These Highlights Do Not Include All The Information Needed To Use Rivaroxaban Tablets Safely And Effectively. See Full Prescribing Information For Rivaroxaban Tablets.

A. Premature discontinuation of rivaroxaban increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. If anticoagulation with rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1)] .

Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature].

Keep out of the reach of children.

Overdose of rivaroxaban may lead to hemorrhage. Discontinue rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.3)] . Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Rivaroxaban, USP, a factor Xa (FXa) inhibitor, is the active ingredient in rivaroxaban tablets, USP with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban, USP is C ₁₉H ₁₈ClN ₃O ₅S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban, USP is a pure ( S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban, USP is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each rivaroxaban tablet, USP contains 2.5 mg of rivaroxaban, USP. The inactive ingredients of rivaroxaban tablets, USP are: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the film coating mixture for rivaroxaban 2.5 mg tablets, USP contains: ferric oxide yellow, ferrosoferric oxide, hypromellose, lactose monohydrate, polyethylene glycol 3350, and titanium dioxide.

For the rivaroxaban 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients.

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Of the total number of adult patients in clinical trials for the approved indications of rivaroxaban (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3)and Clinical Studies (14)] .

Rivaroxaban tablets are contraindicated in patients with:

• active pathological bleeding [see Warnings and Precautions (5.2)]
• severe hypersensitivity reaction to rivaroxaban (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Increased Risk of Stroke After Discontinuation in Another Indication [see Boxed Warningand Warnings and Precautions (5.1)]
• Bleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
• Spinal/Epidural Hematoma [see Boxed Warningand Warnings and Precautions (5.3)]

• Avoid combined P-gp and strong CYP3A inhibitors and inducers ( 7.2, 7.3)
• Anticoagulants: Avoid concomitant use ( 7.4)

Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue rivaroxaban in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y ₁₂platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4)] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2)] .

In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)] .

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.

In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in adult subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of rivaroxaban in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)] .

Avoid the use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

No clinical data are available in pediatric patients with hepatic impairment.

Rivaroxaban is a factor Xa inhibitor indicated:

• to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) ( 1.7)
• to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD ( 1.8)

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.

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).

For adult patients who are unable to swallow whole tablets, rivaroxaban tablets (2.5 mg) may be crushed and mixed with applesauce immediately prior to use and administered orally. Administration with food is not required for the 2.5 mg [see Clinical Pharmacology (12.3)] .

• Risk of bleeding: Rivaroxaban can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. ( 5.2)
• Pregnancy-related hemorrhage: Use rivaroxaban with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7, 8.1)
• Prosthetic heart valves: Rivaroxaban use not recommended. ( 5.8)
• Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Rivaroxaban use not recommended. ( 5.10)

• CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75 to 100 mg) once daily ( 2.1)

• 2.5 mg tablets: Round, light yellow, film-coated and debossed on one side with "□" and "2.5" on the other side

The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders:agranulocytosis, thrombocytopenia

Hepatobiliary disorders:jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders:hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders:hemiparesis

Renal disorders:Anticoagulant-related nephropathy

Respiratory, thoracic and mediastinal disorders:Eosinophilic pneumonia

Skin and subcutaneous tissue disorders:Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

Injury, poisoning and procedural complications: Atraumatic splenic rupture

• Renal impairment: Avoid or adjust dose ( 8.6)
• Hepatic impairment: Avoid use in Child-Pugh B and C hepatic impairment or hepatic disease associated with coagulopathy ( 8.7)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Indication	Renal Considerations Calculate CrCl based on actual weight. [See Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]	Dosage	Food/Timing
Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD	No dose adjustment needed based on CrCl	2.5 mg twice daily, plus aspirin (75 to 100 mg) once daily	Take with or without food
Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD	No dose adjustment needed based on CrCl	2.5 mg twice daily, plus aspirin (75 to 100 mg) once daily When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established.	Take with or without food

For the tablets, advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Rivaroxaban Tablets, USP are available in the strengths and packages listed below:

2.5 mg tablets are round, light yellow, film-coated and debossed on one side with "◻" and "2.5" on the other side. The tablets are supplied in the packages listed:

NDC 51672-4228-4 Bottle containing 60 tablets

NDC 51672-4228-9 Bottle containing 180 tablets

NDC 51672-4228-1 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3)] .

