Edoxaban, a selective factor Xa-inhibitor, has been approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, with a statement in the boxed warning that it should not be used in patients with normal renal function.

The warning reflects the results of a subgroup analysis in the pivotal trial, which found that the 60-mg dose was superior to warfarin in terms of reducing the stroke risk in mildly renally impaired patients, but was worse in patients with normal renal function. This was the main focus of a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Panel meeting in October, in which the panel voted 9-1 to recommend approval of edoxaban for this indication, but had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment.

The approved prescribing information recommends that a patient’s creatinine clearance should be checked before edoxaban is prescribed. “Patients with creatinine clearance greater than 95 mL/min have an increased risk of stroke, compared to similar patients given warfarin,” and should be treated with another anticoagulant, the FDA said in the Jan. 9 statement announcing the approval. The recommended dose for those with a creatinine clearance between 50 mL/min and 95 mL/min is 60 mg once a day; for those with a creatinine clearance of 15-50 mL/min, the recommended dose is 30 mg once a day, according to the prescribing information .

Edoxaban, the fourth novel oral anticoagulant drug approved by the FDA, will be marketed as Savaysa by Daiichi Sankyo. It was also approved to treat deep vein thrombosis and pulmonary embolism following 5-10 days of initial therapy with a parenteral anticoagulant. The recommended dose for this indication is 60 mg once a day. For patients with a creatinine clearance of 15-50 mL/min, or who weigh up to 60 kg (about 132 pounds), or who are taking “certain P-glycoprotein inhibitors,” the 30-mg/day dose is recommended.

Approval for the nonvalvular AF indication was based on ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation) study, comparing once-daily edoxaban (60 mg and 30 mg) to warfarin in 21,015 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events (N. Engl. J. Med. 2013;369:2093-104) . Over a median of almost 3 years, both doses were noninferior to warfarin in the primary efficacy endpoint, the occurrence of first stroke or of a systemic embolic event. Overall, major bleeding events were significantly lower among those on the 60-mg and 30-mg doses, compared with those on warfarin. However, the rate of ischemic stroke was higher relative to warfarin in patients with a creatinine clearance over 95 mL/min.

About half of the edoxaban dose is eliminated by the kidneys, and patients with a creatinine clearance above 95 mL/min have lower plasma edoxaban levels, according to a statement in the clinical trials section of the prescribing information, which adds: “Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Savaysa, compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.”

Approval of the DVT and PE indication was based on the Hokusai-VTE study of about 8,200 people comparing edoxaban to warfarin, which found that the edoxaban 60 mg once a day was noninferior to warfarin in the rate of symptomatic venous thromboembolism (3.2% vs. 3.5% in those on warfarin). The rate of major or clinically relevant nonmajor bleeding events was 8.5% among those on edoxaban vs. 10.3% in those on warfarin ( N. Engl. J. Med. 2013;369:1406-15 ).

Bleeding and anemia were the most common adverse events among patients with nonvalvular atrial fibrillation in clinical trials, and “as with other FDA-approved anticlotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa,” the FDA statement said. Among those treated for DVT and PE, the most common adverse events were bleeding, rash, abnormal liver function tests, and anemia.

Savaysa is the fourth novel oral anticoagulant to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).

Serious adverse events associated with edoxaban should be reported to the FDA’s MedWatch program or at 800-332-1088.