Bleeding events associated with dabigatran etexilate (Pradaxa®): Recommendation to use with caution in the elderly and renally impaired patients

HSA would like to alert healthcare professionals to serious cases of bleeding associated with the use of dabigatran and to remind them to closely monitor patients who are prescribed this medication, especially the elderly and those with renal impairment.

Dabigatran (Pradaxa®) has been licensed locally since August 2009 for the primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip or total knee replacement surgery. In June 2011, the indication for Pradaxa® was extended to include the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

Bleeding is a known side effect for dabigatran as it is an extension of its pharmacological effect. Based on clinical evidence, the risk of major or severe bleeding from dabigatran is rare, even though life-threatening or even fatal outcomes may occur. The local package insert of Pradaxa® currently carries warnings of this risk, including the recommendation to monitor for signs of bleeding or anaemia.¹ Additionally, the local package inserts recommend dose adjustments in the elderly and those with impaired renal function as well as close clinical surveillance in patients with low body weight (<50kg) and high body weight (>110kg). Dabigatran is contraindicated in patients with severe renal impairment.

Recent advisory issued by the Japanese Ministry of Health, Labour and Welfare (MHLW)

In August 2011, the Japanese MHLW issued a safety advisory to warn of the potential for serious adverse events with dabigatran (Pradaxa®) which was approved in Japan in January 2011. This was following the death of five patients who were taking the drug. Between January and 11 August 2011, the patient exposure in Japan was about 64,000 people. At the time of publication of the advisory, there were 81 cases of serious side effects associated with dabigatran reported in Japan, including cases of gastrointestinal bleeding .

The five patients who had bleeding events contributory to their death were elderly, aged between 76 and 100 years old. They were prescribed with age-adjusted doses of dabigatran. The events leading to death include haemorrhage of the digestive tract, pulmonary alveolar haemorrhage, respiratory failure and haemorrhagic shock. The time to onset for these events ranged from eight days to 104 days. Two of these patients had taken aspirin concomitantly. Based on limited data available and a post-hocestimation of creatinine clearance (CLcr), four of the patients were suspected to have severe renal impairment while on dabigatran therapy.

Physicians in Japan were advised to carefully monitor for signs of anaemia and bleeding and the need for immediate response should these side effects develop. They were also recommended to perform renalfunction tests before and during treatment, and to reduce the dose of dabigatran or stop treatment upon signs of renal impairment or bleeding.

Scientific literature

Two clinical cases of major bleeding events in elderly patients were published in the Archives of Internal Medicine in August 2011.² These female patients were both above 80 years old, had moderate to severe renal impairment and had low body weight (≤45kg). One of them had recurrent nosebleeds that stopped upon discontinuation of dabigatran, while the other developed massive rectal bleeding, had a cardiac arrest and died.

Actions taken by the European Medicines Agency (EMA)

As of 6 November 2011, a worldwide total of 256 spontaneous case reports of serious bleeding resulting in death in association with the use of dabigatran were recorded in the EudraVigilance database. Twenty-one out of these 256 cases were reported in the EU. EMA³ has noted that the rapidly increasing use of Pradaxa® worldwide as a result of the recent approval of a new indication (prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation) in several regions of the world and also the increased awareness about the drug could have led to higher than usual reporting of side effects related to the drug. Nonetheless, EMA's Committee for Medicinal Products for Human Use (CHMP) recommended further changes to the product information in October 2011, including new recommendations for pre- and on-treatment renal assessment in patients prescribed with Pradaxa® to mitigate this safety issue. The CHMP will also review all case reports received to confirm that the frequency of occurrence of fatal bleedings has not increased and that the recommended product information is appropriate to manage the risk.

Local situation

To date, HSA has received seven suspected adverse reaction reports associated with dabigatran. These included one case of bleeding, one case of deep vein thrombosis and blood clot in the heart and one case of stroke, all occurring in patients between 77 and 86 years old.The time to onset of these cases were a few months after the initiation of dabigatran. No concomitant medicines were reported and none of these cases had a fatal outcome.

HSA's recommendations

Currently, the post-marketing experience of bleeding events associated with dabigatran has not altered its overall benefit-risk profile. Nevertheless, healthcare professionals are reminded of the contraindication for the use of dabigatran in patients with severe renal impairment (CLcr < 30 ml/min) and to consider the following recommendations when prescribing dabigatran:

a) Use in elderly patients with risk factors

In view that the reports were mainly in the elderly and occurred up to several months following the initiation of therapy, close surveillance for signs of bleeding or anaemia is recommended throughout the treatment period, especially for patients with risk factors, such as moderate renal impairment, concomitant antiplatelet therapy, and for patients above 75 years old.

b) Renal assessment

Pre-treatment renal assessment should be done to exclude patients with severe renal impairment. While on treatment, renal function should be assessed in certain situations when it is suspected that the renal function could decline or deteriorate (eg, hypovolaemia, dehydration and co-administration of certain medications). In patients older than 75 years old or with renal impairment, renal assessment at least once yearly is also recommended.

c) Anticoagulation tests

While routine monitoring of the anticoagulant effect of Pradaxa® is not required, testing of anticoagulant activity may be required in specific circumstances, such as surgery, overdose and bleeding. This can be done through thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) tests. If ECT or TT is not available, the aPTT test provides an approximation of Pradaxa's anticoagulant activity. An aPTT of >80 seconds at trough was associated with an increased risk of bleeding when Pradaxa® was used in atrial fibrillation patients in a clinical study. The INR test should not be performed as it is unreliable in patients on Pradaxa®.

HSA is working with the company to strengthen the package insert for Pradaxa® with this information. HSA will also continue to closely monitor this safety concern and update our healthcare professionals on any new findings. All healthcare professionals are encouraged to report all serious side effects suspected to be associated with dabigatran to the Vigilance Branch of HSA.

References

1. Pradaxa® (dabigatran) package insert. Singapore approved 24 August 2009

2. Arch Intern Med. 2011;171(14):1285-1286

3. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/11/news_detail_001390.jsp&mid=WC0b01ac058004d5c1