Avoid concurrent use of rivaroxaban with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)] .

In pregnant women, rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2)and Use in Specific Populations (8.1)] .

On the basis of the GALILEO study, use of rivaroxaban is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban is not recommended in patients with prosthetic heart valves.

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] .

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban [see Clinical Pharmacology (12.3)] . The next rivaroxaban dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

No clinical data are available for adult patients with severe hepatic impairment.

Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.7)].

No clinical data are available in pediatric patients with hepatic impairment.

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including rivaroxaban should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

NDC 51672-4228-4

60 Tablets

Rivaroxaban Tablets, USP

2.5 mg

Dispense with the accompanying Medication Guide

Rx only

If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2)] . In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1)] . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

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 vitroor 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.

Avoid concomitant use of rivaroxaban with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2)].

Avoid concomitant use of rivaroxaban with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3)].

Premature discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in another indication in patients. If rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4)] .

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 Cardiovascular Outco Mes for People using Anticoagulation Strategie Strial (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 26and 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.

Event	Rivaroxaban Treatment schedule: Rivaroxaban 2.5 mg twice daily vs placebo. All patients received aspirin 100 mg once daily as background therapy. N=8313	Placebo N=8261	Hazard Ratio (95% CI) Rivaroxaban vs. placebo.
n (%)	Event Rate (%/year)	n (%)	Event Rate (%/year)
CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction
Stroke, MI or CV death	347 (4.2)	2.2	460 (5.6)	2.9	0.74 (0.65, 0.86)
- Stroke	74 (0.9)	0.5	130 (1.6)	0.8	0.56 (0.42, 0.75)
- MI	169 (2.0)	1.1	195 (2.4)	1.2	0.86 (0.70, 1.05)
- CV death	139 (1.7)	0.9	184 (2.2)	1.1	0.75 (0.60, 0.93)
Coronary heart disease death, MI, ischemic stroke, acute limb ischemia	299 (3.6)	1.9	411 (5.0)	2.6	0.72 (0.62, 0.83)
- Coronary heart disease death Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure.	80 (1.0)	0.5	107 (1.3)	0.7	0.74 (0.55, 0.99)
- Ischemic stroke	56 (0.7)	0.3	114 (1.4)	0.7	0.49 (0.35, 0.67)
- Acute limb ischemia Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation).	13 (0.2)	0.1	27 (0.3)	0.2	0.48 (0.25, 0.93)
CV death CV death includes CHD death, or death due to other CV causes or unknown death. , MI, ischemic stroke, acute limb ischemia	349 (4.2)	2.2	470 (5.7)	3.0	0.73 (0.64, 0.84)
All-cause mortality	262 (3.2)	1.6	339 (4.1)	2.1	0.77 (0.65, 0.90)

CI: confidence interval

Figure 10: Time to First Occurrence of Primary Efficacy Outcome (Stroke, Myocardial Infarction, Cardiovascular Death) in the COMPASS CAD Population All patients received aspirin 100 mg once daily as background therapy.

Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Warnings and Precautions (5.6)and Clinical Pharmacology (12.3)] .

Direct-acting oral anticoagulants (DOACs), including rivaroxaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Rivaroxaban tablets, in combination with aspirin, are indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.

Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

See full prescribing information for complete boxed warning.

(A) Premature discontinuation of rivaroxaban increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy. ( 2.3, 5.1)

(B) Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. ( 5.2, 5.3, 6.2)

Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated. ( 5.3)

The efficacy and safety of rivaroxaban 2.5 mg orally twice daily versus placebo on a background of aspirin 100 mg once daily in patients with PAD were evaluated in the COMPASS study (n=4996) and will be referred to as the COMPASS PAD population [see Clinical Studies (14.6)] .

The efficacy and safety of rivaroxaban were also evaluated for the reduction in the risk of the composite endpoint of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology in patients undergoing a lower extremity infrainguinal revascularization procedure due to symptomatic peripheral artery disease (PAD) in the double-blinded, placebo-controlled Vascular Outcomes stud Yof ASA alon Gwith rivaroxaban in Endovascular or surgical limb Revascularization for peripheral artery disease (PAD) trial (VOYAGER) [NCT02504216]. A total of 6,564 patients were equally randomized to rivaroxaban 2.5 mg orally twice daily vs placebo on a background therapy of aspirin 100 mg once daily.

