Rivaroxaban 2.5 mg Tablet, Film Coated, 180-count — NDC 59651-849-18 (Billing 59651-0849-18)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Rivaroxaban is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

12.2Pharmacodynamics Rivaroxaban produces dose-dependent inhibition of FXa activity. Clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest ® , are also prolonged dose-dependently. In children treated with rivaroxaban, the correlation between anti-factor Xa to plasma concentrations is linear with a slope close to 1.

Monitoring for anticoagulation effect of rivaroxaban using anti-FXa activity or a clotting test is not recommended. Specific Populations Renal Impairment The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in adult subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations (8.6) ] . Table 18: Percentage Increase in Rivaroxaban PK and PD Measures in Adult Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies * Separate stand-alone study.

PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve Measure Parameter Creatinine Clearance (mL/min) 50 to 79 30 to 49 15 to 29 ESRD (on dialysis) * ESRD (post-dialysis) * Exposure AUC 44 52 64 47 56 FXa Inhibition AUEC 50 86 100 49 33 PT Prolongation AUEC 33 116 144 112 158 Hepatic Impairment Anti-Factor Xa activity was similar in adult subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class).

There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety. Cardiac Electrophysiology In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for rivaroxaban (15 mg and 45 mg, single dose).

12.3Pharmacokinetics Absorption The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg dose, it is estimated to be 80% to 100% and is not affected by food. Rivaroxaban 2.5 mg tablets can be taken with or without food. [see Dosage and Administration (2.1) ].

The maximum concentrations (C max ) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of rivaroxaban (30 mg single dose) with the H 2 -receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3).

Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and C max compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon.

Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure. In a study with 44 healthy subjects, both mean AUC and C max values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and C max was 18% lower.

Distribution Protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding co… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Rivaroxaban is a selective inhibitor of FXa. It does not require a cofactor (such as Anti-thrombin III) for activity. Rivaroxaban inhibits free FXa and prothrombinase activity. Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, rivaroxaban decreases thrombin generation.

12.3Pharmacokinetics Absorption The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg dose, it is estimated to be 80% to 100% and is not affected by food. Rivaroxaban 2.5 mg tablets can be taken with or without food. [see Dosage and Administration (2.1) ].

The maximum concentrations (C max ) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of rivaroxaban (30 mg single dose) with the H 2 -receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3).

Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and C max compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon.

Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure. In a study with 44 healthy subjects, both mean AUC and C max values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and C max was 18% lower.

Distribution Protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L. Metabolism Approximately 51% of an orally administered [ 14 C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%).

Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites. Excretion In a Phase 1 study, following the administration of [ 14 C]-rivaroxaban, approximately one-third (36%) was recovered as unchanged drug in the urine and 7% was recovered as unchanged drug in feces.

Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also known as BCRP). Rivaroxaban’s affinity for influx transporter proteins is unknown.

Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Specific Populations The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 2.

Figure 2: Effect of Specific Adult Populations on the Pharmacokinetics of Rivaroxaban [see Dosage and Administration (2.1) ] Gender Gender did not influence the pharmacokinetics or pharmacodynamics of rivaroxaban. Race Healthy Japanese subjects were found to have 20 to 40% on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight.

Elderly The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [see Use in Specific Populations (8.5) ] . Renal Impairment The safety and pharmacokinetics of single-dose rivaroxaban (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Rivaroxaban produces dose-dependent inhibition of FXa activity. Clotting tests, such as prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest ® , are also prolonged dose-dependently. In children treated with rivaroxaban, the correlation between anti-factor Xa to plasma concentrations is linear with a slope close to 1.

Monitoring for anticoagulation effect of rivaroxaban using anti-FXa activity or a clotting test is not recommended. Specific Populations Renal Impairment The relationship between systemic exposure and pharmacodynamic activity of rivaroxaban was altered in adult subjects with renal impairment relative to healthy control subjects [see Use in Specific Populations (8.6) ] . Table 18: Percentage Increase in Rivaroxaban PK and PD Measures in Adult Subjects with Renal Impairment Relative to Healthy Subjects from Clinical Pharmacology Studies * Separate stand-alone study.

PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the plasma concentration-time curve; AUEC = Area under the effect-time curve Measure Parameter Creatinine Clearance (mL/min) 50 to 79 30 to 49 15 to 29 ESRD (on dialysis) * ESRD (post-dialysis) * Exposure AUC 44 52 64 47 56 FXa Inhibition AUEC 50 86 100 49 33 PT Prolongation AUEC 33 116 144 112 158 Hepatic Impairment Anti-Factor Xa activity was similar in adult subjects with normal hepatic function and in mild hepatic impairment (Child-Pugh A class).

There is no clear understanding of the impact of hepatic impairment beyond this degree on the coagulation cascade and its relationship to efficacy and safety. Cardiac Electrophysiology In a thorough QT study in healthy men and women aged 50 years and older, no QTc prolonging effects were observed for rivaroxaban (15 mg and 45 mg, single dose).

14 CLINICAL STUDIES

14.6Reduction of Risk of Major Cardiovascular Events in Patients with CAD The evidence for the efficacy and safety of rivaroxaban for the reduction in the risk of stroke, myocardial infarction, or cardiovascular death in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) was derived from the double-blind, placebo-controlled Ca rdiovascular O utco M es for P eople using A nticoagulation S trategie S trial (COMPASS) [NCT10776424]. A total of 27,395 patients were evenly randomized to rivaroxaban 2.5 mg orally twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg orally twice daily alone, or aspirin 100 mg once daily alone.

Because the 5 mg dose alone was not superior to aspirin alone, only the data concerning the 2.5 mg dose plus aspirin are discussed below. Patients with established CAD or PAD were eligible. Patients with CAD who were younger than 65 years of age were also required to have documentation of atherosclerosis involving at least two vascular beds or to have at least two additional cardiovascular risk factors (current smoking, diabetes mellitus, an estimated glomerular filtration rate [eGFR] <60 mL per minute, heart failure, or non-lacunar ischemic stroke ≥1 month earlier).

Patients with PAD were either symptomatic with ankle brachial index <0.90 or had asymptomatic carotid artery stenosis ≥50%, a previous carotid revascularization procedure, or established ischemic disease of one or both lower extremities. Patients were excluded for use of dual antiplatelet, other non-aspirin antiplatelet, or oral anticoagulant therapies, ischemic, non-lacunar stroke within 1 month, hemorrhagic or lacunar stroke at any time, or eGFR <15 mL/min. The mean age was 68 years and 21% of the subject population were ≥75 years.

Of the included patients, 91% had CAD (and will be referred to as the COMPASS CAD population), 27% had PAD (and will be referred to as the COMPASS PAD population), and 18% had both CAD and PAD. Of the patients with CAD, 69% had prior MI, 60% had prior percutaneous transluminal coronary angioplasty (PTCA)/atherectomy/ percutaneous coronary intervention (PCI), and 26% had history of coronary artery bypass grafting (CABG) prior to study. Of the patients with PAD, 49% had intermittent claudication, 27% had peripheral artery bypass surgery or peripheral percutaneous transluminal angioplasty, 26% had asymptomatic carotid artery stenosis > 50%, and 4% had limb or foot amputation for arterial vascular disease.

The mean duration of follow-up was 23 months. Relative to placebo, rivaroxaban reduced the rate of the primary composite outcome of stroke, myocardial infarction or cardiovascular death: HR 0.76 (95% CI: 0.66, 0.86; p=0.00004). In the COMPASS CAD population, the benefit was observed early with a constant treatment effect over the entire treatment period (see Table 26 and Figure 10).

A benefit-risk analysis of the data from COMPASS was performed by comparing the number of CV events (CV deaths, myocardial infarctions and non-hemorrhagic strokes) prevented to the number of fatal or life-threatening bleeding events (fatal bleeds + symptomatic non-fatal bleeds into a critical organ) in the rivaroxaban group versus the placebo group. Compared to placebo, during 10,000 patient-years of treatment, rivaroxaban would be expected to result in 70 fewer CV events and 12 additional life-threatening bleeds, indicating a favorable balance of benefits and risks.

The results in the COMPASS CAD population were consistent across major subgroups (see Figure 9). Figure 9: Risk of Primary Efficacy Outcome by Baseline Characteristics in the COMPASS CAD Population (Intent-to-Treat Population)* *All patients received aspirin 100 mg once daily as background therapy. Table 26: Efficacy results from COMPASS CAD Population * * intention to treat analysis set, primary analyses. † Treatment schedule: Rivaroxaban 2.5 mg twice daily vs placebo.

All patients received aspirin 100 mg once daily as back… [Excerpted — this section continues on DailyMed.]

13 NON-CLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Rivaroxaban was not carcinogenic when administered by oral gavage to mice or rats for up to 2 years. The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day. Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.

Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo . No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally. This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.