Rivaroxaban Granule

1 INDICATIONS AND USAGE Rivaroxaban for oral suspension is a factor Xa inhibitor indicated: 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 ) 1.9 Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Rivaroxaban for oral suspension is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment. 1.10 Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Rivaroxaban for oral suspension is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

2 DOSAGE AND ADMINISTRATION Pediatric Patients : See dosing recommendations in the Full Prescribing Information ( 2.2 ) 2.2 Recommended Dosage in Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients Table 2: Recommended Dosage in Pediatric Patients Birth to Less than 18 Years for Treatment of and Reduction in Risk of Recurrent VTE *,† Dosage Form Body Weight 1 mg Rivaroxaban for Oral Suspension = 1 mL Suspension Dosage Total Daily Dose‡ Once a Day§ 2 Times a Day§ 3 Times a Day§ Oral Suspension Only 2.6 kg to 2.9 kg 0.8 mg 2.4 mg 3 kg to 3.9 kg 0.9 mg 2.7 mg 4 kg to 4.9 kg 1.4 mg 4.2 mg 5 kg to 6.9 kg 1.6 mg 4.8 mg 7 kg to 7.9 kg 1.8 mg 5.4 mg 8 kg to 8.9 kg 2.4 mg 7.2 mg 9 kg to 9.9 kg 2.8 mg 8.4 mg 10 kg to 11.9 kg 3 mg 9 mg 12 kg to 29.9 kg 5 mg 10 mg Oral Suspension 30 kg to 49.9 kg 15 mg 15 mg ≥50 kg 20 mg 20 mg * Initiate rivaroxaban for oral suspension treatment following at least 5 days of initial parenteral anticoagulation therapy. † Patients <6 months of age should meet the following criteria: at birth were at least 37 weeks of gestation, have had at least 10 days of oral feeding, and weigh ≥2.6 kg at the time of dosing. ‡ All doses should be taken with feeding or with food since exposures match that of 20 mg daily dose in adults. § Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart; 3 times a day: approximately 8 hours apart Dosing of rivaroxaban for oral suspension was not studied and therefore dosing cannot be reliably determined in the following patient populations. Its use is therefore not recommended in children less than 6 months of age with any of the following: Less than 37 weeks of gestation at birth Less than 10 days of oral feeding Body weight of less than 2.6 kg. To increase absorption, all doses should be taken with feeding or with food. Monitor the child's weight and review the dose regularly, especially for children below 12 kg. This is to ensure a therapeutic dose is maintained. All Pediatric Patients (except <2 years old with catheter-related thrombosis) : Therapy with rivaroxaban for oral suspension should be continued for at least 3 months in children with thrombosis. Treatment can be extended up to 12 months when clinically necessary. The benefit of continued therapy beyond 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding. Pediatric Patients <2 Years Old with Catheter-Related Thrombosis: Therapy with rivaroxaban for oral suspension should be continued for at least 1 month in children less than 2 years old with catheter-related thrombosis. Treatment can be extended up to 3 months when clinically necessary. The benefit of continued therapy beyond 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential risk of bleeding. Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure Table 3: Recommended Dosage for Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease * All doses can be taken with or without food since exposures match that of 10 mg daily dose in adults. † Once a day: approximately 24 hours apart; 2 times a day: approximately 12 hours apart. Dosage Form Body Weight 1 mg Rivaroxaban for Oral Suspension = 1 mL Suspension Dosage Total Daily Dose* Once a Day † 2 Times a Day † Oral Suspension Only 7 kg to 7.9 kg 1.1 mg 2.2 mg 8 kg to 9.9 kg 1.6 mg 3.2 mg 10 kg to 11.9 kg 1.7 mg 3.4 mg 12 kg to 19.9 kg 2 mg 4 mg 20 kg to 29.9 kg 2.5 mg 5 mg 30 kg to 49.9 kg 7.5 mg 7.5 mg Oral Suspension ≥50 kg 10 mg 10 mg Administration in Pediatric Patients Food Effect: For the treatment of VTE in children, the dose should be taken with food to increase absorption. For thromboprophylaxis after Fontan procedure, the dose can be taken with or without food. Vomit or Spit Up: If the patient vomits or spits up the dose within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose is taken, the dose should not be re-administered and the next dose should be taken as scheduled. If the patient vomits or spits up the dose repeatedly, the caregiver should contact the child's doctor right away. For children unable to swallow 10, 15, or 20 mg whole tablets, rivaroxaban for oral suspension should be used. Use in Renal Impairment in Pediatric Patients Patients 1 Year of Age or Older: Mild renal impairment (eGFR: 50 to ≤ 80 mL/min/1.73 m 2 ): No dose adjustment is required. Moderate or severe renal impairment (eGFR: <50 mL/min/1.73 m 2 ): avoid use, as limited clinical data are available. Estimated glomerular filtration rate (eGFR) can be done using the updated Schwartz formula, eGFR (Schwartz) = (0.413 x height in cm)/serum creatinine in mg/dL, if