Just before the end of 2012, German pharmaceutical firm Boehringer-Ingelheim got even more bad news about its flagship product, Pradaxa (dabigatran). On 19 December, the U.S. Food and Drug Administration (FDA) issued a warning against using the drug for patients with mechanical heart valves. A drug study in Europe had to be stopped when it was found that patients who had been fitted with mechanical prosthetic heart valves were at greater risk of forming clots and experiencing dangerous hemorrhages. The safety announcement went on to warn against the use of Pradaxa in patients with a type of artificial heart valve known as biologic heart valves – which are created from natural tissue, stating that such use of the drug “has not been evaluated and cannot be recommended.”

In the wake of this news, Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) is now reconsidering an earlier decision recommending that the country’s government health service cover the cost of the drug for patients.

Still, everyone seems willing to bend over backwards to help BI. The PBAC has invited BI to submit new data on the drug; earlier in November, the FDA went through insurance records going back over four years with a fine-toothed comb in order to demonstrated that “rates of gastrointestinal or intracranial bleeding were no more prevalent” for Pradaxa patients than for those taking Coumadin (warfarin). Naturally, BI’s own data came to the same conclusion.

At the same time, physicians who otherwise appreciate Pradaxa because of its relative lack of side effects are still expressing concern over the lack of an antidote. Part of the problem is that cardiologists may be prescribing Pradaxa to patients with reduced kidney function. BI recommends that patients have their kidneys tested before having Pradaxa prescribed for them. The reason is that Pradaxa leaves the bloodstream through the kidneys (this is why emergency dialysis is usually the only treatment for patients who suffer hemorrhaging). One potential problem here is that Pradaxa is usually prescribed by cardiologists and general practitioners – who may not be aware that a patient may have kidney problems. (In light of the fact that BI does recommend tests for kidney function, this brings up the issue of physician liability.)

Dr. Mark Mosely, who runs the emergency room at Wesley Medical Center in Wichita, Kansas, told the New York Times that he nonetheless found it “shocking” the the FDA approved Pradaxa when there was clearly no antidote for excessive bleeding.

The FDA continues to defend Pradaxa; it is unlikely that the private, profit-driven U.S. health care system will issue any strong warnings when there are billions of dollars at stake. The Australian government on the other hand has no such motivation other than watching out for the health of its citizens.

Sources

N/A.  “FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) Should Not Be Used in Patients With Mechanical Prosthetic Heart Valves.” Available athttp://www.fda.gov/Drugs/DrugSafety/ucm332912.htm.

Palmer, Eric. “Long-Term Study Reinforces Safety Record of Blockbuster Pradaxa.” Fierce Pharma, 7 November 2012. Available at http://www.fiercepharma.com/story/long-term-study-reinforces-safety-record-blockbuster-pradaxa/2012-11-07.

Taylor, Lynn.  “Australia: Warning Over Pradaxa PBS Listing.”  Pharma Times Online. Available athttp://www.pharmatimes.com/Article/12-12-20/Australia_warning_over_Pradaxa_PBS_listing.aspx

Thomas, Katie. “A Promising Drug With a Flaw.” New York Times, 2 November 2012.

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German pharmaceutical giant Boehringer-Ingelheim got some very unwelcome news just before the new year. Unfortunately, it wasn’t about lawsuits, fines and penalties. It was about the competition. As one of its final actions for 2012, the U.S. Food and Drug Administration approved the anti-coagulant drug apixaban – a product that Bristol-Myers Squibb and Pfizer sells under the brand name Eliquis.

This drug has already been approved for use in the E.U. as well as Japan, but in the U.S., the FDA denied approval for Eliquis twice on the grounds that more research was needed.  According to a  recent study  (Apixaban for Reduction In STroke and Other ThromboemboLic Events or ARISTOTLE), Eliquis was more effective than warfarin (Coumadin) in treating patients with atrial fibrillation (AR).  Warfarin, actually a common type of rat poison, has the advantage of being inexpensive (always the primary consideration in the U.S. profit-driven healthcare “system”). However, patients who take it require frequent monitoring for possible interactions and to insure they are getting the correct dose.

This was one of the attractive features of Pradaxa. Because there are far fewer interactions to worry about, patients on Pradaxa require less monitoring.  The danger is that while hemorrhaging from Coumadin can be stopped by dosing with Vitamin K – which allows the blood’s clotting factor to kick in – there is no antidote for hemorrhaging caused by Pradaxa, other than to administer emergency dialysis in order to get the drug out of the patient’s system. The reason is that Pradaxa is a “direct Factor Xa inhibitor” (pronounced “Ten-A” ). Factor Xa is the enzyme that allows blood to clot in the first place. Coumadin suppresses the action of Vitamin K, which allows the production of Factor Xa. This is why doses of the vitamin can help stop bleeding in those patients when it occurs.

