Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Increased risk of stroke with discontinuation of Pradaxa
Discontinuing Pradaxa in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Pradaxa must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.
Haemorrhagic risk

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 Haemodialysis can remove dabigatran. For adult patients, fresh whole blood or fresh frozen plasma, 
Pradaxa 110                                                                      Prescribing Information Boehringer Ingelheim                                                                        January 2022 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.

Risk factors

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
•    NSAID
•    SSRIs or SNRIs
•    Other medicinal products which may impair haemostasis
Diseases / procedures with special                   •    Congenital or acquired coagulation haemorrhagic risks                                        disorders
•    Thrombocytopenia or functional platelet defects
•    Recent biopsy, major trauma
•    Bacterial endocarditis
•    Esophagitis, gastritis or gastroesophageal reflux

Limited data is available in adult patients <50 kg (see section 5.2).

Precautions and management of the haemorrhagic risk
For the management of bleeding complications, see also section 4.9.

Pradaxa 110                                                                      Prescribing Information Boehringer Ingelheim                                                                        January 2022 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. This is especially relevant in specific patient groups at risk, such as elderly (age > 75), patients with impaired renal function (CrCl 30-50ml/min), patients on concomitant use of P-gp inhibitors or a combination of the above. dabigatran etexilate should only be given if the 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 4 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. Haemodialysis can remove dabigatran 
Use of proton-pump inhibitors

The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding.
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.


Pradaxa 110                                                                        Prescribing Information Boehringer Ingelheim                                                                          January 2022 Table 5 shows coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding (see section 5.1).

Table 5: Coagulation test thresholds at trough for adult patients that may be associated with an increased risk of bleeding.

Test (trough value)                                                  Indication Primary prevention of          SPAF and DVT/PE venous thromboembolism(VTE) in orthopaedic surgery 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 
Use of fibrinolytic medicinal products for the treatment of acute ischemic stroke 
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.

Surgery and interventions

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.

Emergency surgery or urgent procedures

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.

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.


Pradaxa 110                                                                        Prescribing Information Boehringer Ingelheim                                                                         January 2022 Subacute surgery/interventions

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.

Elective surgery

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      Estimated half-life      Dabigatran etexilate should be stopped before elective (CrCL in            (hours)                                         surgery mL/min)                                   High risk of bleeding or       Standard risk major surgery
≥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 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.


Postoperative phase

Dabigatran etexilate treatment should be resumed / started 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 4), should be treated with caution (see sections 4.4 and 5.1).

Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events 
There are limited efficacy and safety data for dabigatran etexilate available in these patients and therefore they should be treated with caution.


Pradaxa 110                                                                       Prescribing Information Boehringer Ingelheim                                                                         January 2022 Hip fracture surgery

There is no data on the use of dabigatran etexilate in patients undergoing hip fracture surgery. Therefore treatment is not recommended.

Hepatic impairment

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).

Interaction with P-gp inducers

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).

Patients with antiphospholipid syndrome

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.

Myocardial Infarction (MI)

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 short-term 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 
Active Cancer Patients (DVT/PE, )

The efficacy and safety have not been established for DVT/PE patients with active cancer.

Pradaxa 110                                                                      Prescribing Information Boehringer Ingelheim                                                                       January 2022 

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