Dabifor: detailed information

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

Composition:

Active substance: dabigatran etexilate;

One capsule contains: dabigatran etexilate mesylate – 86.48 mg, equivalent to dabigatran etexilate – 75 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 on the capsule, black in 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 properties: size “2” capsule, cap and body of opaque pink/pink color, printed with “DA75” 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 to dabigatran in blood plasma and the liver via esterase-catalyzed hydrolysis. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active substance in blood plasma.

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

Pharmacodynamic Effects. A clear correlation exists between plasma concentrations of dabigatran and the degree of anticoagulant effect, as demonstrated in Phase II studies. Dabigatran prolongs thrombin time (TT), clotting time (CT), and activated partial thromboplastin time (aPTT).

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

Clotting time (CT) may provide a direct measurement of the activity of direct thrombin inhibitors.

The aPTT test is widely available and provides an approximate indicator of the anticoagulant intensity achieved with dabigatran. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of the anticoagulant effect, especially at high plasma concentrations of dabigatran. Although elevated aPTT values should be interpreted with caution, they indicate the presence of an anticoagulant effect in the patient.

Clinical Efficacy and Safety. In clinical trials involving patients who had recently undergone mechanical heart valve replacement surgery (e.g., during hospitalization) and those who had undergone mechanical heart valve replacement more than 3 months prior, an increased incidence of thromboembolic complications (primarily strokes and symptomatic or asymptomatic prosthetic valve thrombosis) and a higher rate of bleeding events were observed with dabigatran etexilate compared to warfarin. In the early postoperative period, major bleeding occurred predominantly as hemorrhagic exudate into the pericardial cavity, particularly in patients who initiated dabigatran etexilate (e.g., on postoperative day 3) shortly after heart valve replacement surgery (see section "Contraindications").

Pharmacokinetics

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

Following oral administration of dabigatran etexilate, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in concentration, reaching peak plasma concentration (C_max) 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 flat pharmacokinetic profile under the concentration-time curve (AUC), without high C_max in plasma. Peak plasma concentration (C_max) 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 dosage form. An additional study showed that delayed and slow absorption typically occurs only on the day of surgery. In subsequent days, absorption of dabigatran occurs rapidly, with C_max in plasma achieved within 2 hours after drug administration.

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

Bioavailability following oral administration may be increased by 75% after a single dose and by 37% at steady state compared to the capsule formulation when pellets are administered without hydroxypropylmethylcellulose in the capsule coating. Therefore, the integrity of the hydroxypropylmethylcellulose capsule coating must always be maintained during clinical use to prevent unintentional increases in the bioavailability of dabigatran etexilate (see section "Dosage and Administration").

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

Metabolism. The metabolism and elimination of dabigatran were studied after administration of a single intravenous dose of radiolabeled dabigatran to healthy male volunteers. After intravenous administration, radiolabeled dabigatran was primarily excreted in urine (85%). Fecal excretion accounted for 6% of the administered dose. Recovery of radioactivity reached 88–94% 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-acylglucuronides), each constituting less than 10% of total dabigatran in plasma. Traces of other metabolites were detectable only with 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. Plasma concentrations of dabigatran decline biexponentially, with a mean terminal half-life of 11 hours in elderly healthy volunteers. After multiple dosing, the terminal half-life is approximately 12–14 hours. The half-life is independent of dose. The half-life is prolonged in patients with reduced renal function.

Special Patient Populations

Renal Impairment. In Phase I studies, the AUC of dabigatran after oral administration was approximately 2.7-fold higher in adult volunteers with moderate renal impairment (creatinine clearance (CrCl) 30–50 mL/min) compared to those with normal renal function.

In a small number of adult volunteers with severe renal impairment (CrCl 10–30 mL/min), the AUC of dabigatran was approximately 6-fold higher and the elimination half-life approximately twice as long compared to volunteers with normal renal function (see sections "Contraindications," "Special Warnings and Precautions for Use," and "Dosage and Administration").

