabigatran etexilate 110 mg given twice daily was shown to be noninferior to warfarin in preventing stroke and systemic thromboembolism in patients with atrial fibrillation; Also in the dabigatran group there was a decrease in the risk of intracranial bleeding and the overall incidence of bleeding. The use of a higher dose of the drug (150 mg 2 times a day) significantly reduced the risk of ischemic and hemorrhagic strokes, cardiovascular death, intracranial bleeding and the overall incidence of bleeding, compared with warfarin. The lower dose of dabigatran was associated with a significantly lower risk of major bleeding compared with warfarin.

The net clinical effect was assessed by determining a composite endpoint that included the incidence of stroke, systemic thromboembolism, pulmonary thromboembolism, acute myocardial infarction, cardiovascular mortality, and major bleeding.

The annual incidence of these events in patients receiving dabigatran etexilate was lower than in patients receiving warfarin.

Changes in laboratory tests of liver function in patients receiving dabigatran etexilate were observed with comparable or less frequency compared to patients receiving warfarin.

Pharmacokinetics

Following oral administration of dabigatran etexilate, there is a rapid, dose-dependent increase in its plasma concentration and area under the concentration-time curve (AUC). The maximum concentration of dabigatran etexilate (Cmax) is achieved within 0.5-2 hours.

After reaching Cmax, plasma concentrations of dabigatran decrease biexponentially, the final half-life (T1/2) averages about 11 hours (in elderly people). The final T1/2 after repeated use of the drug was about 12-14 hours. T1/2 does not depend on the dose. However, in case of renal dysfunction, T1/2 is prolonged.

The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate in hypromellose-coated capsules is approximately 6.5%.

Food intake does not affect the bioavailability of dabigatran etexilate, however, the time to reach Cmax increases by 2 hours.

When using dabigatran etexilate without a special capsule shell made of hypromellose, oral bioavailability can increase by approximately 1.8 times (75%) compared to the capsule dosage form. Therefore, the integrity of capsules made from hypromellose should be maintained, given the risk of increasing the bioavailability of dabigatran etexilate, and it is not recommended to open the capsules and use their contents in pure form (for example, adding to food or drinks) (see section “Dosage and Administration”).

When using dabigatran etexilate after 1-3 hours in patients after surgical treatment, a decrease in the rate of absorption of the drug is observed compared to healthy volunteers. AUC is characterized by a gradual increase in amplitude without the appearance of a high peak in plasma concentration. Cmax in blood plasma is observed 6 hours after the use of dabigatran etexilate or 7-9 hours after surgery. It should be noted that factors such as anesthesia, gastrointestinal paresis and surgery may play a role in slowing absorption, regardless of the dosage form of the drug. A decrease in the rate of absorption of the drug is usually observed only on the day of surgery. In the following days, absorption of dabigatran occurs rapidly, reaching Cmax 2 hours after oral administration.

Metabolism

After oral administration, during hydrolysis under the influence of esterase, dabigatran etexilate is quickly and completely converted into dabigatran, which is the main active metabolite in the blood plasma. When dabigatran is conjugated, 4 isomers of pharmacologically active acyl glucuronides are formed: 1-O, 2-O, 3-O, 4-O, each of which constitutes less than 10% of the total content of dabigatran in the blood plasma. Traces of other metabolites are only detected using highly sensitive analytical methods.

Distribution

The volume of distribution of dabigatran is 60-70 L and exceeds the volume of total body water, indicating a moderate distribution of dabigatran in tissues.

Removal

Dabigatran is excreted unchanged, mainly by the kidneys (85%), and only 6% through the gastrointestinal tract. It has been established that 168 hours after administration of a radioactive drug, 88-94% of its dose is excreted from the body.

Dabigatran has a low binding ability to plasma proteins (34-35%), it does not depend on the concentration of the drug.

Special patient groups

Elderly patients

In elderly people, the AUC value is higher than in young people by 1.4-1.6 times (40-60%), and Cmax is more than 1.25 times (25%).

The observed changes correlated with an age-related decrease in creatinine clearance (CC).

In elderly women (over 65 years), the values ​​of AUCτ,ss and Cmax,ss were approximately 1.9 times and 1.6 times higher than in young women (18-40 years), and in elderly men they were 2.2 and 2.0 times higher than in young men. A study in patients with atrial fibrillation confirmed the effect of age on dabigatran exposure: baseline dabigatran concentrations in patients aged ≥75 years were approximately 1.3 times (31%) higher, and in patients older

Renal dysfunction

In volunteers with moderate renal impairment (creatinine clearance 30-50 ml/min), the AUC value of dabigatran after oral administration was approximately 3 times greater than in individuals with unchanged renal function.

