Dabigatran (Pradaxa▼): risk of serious haemorrhage
- Medicines and Healthcare products Regulatory Agency
- 11 December 2014
- Therapeutic area:
- Cardiovascular disease and lipidology and Haematology
Contraindications clarified and reminder to monitor renal function.
Article date: July 2012
Dabigatran (Pradaxa▼) is a reversible inhibitor of free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation. It is licensed for primary prevention of venous thromboembolic events in adults who have had elective total hip replacement surgery or total knee replacement surgery (at 220 mg/day), and for prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and one or more cardiovascular risk factors (at 300 mg/day).
Haemorrhage is a common adverse reaction with dabigatran. A review of world-wide data on the risk of bleeding with dabigatran, including results from clinical trials eg, the phase III RELY study and post-marketing surveillance, has resulted in further information and clearer advice on how best to minimise the risk of bleeding.
Updated advice on contraindications and warnings:
Dabigatran is contraindicated in clinical conditions associated with a significant risk of bleeding, such as:
- current or recent gastrointestinal ulceration
- malignant neoplasms
- recent brain or spinal injury
- recent brain, spinal or ophthalmic surgery
- recent intracranial haemorrhage
- oesophageal varices
- arteriovenous malformations
- vascular aneurysms
- major intraspinal or intracerebral vascular abnormalities
The benefits and risks of starting dabigatran should also be considered carefully for patients who may have other conditions that put them at an increased risk of major bleeding (but in whom treatment with dabigatran is not contraindicated).
Use of dabigatran is contraindicated with dronedarone, and with other anticoagulants, except when switching treatment to or from dabigatran, or with the use of unfractionated heparin for maintenance of venous or arterial catheter patency.
Concomitant use of antiplatelet agents increases the risk of major bleeding with dabigatran approximately two-fold, therefore a careful benefit-risk assessment should be made prior to initiation of treatment.
Advice on switching treatment to and from dabigatran
When switching to dabigatran, the first dose of dabigatran should be given 0-2 hours prior to the time that the next dose of the alternate medicine is due, or at the time that continuous alternate treatment is discontinued.
When switching from dabigatran to parenteral anticoagulants, an interval of 12-24 hours (dependent upon treatment indication) is recommended between treatments.
When switching from dabigatran to warfarin in patients with atrial fibrillation, the starting time of warfarin should be adjusted according to creatinine clearance (CrCL): CrCL ≥50 ml/min, start warfarin 3 days before discontinuing dabigatran CrCL ≥30 - <50 ml/min, start warfarin 2 days before discontinuing dabigatran.
For patients switching from warfarin to dabigatran, warfarin should be stopped and dabigatran can be given as soon as the INR is <2.0.
Product information will be updated with the new advice.
Reminder: importance of renal function monitoring
We previously advised on the importance of renal function monitoring in patients who receive dabigatran, as systemic exposure to dabigatran is substantially increased in patients with renal insufficiency (see December 2011 Drug Safety Update).
Renal function should be assessed in all patients before starting dabigatran and at least once a year in patients older than 75 years or those with a suspected decline in renal function. Dabigatran is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).
Additional advice and information for healthcare professionals:
- there is no specific antidote to dabigatran and excessive anticoagulation may require interruption of treatment
- in the event of haemorrhagic complications, dabigatran must be discontinued and the source of the bleeding investigated. Adequate diuresis must be maintained, and surgical haemostasis and blood volume replacement should be undertaken at the clinicians’s discretion
- additional measures may be considered in the treatment of serious haemorrhage, including:
- activated prothrombin complex concentrates
- recombinant factor VIIa
- concentrates of coagulation factors II, IX and X, and platelet concentrates where appropriate
- Coagulation tests may become unreliable following administration of reversing agents and measurements may remain elevated despite administration; caution must be exercised when interpreting these results
A full list of contraindications and warnings, together with updated product information for dabigatran, can be found in the individual summaries of product characteristics (see the European Medicines Agency (EMA) website)
BNF section 2.8.2 Oral anticoagulants
Article citation: Drug Safety Update July 2012, vol 5 issue 12: A1
Published: 11 December 2014