Pradaxa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAKSA® (PRADAXA®)
Composition:
Active substance: dabigatran etexilate;
1 capsule contains dabigatran etexilate (as mesilate) 75 mg;
Excipients: acacia, tartaric acid, hypromellose, dimethicone, talc, hydroxypropylcellulose;
Capsule shell: carrageenan (E 407), potassium chloride, titanium dioxide (E 171), hypromellose, purified water;
Printing ink on capsule, black SW-9008: shellac, butyl alcohol, isopropyl alcohol, black iron oxide (E 172), purified water, propylene glycol (E 1520), anhydrous ethyl alcohol, concentrated ammonium hydroxide solution, potassium hydroxide.
Pharmaceutical form. Hard capsules.
Main physicochemical properties: elongated hydroxypropylmethylcellulose capsules (size 2) with an opaque white cap bearing the Boehringer Ingelheim company symbol in black and an opaque white body with the black marking "R75", containing yellowish pellets.
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 plasma and the liver via esterase-catalyzed hydrolysis. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the primary active substance in plasma.
Since thrombin (a serine protease) promotes 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.
There is a clear correlation between plasma concentrations of dabigatran and the degree of anticoagulant effect observed in phase II studies. Dabigatran prolongs thrombin time (TT), activated partial thromboplastin time (aPTT), and clotting time (CT).
The calibrated diluted thrombin time (dTT) assay provides an approximate value of plasma dabigatran concentration that can be compared with expected levels. If the result of the calibrated diluted thrombin time (dTT) assay is at or below the lower limit of quantification, additional coagulation tests (TT, CT, and aPTT) should be considered.
Clotting time (CT) can 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 quantitative assessment of the anticoagulant effect, especially at high plasma concentrations of dabigatran. Although high aPTT values should be interpreted with caution, they indicate the presence of an anticoagulant effect in the patient.
Clinical efficacy and safety. In clinical studies, an increased incidence of thromboembolic events (primarily strokes and both symptomatic and asymptomatic prosthetic valve thrombosis) and higher rates of bleeding were observed in patients treated with dabigatran etexilate compared to warfarin, both in patients who had recently undergone mechanical heart valve replacement surgery (e.g., during hospitalization) and in those who had undergone such surgery more than 3 months prior. In patients during the early postoperative period, major bleeding primarily manifested as hemorrhagic exudate into the pericardial cavity, particularly in patients who initiated dabigatran etexilate treatment (e.g., on day 3) 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 into 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%.
After oral administration of dabigatran etexilate, the pharmacokinetic profile of dabigatran in plasma is characterized by a rapid increase in concentration, reaching Cmax within 0.5–2 hours after administration.
Absorption. Postoperative absorption of dabigatran etexilate assessed during studies within 1–3 hours after surgery was relatively low compared to absorption in healthy volunteers and showed a similar AUC profile without high peak plasma concentrations. Maximum plasma concentration 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. Additional studies showed that slow and delayed absorption typically occurs only on the day of surgery. In subsequent days, absorption of dabigatran is rapid, with peak plasma concentration achieved within 2 hours after administration.
Food does not affect the bioavailability of dabigatran etexilate but delays the time to maximum plasma concentration by 2 hours.
Cmax and AUC are dose-proportional.
Bioavailability after oral administration may be increased by 75% after a single dose and by 37% at steady state when pellets are administered without the hydroxypropylmethylcellulose (HPMC) capsule coating, compared to the capsule formulation. Therefore, the integrity of HPMC capsules 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 the total body water volume, 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 male volunteers. After intravenous administration, radioactive dabigatran was primarily excreted in urine (85%). Fecal excretion accounted for 6% of the administered dose. Recovery of the original radioactivity to levels of 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, and 4-O-acylglucuronides, each constituting less than 10% of total dabigatran in plasma. Traces of other metabolites could 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
Plasma concentrations of dabigatran decline 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 elimination half-life is prolonged in patients with reduced renal function (see Table 1).
Special patient populations.