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

(CrCl) – half-life, hours (gCV %; range):
≥ 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, exposure to dabigatran (trough and peak levels) was evaluated in a prospective, open-label, randomized pharmacokinetic study involving patients with non-valvular atrial fibrillation (NVAF) and severe renal dysfunction (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. Dialysis was performed with a dialysate flow rate of 700 mL/min for 4 hours and a blood flow rate of either 200 mL/min or 350–390 mL/min. This resulted in a 50% and 60% reduction in dabigatran concentration, respectively. The amount of substance removed by dialysis is proportional to a blood flow rate of 300 mL/min. Anticoagulant activity of dabigatran decreases with decreasing plasma concentration. The procedure did not affect the pharmacokinetic/pharmacodynamic relationship.

Elderly Patients. In a Phase I dedicated pharmacokinetic study in elderly patients, AUC increased by 40% to 60% and C_max 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 concentrations in patients ≥ 75 years and approximately 22% lower concentrations in patients < 65 years compared to patients aged 65–75 years (see sections "Special Warnings and Precautions for Use" 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 Warnings and Precautions for Use" and "Dosage and Administration").

Body Weight. Dabigatran concentrations were approximately 20% lower in adult patients with body weight > 100 kg compared to those with body weight 50–100 kg. The majority of volunteers (80.8%) were in the category ≥ 50 kg and < 100 kg, with no clear difference in dabigatran concentration (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration"). Data for adult patients with body weight < 50 kg are limited.

Sex. Exposure to the active substance in studies on prevention of venous thromboembolic complications was 40–50% higher in female patients; dose adjustment is not recommended.

Race. There are no clinically significant interethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran in patients of Caucasian, African, Latino, Japanese, or Chinese origin.

Pharmacokinetic Interactions. In vitro interaction studies did not show inhibition or induction of major cytochrome P450 isoenzymes. This was confirmed by in vitro studies in healthy volunteers, where no interactions were observed between dabigatran and active substances such as atorvastatin (CYP3A4), digoxin (P-gp transporter interaction), or diclofenac (CYP2C9).

Clinical characteristics.

Indications.

Primary prevention of venous thromboembolic complications in adult patients who have undergone major orthopedic surgery of hip or knee replacement.

Contraindications.

Hypersensitivity to the active substance 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 as a significant risk factor for major bleeding, including current or recent gastrointestinal ulcer, presence of malignant tumors with high bleeding risk, recent injury of brain or spinal cord, recent spinal or ophthalmologic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular pathologies.
Concomitant use of any anticoagulant medicinal product, such as unfractionated heparin (UFH), low-molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except under specific conditions, such as transition from or to anticoagulant therapy (see section "Dosage and administration"), when UFH is used at doses required to maintain patency of central venous or arterial catheters, or when UFH is used during catheter ablation for atrial fibrillation (see section "Interaction with other medicinal products and other forms of interaction").
Liver dysfunction or liver disease that may affect survival.
Concomitant use of strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone, and 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 specified, 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 total 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 used concomitantly with dronedarone, total AUC_0–∞ and C_max of dabigatran increase by approximately 2.4-fold and 2.3-fold, respectively, after multiple doses of 400 mg dronedarone twice daily, and by approximately 2.1-fold and 1.9-fold, respectively, after a single 400 mg dose.

Itraconazole, cyclosporine. Based on in vitro data, an effect similar 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 effect of dabigatran and may increase the risk of bleeding.

Concomitant use is not recommended

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

Caution is required when used concomitantly (see sections "Special precautions" and "Dosage and administration")

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

The greatest increase in dabigatran exposure was observed when immediate-release verapamil was 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 decreased 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 used concomitantly with a single 600 mg dose of amiodarone, the extent and rate of absorption of amiodarone and its active metabolite diethylaminoethanol (DEA) were not significantly altered. AUC and C_max of dabigatran in plasma increased by approximately 1.6-fold and 1.5-fold, respectively. Due to the long elimination half-life of amiodarone, the potential for drug interaction exists 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 administered concomitantly (see sections "Special precautions" and "Dosage and administration").

Clarithromycin. When clarithromycin (500 mg twice daily) was used 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 dabigatran etexilate (75 mg) was administered concomitantly with the highest initial dose of ticagrelor (180 mg), 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), exposure to dabigatran increased by 1.56-fold and 1.46-fold for AUC and C_max, respectively.

