Pradaxa (dabigatran etexilate mesylate), a new oral anticoagulant, achieved Food & Drug Administration (“FDA”) approval on October 19, 2010. One notable advantage of using Pradaxa to replace Warfarin to prevent clot formation is the elimination of INR testing in patients taking Pradaxa. INR is the acronym for International Normalized Ratio, which is used to monitor the effectiveness of anticoagulant such as warfarin.

In fact, the only time INR testing is necessary when using Pradaxa is when physicians switch a patient from Warfarin to Pradaxa; at that time the INR value should be greater than or equal to 2.0 grams per deciliter.

Some critics have stated that Pradaxa has not been adequately studied; they point to a lack of knowledge about the drug’s full effects. Those critics also contend that Pradaxa’s manufacturer, Boehringer Ingelheim, abbreviated the investigative process to beat Pfizer’s Eliquis and Bayer’s Xarelto in a race to introducea new product to replace warfarin in the blood thinner market.

Whenever a new drug comes on the scene, it is not long before physicians investigate the drug’s properties and begin to prescribe it off label, and Pradaxa is no exception. In fact, the Institute for Safety Medication Practices (ISMP) has reported that U.S. physicians are prescribing Pradaxa for off label use as a general anticoagulant twice as much as the FDA approved use as an anticoagulant specific to reducing strokes.

Interestingly enough, an article appearing in the New England Journal of Medicine on April 13, 2011, addressed a multicenter, active control trial called Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) in which patients underwent randomized testing using two doses of Pradaxa, 150 milligrams and 110 milligrams, respectively. The RE-LY trial compared a group of subjects using two separate doses of Pradaxa to a control group using warfarin. During the trial, investigators tested patient’s INR, maintaining a range between 2.0 and 3.0 milligrams per deciliter.

The RE-LY trial indicated that the 150 milligram regimen of Pradaxa was significantly superior to warfarin and the 110 milligram regimen was superior to warfarin, when it came to overcoming the side effect of bleeding. In fact, the 150 milligram dose of Pradaxa was similar to warfarin in that respect.

Ultimately, however, the FDA did not approve the 110 Pradaxa regimen because it was not superior to warfarin in clot reduction. Notably, the 150 milligram Pradaxa regimen caused more bleeding in patients over 75 years of age, and the myocardial infarction (MI) risk from Pradaxa use was higher in all Pradaxa patients. Oddly enough, the FDA did not approve using the lower 110 milligram Pradaxa regimen, but it did approve a half-dose, 75 milligram pill for patients with renal impairment.

Early in November 2011, Boehringer spokesman, Reinhard Malin admitted that Pradaxa had caused death in several German patients. The cause is most likely related to the fact that Pradaxa is eliminated from the body through the kidneys, and renal impairment can cause unusually high levels of Pradaxa to remain behind and cause significant bleeding risks.Because of this development, Boehringer warned European physicians on October 27, 2011, to regularly test the kidney function of patients over 75 years of age, and patients on medication to treat kidney impairment.

Although Boehringer would not comment on the number of deaths related to Pradaxa use, Bloomberg News (Die Zeit) said that 50 deaths worldwide is “probably in the right range.”. Spokesman, Malin, confirmed 14 internal bleeding deaths among Japanese patients using Pradaxa, related to impaired kidney function. The EMA (European Medicines Association) suggested yearly testing in older patients and younger patients with renal impairment (those patients with creatinine clearance less than 30 milliliters per minute).

There is yet another concern about using Pradaxa. If dispensed in a bottle (the primary way that it is prescribed in the U.S.), Pradaxa must be used within 60 days after opening. As a result, there is concern that the unusual 60-day expiration might be overlooked. There seems to be a lack of awareness among pharmacists and others that there is a very short Pradaxa shelf life after opening the dispensing bottle. In fact, Kevin Adams, pharmacy director of TJ Sampson Hospital in Glasgow, KY said that his pharmacy received bottles of the drug and that he was not aware of Pradaxa’s abnormally rapid expiry (customary expiration is usually 12 months); Boehringer sales reps never said a word about this serious potential problem to Mr. Adams. Alarmingly, even D. Michael Ezekowitz, co-principal investigator on the pivotal RE-LY trial (the basis for the FDA approval of Pradaxa) said that he “had not heard of this” issue, either.

If people were to have two bottles opened at once, one at work and one at home, this might cause a problem and elderly people might get confused if they forget the date they opened the bottle. Also, taking the drug beyond the 60 day period after opening the bottle could result in Pradaxa being less effective.

Pradaxa is currently approved for use in 75 countries. A search of the FDA’s MedWatch website states there are reportedly more than 1,000 reported Pradaxa adverse reaction cases. Those MedWatch reports include events such as:

  • venous thrombosis
  • reduced INR
  • cerebrovascular accident
  • atrial fibrillation
  • pulmonary embolism
  • tachycardia
  • abdominal distension
  • decreased blood magnesium levels
  • decreased blood sodium levels
  • decreased blood potassium levels
  • decreased hematocri levels
  • prolonged thromboplastin time
  • deep vein thrombosis
  • decreased oxygen saturation
  • myocardial infarction and
  • gastric hemorrhage.

Perhaps pharmaceutical manufacturers should not wait for aftermarket events to alert them to what should have been discovered during more thorough pre-market testing.

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