Reactions 1514, p2-3 - 16 Aug 2014

critical factors in contributing to the risk of bleeding,"Managing risks of dabigatransaid Dr Sabine Luik, senior vice president.

The safety of dabigatran etexilate in the prevention of * see Clinical Trial Profile 700011604stroke in patients with nonvalvular atrial fibrillation (AF) ** Boehringer Ingelheim provided a therapeutic range of 48-200can be improved in both the US and EU, according to ng/mL for dabigatran, which was included in the product informationThomas J Moore, from the Institute for Safe Medication in the EUPractices in Pennsylvania, and colleagues, in an article 1. Moore TJ, et al. Dabigatran, bleeding, and the regulators. BMJ 349: g4517, 23published in the BMJ.1 Jul 2014. Available from: URL: http://dx.doi.org/10.1136/bmj.g4517.

2. Charlton B, et al. The trouble with dabigatran. BMJ 349: g4681, 23 Jul 2014.When European Medicines Agency (EMA) and USAvailable from: URL: http://dx.doi.org/10.1136/bmj.g4681.FDA regulators assessed the benefits and risks of 3. Boehringer Ingelheim. Benefits and Safety of Pradaxa(Rm) (dabigatran etexilatemesylate) Repeatedly Confirmed. Media Release : 23 Jul 2014. Available from:dabigatran prior to marketing approval, primarily basedURL: http://www.boehringer-ingelheim.com.on data from the pivotal RE-LY* study, they should have

803106589been aware that reducing risk of anticoagulant-associated bleeding was a primary safety issue. TheFDA’s approach was to make dabigatran easy to usewith just one primary dosage (150mg twice daily; exceptin patients with renal impairment), despite increasingthe risk of haemorrhage in elderly patients, believing thismay improve the effectiveness of dabigatran in theprevention of stroke. It rejected Boehringer Ingelheim’sproposal to recommend a lower 110mg twice dailydosage in patients 80 years of age and over. The EMAwas concerned about reducing the risk of haemorrhageand pursued many risk reduction policies includingapproving the lower 110mg dose. However, neither theEMA nor the FDA insisted on optimising the dabigatran’santicoagulant effect in individual patients.

Thousands of cases of serious and fatal bleeding werereported after approval, mostly in older patientsreceiving the 150mg dose in the US. In response, theFDA used a postmarketing surveillance system, Mini-Sentinel, to assess the adverse events and concludedthat bleeding rates did not appear to be higher inpatients receiving dabigatran than with warfarin. TheEMA considered mandatory plasma level testing** butan advisory committee of experts decided this was notnecessary.

Moore and colleagues believe: the manufacturer, theFDA and EMA should agree upon a therapeutic range fordabigatran and recommend adjustment of the initialdosage based on plasma concentrations; dabigatranplasma level testing should be available in the US; theFDA should make the 110mg strength available topermit dose adjustment in patients a high risk ofbleeding; plasma level testing should be recommendedin all new patients; and the recommendation thatdabigatran does not in require routine anticoagulantmonitoring should be removed.

In another article published in the BMJ,2 Dr BlakeCharlton and Professor Rita Redberg from the Universityof California San Francisco suggested that decisions ondabigatran treatment in patients with nonvalvular AF atrisk of stroke should balance "patients’ tolerance ofunknown risks, their tolerance of routine laboratorymonitoring and dose adjustment, and their risk ofstroke".

In response, Boehringer Ingelheim expressed concernthat the above articles may alarm patients and promptthem to stop taking dabigatran (PRADAXA), therebyincreasing their risk of stroke.3 "Boehringer Ingelheimmade a robust effort to find ways to utilize plasma levelsto further improve the risk/benefit profile of PRADAXAand it is irrational to suggest otherwise. The truth is thetotality of scientific evidence does not support dosingdecisions for PRADAXA based on blood levels. Theresearch shows that individual patient characteristics,such as kidney function and certain medications, are

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