Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Boehringer Ingelheim International GmbH, Binger Str. 173, 55216 Ingelheim am Rhein, Germany
Dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding or with concomitant use of medicinal products affecting haemostasis by inhibition of platelet aggregation. Bleeding can occur at any site during therapy. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.
For adult patients in situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent idarucizumab is available. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, coagulation factor concentration (activated or non-activated), recombinant factor VIIa or platelet concentrates are other possible options (see also section 4.9).
In clinical trials, dabigatran etexilate was associated with higher rates of major gastrointestinal (GI) bleeding. An increased risk was seen in the elderly (≥75 years) for the 150 mg twice daily dose regimen. Further risk factors (see also table 4) comprise co-medication with platelet aggregation inhibitors such as clopidogrel and acetylsalicylic acid (ASA) or non steroidal antiinflammatory drugs (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux.
Table 4 summarises factors which may increase the haemorrhagic risk.
Table 4. Factors which may increase the haemorrhagic risk:
| Risk factor | |
|---|---|
| Pharmacodynamic and kinetic factors | Age ≥75 years |
| Factors increasing dabigatran plasma levels | Major: • Moderate renal impairment in adult patients (30-50 mL/min CrCL) • Strong P-gp inhibitors (see section 4.3 and 4.5) • Mild to moderate P-gp inhibitor co-medication (e.g. amiodarone, verapamil, quinidine and ticagrelor; see section 4.5) Minor: • Low body weight (<50 kg) in adult patients |
| Pharmacodynamic interactions (see section 4.5) | • ASA and other platelet aggregation inhibitors such as clopidogrel • NSAIDs • SSRIs or SNRIs • Other medicinal products which may impair haemostasis |
| Diseases / procedures with special haemorrhagic risks | • Congenital or acquired coagulation disorders • Thrombocytopenia or functional platelet |
Limited data is available in patients <50 kg (see section 5.2).
The concomitant use of dabigatran etexilate with P-gp-inhibitors has not been studied in paediatric patients but may increase the risk of bleeding (see section 4.5).
For the management of bleeding complications, see also section 4.9.
Benefit-risk assessment:
The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see section 4.5), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Dabigatran etexilate should only be given if the benefit outweighs bleeding risks.
Limited clinical data are available for paediatric patients with risk factors, including patients with active meningitis, encephalitis and intracranial abscess (see section 5.1). In these patients, dabigatran etexilate should only be given if the expected benefit outweighs bleeding risks.
Close clinical surveillance:
Close observation for signs of bleeding or anaemia is recommended throughout the treatment period, especially if risk factors are combined (see table 5 above). Particular caution should be exercised when dabigatran etexilate is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a reduced renal function (see section 4.5).
Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see section 4.5).
Discontinuation of dabigatran etexilate:
Patients who develop acute renal failure must discontinue dabigatran etexilate (see also section 4.3).
When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent (idarucizumab) may be considered in adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran.
Use of proton-pump inhibitors:
The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding. In case of paediatric patients local labeling recommendations for proton pump inhibitors have to be followed.
Laboratory coagulation parameters:
Although this medicinal product does not in general require routine anticoagulant monitoring, the measurement of dabigatran related anticoagulation may be helpful to detect excessive high exposure to dabigatran in the presence of additional risk factors.
Diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) may provide useful information, but results should be interpreted with caution due to inter-test variability (see section 5.1).
The international normalised ratio (INR) test is unreliable in patients on dabigatran etexilate and false positive INR elevations have been reported. Therefore INR tests should not be performed.
Table 5 shows coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding. Respective thresholds for paediatric patients are not known (see section 5.1).
Table 5. Coagulation test thresholds at trough that may be associated with an increased risk of bleeding:
| Test (trough value) | Indication | |
|---|---|---|
| Primary prevention of VTE in orthopaedic surgery | SPAF and DVT/PE | |
| dTT [ng/mL] | >67 | >200 |
| ECT [x-fold upper limit of normal] | No data | >3 |
| aPTT [x-fold upper limit of normal] | >1.3 | >2 |
| INR | Should not be performed | Should not be performed |
The use of fibrinolytic medicinal products for the treatment of acute ischemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the upper limit of normal (ULN) according to the local reference range.
Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore, surgical interventions may require the temporary discontinuation of dabigatran etexilate.
Patients can stay on dabigatran etexilate while being cardioverted. There are no data available for 110 mg twice daily dabigatran etexilate treatment in patients undergoing catheter ablation for atrial fibrillation (see section 4.2).
Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.
Dabigatran etexilate should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (idarucizumab) to dabigatran is available for adult patients. The efficacy and safety of idarucizumab have not been established in paediatric patients. Haemodialysis can remove dabigatran.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.
Dabigatran etexilate should be temporarily discontinued. A surgery/intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.
If possible, dabigatran etexilate should be discontinued at least 24 hours before invasive or surgical procedures. In patients at higher risk of bleeding or in major surgery where complete haemostasis may be required consider stopping dabigatran etexilate 2-4 days before surgery.
Table 6 summarises discontinuation rules before invasive or surgical procedures for adult patients.
Table 6. Discontinuation rules before invasive or surgical procedures for adult patients:
| Renal function (CrCL in mL/min) | Estimated half-life (hours) | Dabigatran etexilate should be stopped before elective surgery | |
|---|---|---|---|
| High risk of bleeding 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) |
Discontinuation rules before invasive or surgical procedures for paediatric patients are summarised in table 7.
Table 7. Discontinuation rules before invasive or surgical procedures for paediatric patients:
| Renal function (eGFR in mL/min/1.73m²) | Stop dabigatran before elective surgery |
|---|---|
| >80 | 24 hours before |
| 50 – 80 | 2 days before |
| <50 | These patients have not been studied (see section 4.3). |
Procedures such as spinal anaesthesia may require complete haemostatic function.
The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
Dabigatran etexilate should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
Patients at risk for bleeding or patients at risk of overexposure, notably patients with reduced renal function (see also table 5), should be treated with caution (see sections 4.4 and 5.1).
There are limited efficacy and safety data for dabigatran etexilate available in these patients and therefore they should be treated with caution.
There is no data on the use of dabigatran etexilate in patients undergoing hip fracture surgery. Therefore treatment is not recommended.
Patients with elevated liver enzymes >2 ULN were excluded in the main trials. No treatment experience is available for this subpopulation of patients, and therefore the use of dabigatran etexilate is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see section 4.3).
Concomitant administration of P-gp inducers is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2).
Direct acting Oral Anticoagulants (DOACs) including dabigatran etexilate are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti–beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
In the phase III study RE-LY (SPAF, see section 5.1) the overall rate of MI was 0.82, 0.81, and 0.64% / year for dabigatran etexilate 110 mg twice daily, dabigatran etexilate 150 mg twice daily and warfarin, respectively, an increase in relative risk for dabigatran of 29% and 27% compared to warfarin. Irrespective of therapy, the highest absolute risk of MI was seen in the following subgroups, with similar relative risk: patients with previous MI, patients ≥65 years with either diabetes or coronary artery disease, patients with left ventricular ejection fraction <40%, and patients with moderate renal dysfunction. Furthermore a higher risk of MI was seen in patients concomitantly taking ASA plus clopidogrel or clopidogrel alone.
In the three active controlled DVT/PE phase III studies, a higher rate of MI was reported in patients who received dabigatran etexilate than in those who received warfarin: 0.4% vs. 0.2% in the shortterm RE-COVER and RE-COVER II studies; and 0.8% vs. 0.1% in the long-term RE-MEDY trial. The increase was statistically significant in this study (p=0.022).
In the RE-SONATE study, which compared dabigatran etexilate to placebo, the rate of MI was 0.1% for patients who received dabigatran etexilate and 0.2% for patients who received placebo.
