VAROXA

Rivaroxaban is an anticoagulant and the first Oral active direct factor Xa inhibitor.

Unlike warfarin, routine lab monitoring of INR is not necessary.

However there is no antidote available in the event of a major bleed.

Only the 10 mg tablet can be taken without regard to food.

The 15 mg and 20 mg tablet should be taken with food.

FDA approved on

July 1, 2011.

Rivaroxaban is indicated for the prevention of venous thromboembolic events (VTE) in patients who have undergone total hips replacements and total knee replacement surgery; prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); to reduce risk of recurrent DVT and/or PE.

Rivaroxaban is also indicated, in combination with aspirin, for reducing the risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease.

Its use is also not recommended in those with severe renal impairment (<30 mL/min).

Rivaroxaban is also indicated for the treatment and prevention of VTE in pediatric patients (from birth to 18 years of age) and for thromboprophylaxis in pediatric patients ≥2 years old with congenital heart disease following the Fontan procedure.

Rivaroxaban is an anticoagulant which binds directly to factor Xa.

Thereafter, it effectively blocks the amplification of the coagulation cascade, preventing the formation of thrombus.

Rivaroxaban is a unqiue anticoagulant for two reasons.

First of all, it is does not involve antithrombin III (ATIII) to exert its anticoagulant effects.

Secondly, it is an oral agent whereas the widely used unfractionated heparin and low molecular weight heparins are for parenteral use only.

Although the activated partial thromboplastin time (aPTT) and HepTest (a test developed to assay low molecular weight heparins) are prolonged in a dose-dependant manner, neither test is recommended for the assessment of the pharmacodynamic effects of rivaroxaban.

Anti-Xa activity and inhibition of anti-Xa activity monitoring is also not recommended despite being influenced by rivaroxaban.

Following oral administration, rivaroxaban is rapidly absorbed and reaches peak plasma concentration in 2-4 hours.

Bioavailability of the 10 mg dose is >80%.

However, the 15-20 mg dose have a lower bioavailability if taken in the fasted state and consequently should be taken with food.

Approximately two-thirds of the dose is metabolized.

It is metabolized by

CYP3A4, CYP3A5, CYP2J2 and CYP-independant mechanisms.

Approximately two-thirds of rivaroxaban is excreted into urine (via active tubular secretion in which approximately 36% as unchanged drug and 30% as inactive metabolism).

The remaining third of the administered dose is excreted via feces in which 7% is in the form of unchanged drug and 21% as inactive metabolites.

The terminal half life is 5-9 hours in adults and 11-13 hours in the elderly.

Systemic clearance is approximately 10 L/h, so rivaroxaban is considered a drug with low clearance.

Renal clearance is ~3-4 L/h.

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Excessive bleeding.

Overdosages should be treated using activated charcoal and supportive measures such as mechanical compression and hemodynamic support.

If bleeding is not controlled, the following procoagulants can be administered: activated prothrombin complex concentrate, prothrombin complex concentrate and recombinant factor VIIa.

There is also a higher chance of post procedural hemorrhage compared to enoxaparin (1.55% vs. 1.39% respectively).

is contraindicated in patients with: active pathological bleeding severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) Active pathological bleeding Severe hypersensitivity reaction to XARELTO.

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 to 39 days CAD or PAD: 2.5 mg orally twice daily with or without food, in combination with aspirin (75–100 mg) once daily Pediatric Patients: See dosing recommendations in the Full Prescribing Information 2.1 Recommended Dosage in Adults Table 1: Recommended Dosage in Adults Indication Renal Considerations Calculate CrCl based on actual weight.

• Hip Replacement Surgery CrCl ≥15 mL/min 10 mg once daily for 35 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use.

CrCl ≥15 mL/min 10 mg once daily for 12 days, 6–10 hours after surgery once hemostasis has been established Take with or without food CrCl <15 mL/min Avoid Use Prophylaxis of VTE in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding CrCl ≥15 mL/min 10 mg once daily, in hospital and after hospital discharge, for a total recommended duration of to 39 days Take with or without food CrCl <15 mL/min Avoid Use Reduction of Risk of Major Cardiovascular Events (CV Death, MI, and Stroke) in CAD No dose adjustment needed based on CrCl 2.5 mg twice daily, plus aspirin (75–100 mg) once daily Take with or without food Reduction of Risk of Major Thrombotic Vascular Events in PAD, Including Patients after Lower Extremity Revascularization due to Symptomatic PAD No dose adjustment needed based on CrCl 2.5 mg twice daily, plus aspirin (75–100 mg) once daily.