Eligible patients included adults who were at least 50 years of age with documented moderate to severe symptomatic lower extremity atherosclerotic PAD who had a successful peripheral surgical procedure and/or endovascular procedure with or without clopidogrel (up to a maximum of 6 months was allowed; median duration of therapy was 31 days). Patients had either a prior history of limb revascularization with ankle brachial index ≤0.85 or no prior history of limb revascularization with ankle brachial index ≤0.80. Patients in need of dual antiplatelet for >6 months, or any additional antiplatelet other than aspirin and clopidogrel, or oral anticoagulant, as well as patients with a history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA), or patients with eGFR <15 mL/min were excluded.

The mean age was 67 years and 20% of the subject population was ≥75 years. Of the included patients, 35% had surgical revascularization, 47% had endovascular revascularization with clopidogrel, and 18% endovascular revascularization without clopidogrel. The median duration of follow-up was 30.8 months.

Rivaroxaban 2.5 mg twice daily was superior to placebo in reducing the rate of the primary composite outcome of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology. The primary efficacy outcome and its components are provided in Table 27. The Kaplan-Meier plot for the primary efficacy outcome can be seen in Figure 11. The secondary efficacy outcomes were tested for superiority in a prespecified, hierarchical order and the first five of seven endpoints were significantly reduced in the rivaroxaban treatment arm (see Table 27). Compared to placebo during 10,000 patient-years of treatment, rivaroxaban would be expected to result in 181 fewer primary outcome events and 29 more TIMI major bleeding events, indicating a favorable balance of benefits and risks.

Figure 11: Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGER All patients received aspirin 100 mg once daily as background therapy.

Figure 12 shows the risk of primary efficacy outcome across major subgroups. Subgroup analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. The primary efficacy endpoint generally shows homogeneous results across subgroups.

Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population) All patients received aspirin 100 mg once daily as background therapy.

Table 27 provides the efficacy event rates for the prespecified endpoints in VOYAGER and similar endpoints in the COMPASS PAD population.

	VOYAGER	COMPASS PAD
	Rivaroxaban N=3286	Placebo N=3278	Hazard Ratio (95% CI) Rivaroxaban vs. placebo. p-value Two-sided p-values	Rivaroxaban N=2492	Placebo N=2504	Hazard Ratio (95% CI)
Outcome Components	Event Rate (%/year)	Event Rate (%/year)
Efficacy endpoints in COMPASS PAD were analysed according to the pre-specified endpoints in VOYAGER when applicable. ALI=acute limb ischemia, CHD=coronary heart disease; CI=confidence interval, CV=cardiovascular; MI=myocardial infarction, VTE=venous thromboembolism.
5-Component Outcome (Major thrombotic vascular events) Major thrombotic vascular event is the composite of MI, ischemic stroke, CV death, ALI, and major amputation of a vascular etiology.	6.8	8.0	0.85 (0.76, 0.96) p=0.0085	3.4	4.8	0.71 (0.57, 0.87)
MI	1.7	1.9	0.88 (0.70, 1.12)	1.1	1.5	0.76 (0.53, 1.09)
Ischemic Stroke Ischemic stroke for VOYAGER included stroke of uncertain/unknown etiology whereas COMPASS only included ischemic stroke.	0.9	1.0	0.87 (0.63, 1.19)	0.5	0.9	0.55 (0.33, 0.93)
CV death CV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death.	2.5	2.2	1.14 (0.93, 1.40)	1.4	1.7	0.82 (0.59, 1.14)
ALI	2.0	3.0	0.67 (0.55, 0.82)	0.4	0.8	0.56 (0.32, 0.99)
Major amputation of a vascular etiology Adjudicated events in VOYAGER and investigator reported events in COMPASS	1.3	1.5	0.89 (0.68, 1.16)	0.2	0.6	0.40 (0.20, 0.79)
VOYAGER Secondary Efficacy Outcomes Secondary outcomes for VOYAGER were tested sequentially.
MI, ischemic stroke, CHD death, CHD death includes death due to sudden cardiac death, MI, or coronary revascularization procedure ALI, and major amputation due to vascular etiology	5.8	7.3	0.80 (0.71, 0.91) p=0.0008	2.8	4.2	0.66 (0.53, 0.83)
Unplanned index limb revascularization for recurrent limb ischemia Unplanned index limb revascularization for recurrent limb ischemia was not captured in COMPASS study.	8.4	9.5	0.88 (0.79, 0.99) p=0.028	N/A	N/A	N/A
Hospitalization for a coronary or peripheral cause of a thrombotic nature	3.5	4.8	0.72 (0.62, 0.85) p<0.0001	1.7	2.9	0.58 (0.44, 0.77)
MI, ischemic stroke, all-cause mortality, ALI, and major amputation due to vascular etiology	8.2	9.3	0.89 (0.79, 0.99) p=0.029	4.8	6.0	0.80 (0.67, 0.96)
MI, all-cause stroke, CV death, ALI, and major amputation due to vascular etiology	6.9	8.1	0.86 (0.76, 0.96) p=0.010	3.4	4.9	0.70 (0.57, 0.86)
All-cause mortality	4.0	3.7	1.08 (0.92, 1.27)	2.8	3.1	0.91 (0.72, 1.16)
VTE events Investigator reported in VOYAGER and adjudicated events in COMPASS	0.3	0.5	0.61 (0.37, 1.00)	0.2	0.3	0.67 (0.30, 1.49)

