RIVAROXABAN

Rivaroxaban, 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-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl] thiophene-2-carboxamide. The molecular formula of rivaroxaban is C 19 H 18 C 1 N 3 O 5 S and the molecular weight is 435.88. The structural formula is: Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to off-white powder. Freely soluble in dimethyl sulphoxide, dimethyl formamide, Slightly soluble in Dichloromethane, Very slightly soluble in acetone, and methanol and practically insoluble in water, anhydrous ethanol and heptane. Each Rivaroxaban Tablets, USP contains 2.5 mg,of rivaroxaban. The inactive ingredients of Rivaroxaban Tablets, USP are: Anhydrous Lactose NF, Croscarmellose Sodium NF, Hypromellose USP, Magnesium Stearate NF, and Sodium Lauryl Sulfate NF. Additionally, the film coating mixture for Rivaroxaban 2.5 mg tablets is Opadry II Beige, and contains: Polyethylene Glycol, Polyvinyl Alcohol, Red Iron Oxide, Talc, Titanium Dioxide, and Yellow Iron Oxide. Rivaroxaban Structure.jpg

INDICATIONS & USAGE Rivaroxaban Tablets 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 ) 1.7 Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) Rivaroxaban Tablets, in combination with aspirin, is 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, is 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.

CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75 mg to 100 mg) once daily ( 2.1 ) 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 (75-100 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 (75-100 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 ( 5.4 ) and Use in Specific Populations ( 8.6 )] † See Clinical Pharmacology ( 12.3 ) 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 ( 8.4 ) ] 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 3.0 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 Tablets 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 Tablets are 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 Tablets 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 ( 7.4 )]. Switching from Anticoagulants other than Warfarin to Rivaroxaban Tablets – Patients currently receiving an anticoagulant other than warfarin, start Rivaroxaban Tablets 0 hours to 2 hours prior to the next scheduled administration of the drug (e.g., low molecular weight heparin or nonwarfarin 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 ( 5.2 )]. 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 ( 5.1 )]. 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 Tablets 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 (all strengths) 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 ( 12.3 )]. Administration of Rivaroxaban tablets via nasogastric (NG) tube or gastric feeding tube: After confirming gastric placement of the tube, Rivaroxaban tablets (all strengths) 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 ( 12.3 )] . Crushed Rivaroxaban tablets (all strengths) 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 tablet to PVC or silicone nasogastric (NG) tubing.

Rivaroxaban tablets are contraindicated in patients with: active pathological bleeding [see Warnings and Precautions ( 5.2 )] severe hypersensitivity reaction to Rivaroxaban Tablets (e.g., anaphylactic reactions) [see Adverse Reactions ( 6.2 )] Active pathological bleeding ( 4 ) Severe hypersensitivity reaction to Rivaroxaban Tablets ( 4 )

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 ( 5.1 )] Bleeding Risk [see Warnings and Precautions ( 5.2 , 5.4 , 5.5 , 5.6 , 5.7 )] Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions ( 5.3 )] The most common adverse reaction (>5%) in adult patients was bleeding. ( 6.1 ) The most common adverse reactions (>10%) in pediatric patients were bleeding, cough, vomiting, and gastro enteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at (1-855-724-3436) 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 ( 5.2 )]. 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 † N=9134 n(%/year) Placebo† N=9107 n (%/year) Rivaroxabanvs. Placebo HR(95%CI) Modified ISTH Major Bleeding‡ 263 (1.6) 144 (0.9) 1.8 (1.5, 2.3) - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial 12 (<0.1) 6 (<0.1) 6 (<0.1) 8 (<0.1) 3 (<0.1) 5 (<0.1) 1.5 (0.6, 3.7) 2.0 (0.5, 8.0) 1.2 (0.4, 4.0) - Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH 58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) 43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) 1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) 7 (<0.1) 6 (<0.1) 1.2 (0.4, 3.5) - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) 188 (1.1) 91 (0.5) 2.1 (1.6, 2.7) Major GI bleeding 117 (0.7) 49 (0.3) 2.4 (1.7, 3.4) * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. † Treatment schedule: Rivaroxaban Tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization. CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis 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 The incidence of premature permanent discontinuation due to bleeding events for Rivaroxaban Tablets 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively. Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal. Table 11: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 Days Rivaroxaban † N=3256 Placebo† N=3248 Rivaroxaban vs. Placebo Parameter n (%) Event rate %/year n (%) Event rate %/year HR (95 % CI) TIMI Major Bleeding (CABG/non-CABG) 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1.0, 2.1) Fatal bleeding 6 (0.2) 0.09 6 (0.2) 0.09 1.0 (0.3, 3.2) Intracranial bleeding 13 (0.4) 0.20 17 (0.5) 0.26 0.8 (0.4, 1.6) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15% 46 (1.4) 0.71 24 (0.7) 0.36 1.9 (1.2, 3.2) CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: Rivaroxaban Tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of Rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12. Table 12: Other Adverse Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction EINSTEINDVT Study Rivaroxaban Tablets 20 mg N=1718 n (%) Enoxaparin/VKA N=1711 n (%) Gastrointestinaldisorders Abdominal pain 46 (2.7) 25 (1.5) Generaldisordersandadministration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletaland connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) EINSTEIN PE Study Rivaroxaban Tablets 20 mg N=2412 n (%) Enoxaparin/VKA N=2405 n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1) * Adverse reaction with Relative Risk >1.5 for Rivaroxaban Tablets versus comparator Non-hemorrhagic adverse reactions reported in ≥1% of Rivaroxaban-treated patients in RECORD 1–3 studies are shown in Table 13. Table 13: Other Adverse Drug Reactions* Reported by ≥1% of Rivaroxaban-Treated Patients in RECORD 1-3 Studies Body System Adverse Reaction Rivaroxaban 10 mg N=4487 n (%) Enoxaparin† N=4524 n (%) Injury,poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculo skeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * 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 N=64 n (%) Aspirin N=34 n (%) Cough 10 (15.6) 3 (8.8) Vomiting 9 (14.1) 3 (8.8) Gastroenteritis† 8 (12.5) 1 (2.9) Rash † 6 (9.4) 2 (5.9) * Adverse reaction with Relative Risk >1.5 for Rivaroxaban 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 Hepato biliary 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 ( 7.2 , 7.3 ) Anticoagulants: Avoid concomitant use ( 7.4 ) 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 ( 5.6 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 12.3 )]. 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 <80 mL/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 ( 5.4 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 5.6 ) and Clinical Pharmacology ( 12.3 )]. 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 ( 12.3 )]. 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 ( 5.2 )].