Dabifor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dabifor® (Dabifor)

Composition:

Active substance: dabigatran etexilate;

One capsule contains: dabigatran etexilate mesilate – 172.95 mg, equivalent to dabigatran etexilate – 150 mg;

Excipients: microcrystalline cellulose (E 460), sodium croscarmellose (E 468), crospovidone, talc (E 553b), tartaric acid granules, hydroxypropylcellulose, mannitol (E 421), magnesium stearate (E 572);

Capsule shell composition: hypromellose (E 464), titanium dioxide (E 171), iron oxide red (E 172);

printing ink of black color***;

***Ink composition: black ink (shellac (E 904), propylene glycol (E 1520), concentrated ammonia solution (E 527), potassium hydroxide (E 525), iron oxide black (E 172)).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: size "0el" capsule, capsule cap and body of pink/opaque pink color with the inscription "DA150" printed in black ink.

Pharmacotherapeutic group. Antithrombotic agents. Direct thrombin inhibitors.

ATC code B01A E07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Dabigatran etexilate belongs to low-molecular-weight prodrugs that do not exhibit pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted into dabigatran by esterase-catalyzed hydrolysis in blood plasma and the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active substance in plasma.

Since thrombin (a serine protease) activates the conversion of fibrinogen to fibrin in the blood coagulation system, its inhibition prevents thrombus formation. Dabigatran also inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.

Pharmacodynamic effects. A clear correlation exists between plasma concentrations of dabigatran and the degree of anticoagulant effect based on studies. Dabigatran prolongs thrombin time (TT), clotting time (CT), and activated partial thromboplastin time (aPTT).

The calibrated dilute thrombin time (dTT) assay provides an approximate value of dabigatran plasma concentration that can be compared with expected levels. If the dTT test result is at or below the limit of quantification, additional coagulation tests (TT, CT, and aPTT) should be considered.

The CT test allows direct measurement of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indication of the anticoagulant intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not used for precise quantitative assessment of anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted cautiously, they indicate anticoagulant effect in the patient.

Clinical efficacy and safety

Ethnic origin

No clinically relevant ethnic differences were observed among patients of Caucasian, African American, Hispanic, Japanese, or Chinese origin.

In the RE-LY clinical trial, dabigatran etexilate at a dose of 110 mg twice daily was non-inferior to warfarin in preventing stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with a reduced risk of intracranial hemorrhage, overall bleeding, or major bleeding. The dose of dabigatran 150 mg twice daily significantly reduced the risk of ischemic and hemorrhagic stroke, cardiovascular death, intracranial hemorrhage, and overall bleeding compared to warfarin. The rate of major bleeding at these doses was comparable to warfarin. The incidence of myocardial infarction with dabigatran etexilate at doses of 110 mg and 150 mg twice daily compared to warfarin did not significantly increase (risk ratio (RR) 1.29; p = 0.0929 and RR 1.27; p = 0.1240, respectively). A significant positive impact of dabigatran etexilate compared to warfarin is improved monitoring of the international normalized ratio (INR).

Patients undergoing catheter ablation for atrial fibrillation

A prospective, open-label, randomized, multicenter exploratory study with blinded endpoint assessment (RE-CIRCUIT) was conducted in 704 patients receiving stable anticoagulant therapy. The study compared continuous therapy with dabigatran etexilate 150 mg twice daily versus continuous INR-adjusted warfarin therapy in patients undergoing catheter ablation for paroxysmal or persistent atrial fibrillation. Of the 704 patients enrolled, 317 underwent catheter ablation under continuous dabigatran therapy and 318 under continuous warfarin therapy. All patients underwent transesophageal echocardiography prior to catheter ablation. The primary endpoint (defined as major bleeding according to ISTH criteria) was reached in 5 (1.6%) patients in the dabigatran etexilate group and in 22 (6.9%) patients in the warfarin group (risk difference -5.3%; 95% confidence interval (CI) -8.4; -2.2; p = 0.0009). There were no cases of stroke/systemic embolism/transient ischemic attack (TIA) in the dabigatran etexilate group, whereas one case of TIA occurred in the warfarin group from the time of ablation to 8 weeks post-ablation. This exploratory study demonstrated that dabigatran etexilate use is associated with a significant reduction in major bleeding compared to INR-adjusted warfarin therapy during ablation.

Non-interventional study data

In a non-interventional study (GLORIA-AF), prospective data (during Phase II) on safety and efficacy were collected from patients with newly diagnosed non-valvular atrial fibrillation (NVAF) receiving dabigatran etexilate under real-world conditions. The study included 4859 patients receiving dabigatran etexilate (55% received 150 mg twice daily, 43% received 110 mg twice daily, 2% received 75 mg twice daily). Patients were followed for 2 years. Mean CHADS2 and HAS-BLED scores were 1.9 and 1.2, respectively. The mean treatment observation period was 18.3 months. Major bleeding occurred in 0.97 cases per 100 patient-years. Life-threatening bleeding was recorded in 0.46 cases per 100 patient-years, intracranial hemorrhage in 0.17 cases per 100 patient-years, and gastrointestinal bleeding in 0.60 cases per 100 patient-years. Stroke occurred in 0.65 cases per 100 patient-years.

Additionally, in a non-interventional study [Graham DJ et al., Circulation. 2015;131:157-164] involving over 134,000 elderly patients with NVAF in the United States (equivalent to more than 37,500 patient-years of treatment observation), dabigatran etexilate (84% of patients receiving 150 mg twice daily, 16% receiving 75 mg twice daily) was associated with reduced risk of ischemic stroke (RR 0.80, 95% CI 0.67–0.96), intracranial hemorrhage (RR 0.34; CI 0.26–0.46), and mortality (RR 0.86; CI 0.77–0.96), as well as increased risk of gastrointestinal bleeding (RR 1.28; CI 1.14–1.44) compared to warfarin. No difference was observed in the risk of major bleeding (RR 0.97; CI 0.88–1.07).

These real-world observations are consistent with the safety and efficacy profile of dabigatran etexilate established in the RE-LY trial when used for the specified indication.

Patients undergoing percutaneous coronary intervention (PCI) with stenting

A prospective, randomized, open-label study (Phase IIIb) with endpoint masking (PROBE design), aimed at evaluating dual therapy with dabigatran etexilate (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor (P2Y12 antagonist) compared to triple therapy with warfarin (INR-adjusted to 2.0–3.0) plus clopidogrel or ticagrelor and acetylsalicylic acid (ASA), was conducted in 2725 NVAF patients who underwent PCI with stenting (RE-DUAL PCI). Patients were randomized to receive dual therapy with dabigatran etexilate 110 mg twice daily, dual therapy with dabigatran etexilate 150 mg twice daily, or triple therapy with warfarin. Elderly patients outside the United States (aged ≥80 years in all countries and ≥70 years in Japan) were randomized to receive dual therapy with dabigatran etexilate 110 mg or warfarin therapy. The primary endpoint was a composite of major bleeding as defined by ISTH (International Society on Thrombosis and Haemostasis) or clinically relevant non-major bleeding.

The rate of the primary endpoint was 15.4% (151 patients) in the dual therapy group with dabigatran etexilate 110 mg compared to 26.9% (264 patients) in the triple therapy warfarin group (RR 0.52; 95% CI 0.42, 0.63; p < 0.0001 for non-inferiority and p < 0.0001 for superiority) and 20.2% (154 patients) in the dual therapy group with dabigatran etexilate 150 mg compared to 25.7% (196 patients) in the corresponding triple therapy warfarin group (RR 0.72; 95% CI 0.58, 0.88; p < 0.0001 for non-inferiority and p = 0.002 for superiority). According to descriptive analysis, the rate of major bleeding on the TIMI (Thrombolysis in Myocardial Infarction) scale was lower in both dual therapy groups with dabigatran etexilate than in the triple therapy warfarin group: 14 events (1.4%) in the dual therapy group with dabigatran etexilate 110 mg compared to 37 events (3.8%) in the triple therapy warfarin group (RR 0.37; 95% CI 0.20, 0.68; p = 0.002) and 16 events (2.1%) in the dual therapy group with dabigatran etexilate 150 mg compared to 30 events (3.9%) in the corresponding triple therapy warfarin group (RR 0.51; 95% CI 0.28, 0.93; p = 0.03). Both dual therapy groups with dabigatran etexilate showed a lower incidence of intracranial hemorrhage than the corresponding triple therapy warfarin group: 3 events (0.3%) in the dual therapy group with dabigatran etexilate 110 mg compared to 10 events (1.0%) in the triple therapy warfarin group (RR 0.30; 95% CI 0.08, 1.07; p = 0.06) and 1 event (0.1%) in the dual therapy group with dabigatran etexilate 150 mg compared to 8 events (1.0%) in the corresponding triple therapy warfarin group (RR 0.12; 95% CI 0.02, 0.98; p = 0.047). Regarding the rate of the composite efficacy endpoint of death, thromboembolic events (myocardial infarction, stroke, and systemic embolism), or unplanned revascularization, both dual therapy groups with dabigatran etexilate were collectively non-inferior to the triple therapy warfarin group (13.7% vs. 13.4%, respectively; RR 1.04; 95% CI 0.84, 1.29; p = 0.0047 for non-inferiority). No statistically significant differences were observed in individual components of the efficacy endpoints between either dual therapy group with dabigatran etexilate and the triple therapy warfarin group.

Clinical trials on prevention of thromboembolism in patients with mechanical heart valve

In clinical trials involving patients who recently underwent mechanical heart valve replacement (e.g., during hospitalization) and patients who underwent mechanical heart valve replacement more than 3 months prior, increased thromboembolic complications (primarily strokes and prosthetic valve thrombosis with or without clinical symptoms) and more bleeding events were observed with dabigatran etexilate treatment compared to warfarin. In patients in the early postoperative period, major bleeding primarily manifested as hemorrhagic exudate in the pericardial cavity, especially in patients who initiated dabigatran etexilate (e.g., on day 3) after heart valve replacement surgery (see section "Contraindications").

Pharmacokinetics.

After oral administration, dabigatran etexilate is rapidly and completely converted into dabigatran, which is the active form in blood plasma. The conversion of the prodrug dabigatran etexilate into the active substance dabigatran via esterase-catalyzed hydrolysis is the dominant metabolic reaction. The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate is approximately 6.5%.

After oral administration of dabigatran etexilate, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in concentration, reaching maximum concentration (Cmax) within 0.5–2 hours after administration.

Absorption. Postoperative absorption of dabigatran etexilate assessed 1–3 hours after surgery was relatively low compared to absorption in healthy volunteers and showed a similar area under the plasma concentration-time curve (AUC) without a high Cmax in plasma. Cmax in plasma is reached 6 hours after administration in the postoperative period due to concomitant factors such as anesthesia, gastrointestinal paresis, and surgical intervention, regardless of the oral formulation. In an additional study, slow and prolonged absorption was typically observed only on the day of surgery. In subsequent days, absorption of dabigatran is rapid, and Cmax in plasma is reached 2 hours after administration.

Food does not affect the bioavailability of dabigatran etexilate but delays the time to reach maximum plasma concentration (Tmax) by 2 hours. Cmax and AUC are dose-proportional.

Oral bioavailability may increase by 75% after a single dose and by 37% at steady state compared to a formulation without hydroxypropylmethylcellulose-coated capsules containing pellets. Therefore, the integrity of the hydroxypropylmethylcellulose coating of the capsules must always be maintained during clinical use to prevent unintentional increases in the bioavailability of dabigatran etexilate (e.g., sprinkling on food or into drinks) (see section "Dosage and administration").

Distribution. Low (34–35%), concentration-independent binding of dabigatran to human plasma proteins was observed. The volume of distribution of dabigatran (60–70 L) exceeds the volume of total body water, indicating moderate tissue distribution.

Biological transformation. Metabolism and elimination of dabigatran were studied after administration of a single intravenous dose of radiolabeled dabigatran to healthy men. After intravenous administration, radiolabeled dabigatran was primarily excreted in urine (85%). Fecal excretion accounted for 6% of the administered dose. Recovery of radioactivity to 88–94% occurred within 168 hours after dabigatran administration. Dabigatran undergoes conjugation to form pharmacologically active acylglucuronides. There are four positional isomers (1-O-, 2-O-, 3-O-, 4-O-acylglucuronide), each constituting less than 10% of total dabigatran in plasma. Traces of other metabolites can only be detected using highly sensitive analytical methods. Dabigatran is primarily excreted unchanged in urine at a rate of approximately 100 mL/min, corresponding to the glomerular filtration rate.

Elimination. Dabigatran plasma concentration declines biexponentially with a mean terminal half-life of 11 hours in elderly healthy volunteers. After multiple doses, the terminal half-life is approximately 12–14 hours. The half-life is independent of dose. The half-life is prolonged with reduced renal function.

Special patient groups

Renal impairment. In Phase I studies, the AUC of dabigatran after oral administration was approximately 2.7 times higher in adult volunteers with moderate renal impairment (creatinine clearance (CrCl) 30–50 mL/min) compared to those without renal impairment.

In a small number of adult volunteers with severe renal impairment (CrCl 10–30 mL/min), the AUC of dabigatran was approximately 6 times higher and the half-life approximately twice as long compared to those without renal impairment (see sections "Contraindications," "Special precautions," and "Dosage and administration").

Half-life of dabigatran depending on renal function (glomerular filtration rate)

(CrCl) – half-life, hours (gCV %; interval): ≥ 80 mL/min – 13.4 (25.7%; 11.0–21.6); ≥ 50–< 80 mL/min – 15.3 (42.7%; 11.7–34.1); ≥ 30–< 50 mL/min – 18.4 (18.5%; 13.3–23.0); < 30 mL/min – 27.2 (15.3%; 21.6–35.0).

Additionally, dabigatran exposure (trough and peak) was evaluated in a prospective, open-label, randomized pharmacokinetic study involving patients with NVAF and severe renal function impairment (CrCl 15–30 mL/min) receiving dabigatran etexilate 75 mg twice daily.

With this dosing regimen, the geometric mean trough concentration, measured immediately before the next dose, was 155 ng/mL (gCV 76.9%), and the geometric mean peak concentration, measured 2 hours after the last dose, was 202 ng/mL (gCV 70.6%).

Dabigatran clearance during hemodialysis was studied in 7 adult patients with end-stage renal disease without atrial fibrillation. Four-hour dialysis was performed with a dialysate flow rate of 700 mL/min and a blood flow rate of either 200 mL/min or 350–390 mL/min. This resulted in a 50–60% reduction in dabigatran concentration, respectively. The amount of substance removed by dialysis is proportional to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreases with decreasing plasma concentration and does not affect the pharmacokinetic/pharmacodynamic relationship.

Elderly patients. In a Phase I special pharmacokinetic study in elderly patients, AUC increased by 40–60% and Cmax by more than 25% compared to younger patients. The effect of age on dabigatran distribution was confirmed in the RE-LY study: approximately 31% higher concentration in patients aged ≥75 years and approximately 22% lower in patients aged <65 years compared to those aged 65–75 years (see sections "Special precautions" and "Dosage and administration").

Hepatic impairment. No changes in dabigatran distribution were observed in 12 adult patients with moderate hepatic impairment (Child-Pugh class B) compared to 12 control patients (see sections "Special precautions" and "Dosage and administration").

Body weight. Dabigatran concentration was approximately 20% lower in adult patients with body weight >100 kg compared to those with body weight 50–100 kg. The majority (80.8%) of volunteers were in the category ≥50 kg and <100 kg without a clear difference (see sections "Special precautions" and "Dosage and administration"). Data for the category of adult patients with body weight <50 kg are limited.

Sex. Female patients with atrial fibrillation had, on average, 30% higher concentrations during and after administration. Dose adjustment is not required (see section "Dosage and administration").

Race. There are no clinically significant differences in the pharmacokinetics and pharmacodynamics of dabigatran between Caucasian and non-Caucasian, Hispanic, Japanese, or Chinese patients.

Pharmacokinetic interactions. In vitro interaction studies did not show inhibition or induction of major cytochrome P450 isoenzymes. This was confirmed by in vitro studies involving healthy volunteers, in which no interactions were observed when treating with dabigatran etexilate and the following active substances: atorvastatin (CYP3A4), digoxin (P-gp transporter interaction), and diclofenac (CYP2C9).

Clinical characteristics.

Indications.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors such as: prior stroke or transient ischemic attack (TIA), age ≥ 75 years, heart failure (New York Heart Association [NYHA] class ≥ II), diabetes mellitus, or arterial hypertension.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

Contraindications.

• Known hypersensitivity to dabigatran or dabigatran etexilate or to any of the excipients of the medicinal product (see section "Composition").
• Severe renal impairment (CrCl < 30 mL/min).
• Active clinically significant bleeding.
• Injury or condition considered a significant risk factor for major bleeding, including current or recent gastrointestinal ulceration, presence of malignancies with high bleeding risk, recent injury to brain or spinal cord, spinal or ophthalmological surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
• Concomitant use of any anticoagulant agent, such as unfractionated heparin (UFH), low-molecular-weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, rivaroxaban, apixaban), except under specific conditions, including transition from or to anticoagulant therapy (see section "Dosage and administration"), when UFH is used at doses required to maintain a patent central venous or arterial catheter, or when UFH is administered during catheter ablation for atrial fibrillation (see section "Interaction with other medicinal products and other forms of interaction").
• Hepatic dysfunction or liver disease which may affect survival.
• Concomitant use of strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone, and the fixed-dose combination glecaprevir/pibrentasvir (see section "Interaction with other medicinal products and other forms of interaction").
• Mechanical heart valve requiring anticoagulant therapy (see section "Pharmacological properties" ("Pharmacodynamics")).

Interaction with other medicinal products and other forms of interaction.

Transporter interactions

Dabigatran etexilate is a substrate of the efflux transporter P-gp. Concomitant use of P-gp inhibitors is expected to increase plasma concentrations of dabigatran.

Unless otherwise stated, careful clinical monitoring (for signs of bleeding or anemia) is recommended when dabigatran is used concomitantly with strong P-gp inhibitors. Dose reduction of dabigatran may be required when used in combination with certain P-gp inhibitors (see sections "Pharmacodynamics", "Contraindications", "Special precautions", and "Dosage and administration").

P-gp inhibitors

Concomitant use is contraindicated (see section "Contraindications")

Ketoconazole. Ketoconazole increases the overall AUC_0–∞ and C_max of dabigatran by 2.38-fold and 2.35-fold, respectively, after a single oral dose of 400 mg, and by 2.53-fold and 2.49-fold, respectively, after multiple oral doses of 400 mg once daily.

Dronedarone. When dabigatran etexilate is administered concomitantly with dronedarone, overall AUC_0–∞ and C_max of dabigatran are increased approximately 2.4-fold and 2.3-fold, respectively, after multiple doses of 400 mg dronedarone twice daily, and approximately 2.1-fold and 1.9-fold, respectively, after a single 400 mg dose.

Itraconazole, cyclosporine. Based on in vitro data, a similar effect to that with ketoconazole may be expected.

Glecaprevir/pibrentasvir. Concomitant use of dabigatran etexilate with the fixed-dose combination of P-gp inhibitors glecaprevir/pibrentasvir increases the exposure to dabigatran and may increase the risk of bleeding.

Concomitant use not recommended

Tacrolimus. In vitro data indicate that tacrolimus has a similar inhibitory effect on P-gp as itraconazole and cyclosporine. Clinical studies on the use of dabigatran etexilate with tacrolimus have not been conducted. However, limited clinical data with another P-gp substrate (everolimus) suggest that tacrolimus inhibition of P-gp is weaker than that of strong P-gp inhibitors.

Precautions to be observed when used concomitantly (see sections "Special precautions" and "Dosage and administration")

Verapamil. When dabigatran etexilate (150 mg) is administered concomitantly with oral verapamil, C_max and AUC of dabigatran increase depending on the timing of administration and formulation of verapamil (see sections "Special precautions" and "Dosage and administration").

The greatest increase in dabigatran exposure occurs when the first dose of immediate-release verapamil is administered one hour before dabigatran etexilate (increase in C_max by approximately 2.8-fold and AUC by approximately 2.5-fold). The effect gradually decreases with extended-release verapamil (increase in C_max by approximately 1.9-fold and AUC by approximately 1.7-fold) or with multiple doses of verapamil (increase in C_max by approximately 1.6-fold and AUC by approximately 1.5-fold).

No significant interaction was observed when verapamil was administered 2 hours after dabigatran etexilate (increase in C_max by approximately 1.1-fold and AUC by approximately 1.2-fold). This is explained by complete absorption of dabigatran within 2 hours.

Amiodarone. When dabigatran etexilate is administered concomitantly with a single 600 mg dose of amiodarone, the extent and rate of absorption of amiodarone and its active metabolite desethylamiodarone (DEA) are not significantly altered. AUC and C_max increased by approximately 1.6-fold and 1.5-fold, respectively. Due to the long elimination half-life of amiodarone, potential for interaction may persist for several weeks after discontinuation of amiodarone (see sections "Special precautions" and "Dosage and administration").

Quinidine. Quinidine was administered at a dose of 200 mg every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was administered twice daily for 3 days, on day 3 with or without quinidine. AUC_τ,ss and C_max,ss of dabigatran increased overall by 1.53-fold and 1.56-fold, respectively, when quinidine was co-administered (see sections "Special precautions" and "Dosage and administration").

Clarithromycin. When clarithromycin (500 mg twice daily) was administered concomitantly with dabigatran etexilate in healthy volunteers, an increase in AUC by approximately 1.19-fold and C_max by approximately 1.15-fold was observed.

Tickagrelor. When a single dose of 75 mg dabigatran etexilate was administered concomitantly with the highest initial dose of 180 mg ticagrelor, AUC and C_max of dabigatran increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor (90 mg twice daily), dabigatran exposure increased by 1.56-fold and 1.46-fold for AUC and C_max, respectively.

Concomitant administration of the highest initial dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (at steady state) increases AUC and C_max of dabigatran by 1.49-fold and 1.65-fold, respectively, compared to administration of dabigatran etexilate alone. When the highest initial dose of 180 mg ticagrelor was administered 2 hours after 110 mg dabigatran etexilate (at steady state), the increase in AUC_τ,ss and C_max,ss of dabigatran was reduced to 1.27-fold and 1.23-fold, respectively, compared to dabigatran etexilate alone. This staggered administration is recommended at the initiation of high-dose ticagrelor.

Concomitant administration of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg dabigatran etexilate increases AUC_τ,ss and C_max,ss of dabigatran by 1.26-fold and 1.29-fold, respectively, compared to dabigatran etexilate alone.

Posaconazole. Posaconazole also inhibits P-gp to some extent, but has not been clinically studied; therefore, caution should be exercised when co-administering posaconazole with dabigatran etexilate.

P-gp inducers

Concomitant use should be avoided

Rifampicin, St. John’s wort (Hypericum perforatum), carbamazepine, or phenytoin. Concomitant use should be avoided due to the potential for reduced dabigatran concentrations.

Repeated administration of rifampicin 600 mg once daily for 7 days reduces total C_max and overall exposure of dabigatran by 65.5% and 67%, respectively. The inductive effect diminished, resulting in dabigatran exposure approaching baseline levels by day 7 after discontinuation of rifampicin. No further increase in bioavailability was observed during the subsequent 7 days.

Protease inhibitors such as ritonavir

Concomitant use not recommended

Ritonavir and its combinations with other protease inhibitors. These agents affect P-gp (as both inhibitors and inducers). They have not been studied and are therefore not recommended for concomitant use with dabigatran etexilate.

P-gp substrate

Digoxin. In a study involving 24 healthy volunteers, concomitant administration of dabigatran etexilate and digoxin showed no changes in digoxin pharmacokinetics and no clinically significant changes in dabigatran distribution.

Anticoagulants and antiplatelet agents

Medicinal products whose concomitant use has not been studied or experience is limited, and medicinal products that may increase the risk of bleeding when used concomitantly with dabigatran etexilate: anticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), heparin derivatives (fondaparinux, desirudin), thrombolytics, vitamin K antagonists, rivaroxaban, and other oral anticoagulants (see section "Contraindications"), antiplatelet agents such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section "Special precautions").

According to limited data from the RE-LY study, in patients with atrial fibrillation, concomitant use of other oral or parenteral anticoagulants with dabigatran etexilate or warfarin increases the incidence of major bleeding by approximately 2.5-fold, primarily during transition from one anticoagulant to another (see section "Contraindications"). Additionally, concomitant use of antiplatelet agents, acetylsalicylic acid (ASA), or clopidogrel approximately doubles the rate of major bleeding with both dabigatran etexilate and warfarin (see section "Special precautions").

UFH may be used at doses required to maintain a patent central venous or arterial catheter, or during catheter ablation for atrial fibrillation (see section "Contraindications").

Interaction with anticoagulants and antiplatelet agents

Non-steroidal anti-inflammatory drugs (NSAIDs). Short-term use of NSAIDs for perioperative analgesia was not associated with increased bleeding risk when used concomitantly with dabigatran etexilate. However, long-term use of NSAIDs with dabigatran etexilate or warfarin in the RE-LY study increased bleeding risk by approximately 50%.

Clopidogrel. In a study in young healthy male volunteers, concomitant administration of dabigatran etexilate and clopidogrel did not prolong capillary bleeding time compared to clopidogrel monotherapy. Furthermore, AUC_τ,ss and C_max,ss of dabigatran and its effect on platelet aggregation inhibition remained unchanged compared to combination therapy and respective monotherapies. With clopidogrel doses of 300 mg or 600 mg, AUC_τ,ss and C_max,ss of dabigatran increased by approximately 30–40% (see section "Special precautions").

Acetylsalicylic acid (ASA). Study data indicate that concomitant use of 81 mg or 325 mg ASA with dabigatran etexilate at a dose of 150 mg twice daily may increase the risk of major bleeding from 12% to 18% or 24%, respectively (see section "Special precautions").

Low-molecular-weight heparins (LMWHs). Concomitant use of LMWHs such as enoxaparin and dabigatran etexilate has not been studied. After switching from a 3-day treatment with enoxaparin 40 mg once daily, 24 hours after the last enoxaparin dose, dabigatran exposure was slightly lower than after dabigatran etexilate alone (single dose 220 mg). Higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration following enoxaparin pretreatment compared to treatment with dabigatran etexilate alone. This is due to prior enoxaparin treatment and is not clinically significant. Pretreatment with enoxaparin did not affect other anticoagulation tests for dabigatran.

Other interactions

Concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). SSRIs and SNRIs increased the risk of bleeding during the study across all treatment groups.

Substances affecting gastric pH

Pantoprazole. When dabigatran etexilate and pantoprazole were administered concomitantly, a 30% reduction in AUC of dabigatran was observed. Pantoprazole and other proton pump inhibitors (PPIs) were used concomitantly with dabigatran etexilate in clinical trials. Concomitant use of PPIs did not reduce the efficacy of dabigatran etexilate.

Ranitidine. Concomitant administration of ranitidine and dabigatran etexilate had no clinically relevant effect on the extent of dabigatran absorption.

Interactions related to the metabolic profile of dabigatran etexilate and dabigatran

Dabigatran etexilate and dabigatran are not metabolized by the cytochrome P450 system and have no in vitro effect on cytochrome P450 enzymes. Therefore, interactions with corresponding medicinal products are not expected.

Special precautions for use.

Risk of bleeding. Dabigatran etexilate should be used with caution in cases of high risk of bleeding or concomitant use with medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding may occur at any site during therapy. If there is a decrease in haemoglobin level and/or haematocrit of unknown cause or a drop in blood pressure, the presence of bleeding should be investigated.

In life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulant effect is required, the specific reversal agent idarucizumab is available for administration. Dabigatran is dialysable. Administration of fresh whole blood or fresh frozen plasma, coagulation factor concentrates (activated or non-activated), recombinant factor VIIa, or platelet concentrates may be considered (see section "Overdose").

In clinical trials, the use of dabigatran etexilate was associated with a higher rate of major gastrointestinal bleeding. The increased risk was observed in elderly patients (≥75 years) receiving dabigatran 150 mg twice daily. Additional risk factors (see also Table 5) include concomitant use with antiplatelet agents such as clopidogrel and acetylsalicylic acid (ASA), or with NSAIDs, as well as the presence of oesophagitis, gastritis, or gastro-oesophageal reflux.

Factors that may increase the risk of bleeding

Pharmacodynamic and kinetic factors: age ≥ 75 years.

Factors increasing dabigatran plasma levels.
Significant: moderate renal impairment (CrCl 30–50 mL/min); strong P-gp inhibitors (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"); concomitant use of mild to moderate P-gp inhibitors such as amiodarone, verapamil, quinidine, and ticagrelor (see section "Interaction with other medicinal products and other forms of interaction").
Minor: low body weight (< 50 kg). Data in patients with body weight < 50 kg are limited (see section "Pharmacokinetics").

Pharmacodynamic interactions (see section "Interaction with other medicinal products and other forms of interaction"): ASA and other antiplatelet agents such as clopidogrel; NSAIDs; SSRIs or SNRIs; other medicinal products that may impair haemostasis.

Conditions/procedures associated with bleeding risk: congenital or acquired coagulation disorders; thrombocytopenia or platelet function defects; recent biopsy or major trauma; bacterial endocarditis; oesophagitis, gastritis, or gastro-oesophageal reflux.

Preventive measures and bleeding risk management. For treatment of haemorrhagic complications, see section "Overdose".

Benefit-risk assessment. Injuries, conditions, procedures, and/or pharmacological therapies (e.g., NSAIDs, antiplatelet agents, SSRIs, and SNRIs; see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction") that increase the risk of major bleeding require careful assessment of benefits versus risks. Dabigatran etexilate should be used only when the expected benefit outweighs the potential risk of bleeding.

Close clinical monitoring. Close clinical monitoring for signs of bleeding or anaemia is recommended throughout the treatment period, especially when multiple risk factors are present (see Table 5). Caution is advised when dabigatran etexilate is used concomitantly with verapamil, amiodarone, quinidine, or clarithromycin (P-gp inhibitors), particularly in patients with renal impairment (see section "Interaction with other medicinal products and other forms of interaction"). Close monitoring for signs of bleeding is recommended in patients receiving concomitant NSAID therapy (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of dabigatran etexilate. Patients who develop acute renal failure must discontinue dabigatran etexilate (see section "Contraindications").

In the event of severe bleeding, treatment should be discontinued, the source of bleeding investigated, and consideration given to administration of a specific reversal agent (idarucizumab). Dabigatran is eliminated by haemodialysis.

Use of PPIs. The use of proton pump inhibitors (PPIs) may be considered to prevent gastrointestinal bleeding.

Coagulation laboratory parameters. Although routine anticoagulation monitoring is generally not required with this medicinal product, assessing the anticoagulant effect of dabigatran may be useful to identify excessively high dabigatran exposure in the presence of additional risk factors.

Values of aPTT, TT, and ACT may be very useful, but results should be interpreted with caution due to differences between assays (see section "Pharmacodynamics").

The international normalized ratio (INR) test is unreliable in patients taking dabigatran etexilate, as false-positive INR elevation has been observed. Therefore, INR testing should not be performed.

Table 1 lists threshold values for coagulation tests that may be associated with an increased risk of bleeding (see section "Pharmacodynamics").

Table 1

Threshold values of coagulation tests potentially associated with an increased risk of bleeding

Use of fibrinolytic agents for the treatment of acute ischemic stroke. The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if the results of PT, aPTT, or ACT tests do not exceed ULN.

Surgical and interventional procedures. Patients receiving dabigatran etexilate who undergo surgical or invasive procedures are at increased risk of bleeding. Therefore, surgical intervention may require temporary discontinuation of dabigatran etexilate.

Patients may continue dabigatran etexilate during cardioversion. Dabigatran etexilate therapy (150 mg twice daily) does not need to be interrupted in patients with atrial fibrillation undergoing catheter ablation (see section "Dosage and administration").

Care should be taken when temporarily discontinuing treatment for surgical procedures, and anticoagulation should be monitored. Dabigatran clearance may be prolonged in patients with renal impairment (see section "Pharmacokinetics"). Caution is advised for any procedures. In such cases, a coagulation test (see sections "Pharmacodynamics" and "Contraindications") may help determine whether hemostasis is impaired.

Emergency surgery or urgent procedures. Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulant effect is required, a specific reversal agent (idarucizumab) may be administered. Dabigatran is eliminated by hemodialysis.

Reversal of dabigatran therapy may increase thrombotic risk in patients. Dabigatran etexilate may be restarted 24 hours after administration of idarucizumab, provided the patient is clinically stable and adequate hemostasis has been achieved.

Surgical and interventional procedures in subacute conditions. Dabigatran etexilate should be temporarily discontinued. Surgical or interventional procedures should be delayed for at least 12 hours after the last dose of dabigatran, if possible. If surgery cannot be delayed, the risk of bleeding may be increased. The risk of bleeding and urgency of the procedure should be carefully weighed before administering the drug.

Planned surgery. If possible, dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical procedures. For patients at high risk of bleeding or undergoing major surgery where hemostasis management may be required, discontinuation of dabigatran etexilate 2–4 days prior to surgery should be considered.

Table 2

Guidelines for discontinuation prior to invasive or surgical procedures

Spinal anesthesia/epidural anesthesia/lumbar puncture. Procedures such as spinal anesthesia may require full functioning of the hemostasis system.

The risk of spinal or epidural hematoma may be increased in the case of traumatic or repeated puncture and prolonged postoperative use of epidural catheters. After catheter removal, at least 2 hours should be waited before administering the first dose of dabigatran etexilate. Such patients require careful monitoring for neurological symptoms and signs of spinal or epidural hematoma.

Postoperative period. Treatment with dabigatran etexilate should be resumed/started after invasive procedures or surgery as soon as the clinical situation allows and adequate hemostasis has been achieved.

Patients at risk of bleeding or patients at risk of excessive exposure, especially those with reduced renal function, should be treated with caution (see sections "Pharmacodynamics" and "Contraindications").

Patients at high risk of mortality due to surgery and with hereditary risk factors for thromboembolic complications. Data on the efficacy and safety of dabigatran etexilate in this patient group are limited; therefore, treatment should be administered with caution.

Hepatic impairment. Patients with elevated liver enzymes more than twice the ULN were excluded from the main clinical trials. Due to lack of experience, the use of dabigatran etexilate is not recommended in this patient group.

The use of the drug is contraindicated in patients with hepatic insufficiency or liver diseases that may affect survival (see section "Contraindications").

Interaction with P-gp inducers. Concomitant use of P-gp inducers should be avoided due to the potential for reduced dabigatran concentrations (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other forms of interactions").

Patients with antiphospholipid syndrome. Direct oral anticoagulants, including dabigatran etexilate, are not recommended for patients with a history of thrombosis in whom antiphospholipid syndrome has been diagnosed. In particular, in patients with triple positivity (lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with direct oral anticoagulants may be associated with an increased frequency of recurrent thrombotic events compared to vitamin K antagonist therapy.

Myocardial infarction. According to data from the RE-LY clinical trial (INFP, see section "Pharmacodynamics") (dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily, and warfarin), the highest absolute risk of myocardial infarction was observed in the following subgroups with similar relative risk: patients with a history of myocardial infarction, patients aged ≥65 years with diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal impairment. In addition, an increased risk of myocardial infarction was observed in patients receiving aspirin with clopidogrel or clopidogrel alone.

According to data from VTE/PE studies, a higher rate of myocardial infarction was observed in patients treated with dabigatran etexilate compared to those treated with warfarin: 0.4% vs. 0.2% in short-term studies and 0.8% vs. 0.1% in long-term studies.

According to data from another study comparing dabigatran etexilate with placebo, the rate of myocardial infarction was 0.1% in patients receiving dabigatran etexilate and 0.2% in patients receiving placebo.

Cancer patients (VTE/PE). The efficacy and safety of the medicinal product in this patient group have not been studied.

Special precautions for use. When removing a Dabifor® capsule from the blister pack, the following rules should be observed: separate one individual blister from the other blister along the perforated line; remove the hard capsule from the blister immediately before administration; peel off the foil from the blister without pushing the capsule through the foil.

Use during pregnancy or breastfeeding.

Women of reproductive age. Women of reproductive age should avoid pregnancy during treatment with Dabifor®.

Pregnancy. There are no adequate data on the use of Dabifor® in pregnant women. Animal studies have shown reproductive toxicity. The potential risk for pregnant women is unknown. Dabigatran etexilate should not be used during pregnancy except when the expected benefit to the woman outweighs the potential risk to the fetus.

Breastfeeding period. There are no clinical data on the effects of dabigatran on breastfed infants. As a precaution, breastfeeding should be discontinued.

Fertility. There are no data on the effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Dabigatran etexilate has no effect or has a negligible effect on the ability to drive or operate machinery.

Method of administration and dosing.

Dosing.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors (prevention of NVAF-related stroke).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults.

Table 3

Recommended doses of dabigatran etexilate for NVAF, DVT, and PE

In the case of DVT/PE, 220 mg of dabigatran etexilate is recommended: 1 capsule of 110 mg twice daily. This dose is based on pharmacokinetic and pharmacodynamic analyses and has not been studied under clinical conditions.

See information provided below and sections “Pharmacodynamics”, “Pharmacokinetics”, “Interaction with other medicinal products and other forms of interaction”, and “Special precautions for use”.

In case of intolerance to dabigatran etexilate, patients should be instructed to consult their physician immediately regarding switching to an alternative acceptable therapy to prevent stroke and systemic embolism associated with atrial fibrillation, as well as for the treatment of deep vein thrombosis and pulmonary embolism.

Assessment of renal function before and during dabigatran etexilate treatment

In all patients, especially in elderly patients (>75 years of age), since renal impairment may frequently occur in this age group:

• Prior to initiating dabigatran etexilate therapy, renal function should be assessed by calculating creatinine clearance to exclude severe renal impairment (CrCl < 30 mL/min) (see sections “Pharmacokinetics”, “Contraindications”, and “Special precautions for use”).
• Renal function should be assessed if there is suspicion of renal impairment during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use with certain medicinal products).

Additional requirements for patients with mild to moderate renal impairment and patients aged 75 years and older:

• During dabigatran etexilate therapy, renal function should be assessed at least once a year, or more frequently as needed in certain clinical situations where a decline or worsening of renal function is expected (e.g., in cases of hypovolemia, dehydration, or concomitant use with certain medicinal products).

The method used to assess renal function (CrCl, mL/min) is the Cockcroft-Gault formula.

Duration of treatment in NVAF, DVT, and PE

For NVAF, treatment with the medicinal product should be long-term.

For DVT and PE, treatment duration is determined individually after careful assessment of the benefits of treatment and the risk of bleeding (see section “Special precautions for use”).

Short-term treatment (for at least 3 months) should be based on transient risk factors (such as recent surgery, trauma, immobilization), while long-term treatment should be based on permanent risk factors or idiopathic DVT or PE.

Missed dose. A missed dose of dabigatran etexilate may be taken if less than 6 hours remain before the next scheduled dose. If less than 6 hours remain until the next dose, the missed dose should not be taken.

Double dosing should not be used to compensate for a missed dose.

Discontinuation of dabigatran etexilate. Dabigatran etexilate treatment must not be discontinued without consulting a physician. Patients should be warned to contact their physician if gastrointestinal symptoms such as dyspepsia occur (see section “Adverse reactions”).

Switching from dabigatran etexilate to parenteral anticoagulants. It is recommended to wait 12 hours after the last dose before switching from dabigatran etexilate to a parenteral anticoagulant (see section “Interaction with other medicinal products and other forms of interaction”).

Switching from parenteral anticoagulants to dabigatran etexilate. After discontinuation of parenteral anticoagulant therapy, dabigatran etexilate should be initiated 0–2 hours before the next scheduled dose of the parenteral anticoagulant or at the time of discontinuation in the case of continuous therapy (e.g., intravenous UFH) (see section “Interaction with other medicinal products and other forms of interaction”).

Switching from dabigatran etexilate to vitamin K antagonists. Conditions for switching to vitamin K antagonists based on CrCl:

• CrCl ≥ 50 mL/min: initiation of vitamin K antagonists 3 days before discontinuation of dabigatran etexilate;
• CrCl ≥ 30 to <50 mL/min: initiation of vitamin K antagonists 2 days before discontinuation of dabigatran etexilate.

Since dabigatran etexilate may elevate INR, INR will better reflect the effect of vitamin K antagonists only 2 days after discontinuation of dabigatran etexilate. Until then, INR values should be interpreted with caution.

Switching from vitamin K antagonists to dabigatran etexilate. Vitamin K antagonists should be discontinued. Dabigatran etexilate may be administered once the INR is < 2.0.

Cardioversion. Patients may continue taking dabigatran etexilate during cardioversion.

Catheter ablation for atrial fibrillation (prevention of NVAF). Catheter ablation may be performed in patients receiving dabigatran etexilate at a dose of 150 mg twice daily. Dabigatran etexilate treatment does not need to be interrupted (see section “Pharmacological properties” (“Pharmacodynamics”)).

Percutaneous coronary intervention (PCI) with stenting (NVAF). Patients with NVAF who have undergone PCI with stenting may be treated with dabigatran etexilate in combination with antiplatelet agents after achieving hemostasis (see section “Pharmacodynamics”).

Special patient groups

Elderly patients. For dosage recommendations in this patient category, see Table 3 above.

Patients at risk of bleeding. Patients with an increased risk of bleeding (see sections “Pharmacokinetics”, “Interaction with other medicinal products and other forms of interaction”, and “Special precautions for use”) should be closely monitored clinically (for signs of bleeding or anemia). Dose adjustment may be considered at the physician’s discretion after evaluating the potential benefits and risks for each patient (see Table 3). A coagulation test (see section “Special precautions for use”) may help identify patients at increased risk of bleeding due to excessive dabigatran exposure. If excessive dabigatran exposure is detected in patients at high risk of bleeding, a reduced dose (220 mg): 1 capsule of 110 mg twice daily is recommended. In the event of clinically significant bleeding, treatment should be discontinued.

Patients with gastritis, esophagitis, or gastroesophageal reflux disease may be prescribed a reduced dose due to an increased risk of major gastrointestinal bleeding (see Table 3 above and section “Special precautions for use”).

Renal impairment. Treatment with dabigatran etexilate is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) (see section “Contraindications”).

No dose adjustment is required for patients with mild renal impairment (CrCl 50–≤80 mL/min). For patients with moderate renal impairment (CrCl 30–50 mL/min), the recommended dose of dabigatran etexilate is 300 mg: 1 capsule of 150 mg twice daily. However, for patients at high risk of bleeding, the dose of dabigatran etexilate may be reduced to 220 mg: 1 capsule of 110 mg twice daily (see sections “Pharmacokinetics” and “Special precautions for use”). Close clinical monitoring is recommended for patients with renal impairment.

Concomitant use of dabigatran etexilate with P-gp inhibitors of weak to moderate intensity, e.g., amiodarone, quinidine, or verapamil. Dose adjustment is not required when used concomitantly with amiodarone or quinidine (see sections “Pharmacokinetics”, “Interaction with other medicinal products and other forms of interaction”, and “Special precautions for use”).

For patients receiving verapamil concomitantly, dose reduction is recommended (see Table 3 and sections “Interaction with other medicinal products and other forms of interaction” and “Special precautions for use”). In this case, dabigatran etexilate and verapamil should be administered at the same time.

Body weight. Dose adjustment is not required (see section “Pharmacokinetics”), but close clinical monitoring is recommended for patients with body weight < 50 kg (see section “Special precautions for use”).

Gender. Dose adjustment is not required (see section “Pharmacokinetics”).

Route of administration. Dabifor® capsules may be taken independently of food intake. The capsule should be swallowed whole with a glass of water to facilitate passage into the stomach. Patients should be warned not to open the capsule, as this may increase the risk of bleeding (see section “Pharmacokinetics”).

Children.

There is no justification for the use of Dabifor® capsules in pediatric patients for the indications: prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, treatment of deep vein thrombosis (DVT), and pulmonary embolism (PE).

Overdose.

Doses of dabigatran etexilate exceeding the recommended doses lead to an increased risk of bleeding.

In case of suspected overdose, a coagulation test may be used to assess the risk of bleeding (see sections “Pharmacological properties” and “Special precautions for use”). A calibrated quantitative test or repeated aPTT measurement can help predict the time at which specific dabigatran levels will be reached (see section “Pharmacological properties”). As an additional measure, dialysis may be initiated.

Excessive anticoagulant effect may require discontinuation of dabigatran etexilate treatment. Since dabigatran is primarily eliminated via the kidneys, adequate diuresis should be maintained.

Due to low plasma protein binding, dabigatran may be removed by dialysis; however, clinical experience with dialysis is limited (see section “Pharmacokinetics”).

Management of hemorrhagic complications

In the event of hemorrhagic complications, treatment should be discontinued and the source of bleeding should be identified. Appropriate management should be considered depending on the clinical situation, e.g., surgical hemostasis or restoration of circulating blood volume, as determined by the physician.

In life-threatening or uncontrolled bleeding, where rapid reversal of the anticoagulant effect of dabigatran is required, a specific reversal agent (idarucizumab) with antagonistic effect on the pharmacodynamic action of dabigatran may be administered (see section “Special precautions for use”).

The use of coagulation factor concentrates (activated or non-activated) may be considered. There are some experimental data on the role of these agents in reversing the anticoagulant effect of dabigatran, but data on their clinical benefit and potential risk of recurrent thromboembolic events are very limited. Coagulation tests may be unreliable after administration of the proposed coagulation factor concentrates. Caution should be exercised when interpreting these tests. Caution should also be exercised when using platelet concentrates if thrombocytopenia is present or long-acting antiplatelet agents have been used. Symptomatic treatment should be administered according to physician recommendations.

Expert consultation in coagulation may be considered in cases of significant bleeding (if such an expert is available).

Adverse reactions

Summary of safety profile

The safety of dabigatran etexilate has been evaluated in clinical trials involving approximately 64,000 patients, of whom about 35,000 received treatment with dabigatran etexilate.

Overall, adverse reactions were observed in 22% of patients with atrial fibrillation receiving the drug for stroke and systemic embolism prevention (long-term treatment for more than 3 years), in 14% of patients treated for deep vein thrombosis and pulmonary embolism, and in 15% of patients receiving the drug for prevention of DVT and PE.

The most commonly observed adverse reaction was bleeding, occurring in approximately 16.6% of patients with atrial fibrillation who were treated long-term for stroke and systemic embolism prevention, and in 14.4% of patients treated for DVT/PE. Since the patient populations treated for the three indications are not comparable and bleeding events are categorized by organ systems, a brief description of major and any bleeding is separated by indication and presented in Tables 5–8.

Although the frequency was low in clinical studies, major or severe bleeding can occur and, depending on the site, may lead to loss of working capacity, life-threatening condition, or fatal outcome.

Table 4 lists adverse reactions identified during studies and post-marketing data for the indications of stroke and systemic embolism prevention, as well as treatment and prevention of deep vein thrombosis and pulmonary embolism, classified by organ systems and frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Table 4

Adverse reactions

Description of selected adverse reactions

Hemorrhages. Due to its pharmacological mechanism of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding, which may occur in any tissues or organs. Symptoms and severity (including fatal outcome) depend on the location and extent or spread of bleeding and/or anemia. During clinical trials, mucosal bleeding (e.g., gastrointestinal, genitourinary) was observed more frequently with prolonged treatment with dabigatran etexilate compared to treatment with vitamin K antagonists. Therefore, in addition to adequate clinical monitoring, laboratory testing for hemoglobin/hematocrit levels is important for detecting occult bleeding. The risk of bleeding may increase in certain patient groups, such as patients with moderate renal impairment and/or those receiving concomitant therapy affecting hemostasis, or strong P-gp inhibitors (see section "Special precautions" ("Risk of bleeding")). Hemorrhagic complications may present as weakness, pallor, dizziness, headache, or unexplained swelling, dyspnea, and shock of unknown origin.

Complications due to bleeding, such as compartment syndrome, acute kidney injury due to hypoperfusion, and anticoagulant-related nephropathy, have been reported in patients with predisposing risk factors during treatment with dabigatran etexilate. Therefore, the possibility of bleeding should be considered when evaluating any patient receiving anticoagulant therapy. A specific reversal agent for dabigatran, idarucizumab, can be used in the event of uncontrolled bleeding (see section "Overdose").

Prevention of stroke and systemic embolism in adult patients with atrial fibrillation with one or more risk factors

Table 5 presents data on bleeding events ranging from major to any in the core studies for prevention of stroke and systemic embolism in patients with atrial fibrillation.

Table 5

The clinical benefits of dabigatran etexilate in preventing stroke and systemic embolism, as well as reducing the risk of intracranial bleeding compared to warfarin, have been demonstrated in individual subgroups, for example, based on renal impairment, age, and concomitant use of other medicinal products such as antiplatelet agents or P-gp inhibitors. A certain subgroup of patients has an increased risk of major bleeding when using anticoagulants; therefore, the excess bleeding risk associated with dabigatran may be due to gastrointestinal bleeding, which can occur within 3–6 months after initiating dabigatran etexilate therapy.

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults (treatment of DVT/PE)

Table 6 presents data on bleeding events observed during the combined pivotal studies for treatment of DVT/PE. In the combined studies, the primary safety endpoints of major bleeding, major or clinically relevant bleeding, and any bleeding were significantly lower compared to warfarin at the nominal alpha level of 5%.

Table 6

Bleeding events for both treatment methods were assessed after the first administration of dabigatran etexilate or warfarin following the end of parenteral therapy (oral treatment period only). The data presented include all bleeding events observed during dabigatran etexilate administration. For warfarin, all bleeding events were included except those observed during the transition period from parenteral therapy to warfarin.

Table 7 presents data on bleeding events observed during the combined main studies on VTE/PE prevention. Some bleeding events were significantly lower compared to those with warfarin at the nominal alpha level of 5%.

Table 7

*Risk ratio was not estimated because no events were observed in either patient group.

Table 8 presents data on bleeding events observed during the main VTE/PE prevention study. The rate of combined major bleeding and clinically relevant bleeding, as well as the rate of any bleeding at the nominal alpha level of 5%, was significantly lower in patients receiving placebo compared to those receiving dabigatran etexilate.

Table 8

* Risk ratio was not evaluated, as no cases were identified in either patient group.

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during dabigatran etexilate use. Since adverse reactions were reported during post-marketing surveillance in a population of unknown size, their exact frequency cannot be reliably determined. The reporting rate was estimated at 7 events per 1 million patient-years for agranulocytosis and 5 events per 1 million patient-years for neutropenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions in accordance with current legislation.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 10 capsules in blisters. 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Batch control, batch release of the medicinal product

Towa Pharmaceutical Europe S.L., Spain.

Towa Pharmaceutical Europe S.L., Spain.

Batch control, batch release of the medicinal product

Pharmadox Healthcare Limited, Malta.

Pharmadox Healthcare Limited, Malta.

Manufacturer's name and address.

Calle De Sant Marti 75-97, Poligono Industrial Martorelles, Martorelles, 08107, Spain.

Calle De Sant Marti 75-97, Poligono Industrial Martorelles, Martorelles, 08107, Spain.

KW20A Kordin Industrial Park, Paola, PLA 3000, Malta.

KW20A Kordin Industrial Park, Paola, PLA 3000, Malta.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63, Kyrylivska St., Kyiv, 04080, Ukraine.