rivaroxaban

Rivaroxaban is a factor Xa inhibitor indicated: to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD) 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 1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) 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. 1.8 Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD 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.

2 DOSAGE & ADMINISTRATION 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 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations* 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 * Calculate CrCl based on actual weight. [See Warnings and Precautions and Use in Specific Populations ] † See Clinical Pharmacology 2.2 Recommended Dosage in Pediatric Patients Rivaroxaban 2.5 mg tablets are not recommended for use in pediatric patients [see Use in Specific Populations ] . 2.3 Switching to and from Rivaroxaban Tablets Switching from Warfarin to Rivaroxaban Tablets When switching patients from warfarin to rivaroxaban tablets, discontinue warfarin and start rivaroxaban tablets as soon as the International Normalized Ratio (INR) is below 3 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation. Switching from Rivaroxaban Tablets to Warfarin – Adults: No clinical trial data are available to guide converting patients from rivaroxaban tablets to warfarin. Rivaroxaban tablet affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue rivaroxaban tablets and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban tablets would have been taken. Once rivaroxaban is discontinued, INR testing may be done reliably 24 hours after the last dose. Switching from Rivaroxaban Tablets to Anticoagulants other than Warfarin Patients currently taking rivaroxaban tablets and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban tablet and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban tablets dose would have been taken [see Drug Interactions ] . Switching from Anticoagulants other than Warfarin to Rivaroxaban tablets Patients currently receiving an anticoagulant other than warfarin, start rivaroxaban tablets 0 to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban tablets at the same time. 2.4 Discontinuation for Surgery and Other Interventions If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban tablets should be stopped at least 24 hours before the procedure to reduce the risk of bleeding [see Warnings and Precautions ] . In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban tablets, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban tablets 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 ] . If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant. 2.5 Missed Dose Adults For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg rivaroxaban tablet dose as recommended at the next scheduled time. On the following day, the patient should continue with their regular regimen. 2.6 Administration Options For adult patients who are unable to swallow whole tablets, rivaroxaban tablets 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 tablets [see Clinical Pharmacology ] . Administration of Rivaroxaban Tablets via Nasogastric (NG) Tube or Gastric Feeding Tube: After confirming gastric placement of the tube, rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube. Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of rivaroxaban tablets distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure. Enteral feeding is not required following administration of the 2.5 mg tablets [see Clinical Pharmacology ] . Crushed rivaroxaban tablets are stable in water and in applesauce for up to 4 hours. An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed rivaroxaban tablets to PVC or silicone nasogastric (NG) tubing.

12.1 Mechanism 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.

The following clinically significant adverse reactions are also discussed in other sections of the labeling: Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions ] Bleeding Risk [see Warnings and Precautions ] Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions ] The most common adverse reaction (>5%) in adult patients was bleeding. The most common adverse reactions (>10%) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. To report SUSPECTED ADVERSE REACTIONS, contact +1 833 856 0880 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. During clinical development for the approved indications, 34,947 adult patients were exposed to rivaroxaban tablets. Hemorrhage The most common adverse reactions with rivaroxaban tablets were bleeding complications [see Warnings and Precautions ] . Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for rivaroxaban tablets 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar. Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial. Table 10: Major Bleeding Events in COMPASS -On Treatment Plus 2 Days* Parameter Rivaroxaban Tablets † N=9134 n (%/year) Placebo† N=9107 n (%/year) Rivaroxaban Tablets plus Placebo HR (95 % CI) Modified ISTH Major Bleeding‡ 263 144 1.8 -Fatal bleeding event 12 ( 1.5 for rivaroxaban tablets versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in RECORD 1 to 3 studies are shown in Table 13. Table 13: Other Adverse Drug Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in RECORD 1 to 3 Studies Body System Adverse Reaction Rivaroxaban Tablets 10 mg N=4487 n (%) Enoxaparin † N=4524 n (%) Injury, poisoning and procedural complications Wound secretion 125 89 Musculoskeletal and connective tissue disorders Pain in extremity 74 55 Muscle spasm 52 32 Nervous system disorders Syncope 55 32 Skin and subcutaneous tissue disorders Pruritus 96 79 Blister 63 40 *Adverse reaction occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1 to 3) Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 17. Table 17: Other Adverse Reactions* Reported by ≥5% of Rivaroxaban-Treated Patients in UNIVERSE Study (Part B) Adverse Reaction Rivaroxaban Tablets N=64 n (%) Aspirin N=34 n (%) Cough 10 3 Vomiting 9 3 Gastroenteritis † 8 1 Rash † 6 2 *Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rivaroxaban tablets. 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

Avoid combined P-gp and strong CYP3A inhibitors and inducers Anticoagulants: Avoid concomitant use 7.1 General Inhibition and Induction Properties 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. 7.2 Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of rivaroxaban tablets with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology ]. Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with rivaroxaban tablets as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology ] . Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment Rivaroxaban tablets should not be used in patients with CrCl 15 to < 80mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions and Clinical Pharmacology ] . 7.3 Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of rivaroxaban tablets with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology ] . 7.4 Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology ] . Avoid concurrent use of rivaroxaban tablets 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 ] .

Renal Impairment: Avoid or adjust dose Hepatic Impairment: Avoid use in Child-Pugh B and C hepatic impairment or hepatic disease associated with coagulopathy 8.1 Pregnancy Risk Summary The limited available data on rivaroxaban tablets in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use rivaroxaban tablets with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of rivaroxaban tablets cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of rivaroxaban tablets for the mother and possible risks to the fetus when prescribing rivaroxaban tablets to a pregnant woman [see Warnings and Precautions ] . Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss. Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate. Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions ] . The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of rivaroxaban tablets in this setting. Data Human Data There are no adequate or well-controlled studies of rivaroxaban tablets in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta. Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Lactation Risk Summary Rivaroxaban has been detected in human milk.

There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rivaroxaban tablets and any potential adverse effects on the breastfed infant from rivaroxaban tablets or from the underlying maternal condition ( see Data ). Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [ 14 C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose. 8.3 Females and Males of Reproductive Potential 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 tablets should be assessed in females of reproductive potential and those with abnormal uterine bleeding. 8.4 Pediatric Use 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 tablets 2.5 mg tablets are not recommended for use in pediatric patients. 8.5 Geriatric Use Of the total number of adult patients in clinical trials for the approved indications of rivaroxaban tablets (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 tablets 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 and Clinical Studies ] . 8.6 Renal Impairment 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 ] . Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD Patients with Chronic Kidney Disease not on Dialysis: Patients with a CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg rivaroxaban tablets twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology ], whose efficacy and safety outcomes were similar to those with preserved renal function. Patients with End-Stage Renal Disease on Dialysis: No clinical outcome data is available for the use of rivaroxaban tablets with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of rivaroxaban tablets 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology ] . It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. 8.7 Hepatic Impairment 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 tablets in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology ] . Avoid the use of rivaroxaban tablets 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.