RIVAROXABAN

RECENT MAJOR CHANGES Warnings and Precautions ( 5.2 ) 03/2026

1 INDICATIONS AND USAGE Rivaroxaban tablet is a factor Xa inhibitor indicated: • to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation ( 1.1 ) • for treatment of deep vein thrombosis (DVT) ( 1.2 ) • for treatment of pulmonary embolism (PE) ( 1.3 ) • for reduction in the risk of recurrence of DVT or PE ( 1.4 ) • for prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery ( 1.5 ) • for prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients ( 1.6 ) • 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 ) • for treatment of VTE and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years ( 1.9 ) • for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure ( 1.10 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation Rivaroxaban tablets are indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of rivaroxaban tablets and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1)]. 1.2 Treatment of Deep Vein Thrombosis Rivaroxaban tablets are indicated for the treatment of deep vein thrombosis (DVT). 1.3 Treatment of Pulmonary Embolism Rivaroxaban tablets are indicated for the treatment of pulmonary embolism (PE). 1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism Rivaroxaban tablets are indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months. 1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Rivaroxaban tablets are indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery. 1.6 Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Rivaroxaban tablets are indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding [see Warnings and Precautions (5.2) and Clinical Studies (14.5)]. 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. 1.9 Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Rivaroxaban tablets are indicated for the treatment of venous thromboembolism (VTE) an …

2 DOSAGE AND ADMINISTRATION • Nonvalvular Atrial Fibrillation : 15 or 20 mg, once daily with food ( 2.1 ) • Treatment of DVT and/or PE : 15 mg orally twice daily with food for the first 21 days followed by 20 mg orally once daily with food for the remaining treatment ( 2.1 ) • Reduction in the Risk of Recurrence of DVT and/or PE in patients at continued risk for DVT and/or PE : 10 mg once daily with or without food, after at least 6 months of standard anticoagulant treatment ( 2.1 ) • Prophylaxis of DVT Following Hip or Knee Replacement Surgery : 10 mg orally once daily with or without food ( 2.1 ) • Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding : 10 mg once daily, with or without food, in hospital and after hospital discharge for a total recommended duration of 31 to 39 days ( 2.1 ) • 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 ) • Pediatric Patients : See dosing recommendations in the Full Prescribing Information ( 2.2 ) 2.1 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations * Dosage Food/Timing † Reduction in Risk of Stroke in Nonvalvular Atrial Fibrillation CrCl >50 mL/min 20 mg once daily Take with evening meal CrCl ≤50 mL/min ‡ 15 mg once daily Take with evening meal Treatment of DVT and /or PE CrCl ≥ 15 mL/min ‡ 15 mg twice daily ▼after 21 days, transition to ▼ 20 mg once daily Take with food, at the same time each day CrCl 13 and 13 and < 18 years Patients Less than 1 Year of Age Determine renal function using serum creatinine. Avoid use of rivaroxaban tablets in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile, as no clinical data are available. Table 4: Reference Values of Serum Creatinine in Pediatric Patients <1 Year of Age Age 97.5 th Percentile of Creatinine (mg/dL) 97.5 th Percentile of Creatinine (μmol/L) Week 2 0.52 46 Week 3 0.46 41 Week 4 0.42 37 Month 2 0.37 33 Month 3 0.34 30 Month 4 to 6 0.34 30 Month 7 to 9 0.34 30 Month 10 to 12 0.36 32 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 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. • Pediatric Patients: To ensure adequate anticoagulation during the transition from rivaroxaban tablets to warfarin, continue rivaroxaban tablets for at least 2 days after the first dose of warfarin. After 2 days of co-administration, an INR should be obtained prior to the next scheduled dose of rivaroxaban tablets. Co-administration of rivaroxaban tablets and warfarin is advised to continue until the INR is ≥ 2. Once rivaroxaban tablet is discontinued, INR testing may be done reliably 24 hours after the last dose. Switching from Rivaroxaban tablets to Anticoagulants other than Warfarin - For adult and pediatric 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 Rivaroxaba …

3 DOSAGE FORMS AND STRENGTHS • 2.5 mg tablets: Light yellow to yellow round biconvex film-coated tablets debossed with “9” on one side and “C” on other side. • 10 mg tablets: Round, pink, biconvex film-coated tablets debossed with “L” on one side and “10” on the other side. • 15 mg tablets: Round, brown, film-coated biconvex tablets debossed with‘504’ on one side and plain on the other side. • 20 mg tablets: Triangle shaped, brown, film-coated tablets debossed with ‘505’ on one side and plain on the other side. Tablets: 2.5 mg, 10 mg, 15 mg, and 20 mg ( 3 )

