On 8 February 2013, the TGA published information for health professionals regarding dabigatran (Pradaxa) and the risk of bleeding.
The TGA has updated that information below, including details of:
- two safety reviews that have now been completed
- a new contraindication for concomitant use of dronedarone and dabigatran
- advice regarding repackaging dabigatran capsules
- advice that dabigatran may have an effect on some pathology tests
- updated adverse event report numbers.
Dabigatran is an oral anticoagulant medicine used for the prevention of clots and emboli after major orthopaedic surgery (hip or knee replacement) and to prevent stroke and other systemic emboli in people with non-valvular atrial fibrillation (AF), a commonly occurring abnormal heart rhythm. As with any anticoagulants, including warfarin, there is a risk of bleeding when using this medicine.
The TGA has completed two safety reviews of dabigatran - one completed in August 2012 and the other in April 2013. These reviews included consideration of advice from the Advisory Committee on the Safety of Medicines (ACSOM). Both reviews reinforced the importance of appropriate patient selection for the safe use of dabigatran. In particular, when making a decision to prescribe dabigatran, a careful assessment of the risk factors for bleeding needs to be undertaken.
Risk factors for bleeding
Risk factors for bleeding include patients:
- being aged 75 years or over
- having moderate kidney impairment (creatinine clearance 30-50 mL/min)
- certain conditions, situations or medication use.
On this page: Information for health professionals | Additional information | International regulators | Reporting problems | References
Information for health professionals
In this section: Factors known to increase the risk of bleeding | Kidney function testing | Other important considerations | Laboratory tests for dabigatran
The TGA reviews have reinforced the importance of appropriate patient selection to enhance the safe use of dabigatran. It is strongly recommended that prescribers read the Product Information (PI) before prescribing dabigatran.
Prescribers are urged to give careful consideration to the suitability of their patients for dabigatran, particularly with regard to the risks of bleeding and their current stability on warfarin or other anticoagulants.
Prescribers are advised that there appears to be a trend towards a higher incidence of major bleeds in patients aged 75 years or over taking dabigatran 150 mg twice daily compared to warfarin1 (see 'Other important considerations').
Prescribers should continually review all patients for signs of bleeding and anaemia, in particular, those with risk factors.
Factors known to increase the risk of bleeding
Factors known to increase the bleeding risk are outlined in the below table and can also be found in the Precautions section of the PI.
|Factors increasing dabigatran plasma levels|| |
|Pharmacodynamic interactions|| |
|Diseases / procedures with special haemorrhagic risks*|| |
*Prescribers should note that these are contraindications
Kidney function testing
As dabigatran is primarily excreted renally, one of the risk factors for bleeding is having moderate kidney impairment (creatinine clearance 30–50 mL/min).
Below is a summary of the recommendations for assessing kidney function before starting dabigatran:
- Kidney function should be assessed in all patients prior to beginning dabigatran therapy.
- Dabigatran is contraindicated in patients with severe kidney impairment (creatinine clearance < 30 mL/min).
- While on treatment, kidney function should be assessed in clinical situations where a decline in kidney function is suspected. Such situations include low blood volume, dehydration and when certain medications are taken at the same time.
- In elderly patients (aged 75 years or over) or in patients with moderate kidney impairment, kidney function should be assessed at least once a year.
Kidney function should be estimated using the Cockcroft-Gault estimation in all patients:
- before commencing therapy
- in clinical situations likely to result in a change in a patient’s kidney function (for example, dehydration)
- after the addition or discontinuation of medicines that may impact kidney function.
The Cockcroft-Gault formula is:
The sponsor of dabigatran in Australia, Boehringer Ingelheim Pty Ltd, has written to health professionals to advise them of these recommendations and the PI and Consumer Medicine Information have been updated.
Other important considerations
- A specific antidote antagonising the pharmacodynamic effect of dabigatran is not currently available.
- Special consideration should be given to the perioperative management of patients taking dabigatran. See the PI for guidance.
- Guidelines for managing patients on dabigatran who present to hospital have been developed by Queensland Health. Prescribers are referred to these guidelines for further information. Prescribers should note that these guidelines suggest use of charcoal haemofiltration in the management of life threatening bleeds. ACSOM has advised against the use of charcoal haemofiltration. The PI does not suggest use of charcoal haemofiltration.