The efficacy and safety have not been established for DVT/PE patients with active cancer. There is limited data on efficacy and safety for paediatric patients with active cancer.
For some very specific paediatric patients, e.g. patients with small bowel disease where absorption may be affected, use of an anticoagulant with parenteral route of administration should be considered.
Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of P-gp inhibitors (see table 8) is expected to result in increased dabigatran plasma concentrations.
If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. Dose reductions may be required in combination with some P-gp inhibitors (see sections 4.2, 4.3, 4.4 and 5.1).
Table 8. Transporter interactions:
| P-gp inhibitors | |
| Concomitant use contraindicated (see section 4.3) | |
| Ketoconazole | Ketoconazole increased total dabigatran AUC0-∞ and Cmax values 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 dosing of 400 mg ketoconazole once daily. |
| Dronedarone | When dabigatran etexilate and dronedarone were given at the same time total dabigatran AUC0-∞ and Cmax values increased by about 2.4-fold and 2.3-fold, respectively, after multiple dosing of 400 mg dronedarone bid, and about 2.1-fold and 1.9-fold, respectively, after a single dose of 400 mg. |
| Itraconazole, cyclosporine | Based on in vitro results a similar effect as with ketoconazole may be expected. |
| Glecaprevir / pibrentasvir | The concomitant use of dabigatran etexilate with the fixed-dose combination of the P-gp inhibitors glecaprevir/pibrentasvir has been shown to increase exposure of dabigatran and may increase the risk of bleeding. |
| Concomitant use not recommended | |
| Tacrolimus | Tacrolimus has been found in vitro to have a similar level of inhibitory effect on P-gp as that seen with itraconazole and cyclosporine. Dabigatran etexilate has not been clinically studied together with tacrolimus. However, limited clinical data with another P-gp substrate (everolimus) suggest that the inhibition of P-gp with tacrolimus is weaker than that observed with strong P-gp inhibitors. |
| Cautions to be exercised in case concomitant use (see sections 4.2 and 4.4) | |
| Verapamil | When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the Cmax and AUC of dabigatran were increased but the magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4). The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to the dabigatran etexilate intake (increase of Cmax by about 2.8-fold and AUC by about 2.5-fold). The effect was progressively decreased with administration of an extended release formulation (increase of Cmax by about 1.9-fold and AUC by about 1.7-fold) or administration of multiple doses of verapamil (increase of Cmax by about 1.6-fold and AUC by about 1.5-fold). There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increase of Cmax by about 1.1-fold and AUC by about 1.2-fold). This is explained by completed dabigatran absorption after 2 hours. |
| Amiodarone | When dabigatran etexilate was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and Cmax were increased by about 1.6-fold and 1.5-fold, respectively. In view of the long half-life of amiodarone the potential for an interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4). |
| Quinidine | Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1,000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3rd day either with or without quinidine. Dabigatran AUCτ,ss and Cmax,ss were increased on average by 1.53-fold and 1.56-fold, respectively with concomitant quinidine (see sections 4.2 and 4.4). |
| Clarithromycin | When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 1.19-fold and Cmax by about 1.15-fold was observed. |
| Ticagrelor | When a single dose of 75 mg dabigatran etexilate was coadministered simultaneously with a loading dose of 180 mg ticagrelor, the dabigatran AUC and Cmax were increased by 1.73-fold and 1.95-fold, respectively. After multiple doses of ticagrelor 90 mg b.i.d. the increase of dabigatran exposure is 1.56-fold and 1.46-fold for Cmax and AUC, respectively. Concomitant administration of a loading dose of 180 mg ticagrelor and 110 mg dabigatran etexilate (in steady state) increased the dabigatran AUCτ,ss and Cmax,ss by 1.49-fold and 1.65-fold, respectively, compared with dabigatran etexilate given alone. When a loading dose of 180 mg ticagrelor was given 2 hours after 110 mg dabigatran etexilate (in steady state), the increase of dabigatran AUCτ,ss and Cmax,ss was reduced to 1.27-fold and 1.23-fold, respectively, compared with dabigatran etexilate given alone. This staggered intake is the recommended administration for start of ticagrelor with a loading dose. Concomitant administration of 90 mg ticagrelor b.i.d. (maintenance dose) with<br /110 mg dabigatran etexilate increased the adjusted dabigatran AUCτ,ss and Cmax,ss 1.26-fold and 1.29-fold, respectively, compared with dabigatran etexilate given alone. |
