EMA: Medicinal product committee offers 'positive opinion' for Pradaxa

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The Committee for Medicinal Products for Human Use (CHMP) put forth a positive opinion last week about the use of dabigatran for the prevention of stroke and systemic embolism in atrial fibrillation patients, basing the statement on RE-LY trial results published in November that showed dabigatran had similar outcomes to warfarin.

CHMP’s new indication for dabigatran (Pradaxa, Boehringer Ingelheim) includes its use for the prevention of stroke and embolism in AF patients who have either a left ventricular ejection fraction less than 40 percent or NYHA Class 2 indications or those age 75 or older or those age 65 or older if they have diabetes, coronary artery disease or hypertension, according to the European Medicines Agency (EMA).

CHMP's indications would make the drug available in 75mg, 110 mg and 150 mg doses. The drug has been indicated for use for the prevention of venous thromboembolic events in patients who have undergone total hip replacement or knee replacement surgery in the European Union.

While the FDA approved dabigatran in the 150 mg dose in October, it has not approved the lower 110 mg dose.  A perspective published April 13 in the New England Journal of Medicine attempted to explain the FDA’s decision to approve Pradaxa in the higher doses but not the lower 110 mg dose.

According to B. NHi Beasley, PharmD, of the FDA, and colleagues, while the RE-LY trial found that the 150 mg dose of dabigatran reduced the risk of stroke and embolism at a higher rate when compared to the 110 mg dose, the 110 mg dose also was found to cause more bleeding events, particularly in elderly patients over the age of 75. In fact, RE-LY results showed that the rates of stroke and systemic embolism were lower with the 150 mg dose (1.4 per 100 patient-years) compared with the 110 mg dose, but the rate of major bleeding was higher (5.1 vs. 4.4 per 100 patient-years).

The authors wrote, “Any benefit–risk assessment in which strokes and systemic emboli are given more weight than nonfatal bleeding events would find the higher dose more favorable in elderly patients.”

Beasley et al noted that they were “unable to find any population for whom the availability of a lower dose would improve dabigatran’s benefit-risk profile, and it appeared clear that most, if not all, patients should receive the higher dose.”

However, there was one exception to the rule. The researchers noted that patients with severe renal impairment should be administered an even lower dose of dabigatran (75 mg).

“Ultimately, the FDA's decision to approve only the 150 mg strength was based on our inability to identify any subgroup in which use of the lower dose would not represent a substantial disadvantage,” the authors concluded.