RIVAROXABAN

Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in rivaroxaban for oral suspension 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 is C 19 H 18 ClN 3 O 5 S and the molecular weight is 435.89. The structural formula is: Rivaroxaban USP is a pure ( S )-enantiomer. It is a non-hygroscopic, white to yellowish powder. Rivaroxaban is sparingly soluble in dimethyl formamide and is practically insoluble in water. Rivaroxaban for oral suspension is supplied as granules in bottles containing 155 mg of rivaroxaban (1 mg of rivaroxaban per mL after reconstitution). The inactive ingredients are: anhydrous citric acid, hypromellose, mannitol, microcrystalline cellulose and carboxymethylcellulose sodium, sodium benzoate, sucralose, cream/vanilla flavor and xanthan gum. riva-str-u

INDICATIONS & 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.

DOSAGE & ADMINISTRATION Nonvalvular Atrial Fibrillation : 15 or 20 mg, once daily with food 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 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 Prophylaxis of DVT Following Hip or Knee Replacement Surgery : 10 mg orally once daily with or without food 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 CAD or PAD : 2.5 mg orally twice daily with or without food, in combination with aspirin (75 to 100 mg) once daily 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 less than 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 less than 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 less than 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 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 * 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. 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: less than 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 Jaffé 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 greater than 13 and less than 18 years k = 0.70 in boys greater than 13 and less than 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 Less than 1 Year of Age Age 97.5 th Percentile of Creatinine 97.5 th Percentile of Creatinine (mg/dL) (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 ≥ 2.0. 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 suspension via NG tube or gastric feeding tube : Rivaroxaban 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 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 (sweet and creamy). 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 o C to 25 o C (68 o F to 77 o F); excursions permitted between 15 o C to 30 o C (59 o F to 86 o 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.

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

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 (greater than 10%) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 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 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 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 less than 18 years of age, menorrhagia occurred in 23 (27%) female patients in the rivaroxaban group and 5 (10%) female patients in the comparator group. Table 14: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period* Parameter Rivaroxaban † N=329 n (%) Comparator Group ‡ N=162 n (%) Major bleeding § 0 2 (1.2) Clinically relevant non-major bleeding ¶ 10 (3.0) 1 (0.6) Trivial bleeding 113 (34.3) 44 (27.2) Any bleeding 119 (36.2) 45 (27.8) * These events occurred after randomization until 3 months of treatment (1 month for patients less than 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; randomized 2:1 (Rivaroxaban: 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. Non-bleeding adverse reactions reported in ≥5% of rivaroxaban-treated patients are shown in Table 15. Table 15: Other Adverse Reactions * Reported in Rivaroxaban-Treated Patients by ≥5% in EINSTEIN Junior Study Adverse Reaction Rivaroxaban N=329 n (%) Comparator Group N=162 n (%) Pain in extremity 23 (7) 7 (4.3) Fatigue † 23 (7) 7 (4.3) * Adverse reaction with Relative Risk greater than 1.5 for rivaroxaban versus comparator. † The following terms were combined: fatigue, asthenia. A clinically relevant adverse reaction in rivaroxaban-treated patients was vomiting (10.6% in the rivaroxaban 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 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 or aspirin (approximately 5 mg/kg). Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the rivaroxaban 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 * N=64 n (%) Aspirin * N=34 n (%) Major Bleeding † 1 (1.6) 0 Epistaxis leading to transfusion 1 (1.6) 0 Clinically relevant non-major (CRNM) bleeding § 4 (6.3) 3 (8.8) Trivial bleeding 21 (32.8) 12 (35.3) Any bleeding 23 (35.9) 14 (41.2) * Treatment schedule: body weight-adjusted doses of rivaroxaban or aspirin (approximately 5 mg/kg); randomized 2:1 (Rivaroxaban: Aspirin). † 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. § 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. 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 greater than 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. 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 ( 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 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 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 should not be used in patients with CrCl 15 to less than 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 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 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) ] .