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Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events: There are limited efficacy and safety data for Pradaxa available in these patients and therefore they should be treated with caution.
Hip fracture surgery: There is no data on the use of Pradaxa 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 Pradaxa is not recommended in this population. Hepatic impairment or liver disease expected to have any impact on survival is contraindicated (see Contraindications).
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 Interactions; Pharmacology: Pharmacokinetics under Actions).
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 Pharmacology: Pharmacodynamics under Actions) 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.
Effects on ability to drive and use machines: Pradaxa has no or negligible influence on the ability to drive and use machines.
Haemorrhagic risk: Pradaxa 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 with Pradaxa. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.
For situations of life-threatening or uncontrolled bleeding, when rapid reversal of the anticoagulation effect of dabigatran is required, the specific reversal agent (Praxbind, idarucizumab) is available (see Overdosage).
In clinical trials, Pradaxa 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 16) 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 16 summarises factors which may increase the haemorrhagic risk. (See Table 16.)
Click on icon to see table/diagram/imageLimited data is available in patients < 50 kg (see Pharmacology: Pharmacokinetics under Actions).
Precautions and management of the haemorrhagic risk: For the management of bleeding complications, see also Overdosage.
Benefit-risk assessment: The presence of lesions, conditions, procedures and/or pharmacological treatment (such as NSAIDs, antiplatelets, SSRIs and SNRIs, see Interactions), which significantly increase the risk of major bleeding requires a careful benefit-risk assessment. Pradaxa 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 16). Particular caution should be exercised when Pradaxa is co-administered with verapamil, amiodarone, quinidine or clarithromycin (P-gp inhibitors) and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment (see Interactions).
Close observation for signs of bleeding is recommended in patients concomitantly treated with NSAIDs (see Interactions).
Discontinuation of Pradaxa: Patients who develop acute renal failure must discontinue Pradaxa (see also Contraindications).
When severe bleedings occur, treatment must be discontinued, the source of bleeding investigated and use of the specific reversal agent Praxbind (idarucizumab) may be considered (see Management of bleeding complications under Overdosage).
Dose reduction: A dose reduction should be either considered or is recommended as indicated in Dosage & Administration.
Use of proton-pump inhibitors: The administration of a proton-pump inhibitor (PPI) can be considered to prevent GI bleeding.
Laboratory coagulation parameters: Although Pradaxa 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 Pharmacology: Pharmacodynamics under Actions). The International Normalised Ratio (INR) test is unreliable in patients on Pradaxa and false positive INR elevations have been reported. Therefore, INR tests should not be performed.
Table 17 shows coagulation test thresholds at trough that may be associated with an increased risk of bleeding (see Pharmacology: Pharmacodynamics under Actions). (See Table 17.)
Click on icon to see table/diagram/imageSurgery and interventions: Patients on Pradaxa who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of Pradaxa.
Patients can stay on Pradaxa while being cardioverted. There are no data available for 110 mg twice daily Pradaxa treatment in patients undergoing catheter ablation for atrial fibrillation (see Dosage & Administration). Pradaxa treatment (150 mg twice daily) does not need to be interrupted in patients undergoing catheter ablation for atrial fibrillation (see Dosage & Administration).
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 Pharmacology: Pharmacokinetics under Actions). This should be considered in advance of any procedures. In such cases a coagulation test (see Precautions; Pharmacology: Pharmacodynamics under Actions) may help to determine whether haemostasis is still impaired.
Emergency surgery or urgent procedures: Pradaxa should be temporarily discontinued. When rapid reversal of the anticoagulation effect is required the specific reversal agent (Praxbind, idarucizumab) to Pradaxa is available.
Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. Pradaxa treatment can be re-initiated 24 hours after administration of Praxbind (idarucizumab), if the patient is clinically stable and adequate haemostasis has been achieved.
Subacute surgery/interventions: Pradaxa 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, Pradaxa 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 Pradaxa 2-4 days before surgery.
Table 18 summarises discontinuation rules before invasive or surgical procedures. (See Table 18.)
Click on icon to see table/diagram/imageSpinal 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 Pradaxa. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.
Postoperative phase: Pradaxa 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 moderate renal impairment (CrCL 30-50 mL/min), should be treated with caution (see Precautions; Pharmacology: Pharmacodynamics under Actions).