| Posaconazole | Posaconazole also inhibits P-gp to some extent but has not been clinically studied. Caution should be exercised when dabigatran etexilate is co-administered with posaconazole. |
| P-gp inducers | |
| Concomitant use should be avoided. | |
| e.g. rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin | Concomitant administration is expected to result in decreased dabigatran concentrations. Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5% and 67%, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days. |
| Protease inhibitors such as ritonavir | |
| Concomitant use not recommended | |
| e.g. ritonavir and its combinations with other protease inhibitors | These affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with dabigatran etexilate. |
| P-gp substrate | |
| Digoxin | In a study performed with 24 healthy subjects, when dabigatran etexilate was co-administered with digoxin, no changes on digoxin and no clinically relevant changes on dabigatran exposure have been observed. |
There is no or only limited experience with the following treatments 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), thrombolytic medicinal products, and vitamin K antagonists, rivaroxaban or other oral anticoagulants (see section 4.3), and antiplatelet aggregation medicinal products such as GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, ticagrelor, dextran, and sulfinpyrazone (see section 4.4).
From the data collected in the phase III study RE-LY (see section 5.1) it was observed that the concomitant use of other oral or parenteral anticoagulants increases major bleeding rates with both dabigatran etexilate and warfarin by approximately 2.5-fold, mainly related to situations when switching from one anticoagulant to another (see section 4.3). Furthermore, concomitant use of antiplatelets, ASA or clopidogrel approximately doubled major bleeding rates with both dabigatran etexilate and warfarin (see section 4.4).
UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter or during catheter ablation for atrial fibrillation (see section 4.3).
Table 9. Interactions with anticoagulants and antiplatelet aggregation medicinal products:
| NSAIDs | NSAIDs given for short-term analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use in a phase III clinical trial comparing dabigatran to warfarin for stroke prevention in atrial fibrillation patients (RE-LY), NSAIDs increased the risk of bleeding by approximately 50% on both dabigatran etexilate and warfarin. |
| Clopidogrel | In young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUCτ,ss and Cmax,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUCτ,ss and Cmax,ss were increased by about 30-40% (see section 4.4). |
| ASA | Co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12% to 18% and 24% with 81 mg and 325 mg ASA, respectively (see section 4.4). |
| LMWH | The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin. |
Table 10. Other interactions:
| Selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs) | |
| SSRIs, SNRIs | SSRIs and SNRIs increased the risk of bleeding in all treatment groups of a phase III clinical trial comparing dabigatran to warfarin for stroke prevention in atrial fibrillation patients (RE-LY). |
| Substances influencing gastric pH | |
| Pantoprazole | When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran AUC of approximately 30% was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa. |
| Ranitidine | Ranitidine administration together with dabigatran etexilate had no clinically relevant effect on the extent of absorption of dabigatran. |
Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.
Interaction studies have only been performed in adults.
Women of childbearing potential should avoid pregnancy during treatment with Pradaxa.
There is limited amount of data from the use of Pradaxa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Pradaxa should not be used during pregnancy unless clearly necessary.
There are no clinical data of the effect of dabigatran on infants during breast-feeding. Breast-feeding should be discontinued during treatment with Pradaxa.
No human data available.
In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).
Dabigatran etexilate has no or negligible influence on the ability to drive and use machines.
Dabigatran etexilate has been evaluated in clinical trials overall in approximately 64,000 patients; thereof approximately 35,000 patients were treated with dabigatran etexilate.