- When switching patients from warfarin to dabigatran, prescribers are reminded that warfarin should be discontinued and dabigatran started only when the international normalised ratio is below 2.0.
- Use with prosthetic heart valves. Prescribers are advised that dabigatran must not be used in patients with prosthetic heart valves. A clinical trial in Europe and Canada (RE-ALIGN) was recently discontinued as patients taking dabigatran were more likely to experience strokes, heart attacks and blood clots forming on the mechanical heart valves than patients taking warfarin. Prescribers are reminded that dabigatran is indicated for use in patients with non-valvular AF. Patients with prosthetic heart valves who are taking dabigatran should be transitioned to a different anticoagulant medication. Boehringer Ingelheim Pty Ltd has updated the PI to reflect this advice.
- Prescribers should note dabigatran 150 mg twice daily is not recommended in patients aged 75 years or over. Prescribers are advised that there appears to be a trend towards a higher incidence of major bleeds, other than intracranial bleeds, in patients aged 75 years or over taking dabigatran 150 mg twice daily compared to warfarin.1
- Dronedarone now contraindicated. The concomitant use of dronedarone and dabigatran has been added as a contraindication. This follows the evaluation of clinical trial data that shows a 2.3 fold increase in the peak dabigatran concentration when both drugs are given together. Further information on this drug-drug interaction can be found in the PI.
- Health professionals are reminded that dabigatran capsules should be stored and dispensed in the original packaging (blister pack or bottle). Repackaging dabigatran capsules, for example in dose administration aids (such as Webster-paks), increases the risk of exposure to moisture or humidity, potentially causing the medicine to breakdown and lose potency. These aids should not be used unless it can be done without removing the dabigatran capsules from their original packaging. Further information is available on the NPS MedicineWise website.
Laboratory tests for dabigatran
Health professionals are advised that existing standard laboratory tests have not as yet been validated for use with dabigatran. Prothrombin time (INR) should not be used.
In certain situations, such as in the event of bleeding, in emergency situations or a suspected overdose and in the perioperative setting, monitoring should be considered.
In these situations, the most accessible semiquantitative tests are:
- Thrombin Time (TT).
- Diluted Thrombin Time (dTT).
- Ecarin Clotting Time (ECT).
- Activated Partial Thromboplastin Time (aPTT). A trough (taken just before the next dose) aPTT >80 seconds is associated with a higher bleeding risk.
- The Hemoclot test is also available in some centres. This gives a quantitative estimate of dabigatran levels.
When interpreting coagulation assay results, consideration should be given to the dose and time of dabigatran administration relative to time of blood sampling. Health professionals should consult their pathology provider.
Health professionals are advised that dabigatran may have an effect on the results of some other pathology tests, resulting in the potential for misinterpretation of results.1 You should advise your pathology provider if your patient is taking dabigatran when requesting such tests. For additional information about which tests are affected and how to interpret test results for patients taking dabigatran, please consult your pathology provider.
Dabigatran is a direct thrombin inhibitor that inhibits free and clot-bound thrombin. It has a mean half life of 12–17 hours and is mainly excreted by the kidneys; the rate of elimination is related to kidney function.
The TGA approved dabigatran for the prevention of venous thromboembolic events in adult patients who have undergone major orthopaedic surgery of the lower limb (elective total hip or knee replacement) in November 2008. It is currently listed on the Pharmaceutical Benefits Scheme (PBS) for this indication.
In April 2011, the approved indications for dabigatran were extended to include the prevention of stroke and systemic embolism in patients with non-valvular AF and at least one risk factor for stroke. An increase in adverse event reports occurred after this extension of indication was approved.
For more detailed information regarding the considerations of the TGA in approving dabigatran, please see the Australian Public Assessment Report (AusPAR) for dabigatran.
Additional information for health professionals is also available on the NPS MedicineWise website. The NPS launched a new educational program for health professionals - Achieving Good Anticoagulant Practice - on 5 February 2013.