Renal impairment. In phase I studies, exposure (AUC) to dabigatran after oral administration was approximately 2.7 times higher in adult volunteers with moderate renal impairment (creatinine clearance (CrCl) between 30 and 50 mL/min) compared to adult volunteers without renal impairment.
In a small number of adult volunteers with severe renal impairment (creatinine clearance 10–30 mL/min), exposure (AUC) to dabigatran was approximately 6 times higher, and the elimination half-life was about twice as long compared to volunteers without renal impairment (see sections "Dosage and administration," "Contraindications," and "Special precautions").
Table 1
Elimination half-life of dabigatran in healthy volunteers and individuals with impaired renal function
| Glomerular filtration rate (creatinine clearance), mL/min |
Half-life, hours (gCV %; interval) |
| > 80 |
13.4 (25.7 %; 11.0–21.6) |
| > 50–≤ 80 |
15.3 (42.7 %; 11.7–34.1) |
| > 30–≤ 50 |
18.4 (18.5 %; 13.3–23.0) |
| ≤ 30 |
27.2 (15.3 %; 21.6–35.0) |
In addition, dabigatran exposure (trough and peak levels) was evaluated in a prospective, open-label, randomized pharmacokinetic study involving patients with non-valvular atrial fibrillation and severe renal impairment (creatinine clearance (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 (geometric CV 76.9%), and the geometric mean peak concentration, measured two hours after the last dose, was 202 ng/mL (geometric CV 70.6%).
Dabigatran clearance during hemodialysis was studied in 7 adult patients with end-stage renal disease (ESRD) without atrial fibrillation. Dialysis was performed with a dialysate flow rate of 700 mL/min for 4 hours and with 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 drug removed by dialysis is proportional to a blood flow rate of 300 mL/min. The anticoagulant activity of dabigatran decreases as plasma concentration declines. The procedure did not affect the pharmacokinetic/pharmacodynamic relationship.
Elderly patients. In a Phase I dedicated pharmacokinetic study in elderly patients, an increase in AUC of 40% to 60% and Cmax of more than 25% was observed compared to younger patients. The effect of age on dabigatran exposure was confirmed in the RE-LY study: approximately 31% higher concentrations in patients ≥ 75 years of age and approximately 22% lower in patients < 65 years of age compared to patients aged 65 to 75 years (see sections "Dosage and administration" and "Special precautions").
Hepatic impairment. No changes in dabigatran exposure were observed in 12 adult patients with moderate hepatic impairment (Child–Pugh class B) compared to 12 control patients (see sections "Dosage and administration" and "Special precautions").
Body weight. Dabigatran concentrations were approximately 20% lower in adult patients with body weight > 100 kg compared to those with body weight of 50–100 kg. The majority (80.8%) of volunteers were in the category ≥ 50 kg and < 100 kg, with no clear difference in dabigatran concentration observed (see sections "Dosage and administration" and "Special precautions"). Data for adult patients with body weight < 50 kg are limited.
Gender. Exposure to the active substance in studies on prevention of venous thromboembolic events was 40% to 50% higher in female patients; dose adjustment is not recommended.
Race. There are no clinically relevant ethnic differences in the pharmacokinetics and pharmacodynamics of dabigatran in Caucasian, African, Hispanic, Japanese, or Chinese patients.
Pharmacokinetic interactions. In vitro interaction studies showed no inhibition or induction of major cytochrome P450 isoenzymes. This was confirmed by in vivo studies in healthy volunteers, in which 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 events in adult patients who have undergone elective total hip or knee replacement surgery.
Contraindications.
- Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
- Severe renal impairment (creatinine clearance < 30 mL/min).
- Active clinically significant bleeding.
- Injury or condition considered to be a significant risk factor for major bleeding, including current or recent gastrointestinal ulceration, presence of malignant tumors with high bleeding risk, recent injury to the brain or spinal cord, recent surgery on the brain or spinal cord or ophthalmological surgery, recent intracerebral hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
- Concomitant use of any anticoagulant medicinal product, such as unfractionated heparin (UFH), low-molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), or oral anticoagulants (warfarin, rivaroxaban, apixaban, etc.), except under specific circumstances, including transition from or to anticoagulant therapy (see section "Dosage and administration"), when UFH is used at doses required to maintain an open central venous or arterial catheter, or when UFH is used during catheter ablation for atrial fibrillation (see section "Interactions with other medicinal products and other forms of interactions").