In total, 22% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years), 14% of patients treated for DVT/PE and 15% of patients treated for DVT/PE prevention experienced adverse reactions.
The most commonly reported events are bleedings occurring in approximately 16.6% in patients with atrial fibrillation treated long-term for the prevention of stroke and systemic embolism and in 14.4% of adult patients treated for DVT/PE. Furthermore, bleeding occurred in 19.4% of patients in the DVT/PE prevention trial RE-MEDY (adult patients) and in 10.5% of patients in the DVT/PE prevention trial RE-SONATE (adult patients).
Since the patient populations treated in the three indications are not comparable and bleeding events are distributed over several System Organ Classes (SOC), a summary description of major and any bleeding are broken down by indication and are provided in tables 12-15 below.
Although low in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Table 11 shows the adverse reactions identified studies and post-marketing data in the indications prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation, DVT/PE treatment and DVT/PE prevention. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention.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 11. Adverse reactions:
| Frequency | ||
|---|---|---|
| SOC / Preferred term. | Stroke and systemic embolism prevention in patients with atrial fibrillation | DVT/PE treatment and DVT/PE prevention |
| Blood and lymphatic system disorders | ||
| Anaemia Common Uncommon | ||
| Haemoglobin decreased | Uncommon | Not known |
| Thrombocytopenia | Uncommon | Rare |
| Haematocrit decreased | Rare | Not known |
| Neutropenia | Not known | Not known |
| Agranulocytosis | Not known | Not known |
| Immune system disorder | ||
| Drug hypersensitivity | Uncommon | Uncommon |
| Rash | Uncommon | Uncommon |
| Pruritus | Uncommon | Uncommon |
| Anaphylactic reaction | Rare | Rare |
| Angioedema | Rare | Rare |
| Urticaria | Rare | Rare |
| Bronchospasm | Not known | Not known |
| Nervous system disorders | ||
| Intracranial haemorrhage | Uncommon | Rare |
| Vascular disorders | ||
| Haematoma | Uncommon | Uncommon |
| Haemorrhage | Uncommon | Uncommon |
| Respiratory, thoracic and mediastinal disorders | ||
| Epistaxis | Common | Common |
| Haemoptysis | Uncommon | Uncommon |
| Gastrointestinal disorders | ||
| Gastrointestinal haemorrhage | Common | Common |
| Abdominal pain | Common | Uncommon |
| Diarrhoea | Common | Uncommon |
| Dyspepsia | Common | Common |
| Nausea | Common | Uncommon |
| Rectal haemorrhage | Uncommon | Common |
| Haemorrhoidal haemorrhage | Uncommon | Uncommon |
| Gastrointestinal ulcer, including oesophageal ulcer | Uncommon | Uncommon |
| Gastroesophagitis | Uncommon | Uncommon |
| Gastroesophageal reflux disease | Uncommon | Uncommon |
| Vomiting | Uncommon | Uncommon |
| Dysphagia | Uncommon | Rare |
| Hepatobiliary disorders | ||
| Hepatic function abnormal/ Liver function Test abnormal | Uncommon | Uncommon |
| Alanine aminotransferase increased | Uncommon | Uncommon |
| Aspartate aminotransferase increased | Uncommon | Uncommon |
| Hepatic enzyme increased | Rare | Uncommon |
| Hyperbilirubinaemia | Rare | Not known |
| Skin and subcutaneous tissue disorder | ||
| Skin haemorrhage | Common | Common |
| Alopecia | Not known | Not known |
| Musculoskeletal and connective tissue disorders | ||
| Haemarthrosis | Rare | Uncommon |
| Renal and urinary disorders | ||
| Genitourological haemorrhage, including haematuria | Common | Common |
| General disorders and administration site conditions | ||
| Injection site haemorrhage | Rare | Rare |
| Catheter site haemorrhage | Rare | Rare |
| Injury, poisoning and procedural complications | ||
| Traumatic haemorrhage | Rare | Uncommon |
| Incision site haemorrhage | Rare | Rare |
Due to the pharmacological mode of action, the use of dabigatran etexilate may be associated with an increased risk of occult or overt bleeding from any tissue or organ. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. In the clinical studies mucosal bleedings (e.g. gastrointestinal, genitourinary) were seen more frequently during long term dabigatran etexilate treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit is of value to detect occult bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with moderate renal impairment and/or on concomitant treatment affecting haemostasis or strong P-gp inhibitors (see section 4.4 Haemorrhagic risk). Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.