On this page: Bleeding results from clinical trials | Adverse event reports
Bleeding results from clinical trials
In the RE-LY trial, the risk of bleeding (major or minor) was less with dabigatran than with warfarin when the trial was considered as a whole. In clinical trials, the risk of bleeding per year of treatment with dabigatran was 16.6% (1 in 6 patients) when taking 150 mg twice daily, and 14.7% (1 in 6.8 patients) taking 110 mg twice daily compared to 18.4% (1 in 5.4 patients) for warfarin.2
The risks of major bleeding events from the RE-LY trial are shown in the table below. Prescribers should refer to the PI for further information.
|Adverse event type||Drug dose||Hazard ratio compared to warfarin (95% CI)|
|Major bleeds*||Dabigatran 150 mg bd||0.93 (0.81, 1.07)|
|Dabigatran 110 mg bd||0.80 (0.70, 0.93)|
|Life threatening^ major bleeding events||Dabigatran 150 mg bd||0.80 (0.66, 0.98)|
|Dabigatran 110 mg bd||0.67 (0.54, 0.82)|
|Intracranial haemorrhage+||Dabigatran 150 mg bd||0.41 (0.28, 0.60)|
|Dabigatran 110 mg bd||0.30 (0.19, 0.45)|
|Major gastrointestinal bleeds||Dabigatran 150 mg bd||1.47 (1.17, 1.85)|
|Dabigatran 110 mg bd||1.07 (0.84, 1.36)|
|Life-threatening gastrointestinal bleeds||Dabigatran 150 mg bd||1.62 (1.17, 2.26)|
|Dabigatran 110 mg bd||1.17 (0.82, 1.67)|
*Major bleeding was defined as a reduction in the haemoglobin level of at least 20 g per liter, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ.
^ Life-threatening bleeding was a subcategory of major bleeding that consisted of fatal bleeding, symptomatic intracranial bleeding, bleeding with a decrease in the haemoglobin level of at least 50 g per liter, or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery.
+ Intracranial haemorrhage consists of haemorrhagic stroke and subdural and/or subarachnoid haemorrhage.
In addition to the initial RE-LY trial data analysis, a post-hoc analysis of the data showed that the risk of major bleeding is similar between dabigatran and warfarin when the patient is well controlled on warfarin. In patients well controlled on warfarin there was a higher risk of gastrointestinal bleeding associated with dabigatran.3
Adverse event reports
The TGA continues to receive bleeding-related adverse event reports for dabigatran.
|Type of adverse event||Number of events|
|Total adverse events||1054|
|Serious adverse events*||751|
|Serious bleeding adverse events||361|
|Serious gastrointestinal bleeding||192|
|Serious intracranial bleeding||53|
|Events in patients aged 75 years or older|
|Total adverse events||573|
|Serious adverse events||416|
*Serious adverse events are defined as events which result in death, are life-threatening, cause or prolong hospitalisation, cause incapacity/disability or result in a congenital anomaly/birth defect.
An analysis of these reports by the TGA shows:
- some of the bleeding adverse events occurred during the transition period from warfarin to dabigatran
- many of the adverse events are occurring in patients on the reduced dosage regimen
- the most common site of serious bleeding reports for dabigatran is the gastrointestinal tract
- a smaller proportion of intracranial bleeding events were reported for dabigatran than for warfarin.
Reports of adverse events received by the TGA are added to the Database of Adverse Event Notifications (DAEN). Any interested person can search the DAEN for publically available reports, which include reports received between 1971 and 3 months prior to the date of access. The TGA uses this 3 month period of time to investigate the adverse event reports.
International regulators continue to provide updates on dabigatran.
Information on dabigatran from the United States Food and Drug Administration (US FDA) can be found FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran).
Information on dabigatran from the European Medicines Agency (EMA) can be found European Medicines Agency updates patient and prescriber information for Pradaxa.
Consumers and health professionals are encouraged to report problems with medicines, vaccines or medical devices. Your report will contribute to our monitoring of these products.
The TGA cannot give advice about an individual's medical condition. You are strongly encouraged to talk with a health professional if you are concerned about a possible adverse event associated with a medicine, vaccine or medical device.
- Halbmeyer W-M, Weigl G, Quenhenberger P, Tomasits J et al Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests Clin Chem Lab Med 2012;50:1601-1605
- TGA. Australian Public Assessment Report (AusPAR): dabigatran etexilate mesilate. 2 June 2011.
- Wallentin L, Yusuf S, Ezekowita MD, Alings M et al Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010;376:975-83.