serum creatinine (SCr) is measured by an enzymatic creatinine method that has been calibrated to be traceable to isotope dilution mass spectrometry (IDMS). If SCr is measured with routine methods that have not been recalibrated to be traceable to IDMS (e.g., the traditional Jaff¡SR reaction), the eGFR should be obtained from the original Schwartz formula: eGFR (mL/min/1.73 m 2 ) = k * height (cm)/SCr (mg/dL), where k is proportionality constant: k = 0.55 in children 1 year to 13 years k = 0.55 in girls > 13 and < 18 years k = 0.70 in boys > 13 and < 18 years Patients Less than 1 Year of Age: Determine renal function using serum creatinine. Avoid use of rivaroxaban for oral suspension 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 for Oral Suspension Switching from Warfarin to Rivaroxaban for Oral Suspension When switching patients from warfarin to rivaroxaban for oral suspension, discontinue warfarin and start rivaroxaban for oral suspension as soon as the International Normalized Ratio (INR) is below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation. Switching from Rivaroxaban for Oral Suspension to Warfarin Pediatric Patients : To ensure adequate anticoagulation during the transition from rivaroxaban for oral suspension to warfarin, continue rivaroxaban for oral suspension 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 for oral suspension. Co-administration of rivaroxaban for oral suspension and warfarin is advised to continue until the INR is ≥ 2. Once rivaroxaban for oral suspension is discontinued, INR testing may be done reliably 24 hours after the last dose. Switching from Rivaroxaban for Oral Suspension to Anticoagulants other than Warfarin For pediatric patients currently taking rivaroxaban for oral suspension and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban for oral suspension and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban for oral suspension dose would have been taken [see Drug Interactions (7.4)] . Switching from Anticoagulants other than Warfarin to Rivaroxaban for Oral Suspension For pediatric patients currently receiving an anticoagulant other than warfarin, start rivaroxaban for oral suspension 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 for oral suspension 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 for oral suspension 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 for oral suspension, the increased risk of bleeding should be weighed against the urgency of intervention. Rivaroxaban for oral suspension 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 Pediatric Patients If rivaroxaban for oral suspension is taken once a day, the patient should take the missed dose as soon as possible once it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose. If rivaroxaban for oral suspension is taken two times a day, the patient should take the missed morning dose as soon as possible once it is noticed. A missed morning dose may be taken together with the evening dose. A missed evening dose can only be taken in the same evening. If rivaroxaban for oral suspension is taken three times a day, if a dose is missed, the patient should skip the missed dose and go back to the regular dosing schedule at the usual time without compensating for the missed dose. On the following day, the patient should continue with their regular regimen. 2.6 Administration Options Administration of Rivaroxaban for Oral Suspension via NG Tube or Gastric Feeding Tube Rivaroxaban for oral suspension may be given through NG or gastric feeding tube. After the administration, flush the feeding tube with water. For the treatment or reduction in risk of recurrent VTE in pediatric patients, the dose should then be immediately followed by enteral feeding to increase absorption. For the thromboprophylaxis in pediatric patients with congenital heart disease who have undergone the Fontan procedure, the dose does not require to be followed by enteral feeding. An in vitro compatibility study indicated that rivaroxaban for oral suspension can be used with PVC, polyurethane or silicone NG tubing. 2.7 Preparation Instructions for Pharmacy of Rivaroxaban for Oral Suspension Do not add flavor as product is already flavored (tutti frutti). Reconstitute before dispensing: Tap the bottle until all granules flow freely. Add 150 mL of purified water for reconstitution. Shake for 60 seconds. Check that all granules are wetted and the suspension is uniform. Push the adaptor into bottleneck and recap bottle. The suspension must be used within 60 days. Write the "Discard after" date on the bottle and carton. Dispensing Instructions: Dispense in the original bottle. Dispense the bottle upright with the syringes provided in the original carton. Store reconstituted suspension at room temperature between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. It is recommended the pharmacist counsel the caregiver on proper use. Alert the patient or caregiver to read the Medication Guide and Instructions for Use.