Concomitant use of the highest initial dose of ticagrelor (180 mg) and dabigatran etexilate 110 mg (at steady state) increases AUC and C_max of dabigatran by 1.49-fold and 1.65-fold, respectively, compared to 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 increases in AUC_τ,ss and C_max,ss of dabigatran were reduced to 1.27-fold and 1.23-fold, respectively, compared to dabigatran etexilate alone. This staggered administration is recommended at the start of treatment with the highest initial dose of ticagrelor.

Concomitant use 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 moderately inhibits P-gp 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 extract (Hypericum perforatum), carbamazepine, or phenytoin. Concomitant use should be avoided due to the potential decrease in dabigatran concentration.

Overdosing with rifampicin 600 mg once daily for 7 days reduces total C_max and total exposure of dabigatran by 65.5% and 67%, respectively. The inducing effect diminished, resulting in dabigatran exposure close to baseline on 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 is not recommended

Ritonavir and its combinations with other protease inhibitors. These agents affect P-gp (both as 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 use of dabigatran etexilate and digoxin showed no changes in digoxin parameters or clinically significant changes in dabigatran disposition.

Anticoagulants and antiplatelet agents

Medicinal products whose therapy has not been studied or experience with use is limited, and medicinal products that may increase the risk of bleeding when used concomitantly with dabigatran etexilate: anticoagulants such as UFH, low-molecular-weight heparins (LMWH), and 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").

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

Interaction with anticoagulants and antiplatelet agents

Nonsteroidal 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. In phase III clinical trials comparing dabigatran with warfarin for stroke prevention in patients with atrial fibrillation (RE-LY), long-term use of NSAIDs with dabigatran etexilate and warfarin increased bleeding risk by approximately 50%.

Clopidogrel. In a study in young healthy male volunteers, concomitant use 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 the effect of dabigatran on platelet aggregation inhibition remained unchanged compared to combination therapy and respective monotherapies.

When 300 mg or 600 mg of clopidogrel was administered, 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 ASA with dabigatran etexilate 150 mg twice daily may increase the risk of major bleeding from 12% to 18% or 24% (with ASA 81 mg or 325 mg, respectively) (see section "Special precautions").

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

Other interactions

Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs). SSRIs and SNRIs increased the risk of bleeding during phase III clinical trials (RE-LY) in all treatment groups when comparing dabigatran with warfarin for stroke prevention in patients with atrial fibrillation.

Substances affecting gastric pH

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

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

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 between dabigatran etexilate or dabigatran and medicinal products metabolized by the cytochrome P450 system are not expected.

Special precautions for use.

Risk of bleeding. Dabigatran etexilate should be used with caution in conditions associated with a high risk of bleeding or when used concomitantly with medicinal products affecting haemostasis by inhibiting platelet aggregation. Bleeding may occur at any site during treatment. If unexplained decreases in haemoglobin levels and/or haematocrit or a drop in blood pressure occur, the presence of bleeding should be investigated.

In life-threatening or uncontrolled bleeding where rapid reversal of the anticoagulant effect is required, the specific reversal agent idarucizumab is available for administration. Dabigatran is removed by haemodialysis. The use 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").

The use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA), or non-steroidal anti-inflammatory drugs (NSAIDs), as well as the presence of oesophagitis, gastritis, or gastro-oesophageal reflux, increases the risk of gastrointestinal bleeding.

Factors that may increase the risk of bleeding

Pharmacodynamic and kinetic factors: age ≥ 75 years.

Factors increasing plasma levels of dabigatran.
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 weak to moderate P-gp inhibitors such as amiodarone, posaconazole, quinidine, verapamil, 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 platelet aggregation inhibitors 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 prevention of haemorrhagic complications, see section "Overdose".

Benefit-risk assessment. Injuries, conditions, procedures, and/or pharmacological therapies (e.g., NSAIDs, antiplatelet agents, SSRIs, SNRIs; see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction") that significantly increase the risk of major bleeding require careful benefit-risk evaluation. Dabigatran etexilate should be used only if 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. Caution should be exercised when dabigatran etexilate is used concomitantly with verapamil, amiodarone, quinidine, or clarithromycin (P-gp inhibitors), particularly in patients with impaired renal function (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 should discontinue dabigatran etexilate (see section "Contraindications").

