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 pat…

5 WARNINGS AND PRECAUTIONS Risk of Bleeding : Rivaroxaban for oral suspension can cause serious and fatal bleeding. ( 5.2 ) Pregnancy-Related Hemorrhage : Use rivaroxaban for oral suspension with caution in pregnant women due to the potential for obstetric hemorrhage and/or emergent delivery. ( 5.7 , 8.1 ) Prosthetic Heart Valves : Rivaroxaban for oral suspension use not recommended. ( 5.8 ) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome : Rivaroxaban for oral suspension use not recommended. ( 5.10 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including rivaroxaban for oral suspension, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from rivaroxaban tablets to warfarin in clinical trials in another indication in patients. If rivaroxaban for oral suspension is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.3 , 2.4 )] . 5.2 Risk of Bleeding Rivaroxaban for oral suspension increases the risk of bleeding, including in any organ, and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban for oral suspension to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue rivaroxaban for oral suspension in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years. Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y 12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.4 )] , selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions ( 7.2 )] . Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of rivaroxaban for oral suspension for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. rivaroxaban for oral suspension is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology ( 12.3 )] . Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended. Reversal of Anticoagulant Effect A specific agent to reverse the anti-factor Xa activity of rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not di…

4 CONTRAINDICATIONS Rivaroxaban for oral suspension 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 )

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 for oral suspension 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 for oral suspension 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 for oral suspension 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 for oral suspension 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 for oral suspension 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 )].

8.1 Pregnancy Risk Summary The limited available data on rivaroxaban for oral suspension in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. Use rivaroxaban for oral suspension with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of rivaroxaban for oral suspension cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of rivaroxaban for oral suspension for the mother and possible risks to the fetus when prescribing rivaroxaban for oral suspension 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 for oral suspension in this setting. Data Human Data: There are no adequate or well-controlled studies of rivaroxaban for oral suspension 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).

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 Con…