- Hepatic impairment or liver disease that may affect survival.
- Concomitant treatment with strong P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronedarone, and the fixed-dose combination glecaprevir/pibrentasvir (see section "Interactions with other medicinal products and other forms of interactions").
- Mechanical heart valve requiring anticoagulant therapy (see section "Pharmacological properties. Pharmacodynamics").
Interactions with other medicinal products and other forms of interactions.
Transporter interactions.
Dabigatran etexilate is a substrate of the efflux transporter P-gp. Concomitant use of P-gp inhibitors (see Table 2) 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 "Dosage and administration", "Contraindications", "Special precautions", and subsection "Pharmacodynamics").
Table 2
Transporter interactions
| P-gp inhibitors |
||
| Concomitant use is contraindicated (see section "Contraindications") |
||
| Ketoconazole |
Ketoconazole increases total AUC0-∞ and Cmax 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 ketoconazole once daily. |
|
| Dronedarone |
When dabigatran etexilate and dronedarone are used concomitantly, total AUC0-∞ and Cmax of dabigatran increased 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 can be expected. |
|
| Glecaprevir/ piibrentasvir |
Concomitant use of dabigatran etexilate with the fixed-dose combination of P-gp inhibitors glecaprevir/piibrentasvir 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 the 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 advised when used concomitantly (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use") |
||
| Verapamil |
When dabigatran etexilate (150 mg) and oral verapamil are used concomitantly, Cmax and AUC of dabigatran increase depending on the timing and formulation of verapamil (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use"). The greatest increase in dabigatran exposure occurred when immediate-release verapamil was administered one hour before dabigatran etexilate (Cmax increased approximately 2.8-fold and AUC approximately 2.5-fold). The effect gradually decreased with extended-release verapamil (Cmax increased approximately 1.9-fold and AUC approximately 1.7-fold) or after multiple doses of verapamil (Cmax increased approximately 1.6-fold and AUC approximately 1.5-fold). No significant interaction was observed when verapamil was administered 2 hours after dabigatran etexilate (Cmax increased approximately 1.1-fold and AUC approximately 1.2-fold). This is explained by complete absorption of dabigatran within 2 hours. |
|
| Amiodarone |
When dabigatran etexilate was co-administered with a single 600 mg dose of amiodarone, the extent and rate of absorption of amiodarone and its active metabolite desethylamiodarone (DEA) were not significantly altered. Plasma AUC and Cmax of dabigatran increased by approximately 1.6-fold and 1.5-fold, respectively. Due to the long elimination half-life of amiodarone, potential for drug interaction exists for several weeks after discontinuation of amiodarone (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use"). |
|
| Quinidine |
Quinidine was administered at a dose of 200 mg every 2 hours to a total dose of 1000 mg. Dabigatran etexilate was administered twice daily for 3 days, on day 3 with or without quinidine. AUCτ,ss and Cmax,ss of dabigatran increased overall by 1.53-fold and 1.56-fold, respectively, when quinidine was co-administered (see sections "Dosage and Administration" and "Special Warnings and Precautions for Use"). |
|
| Clarithromycin |
When clarithromycin (500 mg twice daily) was administered concomitantly with dabigatran etexilate to healthy volunteers, AUC increased by approximately 1.19-fold and Cmax by approximately 1.15-fold. |
|
| Ticagrelor |
When a single dose of dabigatran etexilate (75 mg) was co-administered with the highest initial dose of ticagrelor (180 mg), AUC and Cmax 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 Cmax and AUC, respectively. Concomitant administration of the highest initial dose of ticagrelor (180 mg) and dabigatran etexilate 110 mg (at steady state) increases AUCτ,ss and Cmax,ss of dabigatran by 1.49-fold and 1.65-fold, respectively, compared to dabigatran etexilate alone. When the 180 mg loading dose of ticagrelor was administered 2 hours after 110 mg dabigatran etexilate (at steady state), the increases in AUCτ,ss and Cmax,ss of dabigatran were reduced to 1.27-fold and 1.23-fold, respectively, compared to dabigatran etexilate alone. This staggered administration is recommended when initiating ticagrelor at the highest loading dose. Concomitant use of 90 mg ticagrelor twice daily (maintenance dose) with 110 mg dabigatran etexilate increases AUCτ,ss and Cmax,ss of dabigatran by 1.26-fold and 1.29-fold, respectively, compared to dabigatran alone. |