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

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

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

The values of PT, aPTT, and TT 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, the INR test should not be performed.

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

Table 1

Test	Lower threshold values of coagulation test
rTP [ng/mL]	> 67
aPTT [x-fold upper limit of normal]	data not available
APTT [x-fold upper limit of normal]	> 1.3
INR	not required

Use of fibrinolytic agents for the treatment of acute ischaemic stroke. Fibrinolytic agents may be considered for the treatment of acute ischaemic stroke if PT, aPTT or ACT test results do not exceed the ULN according to local reference ranges.

Surgery and invasive procedures. Patients receiving dabigatran etexilate who undergo surgical or invasive procedures have an increased risk of bleeding. Therefore, surgical intervention may require temporary discontinuation of dabigatran etexilate. Caution should be exercised when temporarily stopping treatment for surgery, and monitoring of anticoagulation should be ensured. Dabigatran clearance may be prolonged in patients with renal impairment (see section "Pharmacokinetics"). Caution is required for any procedures. In such cases, a coagulation test (see sections "Pharmacodynamics" and "Contraindications") may help determine whether haemostasis 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 haemodialysis. Reversal of dabigatran therapy leads to a thrombotic risk associated with the underlying condition in patients. Dabigatran etexilate therapy may be resumed 24 hours after administration of idarucizumab, provided the patient is clinically stable and adequate haemostasis has been achieved.

Surgery and invasive procedures in subacute conditions. Dabigatran etexilate should be temporarily discontinued. Surgical or invasive 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 proceeding.

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

Table 2

Guidelines for discontinuation of treatment prior to invasive or surgical procedures

Renal function (CrCl, mL/min)	Expected elimination half-life (hours)	Dabigatran etexilate should be discontinued prior to planned surgical procedures
Renal function (CrCl, mL/min)	Expected elimination half-life (hours)	High bleeding risk or major surgery	Standard risk
≥ 80	~ 13	2 days before	24 hours before
≥ 50–< 80	~ 15	2–3 days before	1–2 days before
≥ 30–< 50	~ 18	4 days before	2–3 days before (> 48 hours)

Spinal anaesthesia/epidural anaesthesia/lumbar puncture. Procedures such as spinal anaesthesia may require full haemostatic function. The risk of spinal or epidural haematoma may be increased in the case of traumatic or repeated puncture and prolonged postoperative use of epidural catheters. After removal of the catheter, 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 haematoma.

Postoperative phase. Dabigatran etexilate should be resumed after invasive procedures or surgery as soon as clinically appropriate and adequate haemostasis has been achieved.

Patients at risk of bleeding or patients at risk of excessive effect, especially those with reduced renal function, should be treated with caution (see sections "Pharmacodynamics" and "Special precautions for use").

Patients at high risk of mortality during 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 carried out with caution.

Surgical intervention for hip fracture. There are no data on the use of dabigatran etexilate in patients who have undergone major orthopaedic surgery for hip fracture; therefore, treatment is not recommended.

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

Dabigatran etexilate is contraindicated in patients with hepatic insufficiency or liver disease 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 interaction").

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.

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

Use during pregnancy or breastfeeding.

Women of reproductive potential. Women of reproductive potential 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 to 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. There are no clinical data on the effect 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.

Dosage and Administration

Primary prevention of venous thromboembolism (VTE) in orthopedic surgery

The recommended dose of dabigatran etexilate and duration of therapy for primary prevention of VTE in patients undergoing major orthopedic surgery are shown in Table 3.

Table 3

Recommended doses and duration of therapy for primary prevention of venous thromboembolic complications in patients undergoing major orthopedic surgery

Patient groups	Initiation on the day of surgery, 1–4 hours after completion of surgery	Maintenance dose starting on the first day after surgery	Duration of maintenance dose
Patients undergoing knee replacement surgery	1 capsule (110 mg) of dabigatran etexilate	220 mg of dabigatran etexilate once daily: 2 capsules of 110 mg	10 days
Patients undergoing hip replacement surgery			28–35 days
Recommended dose reduction
Patients with moderate renal impairment (CrCl 30–50 mL/min)	1 capsule of 75 mg dabigatran etexilate	150 mg of dabigatran etexilate once daily: 2 capsules of 75 mg	10 days (knee replacement surgery) or 28–35 days (hip replacement surgery)
Patients receiving verapamil*, amiodarone, quinidine concomitantly
Patients aged 75 years and older

*For patients with moderate renal impairment who are also taking verapamil (see "Special patient groups").