Rivaroxaban tablets, in combination with aspirin, are indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.

A. Premature discontinuation of rivaroxaban increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. If anticoagulation with rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4), Warnings and Precautions (5.1)] .

Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature].

Keep out of the reach of children.

Overdose of rivaroxaban may lead to hemorrhage. Discontinue rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.3)] . Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Rivaroxaban, USP, a factor Xa (FXa) inhibitor, is the active ingredient in rivaroxaban tablets, USP with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban, USP is C ₁₉H ₁₈ClN ₃O ₅S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban, USP is a pure ( S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban, USP is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each rivaroxaban tablet, USP contains 2.5 mg of rivaroxaban, USP. The inactive ingredients of rivaroxaban tablets, USP are: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the film coating mixture for rivaroxaban 2.5 mg tablets, USP contains: ferric oxide yellow, ferrosoferric oxide, hypromellose, lactose monohydrate, polyethylene glycol 3350, and titanium dioxide.

For the rivaroxaban 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients.

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

Of the total number of adult patients in clinical trials for the approved indications of rivaroxaban (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3)and Clinical Studies (14)] .

Rivaroxaban tablets are contraindicated in patients with:

• active pathological bleeding [see Warnings and Precautions (5.2)]
• severe hypersensitivity reaction to rivaroxaban (e.g., anaphylactic reactions) [see Adverse Reactions (6.2)]

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Increased Risk of Stroke After Discontinuation in Another Indication [see Boxed Warningand Warnings and Precautions (5.1)]
• Bleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
• Spinal/Epidural Hematoma [see Boxed Warningand Warnings and Precautions (5.3)]

• Avoid combined P-gp and strong CYP3A inhibitors and inducers ( 7.2, 7.3)
• Anticoagulants: Avoid concomitant use ( 7.4)

Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue rivaroxaban in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y ₁₂platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.4)] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.2)] .

In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3)] .

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.

In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in adult subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of rivaroxaban in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3)] .

Avoid the use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

No clinical data are available in pediatric patients with hepatic impairment.

Rivaroxaban is a factor Xa inhibitor indicated:

• to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) ( 1.7)
• to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD ( 1.8)

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.

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).

For adult patients who are unable to swallow whole tablets, rivaroxaban tablets (2.5 mg) may be crushed and mixed with applesauce immediately prior to use and administered orally. Administration with food is not required for the 2.5 mg [see Clinical Pharmacology (12.3)] .