|
| Posaconazole |
Posaconazole also inhibits P-gp to some extent, but has not been clinically studied. Caution should be exercised when dabigatran etexilate is used concomitantly with posaconazole. |
|
| P-gp inducers |
||
| Concomitant use should be avoided |
||
| For example, rifampicin, St. John’s wort (Hypericum perforatum), carbamazepine, or phenytoin |
Concomitant use is expected to reduce dabigatran concentrations. Pretreatment with rifampicin 600 mg once daily for 7 days reduces total Cmax and total exposure of dabigatran by 65.5% and 67%, respectively. The inductive 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 |
||
| For example, ritonavir and its combinations with other protease inhibitors |
They 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 administration of dabigatran etexilate and digoxin showed no changes in digoxin parameters and no clinically relevant changes in dabigatran exposure. |
|
Anticoagulants and antiplatelet medicinal products.
Medicinal products whose concomitant use with dabigatran etexilate has not been studied or for which experience is limited, and medicinal products which may increase the risk of bleeding when used concomitantly with dabigatran etexilate: anticoagulants such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytics, and vitamin K antagonists, rivaroxaban and other oral anticoagulants (see section "Contraindications"), antiplatelet medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section "Special warnings and precautions for use").
UFH may be administered at doses required to maintain patency of central venous or arterial catheters, or during catheter ablation for atrial fibrillation (see section "Contraindications").
Table 3
Interaction with anticoagulants and antiplatelet medicinal products
| Non-steroidal anti-inflammatory drugs (NSAIDs) |
Short-term use of NSAIDs for perioperative analgesia has not been associated with an increased risk of bleeding when used concomitantly with dabigatran etexilate. In the phase III clinical trial comparing dabigatran with warfarin for stroke prevention in patients with atrial fibrillation (RE-LY), long-term use of NSAIDs increased the risk of bleeding by approximately 50% with both dabigatran etexilate and warfarin. |
| 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, AUCτ,ss and Cmax,ss values of dabigatran, coagulation parameters assessing the effect of dabigatran, or platelet aggregation inhibition as an effect of clopidogrel remained unchanged compared to combination therapy and corresponding monotherapies. When 300 mg or 600 mg of clopidogrel were administered, AUCτ,ss and Cmax,ss of dabigatran increased by approximately 30–40% (see section "Dosage and Administration"). |
| Acetylsalicylic acid |
Data from studies indicate that concomitant use of acetylsalicylic acid (ASA) with dabigatran etexilate at a dose of 150 mg twice daily may increase the risk of any bleeding from 12% to 18% or 24% (with ASA doses of 81 mg or 325 mg, respectively) (see section "Dosage and Administration"). |
| Low molecular weight heparins |
Concomitant use of low molecular weight heparins such as enoxaparin and dabigatran etexilate has not been studied. Following transition from 3-day therapy with enoxaparin 40 mg once daily, 24 hours after the last enoxaparin dose, exposure to dabigatran was slightly lower than after administration of dabigatran etexilate alone (single 220 mg dose). Higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration following pre-treatment with enoxaparin compared to treatment with dabigatran etexilate alone. This is due to prior enoxaparin treatment and is not clinically significant. Pre-treatment with enoxaparin did not significantly affect other anticoagulant tests for dabigatran. |
Table 4
Other interactions
| Selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) |
|
| SSRIs and 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 PRADAXA was co-administered with pantoprazole, a reduction in dabigatran AUC of approximately 30% was observed. During clinical trials, pantoprazole and other proton pump inhibitors (PPIs) were used concomitantly with PRADAXA. Concomitant use of PPIs did not reduce the effectiveness of PRADAXA. |
| Ranitidine |
Concomitant administration 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.
Bleeding risk. Dabigatran etexilate should be used with caution in conditions associated with a high risk of bleeding or when using medicinal products affecting hemostasis by inhibiting platelet aggregation. Bleeding may occur at any site during treatment. If hemoglobin levels decrease for unknown reasons and/or hematocrit decreases or arterial blood pressure drops, the presence of bleeding should be investigated.
In life-threatening situations or uncontrolled bleeding where rapid reversal of the anticoagulant effect of dabigatran is required, the specific reversal agent idarucizumab is available for administration. Dabigatran can be removed by hemodialysis. The use of fresh whole blood or fresh frozen plasma, coagulation factor concentrates (activated or non-activated), recombinant factor VIIa, platelet concentrates, and other possible options may be considered (see section "Overdose").
The use of platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA), or nonsteroidal anti-inflammatory drugs, as well as the presence of esophagitis, gastritis, or gastroesophageal reflux, increases the risk of gastrointestinal bleeding.
Risk factors
Table 5 lists factors that may increase the risk of bleeding.
Table 5
| Factors that may increase the risk of bleeding |
Risk factors |
| Pharmacodynamic and pharmacokinetic factors |
Age ≥ 75 years |
| Factors increasing dabigatran plasma levels |
Major
Minor
|
| Pharmacodynamic interactions (see section "Interaction with other medicinal products and other forms of interaction"). |
|
| Diseases/procedures with risk of bleeding |
|
Data in patients with body weight < 50 kg are limited (see section "Pharmacokinetics").
Precautionary measures and bleeding risk management
For prevention of hemorrhagic complications, see section "Overdose".
Benefit-risk assessment
Injuries, conditions, procedures and/or pharmacological therapies (e.g. NSAIDs, antiplatelet agents, SSRIs and SNRIs; see section "Interaction with other medicinal products and other forms of interaction") that significantly increase the risk of major bleeding require careful benefit-risk assessment. Dabigatran etexilate should be used only when benefits outweigh the risks of bleeding.
Close clinical monitoring
Close clinical monitoring for signs of bleeding or anaemia is recommended throughout the treatment period, especially in the presence of multiple risk factors (see Table 5 above). Caution is advised when dabigatran etexilate is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and in the event of bleeding, particularly in patients with mild and moderately reduced 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 non-steroidal anti-inflammatory drugs (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 and the source of bleeding investigated; consideration may also be given to using a specific reversal agent (idarucizumab). Dabigatran is eliminated by haemodialysis.
Use of proton pump inhibitors
The use of proton pump inhibitors may be considered to prevent gastrointestinal bleeding.
Coagulation laboratory parameters
Although routine anticoagulant monitoring is generally not required with this medicinal product, measuring the anticoagulant effect related to dabigatran may be useful to detect excessively high dabigatran exposure in the presence of additional risk factors.
The diluted thrombin time (dTT), thrombin clotting time (TCT) and activated partial thromboplastin time (aPTT) may provide useful information; results should be interpreted with caution due to variability between assays (see section "Pharmacodynamics").
The INR (International Normalized Ratio) test is unreliable in patients taking dabigatran etexilate, as false-positive elevations in INR have been observed. Therefore, the INR test should not be used.
Table 6 provides threshold lower values of coagulation tests that may be associated with an increased risk of bleeding (see section "Pharmacodynamics").
Table 6
Threshold values of coagulation tests that may be associated with an increased risk of bleeding
| Test |
Lower threshold values of coagulation test |
| rTF [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 ischemic stroke. The use of fibrinolytic agents for the treatment of acute ischemic stroke may be considered if PT, aPTT, or ACT test results do not exceed the upper limit of the local reference normal range.
