Edoxaban for Stroke Prevention

Edoxaban for Stroke Prevention 1. Indication (86words) Edoxaban, a drug part of the direct factor Xa group is licensed on two indications. The first indication, treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT). (1). Treatment is only conducted following the use of parenteral anticoagulants on a minimum 5-day course. Second, prevention of systemic embolism (SE) and stroke in nonvalvular atrial fibrillation (NVAF). Treatment conducted in line with risk factors such as transient ischaemic attack (TIA), diabetes mellitus, congestive heart failure, hypertension, prior stroke, or age>75 years. (2) 2. Design (278) Edoxaban is part of NOAC, which includes apixaban and rivaroxaban. The development of edoxaban is primarily focused on overcoming the drawbacks of warfarin which requires frequent monitoring, unpredictable dosing and interactions with various food and drugs. (3) The API of edoxaban, edoxaban tosilate is accessible in two polymorphic forms, form I and form II with form I being the most thermodynamically stable. The crystalline form I of edoxaban tosilate is synthetically produced with no conversion of forms during the drug manufacturing process. (4) Edoxaban is available in 15, 30 and 60 mg immediate release film coated tablets that disintegrates quickly. Having a relatively long half-life of up to 14 hours, with dose-dependent, linear pharmacokinetic parameters, it is suitable for once a day dosing. Oral bioavailability is approximated to be at 62% and concentration levels reach a steady state within 3 days of oral administration and is unaffected by food. Edoxaban is 50% renally cleared, requiring doses for elderly and renally impaired patients to be reduced. The pharmacodynamics effects are usually produced within 1-2 hours in correspondence to the peak exposure levels of edoxaban. (5) Edoxaban tablets are manufactured from common granulate and are quantitatively proportional when manufactured. API particle sizes are reduced during the final steps of the API manufacturing process utilising milling. The final manufacturing process involves four main stages, fluid bed granulation; blending; tableting and film coating. Final product requires no special storage as it is photostable and is packaged in a PVC and aluminium blister. Storage of edoxaban ranges from 24 months for long and intermediate conditions and as low as 6 months in accelerated conditions. All excipients used in this formulation are compliant to European Pharmacopoeia Standards. (4) Figure 1: Structure of Rivaroxaban, Apixiban and Edoxaban. (6) 3) Safety (199 words) Warfarin is the current GOLD standard indicator for DVT and AF. Large scale pivotal phase II studies have been conducted to compare the safety and efficacy profile of edoxaban and warfarin. The results of studies; ENGAGE AF(7) and Hokusai VTE(8), are tabulated for analysis below in Table 1. Findings of the study place the adverse events (AE) among patients of each drug be well within tolerable range with only mild to moderate events occurring. However, the Treatment-emergent adverse event (TEAE) and serious TEAR were found be higher in warfarin. This is clearly seen in Table 2. Major bleeding is the primary safety endpoint for safety as defined by the International Society on Thrombosis and Haemostasis (ISTH). The ENGANGE AF study showed reduced major bleeding against warfarin with the annualized rate of 3.43% as compared to 2.75% for Edoxaban. Intracranial, major or nonmajor relevant bleeding and fatal bleeding were found to be significantly lower compared to warfarin (p