For both surgical procedures: if hemostasis at the wound surface area has not occurred, treatment initiation should be delayed. If treatment has not started on the day of surgery, it should be initiated with 2 capsules once daily.

Assessment of renal function before and during dabigatran etexilate therapy

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

Before 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 instructions").
Renal function should be assessed if renal impairment is suspected during therapy (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.

Missed dose. It is recommended to continue the daily dose of dabigatran etexilate at the usual time on the following day.

A double dose should not be taken to compensate for a missed dose.

Discontinuation of dabigatran etexilate. Dabigatran etexilate therapy 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 anticoagulant therapy. Before switching from dabigatran etexilate to a parenteral anticoagulant, it is recommended to wait 24 hours after the last dose (see section "Interaction with other medicinal products and other forms of interaction").

Switching from parenteral anticoagulant therapy to dabigatran etexilate.

Discontinue parenteral anticoagulant therapy and take dabigatran etexilate 0–2 hours before the scheduled administration time of the alternative therapy or at the time of discontinuation, if ongoing anticoagulation is required (e.g., intravenous unfractionated heparin) (see section "Interaction with other medicinal products and other forms of interaction").

Special patient groups

Patients with renal impairment. Dabigatran etexilate is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) (see section "Contraindications").

In patients with moderate renal impairment (CrCl 30–50 mL/min), dose reduction is recommended (see Table 3 above and sections "Pharmacodynamics" and "Special instructions").

Concomitant use of dabigatran etexilate with mild to moderate P-gp inhibitors, such as amiodarone, quinidine, or verapamil. The dose of dabigatran etexilate should be reduced as indicated in Table 3 (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special instructions"). In this case, dabigatran etexilate and the specified medicinal products should be administered at the same time.

In patients with moderate renal impairment who are also taking verapamil, the dose of dabigatran etexilate should be reduced to 75 mg once daily (see sections "Interaction with medicinal products and other forms of interaction" and "Special instructions").

Elderly patients. Dose reduction is recommended for elderly patients (> 75 years of age) (see Table 3 and sections "Pharmacodynamics" and "Special instructions").

Body weight. Clinical experience with the medicinal product in patients with body weight < 50 kg or > 110 kg under the recommended dosing regimen is limited. Based on available clinical and pharmacokinetic data, dose adjustment is not required (see section "Pharmacokinetics"), but careful clinical monitoring is recommended (see section "Special instructions").

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

Route of administration. The medicinal product Dabifor®, capsules, can 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 established basis for the use of the medicinal product Dabifor® in children for the indication of primary prevention of venous thromboembolic complications in patients undergoing major orthopedic surgery of the hip or knee joint.

Overdose.

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

In case of suspected overdose, coagulation tests can be used to assess bleeding risk (see sections "Pharmacological properties" and "Special instructions"). A calibrated quantitative aPTT test or repeated aPTT measurement can help predict when specific dabigatran levels are reached (see section "Pharmacological properties"). Dialysis may also be considered as an additional measure.

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

Due to its 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 case of hemorrhagic complications, dabigatran etexilate therapy should be discontinued and the source of bleeding identified. Appropriate management should be considered based on the clinical situation, such as 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 instructions").

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; however, data on their clinical benefit and the potential risk of thromboembolic events upon reversal are very limited. Coagulation tests may become unreliable after administration of the proposed reversal agents. Caution should be exercised when interpreting these tests. Caution should also be exercised when using platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet agents have been used. Symptomatic treatment should be performed according to recommendations.

Consultation with a coagulation expert may be considered in cases of major 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.

In active-controlled studies for VTE prevention involving 6684 patients treated with dabigatran etexilate at a dose of 150 mg or 220 mg daily, the most commonly reported adverse reaction was bleeding, observed in approximately 14% of patients; the incidence of major bleeding (including wound bleeding) was less than 2%. Although the frequency was low during clinical trials, major or severe bleeding may occur and, depending on the site, may lead to loss of functional capacity, life-threatening conditions, or fatal outcomes.

