On Friday, January 9, the Food and Drug Administration approved edoxaban (Savaysa) as the fourth new oral anticoagulant (NOAC), giving it an indication in nonvalvular atrial fibrillation for renally impaired patients and in treating deep vein thrombosis and pulmonary embolism.
The agency followed the recommendation of its advisory panel in October, favoring approval for stroke and systemic embolism prevention in nonvalvular afib despite dissension over dosing and the appropriate patient population.
Those same issues had been raised by the FDA’s own reviewers, noting that the lower, 30-mg dose studied in the pivotal ENGAGE AF trial trended toward inferiority to warfarin. Another concern was that the overall stroke risk was only significantly reduced by the higher 60-mg dose in patients with mild renal impairment, not those with normal renal function.
The final approval included not only the 30- and 60-mg doses but also a 15-mg dose of the factor Xa inhibitor in a complicated scheme by kidney function.
For nonvalvular atrial fibrillation, the label mandated creatinine clearance assessment before starting therapy with the renally-excreted drug.
The recommended dose was 60 mg once a day in patients with creatinine clearance above 50 to 95 mL/min and a dose reduction to 30 mg once daily for those with moderate to severe renal impairment (creatinine clearance 15 to 50 mL/min).
For patients with normal renal unction (creatinine clearance of greater than 95 mL/min), a black box warning cautioned against use due to reduced efficacy.
That stratification by kidney function is both “clinically cumbersome” and makes edoxaban a less attractive option compared with the other NOACs for prevention in atrial fibrillation, commented Stephan Moll, MD, medical director of the Clot Connect education program of the University of North Carolina at Chapel Hill.
“I don’t know of any other drug that is to be avoided if the kidney function is particularly good,” he told MedPage Today.
For the indication in treatment of deep vein thrombosis and pulmonary embolism after trying parenteral anticoagulant for 5 to 10 days, renal function assessment wasn’t required.
But the standard 60 mg dose was recommended to be cut to 30 mg once daily for patients with moderate to severe renal impairment, a body weight of 60 kg (132 lb) or less, or who are on P-glycoprotein inhibitors except amiodarone (Cordarone).
Even without the upper limit on renal function for edoxaban in venous thromboembolism (VTE), the labeling set up the drug as a less appealing option, Moll noted.
It “has no advantage, but rather a disadvantage compared with Xarelto [rivaroxaban] and Eliquis [apixaban] in VTE treatment, given that for the first 5 to 10 days a parenteral anticoagulant should be given (was given in the clinical trial) before Savaysa is started,” he told MedPage Today.
The label gave little instruction on the 15 mg dose that was approved, other than a table buried in the document recommending it in the transition from edoxaban to warfarin for patients who had been on the 30-mg dose.
The FDA staff review had suggested that boosting dose to 75 to 90 mg might be effective for renally-normal individuals, but the label did not address that strategy of adding the 15 mg pill, instead ruling out use in that population.
The black box warning also cautioned that premature discontinuation of edoxaban increases ischemic event risk and that the drug can cause spinal or epidural hematoma.
By Crystal Phend, Senior Staff Writer, MedPage Today