Medication Safety News Review – November 2015

FDA approves Pradaxa antidote (Praxbind):

The Food and Drug Agency (US) has approved the use of the first specific reversal agent for the new oral anticoagulant dabigatran (Praxbind ™) called idarucizumab (Praxbind  ™). It was approved by the accelerated approval program in which regulators rely on surrogate data or intermediate clinical outcomes reasonably likely to result in clinical benefit to patients (1,2).

Pharmacology: idarucizumab is a humanized monoclonal antibody fragment (Fab) indicated for patients who are on dabigatran (Pradaxa) which need: 1) reversal of the anticoagulant effects for emergency surgery or urgent procedures, or 2) in the event of life-threatening or uncontrolled bleeding. Idarucizumab is specific antidote for dabigatran, with no effect of other anticoagulant or antithrombotic agents. Contains sorbitol (precaution in hereditary fructose intolerance).

Its mechanism of action is the binding of dabigatran and metabolites to the idarucizumab molecule with a higher affinity than the binding of dabigatran to thrombin, resulting in an reduction of unbound anticoagulant and reversal of the it’s effect on coagulation parameters (e.g., ecarine clotting time (ECT) and/or activated partial thromboplastin time (aPTT)). It immediately reduces the levels of unbound dabigatran and ECT in the blood, and also sustains this reduction for at least 24 hours of a single dose.In one preliminary trial in patients with uncontrolled bleeding, homeostasis was achieved in the majority of cases with one case of thrombotic event (3). Further results in bleeding patients are pending.

Dosage: two consecutive infusions (over 5-10 minutes each) or bolus IV injections of 2.5g each ( 2.5g/50ml solution vials ) totalling 5 g per dose; due to the underlying clotting disease and thromboembolic risk of temporarily stopping the anticoagulant, dabigatran can be re-initiated 24 hours after antidote or as soon as medically appropriate. No adjustment needed in renal insufficiency and no data exists on hepatic insufficiency or pregnancy/lactation.

Safety: side-effects observed from small sampled clinical trials are hypokalemia (7%), delerium (7%), constipation (7%), pyrexia (6%), pneumonia (6%), headache (5%). Precaution should be observed due to limited evidence for hypersensitivity reactions and thromboembolic events or otherwise uncommon/rare adverse effects (4). There is also limited evidence on the safety and efficacy of repeat treatment of idarucizumab.

Role in Therapy: cerebral vascular accidents (strokes) have an estimated yearly rate of nearly 800 000 new or recurrent cases in the US alone, of which 10% are classified as intracerebral hemorrhage (ICH). Oral anticoagulants have a 7-10 fold higher risk of spontaneous ICH. It has also been estimated that OACs may be related to nearly 12% of all ICHs with a mortality rate of around 50%.

The absence of a direct reversal agent (i.e.: beyond the inconclusive evidence and numerous limitations of PCCs, rFVIIa, FFP and hemodialysis, etc) had been a major disadvantage of the newer direct anticoagulant agents (DOAC) such as Pradaxa, especially as opposed to warfarin. But now with the first antidote being approved in the US and Europe (not yet approved in Canada as of this writing) should help substantially decrease the rate of sudden dabigatran-related ICHs, pending further studies.

New Updated Beers Criteria list

The American Geriatrics Society (AGS) has released its second updated version of the Beers Criteria (5), which is one of the most frequently cited reference tools in the field of geriatrics. The updated and expanded edition, developed by a panel of 13 geriatric and pharmacotherapeutic experts, features lists of potentially inappropriate medications or classes of medications to be avoided in older adults who are not in hospice or palliative care.  The new edition also includes:

– new lists of select medications to avoid and/or for which dose adjustments are to be based on a patient’s kidney function

– select drug-drug interactions to avoid

– exceptions to Beers criterias deemed clinically appropriate by the panel

– updated Potentially Inappropriate Medication (PIM) statements based on the strength of evidence and strength of recommendation

Role of Beers Criteria list: This tool is intended to improve prescribing; educate clinicians and patients; prevent and reduce adverse drug events; and serve as a tool for evaluating quality of care, cost, and patterns of drug use of older adults and elderly people. It is not intended to be used in a punitive manner nor to deny coverage to patients by medical insurance companies.  Its stated goal is “ to improve the care of older adults by reducing their exposure to PIMs”.

It is a useful tool for all practicing clinicians caring for ambulatory, acute care and institutionalized settings of people of 65 years of age or older. It is not, however, a complete and comprehensive list of inappropriate medications since such a list would be too exhaustive, and therefore only meant as a clinical decision-making tool to be used in conjunction with practitioners’ own expertise and judgement.

The AGS has also published additional material including guides on how to use the Beers Criteria tool; teaching slides; numerous patient resources; and pocketcards available through free subscription or purchase (6).


1) FDA Full Prescribing Monograph, idarucizumab (Praxbind ™), 10/15 (accessed 05/11/15) :

2) Medscape Drugs and Disease Monograph, idarucizumab (Praxbind), accessed 21/10/15:

3) CV Pollack, et al., Idarucizumab for Dabigatran Reversal, Idarucizumab for Dabigatran Reversal.N Engl J Med. 2015 Aug 6;373(6):511-20. doi: 10.1056/NEJMoa1502000. Epub 2015 Jun 22.

4) Glund S et al., Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial, Lancet. 2015 Aug 15;386(9994):680-90. doi: 10.1016/S0140-6736(15)60732-2. Epub 2015 Jun 15.

5) MA Steinman et al., American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, J Am Geriatr Soc 2015 : (free access to pdf through subscription)

6) Additional information and tools by the AGS  :