4 CONTRAINDICATIONS Rivaroxaban tablets is 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 )

6 ADVERSE REACTIONS 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 gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Indoco Remedies Limited at +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 ( 5.2 )] . Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for rivaroxaban tablets vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups. Table 5 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial. Table 5: Bleeding Events in ROCKET AF*-On Treatment Plus 2 Days Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * 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. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding. Parameter Rivaroxaban Tablets N=7111 n (%/year) Warfarin N=7125 n (%/year) Rivaroxaban Tablets vs. Warfarin HR (95% CI) Major Bleeding † 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20) Intracranial Hemorrhage (ICH) ‡ 55 (0.5) 84 (0.7) 0.67 (0.47, 0.93) Hemorrhagic Stroke§ 36 (0.3) 58 (0.5) 0.63 (0.42, 0.96) Other ICH 19 (0.2) 26 (0.2) 0.74 (0.41, 1.34) Gastrointestinal (GI)¶ 221 (2.0) 140 (1.2) 1.61 (1.30, 1.99) Fatal Bleeding# 27 (0.2) 55 (0.5) 0.50 (0.31, 0.79) ICH 24 (0.2) 42 (0.4) 0.58 (0.35, 0.96) Non-intracranial 3 (0.0) 13 (0.1) 0.23 (0.07, 0.82) Figure 1 shows the risk of major bleeding events across major subgroups. Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homog …

7 DRUG INTERACTIONS 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, the latter also known as breast cancer resistance protein (BCRP). 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 )] .

8 USE IN SPECIFIC POPULATIONS 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 ) 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 (5.2, 5.7)] . 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 (5.7)]. 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). 8.2 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 condi …

12.1 Mechanism of Action Rivaroxaban tablets are 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.

11 DESCRIPTION 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 19 H 18 ClN 3 O 5 S and the molecular weight is 435.88. The structural formula is: Rivaroxaban, USP is a pure ( S )-enantiomer. It is an white to yellowish powder. Rivaroxaban, USP is soluble in dimethyl sulfoxide, practically insoluble to very slightly soluble in acetone and water. Each rivaroxaban tablet, USP contains 2.5 mg, 10 mg, 15 mg or 20 mg of rivaroxaban, USP. The inactive ingredients of rivaroxaban tablets, USP are: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for rivaroxaban 2.5 mg tablet is Opadry ® Yellow containing D&C yellow #10 aluminium lake, hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol 6000, titanium dioxide, and for rivaroxaban 10 mg tablet is Opadry ® Pink containing hypromellose, iron oxide red, polyethylene glycol 6000, talc, titanium dioxide, and for rivaroxaban 15 mg tablet and 20 mg tablet is Opadry ® Brown containing hypromellose, iron oxide black, iron oxide red, polyethylene glycol 8000, and titanium dioxide. FDA approved dissolution test specifications differ from USP. rivaroxaban-str

10 OVERDOSAGE Overdose of Rivaroxaban tablets may lead to hemorrhage. Discontinue rivaroxaban tablets 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 tablets 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. A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available.

16 HOW SUPPLIED/STORAGE AND HANDLING Rivaroxaban tablets, USP are available in the strengths and packages listed below: 2.5 mg tablets: Light yellow to yellow round biconvex film-coated tablets debossed with “9” on one side and “C” on other side. NDC 46708-683-60 Bottle of 60 tablets with child-resistant closure NDC 46708-683-45 Bottle of 180 tablets with child-resistant closure NDC 46708-683-91 Bottle of 1000 tablets NDC 46708-683-10 100 (10 x 10) tablets unit dose blister pack 10 mg tablets are round, pink, biconvex film-coated tablets debossed with “L” on one side and “10” on the other side. The tablets are supplied in the packages listed: NDC 46708-346-30 Bottle of 30 tablets with child-resistant closure NDC 46708-346-90 Bottle of 90 tablets with child-resistant closure NDC 46708-346-91 Bottle of 1000 tablets NDC 46708-346-10 100 (10 x 10) tablets unit dose blister pack 15 mg tablets are round, brown, film-coated biconvex tablets debossed with ‘504’ on one side and plain on the other side. The tablets are supplied in the packages listed: NDC 46708-347-30 Bottle of 30 tablets with child-resistant closure NDC 46708-347-90 Bottle of 90 tablets with child-resistant closure NDC 46708-347-91 Bottle of 1000 tablets NDC 46708-347-10 100 (10 x 10) tablets unit dose blister pack 20 mg tablets are triangle shaped, brown, film-coated tablets debossed with ‘505’ on one side and plain on the other side. The tablets are supplied in the packages listed: NDC 46708-348-30 Bottle of 30 tablets with child-resistant closure NDC 46708-348-90 Bottle of 90 tablets with child-resistant closure NDC 46708-348-91 Bottle of 1000 tablets NDC 46708-348-10 100 (10 x 10) tablets unit dose blister pack Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 46708-240-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Preserve in well-closed containers. Keep out of the reach of children.