Adverse reactions are listed by system organ class and frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Common: decreased hemoglobin levels;
Uncommon: anemia, decreased hematocrit;
Rare: thrombocytopenia;
Frequency not known: neutropenia; agranulocytosis.

Immune system disorders:
Uncommon: hypersensitivity;
Rare: anaphylactic reactions, angioedema, urticaria, rash, pruritus;
Frequency not known: bronchospasm.

Nervous system disorders:
Rare: intracranial hemorrhage.

Vascular disorders:
Uncommon: hematoma, wound bleeding;
Rare: hemorrhage.

Respiratory, thoracic and mediastinal disorders:
Uncommon: epistaxis;
Rare: hemoptysis.

Gastrointestinal disorders:
Uncommon: gastrointestinal hemorrhage, rectal hemorrhage, hemorrhoidal hemorrhage, diarrhea, nausea, vomiting;
Rare: gastrointestinal ulceration, including esophageal ulcer, gastroesophagitis, gastroesophageal reflux disease, abdominal pain, dyspepsia, dysphagia.

Hepatobiliary disorders:
Common: liver function abnormalities/liver function test abnormalities;
Uncommon: increased alanine aminotransferase, increased aspartate aminotransferase, increased liver enzymes, hyperbilirubinemia.

Skin and subcutaneous tissue disorders:
Uncommon: skin hemorrhage;
Frequency not known: alopecia.

Musculoskeletal and connective tissue disorders:
Uncommon: hemarthrosis.

Renal and urinary disorders:
Uncommon: genitourinary hemorrhage, including hematuria.

General disorders and administration site conditions:
Rare: injection site hemorrhage, catheter site hemorrhage, bloody discharge.

Injury, poisoning and procedural complications:
Uncommon: traumatic hemorrhage, postprocedural hematoma, postprocedural hemorrhage, postprocedural discharge, wound discharge;
Rare: incision site hemorrhage, postoperative anemia.

Surgical and medical procedures:
Rare: wound drainage, postprocedural wound drainage.

Description of selected adverse reactions

Bleeding *

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 tissue or organ. The symptoms and severity (including fatal outcomes) depend on the location, extent, and/or progression of bleeding and/or anemia. In clinical trials, mucosal bleeding (e.g., gastrointestinal, genitourinary) was observed more frequently with prolonged treatment with dabigatran etexilate compared to vitamin K antagonist therapy. Therefore, in addition to adequate clinical monitoring, laboratory testing for hemoglobin/hematocrit levels is important for detecting occult bleeding. The risk of bleeding may be increased in certain patient groups, such as patients with moderate renal impairment and/or concomitant therapy affecting hemostasis, or strong P-gp inhibitors (see section "Special precautions" ("Risk of bleeding")). Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or unexplained shock.

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

Table 4 presents data on the number (%) of patients who experienced bleeding as an adverse reaction during treatment for the indication of primary prevention of venous thromboembolic complications after elective hip or knee replacement surgery in two pivotal clinical studies, specifying the tested doses.

Table 4

Parameter	Dabigatran etexilate 150 mg N (%)	Dabigatran etexilate 220 mg N (%)	Enoxaparin N (%)
Number of patients	1866 (100.0)	1825 (100.0)	1848 (100.0)
Major bleeding	24 (1.3)	33 (1.8)	27 (1.5)
Any bleeding	258 (13.8)	251 (13.8)	247 (13.4)

Agranulocytosis and neutropenia

Agranulocytosis and neutropenia have been reported very rarely during treatment with dabigatran etexilate. As adverse reactions were reported during post-marketing surveillance in a population of unknown size, the exact frequency of their occurrence 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 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 required 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 in a carton.

Prescription status. Prescription only.

Manufacturer.

Batch control, batch release of the medicinal product

Towa Pharmaceutical Europe S.L., Spain.

Batch control, batch release of the medicinal product

Pharmadox Healthcare Limited, Malta.

Manufacturer's name and address of the place of business.

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

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

Marketing Authorization Holder. JSC "Farmak".

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