Known bleeding complications such as compartment syndrome and acute renal failure due to hypoperfusion and anticoagulant-related nephropathy in patients with predisposing risk factors have been reported for dabigatran etexilate. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient. For adult patients, a specific reversal agent for dabigatran, idarucizumab, is available in case of uncontrollable bleeding (see Section 4.9).
The table 12 shows bleeding events broken down to major and any bleeding in the pivotal study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation.
Table 12. Bleeding events in a study testing the prevention of thromboembolic stroke and systemic embolism in patients with atrial fibrillation:
| Dabigatran etexilate 110 mg twice daily | Dabigatran etexilate 150 mg twice daily | Warfarin | |
|---|---|---|---|
| Subjects randomised | 6,015 | 6,076 | 6,022 |
| Major bleeding | 347 (2.92 %) | 409 (3.40 %) | 426 (3.61 %) |
| Intracranial bleeding | 27 (0.23 %) | 39 (0.32 %) | 91 (0.77 %) |
| GI bleeding | 134 (1.13 %) | 192 (1.60 %) | 128 (1.09 %) |
| Fatal bleeding | 26 (0.22 %) | 30 (0.25 %) | 42 (0.36 %) |
| Minor bleeding | 1,566 (13.16 %) | 1,787 (14.85 %) | 1,931 (16.37 %) |
| Any bleeding | 1,759 (14.78 %) | 1,997 (16.60 %) | 2,169 (18.39 %) |
Subjects randomised to dabigatran etexilate 110 mg twice daily or 150 mg twice daily had a significantly lower risk for life-threatening bleeds and intracranial bleeding compared to warfarin [p <0.05]. Both dose strengths of dabigatran etexilate had also a statistically significant lower total bleed rate. Subjects randomised to 110 mg dabigatran etexilate twice daily had a significantly lower risk for major bleeds compared with warfarin (hazard ratio 0.81 [p=0.0027]). Subjects randomised to 150 mg dabigatran etexilate twice daily had a significantly higher risk for major GI bleeds compared with warfarin (hazard ratio 1.48 [p=0.0005]. This effect was seen primarily in patients ≥75 years. The clinical benefit of dabigatran with regard to stroke and systemic embolism prevention and decreased risk of ICH compared to warfarin is preserved across individual subgroups, e.g. renal impairment, age, concomitant medicinal product use such as anti-platelets or P-gp inhibitors. While certain patient subgroups are at an increased risk of major bleeding when treated with an anticoagulant, the excess bleeding risk for dabigatran is due to GI bleeding, typically seen within the first 3-6 months following initiation of dabigatran etexilate therapy.
Table 13 shows bleeding events in the pooled pivotal studies RE-COVER and RE-COVER II testing the treatment of DVT and PE. In the pooled studies the primary safety endpoints of major bleeding, major or clinically relevant bleeding and any bleeding were significantly lower than warfarin at a nominal alpha level of 5%.