When starting therapy after a successful lower extremity revascularization procedure, initiate once hemostasis has been established.

Take with or without food 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 Initiate XARELTO 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.

Weight 1 mg XARELTO = 1 mL Suspension Dosage Total Daily Dose 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 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 or Tablets 30 kg to 49.9 kg 15 mg 15 mg ≥50 kg 20 mg 20 mg Dosing of XARELTO 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 XARELTO 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 XARELTO 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 XARELTO = 1 mL Suspension Dosage Total Daily Dose 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.

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 or Tablets ≥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.

XARELTO tablet must not be split in an attempt to provide a fraction of a tablet dose.

For children unable to swallow 10, 15, or 20 mg whole tablets, XARELTO oral suspension should be used.

XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.

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 × 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 > 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

XARELTO 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 4–6 0.34 30 Month 7–9 0.34 30 Month 10–12 0.36 32 2.3 Switching to and from XARELTO Switching from Warfarin to XARELTO.

• When switching patients from warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the International Normalized Ratio (INR) is below 3.0 in adults and below 2.5 in pediatric patients to avoid periods of inadequate anticoagulation.

Switching from XARELTO to

Warfarin – Adults: No clinical trial data are available to guide converting patients from XARELTO to warfarin.

XARELTO affects

INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue

XARELTO and begin both a parenteral anticoagulant and warfarin at the time the next dose of XARELTO would have been taken.

To ensure adequate anticoagulation during the transition from XARELTO to warfarin, continue XARELTO 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 XARELTO.

Co-administration of

XARELTO and warfarin is advised to continue until the INR is ≥ 2.0.

XARELTO is discontinued, INR testing may be done reliably 24 hours after the last dose.

Switching from XARELTO to Anticoagulants other than Warfarin.

• For adult and pediatric patients currently taking XARELTO and transitioning to an anticoagulant with rapid onset, discontinue XARELTO and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next XARELTO dose would have been taken.

Switching from Anticoagulants other than Warfarin to XARELTO.

• For adult and pediatric patients currently receiving an anticoagulant other than warfarin, start XARELTO 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 XARELTO 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, XARELTO should be stopped at least 24 hours before the procedure to reduce the risk of bleeding.

In deciding whether a procedure should be delayed until 24 hours after the last dos.

® (rivaroxaban) Tablets are available in the strengths and packages listed below: 2.5 mg tablets are round, light yellow, and film-coated with a triangle pointing down above a "2.5" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-577-60 Bottle containing 60 tablets NDC 50458-577-18 Bottle containing 180 tablets NDC 50458-577-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-580-30 Bottle containing 30 tablets NDC 50458-580-90 Bottle containing 90 tablets NDC 50458-580-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-578-30 Bottle containing 30 tablets NDC 50458-578-90 Bottle containing 90 tablets NDC 50458-578-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side.

The tablets are supplied in the packages listed: NDC 50458-579-30 Bottle containing 30 tablets NDC 50458-579-90 Bottle containing 90 tablets NDC 50458-579-89 Bulk bottle containing 1000 tablets NDC 50458-579-10 Blister package containing 100 tablets (10 blister cards containing 10 tablets each) Starter Pack for treatment of deep vein thrombosis and treatment of pulmonary embolism: NDC 50458-584-51 30-day starter blister pack containing 51 tablets: 42 tablets of 15 mg and 9 tablets of 20 mg XARELTO ® (rivaroxaban) for oral suspension is available in the strength and package listed below: NDC 50458-575-01 Supplied as white to off-white granules in an amber glass bottle containing 155 mg rivaroxaban packaged with two oral dosing syringes.

After reconstitution with 150 mL of purified water, 1 mL of the suspension contains 1 mg rivaroxaban.

Discard reconstituted suspension after "Discard after" date written on the bottle.

Storage of tablets, granules and reconstituted suspension: Store at room temperature between 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Do not freeze the granules or reconstituted suspension.

Keep out of the reach of children.

Storage of tablets, granules and reconstituted suspension: Store at room temperature between 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Do not freeze the granules or reconstituted suspension.

Keep out of the reach of children.

Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes.

XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery.

The anticoagulant effect of

XARELTO cannot be reliably monitored with standard laboratory testing.

Consider the benefits and risks of

XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman.

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 2–4% and 15–20%, respectively.

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.

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery.

The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data Human Data There are no adequate or well-controlled studies of XARELTO 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.

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).

The safety and effectiveness of

XARELTO 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

XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO 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.

XARELTO 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.

XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO 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 XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure.

Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients.

For the

XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients.

Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.

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.

Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over.

In clinical trials the efficacy of

XARELTO 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.