Eliquis is also a Factor Xa inhibitor – meaning it also acts directly on the clotting enzyme, and may pose some danger of fatal bleeding like Pradaxa. There is a difference, however; while Pradaxa is eliminated from the blood by the kidneys, Eliquis leaves the system by way of the liver. A study published on the American Heart Association website in July of 2012 showed that all three major direct Factor Xa inhibitors – Pradaxa, Xarelto (rivaoxaban) and Eliquis were approximately equal in terms of their effectiveness when it came to preventing strokes and treating AR. However, there was a lower risk of fatal hemorrhaging in patients who were treated with Eliquis. One reason may be due to the fact that elderly patients frequently suffer from reduced kidney function; their livers on the other hand may do a better job of eliminating the drug from the bloodstream.

This is all good news for Bristol-Myers Squibb and Pzifer; stock prices for both companies shot up in the wake of the news. On the other hand, Pradaxa has a two-year head start on Eliquis; the companies’ sales reps will have their work cut out for them convincing doctors to switch their patients over to the new medication. A New York Times article suggests that many doctors are taking a “wait-and-see” approach before they consider changing their patients’ prescriptions.

There’s a great deal at stake; approximately one-fourth of people over the age of forty develop AR at some point. With an aging population and a health care “system” that continues to focus on profits and the bottom line more than the good of patients, the manufacturers of Eliquis stand to make between one and five billion dollars before its all said and done.

Sources

N/A. “FDA Clears Anti-Clotting Drug Eliquis.” USA Today, 28 December 2012.

McBride, Ryan.  “Pfizer, BMS win blockbuster FDA approval for Eliquis.” Fierce Biotech, 28 December 2012.  Available at http://www.fiercebiotech.com/story/pfizer-bms-win-coveted-fda-approval-bloodthinner-eliquis/2012-12-28.

Rosenbaum, Lisa. “Another Choice for Combatting Clot? Apixaban for Patients with atrial Fibrillation.”Now@NEJM, 14 September 2011. Available at http://blogs.nejm.org/now/index.php/another-choice-for-combatting-clot-apixaban-for-patients-with-atrial-fibrillation/2011/09/14/ .

Schneeweiss, Sebastian MD et. al. “Comparative Efficacy and Safety of New Oral Anticoagulants in Patients With Atrial Fibrillation.” American Heart Association, 10 July 2012. Available athttp://circoutcomes.ahajournals.org/content/5/4/480.

Thomas, Katie. “F.D.A. Clears Anticlotting Drug by Bristol and Pfizer.” New York Times, 28 December 2012.

Warner, Jennifer. “FDA Approves New Blood Thinner Eliquis.” WebMD, 31 December 2012. Available athttp://www.webmd.com/heart-disease/atrial-fibrillation/news/20121231/fda-blood-thinner-eliquis.

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Has Boehringer-Ingelheim experienced a “Come to Jesus Moment”?

Several news sources recently announced that the German pharmaceutical giant, whose flagship product Pradaxa has been implicated in several cases of fatal bleeding, has issued a recall – of Pradaxa.

But only one lot. And not because it may be dangerous and there is no antidote for the hemorrhaging. No…it turns out there was a packaging defect. Apparently, the machinery used to package the medication has caused a defect in the bottles that may allow moisture to enter and prevent patients from receiving a “fully effective dose.”  BI advises patients who have a bottle with Lot Number 201900 and an expiration date of January 2015 should return it to the pharmacy for exchange. The company also warns patients to continue taking the medication until their bottle has been replaced.

Both the Food and Drug Administration and BI have said that the danger of hemorrhaging is no worse when taking Pradaxa than it is when using warfarin. This isn’t the issue. The problem is that when a patient starts hemorrhaging while taking warfarin, it can be stopped with doses of Vitamin K, which allows the blood’s clotting factor (thrombin) to kick in.  Pradaxa (dabigatran) operates on the clotting factor itself, preventing it from working – so once hemorrhaging stops, there is virtually no way to stop it, except to attempt emergency dialysis. This issue was not addressed by either the FDA or BI.

Where BI allegedly went wrong was in its failure to warn physicians and patients. The objective of current litigation against the company is to determine what management knew and whether or not there was a duty to warn consumers of the drug.

Meanwhile, Pradaxa has generated over $1 billion in sales. At the same time, a recent report in Forbes raises serious questions about the FDA’s methods in analyzing the risks associated with Pradaxa. The FDA relied on data from insurance claims and administrators, not medical case files. According to the Observational Medical Outcomes Project, a non-profit organization devoted to the study and analysis of new medications, reliance on such non-medical data is questionable at best.

Sources

FDA Drug Safety Communication: “Update On The Risk For Serious Bleeding Events With The Anticoagulant Pradaxa,” 02 November 2012. Available at http://www.fda.gov/Drugs/DrugSafety/ucm326580.htm .

MacDonald, Gareth. “Boehringer Withdraws Pradaxa Lot After Packaging Line Problems.” InPharma Technologist, 12 November 2012.  Available at  http://www.in-pharmatechnologist.com/Processing/Boehringer-withdraws-Pradaxa-lot-after-packaging-line-problems.

N/A. “Boehringer Recalls Manufacturing Lot of Pradaxa.” Bloomberg Businessweek,  7 November 2012.

Silverman, Ed. “Was The FDA Safety Analysis For A Popular Bloodthinner Flawed?” Forbes, 6 November 2012.

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