• Risk of bleeding: Rivaroxaban can cause serious and fatal bleeding. An agent to reverse the activity of rivaroxaban is available. ( 5.2)
• Pregnancy-related hemorrhage: Use rivaroxaban with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7, 8.1)
• Prosthetic heart valves: Rivaroxaban use not recommended. ( 5.8)
• Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Rivaroxaban use not recommended. ( 5.10)

• CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75 to 100 mg) once daily ( 2.1)

• 2.5 mg tablets: Round, light yellow, film-coated and debossed on one side with "□" and "2.5" on the other side

The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders:agranulocytosis, thrombocytopenia

Hepatobiliary disorders:jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune system disorders:hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous system disorders:hemiparesis

Renal disorders:Anticoagulant-related nephropathy

Respiratory, thoracic and mediastinal disorders:Eosinophilic pneumonia

Skin and subcutaneous tissue disorders:Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

Injury, poisoning and procedural complications: Atraumatic splenic rupture

• Renal impairment: Avoid or adjust dose ( 8.6)
• Hepatic impairment: Avoid use in Child-Pugh B and C hepatic impairment or hepatic disease associated with coagulopathy ( 8.7)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Indication	Renal Considerations Calculate CrCl based on actual weight. [See Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]	Dosage	Food/Timing
Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD	No dose adjustment needed based on CrCl	2.5 mg twice daily, plus aspirin (75 to 100 mg) once daily	Take with or without food
Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD	No dose adjustment needed based on CrCl	2.5 mg twice daily, plus aspirin (75 to 100 mg) once daily When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established.	Take with or without food

For the tablets, advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Rivaroxaban Tablets, USP are available in the strengths and packages listed below:

2.5 mg tablets are round, light yellow, film-coated and debossed on one side with "◻" and "2.5" on the other side. The tablets are supplied in the packages listed:

NDC 51672-4228-4 Bottle containing 60 tablets

NDC 51672-4228-9 Bottle containing 180 tablets

NDC 51672-4228-1 Blister package containing 100 tablets (10 blister cards containing 10 tablets each)

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3)] .

Avoid concurrent use of rivaroxaban with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)] .

In pregnant women, rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban dosing in pregnancy has not been studied. The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions (5.2)and Use in Specific Populations (8.1)] .

On the basis of the GALILEO study, use of rivaroxaban is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to rivaroxaban experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of rivaroxaban have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of rivaroxaban is not recommended in patients with prosthetic heart valves.

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] .

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban [see Clinical Pharmacology (12.3)] . Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of rivaroxaban [see Clinical Pharmacology (12.3)] . The next rivaroxaban dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of rivaroxaban for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

No clinical data are available for adult patients with severe hepatic impairment.

Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations (8.7)].

No clinical data are available in pediatric patients with hepatic impairment.

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including rivaroxaban should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

NDC 51672-4228-4

60 Tablets

Rivaroxaban Tablets, USP

2.5 mg

Dispense with the accompanying Medication Guide

Rx only

If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions (5.2)] . In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short [see Warnings and Precautions (5.1)] . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.

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 vitroor 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.

Avoid concomitant use of rivaroxaban with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions (7.2)].

Avoid concomitant use of rivaroxaban with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions (7.3)].

Premature discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in another indication in patients. If rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4)] .

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 Cardiovascular Outco Mes for People using Anticoagulation Strategie Strial (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 26and 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.

Event	Rivaroxaban Treatment schedule: Rivaroxaban 2.5 mg twice daily vs placebo. All patients received aspirin 100 mg once daily as background therapy. N=8313	Placebo N=8261	Hazard Ratio (95% CI) Rivaroxaban vs. placebo.
n (%)	Event Rate (%/year)	n (%)	Event Rate (%/year)
CHD: coronary heart disease, CI: confidence interval; CV: cardiovascular; MI: myocardial infarction
Stroke, MI or CV death	347 (4.2)	2.2	460 (5.6)	2.9	0.74 (0.65, 0.86)
- Stroke	74 (0.9)	0.5	130 (1.6)	0.8	0.56 (0.42, 0.75)
- MI	169 (2.0)	1.1	195 (2.4)	1.2	0.86 (0.70, 1.05)
- CV death	139 (1.7)	0.9	184 (2.2)	1.1	0.75 (0.60, 0.93)
Coronary heart disease death, MI, ischemic stroke, acute limb ischemia	299 (3.6)	1.9	411 (5.0)	2.6	0.72 (0.62, 0.83)
- Coronary heart disease death Coronary heart disease death: death due to acute MI, sudden cardiac death, or CV procedure.	80 (1.0)	0.5	107 (1.3)	0.7	0.74 (0.55, 0.99)
- Ischemic stroke	56 (0.7)	0.3	114 (1.4)	0.7	0.49 (0.35, 0.67)
- Acute limb ischemia Acute limb ischemia is defined as limb-threatening ischemia leading to an acute vascular intervention (i.e., pharmacologic, peripheral arterial surgery/reconstruction, peripheral angioplasty/stent, or amputation).	13 (0.2)	0.1	27 (0.3)	0.2	0.48 (0.25, 0.93)
CV death CV death includes CHD death, or death due to other CV causes or unknown death. , MI, ischemic stroke, acute limb ischemia	349 (4.2)	2.2	470 (5.7)	3.0	0.73 (0.64, 0.84)
All-cause mortality	262 (3.2)	1.6	339 (4.1)	2.1	0.77 (0.65, 0.90)