Surgery and invasive 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. 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 should be exercised with any procedure. In such cases, a coagulation test (see section "Contraindications" and subsection "Pharmacodynamics") 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 dialyzable by hemodialysis.
Reversal of dabigatran therapy increases the thrombotic risk in patients related to their underlying condition. Dabigatran etexilate may be restarted 24 hours after administration of idarucizumab, provided the patient is clinically stable and adequate hemostasis 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 effective hemostasis may be required, discontinuation of dabigatran etexilate 2–4 days prior to surgery should be considered.
Table 7
Guidelines for discontinuation of treatment prior to invasive or surgical procedures
| Renal function (creatinine clearance, mL/min) |
Expected elimination half-life (hours) |
Dabigatran etexilate should be discontinued prior to planned surgical intervention |
|
| 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 the clinical situation allows and adequate haemostasis has been achieved.
Patients at risk of bleeding or patients at risk of excessive effect, particularly those with reduced renal function (see also Table 5), should be treated with caution (see section "Special precautions for use" and subsection "Pharmacodynamics").
Patients with high mortality risk associated with surgery and hereditary risk factors for thromboembolic events. Data on the efficacy and safety of dabigatran etexilate in this patient group are limited; therefore, therapy should be administered with caution.
Surgical intervention for hip fracture. There are no data on the use of dabigatran etexilate in patients who have undergone surgery for hip fracture; therefore, treatment is not recommended.
Hepatic impairment. Patients with elevated liver enzymes more than twice the ULN were excluded from the main clinical trials. Due to lack of treatment experience, dabigatran etexilate is not recommended for this patient group.
The use of the drug 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 expected reduction in dabigatran concentrations (see section "Interaction with other medicinal products and other forms of interaction" and subsection "Pharmacokinetics").
Patients with antiphospholipid syndrome
Direct oral anticoagulants (DOACs), 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-positive test results (lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with DOACs may be associated with an increased frequency of recurrent thrombotic events compared to vitamin K antagonist therapy.
Special precautions for use. When removing a PRADAXA capsule from the blister, 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 without pushing the capsule through the foil.
Use during pregnancy or breastfeeding.
Women of childbearing potential. Women of childbearing potential should avoid pregnancy during treatment with PRADAXA.
Pregnancy. There are no adequate data on the use of PRADAXA 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 effects of dabigatran on breastfed infants. As a precaution, breastfeeding should be discontinued during treatment with PRADAXA.
Fertility. There are no data on the effect on fertility in humans.
In animal studies, effects on female fertility were observed, including reduced number of implantations and increased pre-implantation loss at a dose of 70 mg/kg (plasma exposure level 5 times higher than in humans). No other effects on female fertility were observed. No effects on male fertility were detected. At doses toxic to females (plasma exposure levels 5–10 times higher than in humans), reduced fetal body weight and embryonic viability, along with increased fetal abnormalities, were observed in rats and rabbits. In pre- and postnatal studies, increased intrauterine mortality was observed at doses toxic to females (dose at which plasma exposure was 4 times higher than in humans).
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 prophylaxis of venous thromboembolism (further referred to as VTE) in orthopedic surgery.
The recommended dose of dabigatran etexilate and duration of therapy for primary prophylaxis of venous thromboembolic events in patients undergoing orthopedic surgery are shown in Table 8.
Table 8
Recommended doses and duration of therapy for primary prophylaxis of venous thromboembolic events in patients undergoing orthopedic surgery
| Groups of patients |
Initiation on the day of surgery, 1–4 hours after completion of surgery |
Maintenance dose starting from the first day after surgery |
Duration of maintenance dose administration |
| 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 (creatinine clearance 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 populations".
For both surgical procedures: if hemostasis 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 per day.
Assessment of renal function before and during dabigatran etexilate therapy
For all patients, and especially elderly patients (>75 years), since renal impairment may frequently occur in this age group:
- Before starting dabigatran etexilate therapy, renal function should be assessed by calculating creatinine clearance (CrCL) to exclude severe renal impairment (CrCL < 30 mL/min) (see sections "Contraindications", "Special precautions", and "Pharmacokinetics").
