On August 12, 2011, the Japanese Ministry of Health, Labour and Welfare,
Pharmaceutical and Medical Devices Agency (PMDA) issued a press release requiring
Boehringer-Ingleheim Inc., the patent holder of Prazaxa® (dabigatran etexilate, brand name
Pradaxa® in the US), to add a boxed warning to their label regarding the risk of fatal
hemorrhage based on several recently reported cases of death possibly associated with the drug.
Pradaxa® is an oral direct thrombin inhibitor indicated to reduce stroke
and systemic embolism in patients with non-valvular atrial fibrillation. It was approved by the FDA in October 2010 in the US, and
was launched in Japan in March of 2011. More information on this medication can be found in a
previous issue of the LECOM
In the press release, the PMDA bases its warning on five cases of fatal
hemorrhagic adverse events reported as of August 11, 2011.
Full details are not disclosed, except for mentioning that one of the patients was aged in
their 70s, while the other four were aged in their 80s.
In addition, the release mentions “one fatal case caused by serious hemorrhagic
adverse effect has been reported in patient with renal failure who received this drug.” It is noteworthy
that the official Pradaxa® prescribing guidelines recommend dose reductions for those patients
with a creatinine clearance between 15-30 ml/min, and no guidelines are specifically recommended
for patients with established renal failure. However,
considering that more than 80% of the systemically available drug is eliminated by renal excretion
(including the parent drug and active metabolites), this drug is likely not suitable for patients
with renal failure. Another important point to realize is that in all of
these reported fatal cases, the drug has not yet been specifically identified as the cause of fatal
hemorrhage, rather they were stated as “caused by hemorrhagic adverse events for which a
causality of the drug cannot be ruled out.”
These developments may have relevance here in the United States. In a sub-analysis of the Japanese population studied in the
RE-LY trial, it was found that there were no significant differences between the Japanese and
overall populations in terms of safety and efficacy of dabigatran. Therefore, the concerns expressed by the Japanese PMDA may
not be unique to the Japanese clinical setting, nor may they be unique to the Asian population as a
whole. Especially since Pradaxa® is a relatively new
medication, it is recommended for all practitioners to remain within the prescribing
guidelines set forth by Boehringer-Ingleheim until further information is released.
1. PMDA press release, Severe
haemorrhages in patients treated with an anticoagulant “Prazaxa capsules”. Found at: http://www.pmda.go.jp/english/service/pdf/mhlw/Prazaxa_capsules.pdf. Accessed 29 August 2011.
2. Pradaxa full prescribing
information. Found at: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed 29 August 2011.
3. Blech S., et al. The Metabolism and Disposition of the Oral Direct
Thrombin Inhibitor, Dabigatran, In Humans. Drug Metabolism and Disposition. 2008 Feb;36(2):386-99.
Found at: http://www.ncbi.nlm.nih.gov/pubmed/18006647. Accessed 08 September 2011.
4. Hori M., et al. Efficacy and Safety of Dabigatran vs. Warfarin in
patients with atrial fibrillation-sub-analysis in Japanese population in RE-LY trial. Circulation
Journal. 2011 April; 75(4): 800-5. Found
at: http://www.ncbi.nlm.nih.gov/pubmed/21436594. Accessed 29 August 2011.