CI: confidence interval

Figure 10: Time to First Occurrence of Primary Efficacy Outcome (Stroke, Myocardial Infarction, Cardiovascular Death) in the COMPASS CAD Population All patients received aspirin 100 mg once daily as background therapy.

Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Warnings and Precautions (5.6)and Clinical Pharmacology (12.3)] .

Direct-acting oral anticoagulants (DOACs), including rivaroxaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Rivaroxaban tablets, in combination with aspirin, are indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.

Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

WARNING: (A) PREMATURE DISCONTINUATION OF RIVAROXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

See full prescribing information for complete boxed warning.

(A) Premature discontinuation of rivaroxaban increases the risk of thrombotic events

Premature discontinuation of any oral anticoagulant, including rivaroxaban, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy. ( 2.3, 5.1)

(B) Spinal/epidural hematoma

Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. ( 5.2, 5.3, 6.2)

Monitor patients frequently for signs and symptoms of neurological impairment and if observed, treat urgently. Consider the benefits and risks before neuraxial intervention in patients who are or who need to be anticoagulated. ( 5.3)

The efficacy and safety of rivaroxaban 2.5 mg orally twice daily versus placebo on a background of aspirin 100 mg once daily in patients with PAD were evaluated in the COMPASS study (n=4996) and will be referred to as the COMPASS PAD population [see Clinical Studies (14.6)] .

The efficacy and safety of rivaroxaban were also evaluated for the reduction in the risk of the composite endpoint of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology in patients undergoing a lower extremity infrainguinal revascularization procedure due to symptomatic peripheral artery disease (PAD) in the double-blinded, placebo-controlled Vascular Outcomes stud Yof ASA alon Gwith rivaroxaban in Endovascular or surgical limb Revascularization for peripheral artery disease (PAD) trial (VOYAGER) [NCT02504216]. A total of 6,564 patients were equally randomized to rivaroxaban 2.5 mg orally twice daily vs placebo on a background therapy of aspirin 100 mg once daily.

Eligible patients included adults who were at least 50 years of age with documented moderate to severe symptomatic lower extremity atherosclerotic PAD who had a successful peripheral surgical procedure and/or endovascular procedure with or without clopidogrel (up to a maximum of 6 months was allowed; median duration of therapy was 31 days). Patients had either a prior history of limb revascularization with ankle brachial index ≤0.85 or no prior history of limb revascularization with ankle brachial index ≤0.80. Patients in need of dual antiplatelet for >6 months, or any additional antiplatelet other than aspirin and clopidogrel, or oral anticoagulant, as well as patients with a history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA), or patients with eGFR <15 mL/min were excluded.

The mean age was 67 years and 20% of the subject population was ≥75 years. Of the included patients, 35% had surgical revascularization, 47% had endovascular revascularization with clopidogrel, and 18% endovascular revascularization without clopidogrel. The median duration of follow-up was 30.8 months.

Rivaroxaban 2.5 mg twice daily was superior to placebo in reducing the rate of the primary composite outcome of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia (ALI), and major amputation of a vascular etiology. The primary efficacy outcome and its components are provided in Table 27. The Kaplan-Meier plot for the primary efficacy outcome can be seen in Figure 11. The secondary efficacy outcomes were tested for superiority in a prespecified, hierarchical order and the first five of seven endpoints were significantly reduced in the rivaroxaban treatment arm (see Table 27). Compared to placebo during 10,000 patient-years of treatment, rivaroxaban would be expected to result in 181 fewer primary outcome events and 29 more TIMI major bleeding events, indicating a favorable balance of benefits and risks.