In patients with severely impaired renal function (creatinine clearance – 10-30 ml/min), the AUC values ​​of dabigatran etexilate and T1/2 increased by 6 and 2 times, respectively, compared with similar indicators in individuals without impaired renal function.

In patients with atrial fibrillation and moderate renal failure (creatinine clearance 30-50 ml/min), dabigatran concentrations before and after drug use were on average 2.29 and 1.81 times higher than in patients without renal impairment.

When using hemodialysis in patients without atrial fibrillation, it was found that the amount of drug excreted is proportional to the speed of blood flow. The duration of dialysis, with a dialysate flow rate of 700 ml/min, was 4 hours, and the blood flow rate was 200 ml/min or 350-390 ml/min. This resulted in the removal of 50% and 60% of free and total dabigatran concentrations, respectively. The anticoagulant activity of dabigatran decreased as plasma concentrations decreased; the relationship between PK and PD did not change.

Liver dysfunction

In patients with moderate hepatic impairment (Child-Pugh score 7-9) there were no changes in plasma dabigatran concentrations compared to patients without hepatic impairment.

Body weight

In studies, basal dabigatran concentrations in patients weighing >100 kg were approximately 20% lower than in patients weighing 50–100 kg. The body weight of the majority (80.8%) of patients was ≥50 – <100 kg, within this range there were no obvious differences in dabigatran concentrations. Data for patients weighing ≤50 kg are limited.

Floor

In the main studies on the prevention of VTE, it was found that the effect of the drug in female patients was approximately 1.4-1.5 times (40-50%) higher. In patients with atrial fibrillation, basal concentrations and concentrations after drug use were on average 1.3 (30%) higher. The differences found were not clinically significant.

Ethnic groups

In a comparative study of the pharmacokinetics of dabigatran in Europeans and Japanese after a single and repeated dose of the drug in the studied ethnic groups, no clinically significant differences were identified. Pharmacokinetic studies in black patients are limited, but available data indicate no significant differences.

Active ingredient

Dabigatran etexilate

Composition

Active ingredient:

dabigatran etexilate mesylate;

Excipients:

acacia gum;

coarse tartaric acid;

tartaric acid powder;

crystalline tartaric acid;

hypromellose;

dimethicone;

talc;

hyprolose (hydroxypropylcellulose);

Shell:

hypromellose capsule (HPMC) printed with black ink (Colorcon S-1-27797);

HPMC capsules:

carrageenan; potassium chloride; titanium dioxide; indigo carmine (E132); sunset yellow dye (E110); hypromellose (hydroxypropyl methylcellulose), purified water;

Composition of black ink Colorcon S-1-27797, (%, wt.):

shellac 52.500%, butanol 6.550%, purified water 1.940%, denatured ethanol (methylated alcohol) 0.650%, black iron oxide dye (E172) 33.770%, isopropanol 3.340%, propylene glycol 1.250%

Contraindications

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 disorder of hemostasis;
Organ damage as a result of clinically significant bleeding, including hemorrhagic stroke within 6 months before the start of therapy;
Simultaneous administration of ketoconazole for systemic use;
Liver dysfunction and liver disease that may affect survival;
Age under 18 years (no clinical data available).

Side Effects

Disorders of the hematopoietic and lymphatic system: anemia, thrombocytopenia.

Immune system disorders: hypersensitivity reactions, including urticaria, rash and itching, bronchospasm.

Nervous system disorders: intracranial bleeding.

Vascular disorders: hematoma, bleeding.

Respiratory, thoracic and mediastinal disorders: nosebleeds, hemoptysis.

Gastrointestinal disorders: gastrointestinal bleeding, rectal bleeding, hemorrhoidal bleeding, abdominal pain, diarrhea, dyspepsia, nausea, ulceration of the gastrointestinal mucosa, gastroesophagitis, gastroesophageal reflux disease, vomiting, dysphagia.

Disorders of the hepatobiliary system: increased activity of liver transaminases, impaired liver function, hyperbilirubinemia.

Changes in the skin and subcutaneous tissues: cutaneous hemorrhagic syndrome.

Musculoskeletal disorders, connective tissue and bone disorders: hemarthrosis.

Changes in the kidneys and urinary tract: urogenital bleeding, hematuria.

General disorders and changes at the injection site: bleeding from the injection site, bleeding from the catheter insertion site.

Damage, toxicity and complications from procedures: post-traumatic hematoma, bleeding from the surgical access site.

Vascular disorders: bleeding from the surgical wound.

General disorders and disorders at the injection site: spotting.

Damage, toxicity and complications of postoperative treatment: hematoma after wound treatment, bleeding after wound treatment, anemia in the postoperative period, discharge from the wound after procedures, secretion from the wound.

Surgical and therapeutic procedures: wound drainage, drainage after wound treatment.

Interaction

Concomitant use of PRADAXA with drugs that affect hemostasis or the coagulation system, including vitamin K antagonists, may significantly increase the risk of bleeding.

Pharmacokinetic interactions

In vitro studies have not established an inducing or inhibitory effect of dabigatran on cytochrome P450. In in vivo studies in healthy volunteers, no interaction was observed between dabigatran etexilate and atorvastatin (CYP3A4 substrate) and diclofenac (CYP2C9 substrate).

Interactions with P-glycoprotein inhibitors/inducers:

The substrate for the transport molecule P-glycoprotein is dabigatran etexilate. The simultaneous use of P-glycoprotein inhibitors (amiodarone, verapamil, quinidine, ketoconazole for systemic use or clarithromycin) leads to an increase in the concentration of dabigatran in the blood plasma.

Concomitant use with P-glycoprotein inhibitors:

Dose selection in the case of using the listed P-glycoprotein inhibitors for the prevention of stroke, systemic thromboembolism and reduction of cardiovascular mortality in patients with atrial fibrillation is not required.

If used for the prevention of venous thromboembolism in patients after orthopedic surgery, see sections “Method of administration and dosage” and “Interaction with other drugs.”

Amiodarone. With simultaneous use of dabigatran etexilate with a single dose of amiodarone (600 mg) taken orally, the degree and rate of absorption of amiodarone and its active metabolite, desethylamiodarone, did not change. The AUC and Cmax values ​​of dabigatran increased approximately 1.6-fold and 1.5-fold (60% and 50%), respectively.

In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 14%, and no increased risk of bleeding was observed.

Dronedarone. After simultaneous use of dabigatran etexilate and dronedarone at a dose of 400 mg once,

The AUC0-∞ and Cmax of dabigatran increased by 2.1 and 1.9 times (by 114% and 87%), respectively, and after repeated use of dronedarone at a dose of 400 mg per day – by 2.4 and 2.3 (by 136% and 125%), respectively. After single and multiple doses of dronedarone, 2 hours after administration of dabigatran etexilate, AUC0-∞ increased by 1.3 and 1.6 times, respectively. Dronedarone had no effect on final T1/2 and renal clearance of dabigatran.

Verapamil. When dabigatran etexilate was co-administered with verapamil administered orally, the Cmax and AUC values ​​of dabigatran increased depending on the time of administration and the dosage form of verapamil.

The greatest increase in the effect of dabigatran was observed with the first dose of immediate-release verapamil administered 1 hour before dosing with dabigatran etexilate (Cmax increased by 180% and AUC increased by 150%). This effect was progressively reduced when the sustained-release formulation of verapamil was used (Cmax increased by 90% and AUC increased by 70%), as well as when multiple doses of verapamil were used (Cmax increased by 60% and AUC increased by 50%), which may be explained by the induction of P-glycoprotein in the gastrointestinal tract with long-term use of verapamil.

When using verapamil 2 hours after taking dabigatran etexilate, no clinically significant interactions were observed (Cmax increased by 10% and AUC by 20%), since dabigatran is completely absorbed after 2 hours (see section “Dosage and Administration”).

In a study in patients with atrial fibrillation, dabigatran concentrations increased by no more than 21%, and no increased risk of bleeding was observed.

There are no data on the interaction of dabigatran etexilate with verapamil administered parenterally; no clinically significant interaction is expected.

Ketoconazole. Ketoconazole for systemic use after a single dose of 400 mg increases the AUC0-∞ and Cmax of dabigatran by approximately 2.4 times (by 138% and 135%), respectively, and after repeated administration of ketoconazole at a dose of 400 mg per day – by approximately 2.5 times (by 153% and 149%), respectively. Ketoconazole did not affect Tmax and final T1/2. The simultaneous use of PRADAXA and ketoconazole for systemic use is contraindicated.

Clarithromycin. When simultaneous use of clarithromycin at a dose of 500 mg 2 times a day with dabigatran etexilate, no clinically significant pharmacokinetic interaction was observed (Cmax increased by 15% and AUC by 19%).

Quinidine. The AUCτ,ss and Cmax,ss values ​​of dabigatran when used 2 times a day in the case of simultaneous administration with quinidine at a dose of 200 mg every 2 hours until a total dose of 1000 mg were increased on average by 53% and 56%, respectively.

Concomitant use with P-glycoprotein substrates:

Digoxin. No pharmacokinetic interaction was observed with simultaneous use of dabigatran etexilate with digoxin, which is a P-glycoprotein substrate. Neither dabigatran nor the prodrug dabigatran etexilate are clinically significant P-gp inhibitors.

Concomitant use with P-glycoprotein inducers:

The simultaneous administration of PRADAXA and P-glycoprotein inducers should be avoided, since combined use leads to a decrease in the effect of dabigatran (see section “Special Instructions”).

Rifampicin. Pretreatment with the test inducer rifampicin at a dose of 600 mg per day for 7 days resulted in decreased exposure to dabigatran. After discontinuation of rifampicin, this inductive effect decreased; on day 7, the effect of dabigatran was close to the initial level. Over the next 7 days, no further increase in the bioavailability of dabigatran was observed.

It is expected that other P-glycoprotein inducers, such as St. John’s wort or carbamazepine, may also reduce plasma concentrations of dabigatran and should be used with caution.

Simultaneous use with antiplatelet agents

Acetylsalicylic acid (ASA). When studying the simultaneous use of dabigatran etexilate at a dose of 150 mg 2 times a day and acetylsalicylic acid (ASA) in patients with atrial fibrillation, it was found that the risk of bleeding may increase from 12% to 18% (using ASA at a dose of 81 mg) and up to 24% (using ASA at a dose of 325 mg). It has been shown that ASA or clopidogrel, used concomitantly with dabigatran etexilate at a dose of 110 mg or 150 mg 2 times a day, may increase the risk of major bleeding. Bleeding is also observed more often with the simultaneous use of warfarin with ASA or clopidogrel.

NSAIDs. NSAIDs (non-steroidal anti-inflammatory drugs) used for short-term analgesia after surgery did not increase the risk of bleeding when used simultaneously with dabigatran etexilate. Experience with long-term use of NSAIDs with a half-life of less than 12 hours with dabigatran etexilate is limited, and there is no evidence of an additional increase in the risk of bleeding.

Clopidogrel. It was found that the simultaneous use of dabigatran etexilate and clopidogrel does not lead to an additional increase in capillary bleeding time compared to clopidogrel monotherapy. In addition, it was shown that the AUCτ,ss and Cmax,ss values ​​of dabigatran, as well as the blood coagulation parameters that were monitored to evaluate the effect of dabigatran (aPTT, ecarin clotting time or thrombin time (anti FIIa), as well as the degree of inhibition of platelet aggregation (the main indicator of the effect of clopidogrel) during combination therapy did not change compared with the corresponding indicators in monotherapy. When used “loading” dose of clopidogrel (300 or 600 mg), the AUCt,ss and Cmax,ss values ​​of dabigatran increased by 30-40%.

Concomitant use with drugs that increase the pH of the stomach contents

Pantoprazole. When dabigatran etexilate and pantoprazole were co-administered, a 30% decrease in the AUC of dabigatran was observed. Pantoprazole and other proton pump inhibitors were used with dabigatran etexilate in clinical studies and no effect on bleeding risk or efficacy was observed.

Ranitidine. Ranitidine, when used concomitantly with dabigatran etexilate, did not have a significant effect on the degree of absorption of dabigatran.

The changes in the pharmacokinetic parameters of dabigatran identified during the population analysis under the influence of proton pump inhibitors and antacid drugs turned out to be clinically insignificant, since the severity of these changes was small (the decrease in bioavailability was not significant for antacids, but for proton pump inhibitors it was 14.6%). It was found that the simultaneous use of proton pump inhibitors is not accompanied by a decrease in the concentration of dabigatran and, on average, only slightly reduces the concentration of the drug in the blood plasma (by 11%). Therefore, concomitant use of proton pump inhibitors does not appear to lead to an increased incidence of stroke or systemic thromboembolism, especially when compared with warfarin, and therefore the decrease in dabigatran bioavailability caused by concomitant use of pantoprazole is probably not clinically significant.

Overdose

An overdose when using the drug PRADAXA may be accompanied by hemorrhagic complications, which is due to the pharmacodynamic properties of the drug. If bleeding occurs, stop using the drug. Symptomatic treatment is indicated. There is no specific antidote.

Given the main route of elimination of dabigatran (renal), it is recommended to ensure adequate diuresis. Surgical hemostasis and replenishment of circulating blood volume (CBV) are performed. It is possible to use fresh whole blood or transfuse fresh frozen plasma. Since dabigatran has a low ability to bind to plasma proteins, the drug can be eliminated by hemodialysis, however, clinical experience with the use of dialysis in these situations is limited (see section “Pharmacokinetics”).

In case of an overdose of PRADAXA, it is possible to use concentrates of activated prothrombin complex or recombinant factor VIIa or concentrates of coagulation factors II, IX or X. There is experimental evidence to support the effectiveness of these agents in counteracting the anticoagulant effect of dabigatran, but no specific clinical studies have been conducted.

In the event of thrombocytopenia, or when using long-acting antiplatelet agents, the use of platelet mass may be considered.

Storage conditions

In a dry place, at a temperature not exceeding 25 °C

Shelf life

3 years

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co.KG, Germany