Table 13. Bleeding events in the studies RE-COVER and RE-COVER II testing the treatment of DVT and PE:
| Dabigatran etexilate 150 mg twice daily | Warfarin | Hazard ratio vs. warfarin (95% confidence interval) | |
|---|---|---|---|
| Patients included in safety analysis | 2,456 | 2,462 | |
| Major bleeding events | 24 (1.0 %) | 40 (1.6 %) | 0.60 (0.36, 0.99) |
| Intracranial Bleeding | 2 (0.1 %) | 4 (0.2 %) | 0.50 (0.09, 2.74) |
| Major GI bleeding | 10 (0.4 %) | 12 (0.5 %) | 0.83 (0.36, 1.93) |
| Life-threatening bleed | 4 (0.2 %) | 6 (0.2 %) | 0.66 (0.19, 2.36) |
| Major bleeding events/clinically relevant bleeds | 109 (4.4 %) | 189 (7.7 %) | 0.56 (0.45, 0.71) |
| Any bleeding | 354 (14.4 %) | 503 (20.4 %) | 0.67 (0.59, 0.77) |
| Any GI bleeding | 70 (2.9 %) | 55 (2.2 %) | 1.27 (0.90, 1.82) |
Bleeding events for both treatments are counted from the first intake of dabigatran etexilate or warfarin after the parenteral therapy has been discontinued (oral only treatment period). This includes all bleeding events, which occurred during dabigatran etexilate therapy. All bleeding events which occurred during warfarin therapy are included except for those during the overlap period between warfarin and parenteral therapy.
Table 14 shows bleeding events in pivotal study RE-MEDY testing prevention of DVT and PE. Some bleeding events (MBEs/CRBEs; any bleeding) were significantly lower at a nominal alpha level of 5% in patients receiving dabigatran etexilate as compared with those receiving warfarin.
Table 14. Bleeding events in study RE-MEDY testing prevention of DVT and PE:
| Dabigatran etexilate 150 mg twice daily | Warfarin | Hazard ratio vs warfarin (95% Confidence Interval) | |
|---|---|---|---|
| Treated patients | 1,430 | 1,426 | |
| Majory bleeding events | 13 (0.9 %) | 25 (1.8 %) | 0.54 (0.25, 1.16) |
| Intracranial bleeding | 2 (0.1 %) | 4 (0.3 %) | Not calculable* |
| Major GI bleeding | 4 (0.3%) | 8 (0.5%) | Not calculable* |
| Life-threatening bleed | 1 (0.1 %) | 3 (0.2 %)) | Not calculable* |
| Major bleeding event /clinically relevant bleeds | 80 (5.6 %) | 145 (10.2 %) | 0.55 (0.41, 0.72) |
| Any bleeding | 278 (19.4 %) | 373 (26.2 %) | 0.71 (0.61, 0.83) |
| Any GI bleeds | 45 (3.1%) | 32 (2.2%) | 1.39 (0.87, 2.20) |
* HR not estimable as there is no event in either one cohort/treatment
Table 15 shows bleeding events in pivotal study RE-SONATE testing prevention of DVT and PE. The rate of the combination of MBEs/CRBEs and the rate of any bleeding was significantly lower at a nominal alpha level of 5% in patients receiving placebo as compared with those receiving dabigatran etexilate.
Table 15. Bleeding events in study RE-SONATE testing prevention of DVT and PE:
| Dabigatran etexilate 150 mg twice daily | Placebo | Hazard ratio vs placebo (95% confidence interval) | |
|---|---|---|---|
| Treated patients | 684 | 659 | |
| Major bleeding events | 2 (0.3 %) | 0 | Not calculable* |
| Intracranial bleeding | 0 | 0 | Not calculable* |
| Major GI bleeding | 2 (0.3%) | 0 | Not calculable* |
| Life-threatening bleeds | 0 | 0 Not calculable* | |
| Major bleeding event/clinical relevant bleeds | 36 (5.3 %) | 13 (2.0 %) | 2.69 (1.43, 5.07) |
| Any bleeding | 72 (10.5 %) | 40 (6.1 %) | 1.77 (1.20, 2.61) |
| Any GI bleeds | 5 (0.7%) | 2 (0.3%) | 2.38 (0.46, 12.27) |
* HR not estimable as there is no event in either one treatment
Agranulocytosis and neutropenia have been reported very rarely during post approval use of dabigatran etexilate. Because adverse reactions are reported in the postmarketing surveillance setting from a population of uncertain size, it is not possible to reliably determine their frequency. The reporting rate was estimated as 7 events per 1 million patient years for agranulocytosis and as 5 events per 1 million patient years for neutropenia.