- Renal function should be assessed if there is suspicion of worsening renal function during therapy (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medications).
The method used to assess renal function (CrCL in 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 treatment must not be discontinued without consulting a physician. Patients should be advised to contact their doctor if gastrointestinal symptoms such as dyspepsia occur (see section "Adverse reactions").
Switching from dabigatran etexilate to parenteral anticoagulants
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 the parenteral anticoagulant and take dabigatran etexilate 0–2 hours before the next scheduled dose of the alternative therapy or at the time of discontinuation if continued therapy is required (e.g., intravenous unfractionated heparin) (see section "Interaction with other medicinal products and other forms of interaction").
Special patient populations
Patients with renal impairment
Dabigatran etexilate therapy is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section "Contraindications").
A reduced dose is recommended for patients with moderate renal impairment (creatinine clearance 30–50 mL/min) (see Table 8 above and sections "Special precautions" and subsection "Pharmacodynamics").
Concomitant use of dabigatran etexilate with mild to moderate P-glycoprotein inhibitors, such as amiodarone, quinidine, or verapamil
The dose of dabigatran etexilate should be reduced as specified in Table 8 (see also sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction"). In this case, dabigatran etexilate and the mentioned medicinal products should be administered at the same time.
For 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 "Special precautions" and "Interaction with medicinal products and other forms of interaction").
Elderly patients
A reduced dose is recommended for elderly patients (>75 years) (see Table 8 above and sections "Special precautions" and subsection "Pharmacodynamics").
Body weight
Clinical experience with use in patients with body weight < 50 kg or > 110 kg at the recommended dosing regimen is limited. Based on available clinical and pharmacokinetic data, dose adjustment is not required (see subsection "Pharmacokinetics"), but careful clinical monitoring is recommended (see section "Special precautions").
Gender
Dose adjustment is not required (see subsection "Pharmacokinetics").
Method of administration
This medicinal product is administered orally. The capsule can be taken regardless of food intake. The capsule should be swallowed whole with a glass of water to facilitate passage into the stomach. Patients should be advised not to open the capsule, as this may increase the risk of bleeding (see subsection "Pharmacokinetics").
Children
There is no justification for the use of PRADAXA for the indication of primary prevention of venous thromboembolic events in children who have undergone elective total hip or knee replacement surgery.
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 help determine the risk of bleeding (see section "Special precautions" and subsection "Pharmacodynamics"). A calibrated quantitative aPTT test or repeated aPTT measurement can help predict when specific dabigatran levels will be reached (see subsection "Pharmacodynamics"). Dialysis may also be initiated 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 low plasma protein binding, dabigatran may be removed by dialysis; however, clinical experience with dialysis is limited (see subsection "Pharmacokinetics").
Management of hemorrhagic complications
In the event of hemorrhagic complications, dabigatran etexilate therapy should be discontinued and the source of bleeding identified. Appropriate supportive treatment 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 situations 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").
The use of coagulation factor concentrates (activated or non-activated) or recombinant factor VIIa 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 thromboembolic recurrence 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 of thrombocytopenia or when 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 on VTE prophylaxis in 6,684 patients receiving dabigatran etexilate at a dose of 150 mg or 220 mg daily, the most common adverse reaction was bleeding, observed in approximately 14% of patients; the rate of major bleeding (including wound bleeding) was less than 2%. Although bleeding events were rare in clinical trials, they may be massive or severe, and regardless of the site, may lead to loss of working capacity, be life-threatening, or even result in fatal outcomes.
Table 9 lists the adverse reactions by system organ class 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), not known (cannot be estimated from the available data).
