The Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for Savaysa (edoxaban tosylate; Daiichi Sankyo) that provides for changes to the labeling based on a trial that evaluated the effects of Prothrombin Complex Concentrate (PCCs) on reversing the pharmacological activity of the drug. In addition, new information on the concurrent use of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) has been added.
The effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following a punch biopsy. Following administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo. Mean ETP levels continued to increase and exceeded pre-edoxaban baseline, reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours after initiating PCC dose, which was the last observation of ETP. The clinical relevance of this ETP increase is unknown.
There is no established way to reverse the anticoagulant effects of edoxaban, which can be expected to persist for approximately 24 hours after the last dose; protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity. The use of PCC, or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies. When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.
The Warnings and Precautions section of the labeling has also been updated to add to the list of concomitant drugs that may increase bleeding risk by affecting hemostasis. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), and now, selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
Savaysa, a factor Xa inhibitor, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5–10 days of initial therapy with parenteral anticoagulant. Savaysa is available in three tablet strengths: 15mg, 30mg, and 60mg.
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