rivaroxaban granule

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 for thromboprophylaxis in pediatric patients 2 years and older with congenital heart disease after the Fontan procedure 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.

Pediatric Patients : See dosing recommendations in the Full Prescribing Information 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 13 and 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 ] . 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 ] . 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 ] . 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.

12.1 Mechanism of Action Rivaroxaban is 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.

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 ] Bleeding Risk [see Warnings and Precautions ] Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions ] The most common adverse reactions (>10 %) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. 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 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 Fatigue † 23 7 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 0 Epistaxis leading to transfusion 1 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 3 Trivial bleeding 21 12 Any bleeding 23 14 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 3 Vomiting 9 3 Gastroenteritis † 8 1 Rash † 6 2 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

Avoid combined P-gp and strong CYP3A inhibitors and inducers Anticoagulants : Avoid concomitant use 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 for oral suspension with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology ] . 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 ] . 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 and Clinical Pharmacology ] . 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 and Clinical Pharmacology ] . 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 ]. 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 ].

Renal Impairment : Avoid or adjust dose Hepatic Impairment : Avoid use in Child-Pugh B and C hepatic impairment or hepatic disease associated with coagulopathy 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 ] . 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 ]. 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).

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 for oral suspension and any potential adverse effects on the breastfed infant from rivaroxaban for oral suspension or from the underlying maternal condition (see Data) . Data Animal Data: Following a single oral administration of 3 mg/kg of radioactive [ 14 C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1 % of the maternal dose. 8.3 Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including rivaroxaban for oral suspension should be assessed in females of reproductive potential and those with abnormal uterine bleeding. 8.4 Pediatric Use The safety and effectiveness of rivaroxaban for oral suspension have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of rivaroxaban for oral suspension is supported in these age groups by evidence from adequate and well-controlled studies of rivaroxaban in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. Rivaroxaban for oral suspension was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg [see Dosage and Administration , Adverse Reactions , Clinical Pharmacology and Clinical Studies . The safety and effectiveness of rivaroxaban for oral suspension have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of rivaroxaban for oral suspension is supported in these age groups by evidence from adequate and well- controlled studies of rivaroxaban in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of rivaroxaban for oral suspension and the safety and efficacy of rivaroxaban for oral suspension when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure [see Dosage and Administration , Adverse Reactions , Clinical Pharmacology and Clinical Studies ] . Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents. 8.5 Geriatric Use Of the total number of adult patients in clinical trials for the approved indications of rivaroxaban (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology and Clinical Studies ] . 8.6 Renal Impairment In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64 % in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology ] . Pediatric Use No dosage adjustment is required in patients 1 year of age or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m 2 ). There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m 2 ); therefore, avoid the use of rivaroxaban for oral suspension in these patients. There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5 th percentile; therefore, avoid the use of rivaroxaban for oral suspension in these patients [see Dosage and Administration ]. 8.7 Hepatic Impairment In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127 % were observed in adult subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of rivaroxaban for oral suspension in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology ] . Avoid the use of rivaroxaban for oral suspension in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. No clinical data are available in pediatric patients with hepatic impairment.