Table 9
Adverse reactions
| System organ class |
Frequency |
| Blood and lymphatic system disorders |
|
| decreased hemoglobin level |
common |
| anemia |
uncommon |
| decreased hematocrit |
uncommon |
| thrombocytopenia |
rare |
| neutropenia |
unknown |
| agranulocytosis |
unknown |
| Immune system disorders |
|
| drug hypersensitivity |
uncommon |
| anaphylactic reactions |
rare |
| angioedema |
rare |
| urticaria |
rare |
| rash |
rare |
| pruritus |
rare |
| bronchospasm |
unknown |
| Nervous system disorders |
|
| intracranial hemorrhage |
rare |
| Vascular disorders |
|
| hematoma |
uncommon |
| wound hemorrhage |
uncommon |
| bleeding |
rare |
| Respiratory, thoracic and mediastinal disorders |
|
| epistaxis |
uncommon |
| hemoptysis |
rare |
| Gastrointestinal disorders |
|
| gastrointestinal hemorrhage |
uncommon |
| rectal hemorrhage |
uncommon |
| hemorrhoidal hemorrhage |
uncommon |
| diarrhea |
uncommon |
| nausea |
uncommon |
| vomiting |
uncommon |
| gastrointestinal ulceration, including esophageal ulcer |
rare |
| gastroesophagitis |
rare |
| gastroesophageal reflux disease |
rare |
| abdominal pain |
rare |
| dyspepsia |
rare |
| dysphagia |
rare |
| Hepatobiliary disorders |
|
| liver function test abnormality/liver function disorder |
common |
| increased alanine aminotransferase level |
uncommon |
| increased aspartate aminotransferase level |
uncommon |
| increased liver enzyme levels |
uncommon |
| hyperbilirubinemia |
uncommon |
| Skin and subcutaneous tissue disorders |
|
| skin hemorrhage |
uncommon |
| alopecia |
unknown |
| Musculoskeletal and connective tissue disorders |
|
| hemarthrosis |
uncommon |
| Renal and urinary disorders |
|
| urogenital hemorrhage, including hematuria |
uncommon |
| General disorders and administration site conditions |
|
| injection site hemorrhage |
rare |
| catheter site hemorrhage |
rare |
| blood discharge |
rare |
| Injury, poisoning and procedural complications |
|
| traumatic hemorrhage |
uncommon |
| postprocedural hematoma |
uncommon |
| postprocedural hemorrhage |
uncommon |
| postprocedural discharge |
uncommon |
| wound discharge |
uncommon |
| incision site hemorrhage |
rare |
| postoperative anemia |
rare |
| Surgical and medical procedures |
|
| wound drainage |
rare |
| postprocedural drainage |
rare |
Description of selected adverse reactions
Hemorrhage
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 and extent or spread of the 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 VKAs (vitamin K antagonists). Therefore, in addition to adequate clinical monitoring, laboratory assessments of hemoglobin/hematocrit levels are important for detecting occult bleeding. The risk of bleeding may increase in certain patient groups, for example, in patients with moderate renal impairment and/or in patients receiving concomitant therapy affecting hemostasis or strong P-gp inhibitors (see section "Special precautions": Risk of bleeding). Signs suggestive of hemorrhagic complications include weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, and unexplained shock.
Reported hemorrhagic complications such as compartment syndrome, acute kidney injury due to hypoperfusion, and anticoagulant-related nephropathy have been observed in patients with predisposing risk factors during treatment with dabigatran etexilate. Therefore, the likelihood of bleeding should be considered when evaluating the condition of 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 10 provides data on the number (%) of patients in whom bleeding was observed as an adverse reaction during treatment for the indication of primary prevention of venous thromboembolic events following hip or knee replacement surgery in two pivotal clinical trials, with specified tested doses.
Table 10
Number (%) of patients with bleeding as an adverse reaction
| 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 dabigatran etexilate use. As adverse reactions have been reported during post-marketing surveillance in a population of unknown size, the true frequency of occurrence cannot be reliably determined. The reporting rate was estimated at 7 events per million patient-years for agranulocytosis and 5 events per million patient-years for neutropenia.
Reporting of suspected adverse reactions
Reporting of adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua
Shelf life.
3 years.
Storage conditions.
Store in the original packaging to protect from moisture at a temperature not exceeding 25 °C. Keep out of reach of children!
Packaging.
10 capsules per blister; 1, 3, or 6 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Manufacturer's address and place of business.
Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.