Boehringer Ingelheim GmbH's breakthrough anticoagulant Pradaxa (dabigatran) will be available to physicians and patients in the "next several days," the company said after FDA cleared the drug Oct. 19.

The first anticoagulant to enter the U.S. market since warfarin was approved in the 1950s, Pradaxa, an oral direct thrombin inhibitor, is indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, or abnormal heart rhythm. It is approved in a 150 mg dose for most patients and a 75 mg dose for patients with reduced renal function. Both are to be taken twice daily.

Although the private company said pricing was not yet available, outside estimates are ranging from $6 to $9 per day. While that is considerably more than the cost of warfarin, it will be offset by not insubstantial savings to insurers and patients used to the direct costs of regular office visits and blood draws necessary to regulate warfarin dosing. As well, there will be indirect savings related to quality of life and work and from the cost of caregivers and emergency rooms.

The company has not yet released pricing, but early estimates range from $6 to $9 per day.

But while dabigatran use shouldn't have to be heavily monitored, the anticoagulant is not without risk. It carries the potential for bleeding events that is a concern for all anticoagulants. In fact, patients taking the 150 mg dose in the pivotal trial that led to the approval had the same bleeding risk as with warfarin; it's the efficacy that proves the clincher. With 150 mg dabigatran, patients had 34% fewer strokes and systemic embolisms than with the vitamin K antagonist, a statistically superior finding in a study powered for non-inferiority.

Language alongside the study findings in labeling allows that "relative to warfarin and to Pradaxa 110 mg twice daily, Pradaxa 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism." Inclusion of language acknowledging the superior result is a win for the German drug maker, which can turn it into a more overt superiority claim in Pradaxa promotions.

The second trial dose, 110 mg, had a better safety profile but proved only non-inferior to warfarin. During the drug's Sept. 20 advisory committee review, members debated the tradeoff between risk of bleeding events and better prevention of strokes, though the majority felt strongly that preventing strokes outweighed potential bleeds. In the end, they were mixed over whether both doses should be cleared, with an eye toward preserving the lower dose for high-risk patients (Also see "FDA's Pradaxa Quandary: Clearing Both Doses Could Mask Dabigatran's Superiority" - Pink Sheet, 27 September, 2010.).

However, concerns from both the advisory panel and FDA reviewers that physicians might play it safe by broadly prescribing the lower dose despite the efficacy to be had with the higher one carried over into the agency's labeling decision (Also see "FDA Plays It Safe With Boehringer Ingelheim's Pradaxa By Approving A Single Dosing Option" - Pink Sheet, 20 October, 2010.).

Approval Comes With A REMS

The approval carries with it a Medication Guide, which under FDA's current policy constitutes a Risk Evaluation and Mitigation strategy. And the MedGuide is devoted entirely to bleeding risk, driving home the message to patients who will have more responsibility for their own care than perhaps they had while in a warfarin regimen.

The document starts out stressing that because it is a blood thinner that lowers the chance of clots, "Pradaxa can cause bleeding which can be serious and sometimes lead to death."

The MedGuide also takes the unusual step of emphasizing the importance of compliance, a move forecast by Office of Drug Evaluation I Director Bob Temple at the panel meeting. At issue is dabigatran's short half-life compared to warfarin, which means missing even one dose could be dangerous. Bolded language in the MedGuide warns patients repeatedly that "Stopping Pradaxa may increase your risk of a stroke" and to "Take Pradaxa exactly as prescribed."

Not reflected in the REMS is the higher rate of myocardial infarction observed in the dabigatran arms of the pivotal RE-LY study. Labeling does mention the finding, via a sentence in the Clinical Studies section noting that "the risk of myocardial infarction was numerically greater in patients who received Pradaxa (1.5% for 150 mg dose) than in those who received warfarin (1.1%)." [Editor's note: This story has been updated to correct the incidence of MI at the 150 mg dose.]

Boehringer Ingelheim is studying dabigatran in ongoing Phase III trials for acute coronary syndromes that could shed light on the MI data.

First Shot At A Sizeable Market

Pradaxa was approved in the EU in March 2008 for primary prevention of venous thromboembolic events in adults after elective total hip or knee replacement surgery.

But the U.S. market opportunity in non-valvular atrial fibrillation is huge. An estimated 2.3 million Americans live with the condition, and that number is expected to increase with the aging population to 5.6 million by 2050 (Also see "Oral Anticoagulants Market Snapshot: Big Bucks, But Payers Are On Guard" - Pink Sheet, 25 October, 2010.).

Pradaxa's first-to-market advantage won't last long, however. An army of anticoagulant candidates in the industry pipeline is advancing, and some, like Bristol-Myers Squibb/Pfizer's oral Factor Xa inhibitor apixaban, are set to claim a safety advantage.

By Shirley Haley

FDA Pradaxa Approval Balances Efficacy And Bleeding Risk

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