Figure 11: Time to First Occurrence of Primary Efficacy Outcome (Myocardial Infarction, Ischemic Stroke, Cardiovascular Death, Acute Limb Ischemia, Major Amputation due to Vascular Origins) in VOYAGER All patients received aspirin 100 mg once daily as background therapy.

Figure 12 shows the risk of primary efficacy outcome across major subgroups. Subgroup analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. The primary efficacy endpoint generally shows homogeneous results across subgroups.

Figure 12: Risk of Primary Efficacy Outcome by Baseline Characteristics in VOYAGER (Intent-to-Treat Population) All patients received aspirin 100 mg once daily as background therapy.

Table 27 provides the efficacy event rates for the prespecified endpoints in VOYAGER and similar endpoints in the COMPASS PAD population.

	VOYAGER	COMPASS PAD
	Rivaroxaban N=3286	Placebo N=3278	Hazard Ratio (95% CI) Rivaroxaban vs. placebo. p-value Two-sided p-values	Rivaroxaban N=2492	Placebo N=2504	Hazard Ratio (95% CI)
Outcome Components	Event Rate (%/year)	Event Rate (%/year)
Efficacy endpoints in COMPASS PAD were analysed according to the pre-specified endpoints in VOYAGER when applicable. ALI=acute limb ischemia, CHD=coronary heart disease; CI=confidence interval, CV=cardiovascular; MI=myocardial infarction, VTE=venous thromboembolism.
5-Component Outcome (Major thrombotic vascular events) Major thrombotic vascular event is the composite of MI, ischemic stroke, CV death, ALI, and major amputation of a vascular etiology.	6.8	8.0	0.85 (0.76, 0.96) p=0.0085	3.4	4.8	0.71 (0.57, 0.87)
MI	1.7	1.9	0.88 (0.70, 1.12)	1.1	1.5	0.76 (0.53, 1.09)
Ischemic Stroke Ischemic stroke for VOYAGER included stroke of uncertain/unknown etiology whereas COMPASS only included ischemic stroke.	0.9	1.0	0.87 (0.63, 1.19)	0.5	0.9	0.55 (0.33, 0.93)
CV death CV death includes Coronary Heart Disease death, or death due to other CV causes or sudden cardiac arrest and unknown death.	2.5	2.2	1.14 (0.93, 1.40)	1.4	1.7	0.82 (0.59, 1.14)
ALI	2.0	3.0	0.67 (0.55, 0.82)	0.4	0.8	0.56 (0.32, 0.99)
Major amputation of a vascular etiology Adjudicated events in VOYAGER and investigator reported events in COMPASS	1.3	1.5	0.89 (0.68, 1.16)	0.2	0.6	0.40 (0.20, 0.79)
VOYAGER Secondary Efficacy Outcomes Secondary outcomes for VOYAGER were tested sequentially.
MI, ischemic stroke, CHD death, CHD death includes death due to sudden cardiac death, MI, or coronary revascularization procedure ALI, and major amputation due to vascular etiology	5.8	7.3	0.80 (0.71, 0.91) p=0.0008	2.8	4.2	0.66 (0.53, 0.83)
Unplanned index limb revascularization for recurrent limb ischemia Unplanned index limb revascularization for recurrent limb ischemia was not captured in COMPASS study.	8.4	9.5	0.88 (0.79, 0.99) p=0.028	N/A	N/A	N/A
Hospitalization for a coronary or peripheral cause of a thrombotic nature	3.5	4.8	0.72 (0.62, 0.85) p<0.0001	1.7	2.9	0.58 (0.44, 0.77)
MI, ischemic stroke, all-cause mortality, ALI, and major amputation due to vascular etiology	8.2	9.3	0.89 (0.79, 0.99) p=0.029	4.8	6.0	0.80 (0.67, 0.96)
MI, all-cause stroke, CV death, ALI, and major amputation due to vascular etiology	6.9	8.1	0.86 (0.76, 0.96) p=0.010	3.4	4.9	0.70 (0.57, 0.86)
All-cause mortality	4.0	3.7	1.08 (0.92, 1.27)	2.8	3.1	0.91 (0.72, 1.16)
VTE events Investigator reported in VOYAGER and adjudicated events in COMPASS	0.3	0.5	0.61 (0.37, 1.00)	0.2	0.3	0.67 (0.30, 1.49)

Rivaroxaban tablets, in combination with aspirin, are indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD.