Savaysa Edoxaban Tosylate 60 mg Tablet, Film Coated, 7-count — NDC 65597-203-70 (Billing 65597-0203-70)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.

12.2Pharmacodynamics As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (C max ).

Cardiac Electrophysiology In a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg). Effect of PCCs on Pharmacodynamics of SAVAYSA There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA. 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.

Pharmacodynamic Interactions Aspirin Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone. NSAID (Naproxen) Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.

12.3Pharmacokinetics Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects. Absorption Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%.

Food does not affect total systemic exposure to edoxaban. SAVAYSA was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials. Administration of a crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through a nasogastric tube, showed similar exposure compared to administration of an intact tablet.

Distribution Disposition is biphasic. The steady-state volume of distribution (Vd ss ) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%.

There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing. Steady-state concentrations are achieved within 3 days. Metabolism Unchanged edoxaban is the predominant form in plasma.

There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.

Elimination Edoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance.

The terminal elimination half-life of edoxaban following oral adminis… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.

12.3Pharmacokinetics Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects. Absorption Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%.

Food does not affect total systemic exposure to edoxaban. SAVAYSA was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials. Administration of a crushed 60 mg tablet, either mixed into applesauce or suspended in water and given through a nasogastric tube, showed similar exposure compared to administration of an intact tablet.

Distribution Disposition is biphasic. The steady-state volume of distribution (Vd ss ) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%.

There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing. Steady-state concentrations are achieved within 3 days. Metabolism Unchanged edoxaban is the predominant form in plasma.

There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4. The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.

Elimination Edoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance.

The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours. Specific Populations Hepatic Impairment In a dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh A or Child-Pugh B) exhibited similar pharmacokinetics and pharmacodynamics to their matched healthy control group. There is no clinical experience with edoxaban in patients with severe hepatic impairment [see Use in Specific Populations (8.7) ] .

Renal Impairment In a dedicated pharmacokinetic study, total systemic exposure to edoxaban for subjects with CrCL > 50 to < 80 mL/min, CrCL 30 to 50 mL/min, CrCL < 30 mL/min, or undergoing peritoneal dialysis, were increased by 32%, 74%, 72%, and 93%, respectively, relative to subjects with CrCL ≥ 80 mL/min [see Use in Specific Populations (8.6) ] . Hemodialysis A 4-hour hemodialysis session reduced total edoxaban exposure by less than 7%. Age In a population pharmacokinetic analysis, after taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics.

Weight In a population pharmacokinetic analysis, total exposure in patients with median low body weight (55 kg) was increased by 13% as compared with patients with median high body weight (84 kg). Gender In a population pharmacokinetic analysis, after accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics. Race In a population pharmacokinetic analysis, edoxaban exposures in Asian patients and non-Asian patients were similar.

Drug Interactions In vitro Drug Interactions Studies In vitro studies indicate that edoxaban does not inhibit the major cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and does not induce CYP1A2, CYP3A4 or the P-gp transporter (MDR1). In vitro data also indicate that edoxaban does not inhibit the following transporters at clinically relevant concentrations: P-gp, the organic anion transporters OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the organic ion transporting polypeptides OATP1B1 or OATP1B3.

Edoxaban is a substrate of P-gp transporter. Impact of Other Drugs on SAVAYSA The effect of co-administered amiodaron… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (C max ).

Cardiac Electrophysiology In a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg). Effect of PCCs on Pharmacodynamics of SAVAYSA There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received SAVAYSA. 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.

Pharmacodynamic Interactions Aspirin Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone. NSAID (Naproxen) Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.

14 CLINICAL STUDIES

14.1Nonvalvular Atrial Fibrillation The ENGAGE AF-TIMI 48 Study The ENGAGE AF-TIMI 48 (NCT00781391) study was a multi-national, double-blind, non-inferiority study comparing the efficacy and safety of two SAVAYSA treatment arms (60 mg and 30 mg) to warfarin (titrated to INR 2.0 to 3.0) in reducing the risk of stroke and systemic embolic events in patients with NVAF. The non-inferiority margin (degree of inferiority of SAVAYSA to warfarin that was to be ruled out) was set at 38%, reflecting the substantial effect of warfarin in reducing strokes.

The primary analysis included both ischemic and hemorrhagic strokes. To enter the study, patients had to have one or more of the following additional risk factors for stroke: a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or 2 or more of the following risk factors: – age ≥ 75 years, – hypertension, – heart failure, or – diabetes mellitus A total of 21,105 patients were randomized and followed for a median of 2.8 years and treated for a median of 2.5 years. Patients in the SAVAYSA treatment arms had their dose halved (60 mg halved to 30 mg or 30 mg halved to 15 mg) if one or more of the following clinical factors were present: CrCL ≤ 50 mL/min, low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors (verapamil, quinidine, dronedarone).

Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the study. Approximately 25% of patients in all treatment groups received a reduced dose at baseline, and an additional 7% were dose-reduced during the study. The most common reason for dose reduction was a CrCL ≤ 50 mL/min at randomization (19% of patients).

Patients were well balanced with respect to demographic and baseline characteristics. The percentages of patients age ≥ 75 years and ≥ 80 years were approximately 40% and 17%, respectively. The majority of patients were Caucasian (81%) and male (62%).

Approximately 40% of patients had not taken a Vitamin K Antagonist (VKA) (i.e., never took a VKA or had not taken a VKA for more than 2 months). The mean patient body weight was 84 kg (185 lbs) and 10% of patients had a body weight of ≤ 60 kg. Concomitant diseases of patients in this study included hypertension (94%), congestive heart failure (58%), and prior stroke or transient ischemic attack (28%).

At baseline, approximately 30% of patients were on aspirin and approximately 2% of patients were taking a thienopyridine. Patients randomized to the warfarin arm achieved a mean TTR (time in therapeutic range, INR 2.0 to 3.0) of 65% during the course of the study. The primary endpoint of the study was the occurrence of first stroke (either ischemic or hemorrhagic) or of a systemic embolic event (SEE) that occurred during treatment or within 3 days from the last dose taken.

In the overall results of the study, shown in Table 14.1, both treatment arms of SAVAYSA were non-inferior to warfarin for the primary efficacy endpoint of stroke or SEE. However, the 30 mg (15 mg dose-reduced) treatment arm was numerically less effective than warfarin for the primary endpoint, and was also markedly inferior in reducing the rate of ischemic stroke. Based on the planned superiority analysis (ITT, which required p < 0.01 for success), statistical superiority of the 60 mg (30 mg dose-reduced) treatment arm compared to warfarin was not established in the total study population, but there was a favorable trend [HR (99% CI): 0.87 (0.71, 1.07)].

Table 14.1: Strokes and Systemic Embolic Events in the ENGAGE AF-TIMI 48 Study (mITT, on Treatment Includes events during treatment or within 3 days of stopping study treatment ) Events SAVAYSA 30 mg Includes patients dose-reduced to 15 mg for the 30 mg treatment group and 30 mg for the 60 mg treatment group (N = 7002) n (%/yr) The event rate (%/yr) is calculated as number of events/subject-year exposure. SAVAYSA 60 mg (… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day. Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.

Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).