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 Another Indication [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 reactions (>10 %) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561, 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. Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients: The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight- adjusted doses of rivaroxaban for oral suspension or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA). Discontinuation due to bleeding events occurred in 6 (1.8 %) patients in the rivaroxaban for oral suspension group and 3 (1.9 %) patients in the comparator group. Table 14 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27 %) female patients in the rivaroxaban for oral suspension group and 5 (10 %) female patients in the comparator group. Table 14: Bleeding Events in EINSTEIN Junior Study–Safety Analysis Set - Main Treatment Period * * These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event. † Treatment schedule: body weight-adjusted doses of rivaroxaban for oral suspension; randomized 2:1 (rivaroxaban for oral suspension: Comparator). ‡ Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. § 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. ¶ Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. Parameter Rivaroxaban for Oral Suspension † N=329 n (%) Comparator Group ‡ N=162 n (%) Major bleeding § 0 2 (1.2) Clinically relevant non-major bleeding ¶ 10 (3) 1 (0.6) Trivial bleeding 113 (34.3) 44 (27.2) Any bleeding 119 (36.2) 45 (27.8) Non-bleeding adverse reactions reported in ≥5 % of rivaroxaban for oral suspension -treated patients are shown in Table 15. Table 15: Other Adverse Reactions * Reported in Rivaroxaban for Oral Suspension-Treated Patients by ≥5 % in EINSTEIN Junior Study * Adverse reaction with Relative Risk >1.5 for rivaroxaban for oral suspension versus comparator. † The following terms were combined: fatigue, asthenia. Adverse Reaction Rivaroxaban for Oral Suspension N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4.3) Fatigue † 23 (7) 7 (4.3) A clinically relevant adverse reaction in rivaroxaban for oral suspension -treated patients was vomiting (10.6 % in the rivaroxaban for oral suspension group vs 8 % in the comparator group). Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure: The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of rivaroxaban for oral suspension for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of rivaroxaban for oral suspension or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6 %) patient in the rivaroxaban for oral suspension group and no patients in the aspirin group. Table 16 shows the number of patients experiencing bleeding events in the UNIVERSE study. Table 16: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days Parameter Rivaroxaban for Oral Suspension Treatment schedule: body weight-adjusted doses of rivaroxaban for oral suspension or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban for Oral Suspension:Aspirin). N=64 n (%) Aspirin N=34 n (%) Major Bleeding Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life. 4 (6.3) 3 (8.8) Trivial bleeding 21 (32.8) 12 (35.3) Any bleeding 23 (35.9) 14 (41.2) Non-bleeding adverse reactions reported in ≥5 % of rivaroxaban for oral suspension-treated patients are shown in Table 17. Table 17: Other Adverse Reactions * Reported by ≥5 % of Rivaroxaban for Oral Suspension-Treated Patients in UNIVERSE Study (Part B) * Adverse reaction with Relative Risk >1.5 for rivaroxaban for oral suspension versus aspirin. † The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash Adverse Reaction Rivaroxaban for Oral Suspension 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) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of rivaroxaban for oral suspension. 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

12.3 Pharmacokinetics Absorption The absolute bioavailability of rivaroxaban is dose-dependent. For the 2.5 mg and 10 mg dose, it is estimated to be 80 % to 100 % and is not affected by food. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. Rivaroxaban 20 mg administered in the fasted state has an absolute bioavailability of approximately 66%. Coadministration of rivaroxaban with food increases the bioavailability of the 20 mg dose (mean AUC and C max increasing by 39 % and 76 % respectively with food). Rivaroxaban 15 mg and 20 mg tablets should be taken with food . The maximum concentrations (C max ) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of rivaroxaban (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban (see Figure 3). Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29 % and 56 % decrease in AUC and C max compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure. In a study with 44 healthy subjects, both mean AUC and C max values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and C max was 18 % lower. Distribution Protein binding of rivaroxaban in human plasma is approximately 92 % to 95 %, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L. Metabolism Approximately 51 % of an orally administered [ 14 C]-rivaroxaban dose was recovered as inactive metabolites in urine (30 %) and feces (21 %). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites. Excretion In a Phase 1 study, following the administration of [ 14 C]-rivaroxaban, approximately one-third (36 %) was recovered as unchanged drug in the urine and 7 % was recovered as unchanged drug in feces. Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated BCRP). Rivaroxaban's affinity for influx transporter proteins is unknown. Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Specific Populations The effects of level of renal impairment, age, body weight, and level of hepatic impairment on the pharmacokinetics of rivaroxaban are summarized in Figure 2. Figure 2: Effect of Specific Adult Populations on the Pharmacokinetics of Rivaroxaban Gender: Gender did not influence the pharmacokinetics or pharmacodynamics of rivaroxaban for oral suspension. Race: Healthy Japanese subjects were found to have 20 to 40 % on average higher exposures compared to other ethnicities including Chinese. However, these differences in exposure are reduced when values are corrected for body weight. Elderly: The terminal elimination half-life is 11 to 13 hours in the elderly subjects aged 60 to 76 years [See Use in Specific Populations ( 8.5 )]. Pediatric Patients: The rate and extent of absorption were similar between the tablet and suspension. After repeated administration of rivaroxaban for the treatment of VTE, the C max of rivaroxaban in plasma was observed at median times of 1.5 to 2.2 hours in subjects who ranged from birth to less than 18 years of age. In children who were 6 months to 9 years of age, in vitro plasma protein binding of rivaroxaban is approximately 90 %. The half-life of rivaroxaban in plasma of pediatric patients treated for VTE decreased with decreasing age. Mean half-life values were 4.2 hours in adolescents, 3 hours in children 2 to 12 years of age, 1.9 hours in children 0.5 to <2 years of age, and 1.6 hours in children <0.5 years of age. An exploratory analysis in pediatric patients treated for VTE did not reveal relevant differences in rivaroxaban exposure based on gender or race. Renal Impairment: The safety and pharmacokinetics of single-dose rivaroxaban (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Figure 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Use in Specific Populations ( 8.6 )] . Hemodialysis in ESRD Subjects : Systemic exposure to rivaroxaban administered as a single 15 mg dose in ESRD subjects dosed 3 hours after the completion of a 4-hour hemodialysis session (post-dialysis) is 56 % higher when compared to subjects with normal renal function (see Table 18). The systemic exposure to rivaroxaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 600 mL/min and a blood flow rate in the range of 320 to 400 mL/min is 47 % higher compared to those with normal renal function. The extent of the increase is similar to the increase in patients with CrCl 15 to 50 mL/min taking rivaroxaban 15 mg. Hemodialysis had no significant impact on rivaroxaban exposure. Protein binding was similar (86 % to 89 %) in healthy controls and ESRD subjects in this study. Pediatric Patients : Limited clinical data are available in children 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ) or in children younger than 1 year with serum creatinine results above 97.5 th percentile [see Dosage and Administration ( 2.2 ) and Use in Specific Populations ( 8.6 )] . Hepatic Impairment: The safety and pharmacokinetics of single-dose rivaroxaban (10 mg) were evaluated in a study in healthy adult subjects (n=16) and adult subjects with varying degrees of hepatic impairment (see Figure 2). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B) (see Figure 2). Increases in pharmacodynamic effects were also observed [see Use in Specific Populations ( 8.7 )] . No clinical data are available in pediatric patients with hepatic impairment. Drug Interactions In vitro studies indicate that rivaroxaban neither inhibits the major cytochrome P450 enzymes CYP1A2, 2C8, 2C9, 2C19, 2D6, 2J2, and 3A nor induces CYP1A2, 2B6, 2C19, or 3A. In vitro data also indicates a low rivaroxaban inhibitory potential for P-gp and ABCG2 transporters. The effects of coadministered drugs on the pharmacokinetics of rivaroxaban exposure are summarized in Figure 3 [see Drug Interactions ( 7 )] . Figure 3: Effect of Coadministered Drugs on the Pharmacokinetics of Rivaroxaban in Adults Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. In another study, single doses of warfarin (15 mg) and rivaroxaban (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Neither enoxaparin nor warfarin affected the pharmacokinetics of rivaroxaban (see Figure 3). NSAIDs/Aspirin: In a study for another indication, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with rivaroxaban for oral suspension. Neither naproxen nor aspirin affected the pharmacokinetics of rivaroxaban (see Figure 3). Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45 % and 30 % of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug. Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems: In a pharmacokinetic trial, rivaroxaban tablets was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A inhibitor). Compared to rivaroxaban tablets administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76 % and 99 % increase in AUC inf and a 56 % and 64 % increase in C max , respectively. Similar trends in pharmacodynamic effects were also observed.