Summary Safety Review - PRADAXA (dabigatran) and MULTAQ (dronedarone) or CORDARONE (amiodarone) - Drug-Drug Interaction
Review decision
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Issued: 2015-02-12
issue
A safety review was initiated to evaluate the available information on the interaction between PRADAXA (dabigatran), an anti-blood clotting drug, and MULTAQ (dronedarone) or CORDARONE (amiodarone), both used to control abnormal heart rates. This possible interaction can raise the blood level of dabigatran and potentially increase the bleeding risk associated with it. This review was prompted by cumulative evidence received by Health Canada, including evidence assessed by the European Medicines Agency, regarding the interaction between dronedarone and dabigatran.
Background
Approved use of dabigatran, amiodarone and dronedarone in Canada
Dabigatran is used for the treatment and prevention of blood clots in the veins of legs and lungs, including in patients with knee or hip replacement surgery. It is also approved for the prevention of stroke or blood vessel blockage due to blood clotting in patients with an abnormal heart rhythm called atrial fibrillation.
Amiodarone is approved for the treatment of certain abnormal heart rhythms called ventricular arrhythmias. Dronedarone is approved for the treatment of certain abnormal heart rhythms called atrial fibrillation.
Generic amiodarone products are approved in Canada. There are no generics for dabigatran nor dronedarone.
Bleeding risk
Bleeding is a known risk of dabigatran. Bleeding of any type or severity may occur with the use of dabigatran, from minor bruising to major or severe bleeding in any part of the body. It is possible that amiodarone or dronedarone can block one of the mechanisms by which dabigatran is transported out of the body (P-glycoprotein) and eliminated. This may raise the blood level of dabigatran leading to an increased risk of bleeding.
Objective
To review the available evidence concerning the interaction between dabigatran and dronedarone or amiodarone. This review considered information from Canadian adverse reaction reports, scientific literature, international safety data as well as what is known about the use of these products in Canada and internationally. The review evaluated the risk and suggested ways to minimize it.
Objective
To review the available evidence concerning the interaction between dabigatran and dronedarone or amiodarone. This review considered information from Canadian adverse reaction reports, scientific literature, international safety data as well as what is known about the use of these products in Canada and internationally. The review evaluated the risk and suggested ways to minimize it.
Key findings
Use of dabigatran, amiodarone, and dronedarone in Canadaa
Amiodarone, dabigatran and dronedarone were marketed in Canada in 1994, 2008 and 2009 respectively. Available information showed that the total number of dabigatran prescriptions was low from 2008 to 2010 and has increased from the year 2010 to 2012.
Canadian reports of bleeding due to this drug-drug interaction
At the time of the review, Health Canada received 6 reports of bleeding in patients who were using dabigatran and dronedarone at the same time. Health Canada also received 19 reports of bleeding in patients who were using dabigatran and amiodarone at the same time. Some specific side effects that were mentioned in the reports included hemorrhage (heavy or uncontrollable bleeding) in the stomach and intestines, rectal bleeding and blood in the stools, hemorrhage in the lungs, pericardial effusion (too much fluid built up around the heart), increased International Normalised Ratio (increased blood clotting time) and decreased hemoglobin (decreased red blood cells).
Health Canada found that bleeding was possibly associated with the interaction between dabigatran and dronedarone in 4 cases, and possibly associated with the interaction between dabigatran and amiodarone in 7 cases.
Scientific reports
The published scientific evidence on the interaction between dabigatran and amiodarone or dronedarone includes one clinical trial abstract (summary of a research study, Brunet et al, 2011) for the dabigatran and dronedarone interaction and 3 published case reports (one for the dabigatran and dronedarone interaction, and 2 for the dabigatran and amiodarone interaction).
The clinical trial (Brunet et al, 2011) was conducted on 16 healthy volunteers and suggested that dronedarone increased the body's exposure to dabigatran as well as patient blood clotting times.
In the published case report discussing an interaction between dronedarone and dabigatran, dabigatran was considered possibly associated with hemopericardium (a condition where blood leaks into the outer casing of the heart). In one of the two published case reports on the amiodarone and dabigatran interaction, the patient was bleeding in his digestive tract; this side effect was considered probably caused by the interaction between amiodarone and dabigatran. In the other case report, the patient had a stroke but no bleeding complications.
International datab
At the time of this review, the World Health Organization (WHO) VigiBase database contained 254 cases of bleeding related side effects reported in patients using both dabigatran and amiodarone. The database also had 199 cases of bleeding related side effects reported in patients using both dabigatran and dronedarone. Most of these cases were from the United States (175 suspecting the dabigatran-amiodarone interaction and 185 suspecting the dabigatran-dronedarone interaction). While a drug-drug interaction may be suspected in these bleeding events, other causes cannot be ruled out as detailed case reports were not available.
Conclusions and actions
At the time the safety review was completed, the available evidence supported that bleeding related side effects may be associated with the drug-drug interaction between dabigatran and dronedarone or amiodarone.
In order to address these safety concerns, Health Canada has reviewed the prescribing information for these drugs. The prescribing information for PRADAXA, MULTAQ and CORDARONE now includes information regarding this drug-drug interaction. The prescribing information for applicable generic amiodarone products is also being updated to include warnings regarding their possible interaction with dabigatran.
References
- Assessment report - MULTAQ. London (UK): European Medicines Agency; 2012 September 20. (accessed 2014 November 28).
- Brunet A, Hermabessiere S, Benain X. Pharmacokinetic and pharmacodynamic interaction of dronedarone and dabigatran in healthy subjects [abstract P3566]. Eur Heart J 2011;32(Suppl):618-9.
- Barton CA, McMillian WD, Raza SS, et al. Hemopericardium in a patient treated with dabigatran etexilate. Pharmacotherapy 2012;32(5):e103-7.
- Manso G, Jimeno FJ, Ordonez L, et al. Drug interactions of dabigatran: Report of one case [poster abstract P56]. Basic Clin Pharmacol Toxicol 2012;111(Suppl. s1):12-40.
- Neuffer EM, Tofade TS, Galpin LE, et al. Significant bleeding in elderly patient with atrial fibrillation due to probable interaction between dabigatran and amiodarone. J Pharm Technol 2012; 28(4):139-45.
Footnotes
- IMS utilization data provided by: IMS Health Canada Inc, An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.
- World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.