The safety of dabigatran etexilate in the treatment of VTE and prevention of recurrent VTE in paediatric patients was studied in two phase III trials (DIVERSITY and 1160.108). In total, 328 paediatric patients had been treated with dabigatran etexilate. The patients received age and weight adjusted doses of an age-appropriate formulation of dabigatran etexilate.
Overall, the safety profile in children is expected to be the same as in adults.
In total, 26% of paediatric patients treated with dabigatran etexilate for VTE and for prevention of recurrent VTE experienced adverse reactions.
Table 16 shows the adverse reactions identified from the studies in the treatment of VTE and prevention of recurrent VTE in paediatric patients. They are ranked under headings of System Organ Class (SOC) and frequency using the following convention: 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 16. Adverse reactions:
| Frequency | |
|---|---|
| SOC / Preferred term. | treatment of VTE and prevention of recurrent VTE in paediatric patients |
| Blood and lymphatic system disorders | |
| Anaemia | Common |
| Haemoglobin decreased | Uncommon |
| Thrombocytopenia | Common |
| Haematocrit decreased | Uncommon |
| Neutropenia | Uncommon |
| Agranulocytosis | Not known |
| Immune system disorder | |
| Drug hypersensitivity | Uncommon |
| Rash | Common |
| Pruritus | Uncommon |
| Anaphylactic reaction | Not known |
| Angioedema | Not known |
| Urticaria | Common |
| Bronchospasm | Not known |
| Nervous system disorders | |
| Intracranial haemorrhage | Uncommon |
| Vascular disorders | |
| Haematoma | Common |
| Haemorrhage | Not known |
| Respiratory, thoracic and mediastinal disorders | |
| Epistaxis | Common |
| Haemoptysis | Uncommon |
| Gastrointestinal disorders | |
| Gastrointestinal haemorrhage | Uncommon |
| Abdominal pain | Uncommon |
| Diarrhoea | Common |
| Dyspepsia | Common |
| Nausea | Common |
| Rectal haemorrhage | Uncommon |
| Haemorrhoidal haemorrhage | Not known |
| Gastrointestinal ulcer, including oesophageal ulcer | Not known |
| Gastroesophagitis | Uncommon |
| Gastroesophageal reflux disease | Common |
| Vomiting | Common |
| Dysphagia | Uncommon |
| Hepatobiliary disorders | |
| Hepatic function abnormal/ Liver function Test abnormal | Not known |
| Alanine aminotransferase increased | Uncommon |
| Aspartate aminotransferase increased | Uncommon |
| Hepatic enzyme increased | Common |
| Hyperbilirubinaemia | Uncommon |
| Skin and subcutaneous tissue disorder | |
| Skin haemorrhage | Uncommon |
| Alopecia | Common |
| Musculoskeletal and connective tissue disorders | |
| Haemarthrosis | Not known |
| Renal and urinary disorders | |
| Genitourological haemorrhage, including haematuria | Uncommon |
| General disorders and administration site conditions | |
| Injection site haemorrhage | Not known |
| Catheter site haemorrhage | Not known |
| Injury, poisoning and procedural complications | |
| Traumatic haemorrhage | Uncommon |
| Incision site haemorrhage | Not known |
In the two phase III trials in the indication treatment of VTE and prevention of recurrent VTE in paediatric patients, a total of 7 patients (2.1%) had a major bleeding event, 5 patients (1.5%) a clinically relevant non-major bleeding event and 75 patients (22.9%) a minor bleeding event. The frequency of bleeding events was overall higher in the oldest age group (12 to <18 years: 28.6%) than in the younger age groups (birth to <2 years: 23.3%; 2 to <12 years: 16.2%). Major or severe bleeding, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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