Rivaroxaban

Rivaroxaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Rivaroxaban is a factor Xa inhibitor used to treat deep vein thrombosis (DVT) and pulmonary embolism (PE). May also be used as thrombosis prophylaxis in specific situations.

The absolute bioavailability of rivaroxaban is dose-dependent. The 10 mg dose, is estimated to be 80% to 100% and is not affected by food. The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Plasma 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. Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. The terminal elimination half-life of rivaroxaban is 5 to 9 hours.

Rivaroxaban shows common side effects Muscle spasms, pain in arms or legs, vomiting, stomach pain, cough, and rash.

Rivaroxaban is available in the form of Oral Tablets and Granules for Oral Suspension.

Rivaroxaban is available in India, the US, the UK, Portugal, the Netherlands, China, Japan, Germany, France, Greece, and Australia.

Rivaroxaban belonging to the Factor Xa (FXa) inhibitor, acts as an anticoagulant agent.

Rivaroxaban competitively inhibits free, and clot-bound factor Xa. Factor Xa is needed to activate prothrombin (factor II) to thrombin (factor IIa). Thrombin is a serine protease that is required to activate fibrinogen to fibrin, which is the loose meshwork that completes the clotting process. Since one molecule of factor Xa can generate more than 1000 molecules of thrombin, selective inhibitors of factor Xa are profoundly useful in terminating the amplification of thrombin generation. The action of rivaroxaban is irreversible.

The data on the onset of action and duration of Action of Rivaroxaban is not available.

The Tmax was found within 2-4 hours following the administration of Rivaroxaban.

Rivaroxaban is available in the form of Oral Tablets and Granules for Oral Suspension.

Rivaroxaban tablets and granules for suspension are taken orally usually once or twice daily.

Rivaroxaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Rivaroxaban is an anticoagulant that selectively and directly inhibits factor Xa (activated factor X) in both the intrinsic and extrinsic pathways of the blood coagulation cascade thereby, inhibiting thrombin formation and development of thrombi. Factor Xa converts prothrombin to thrombin leading to fibrin clot formation and platelet activation.

Rivaroxaban is approved for use in the following clinical indications

Adult Indication

• Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications not at High Risk of Bleeding

Rivaroxaban is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and post-hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding.

• Treatment Of Deep Vein Thrombosis

Rivaroxaban is indicated for the treatment of deep vein thrombosis (DVT).

• Treatment Of Pulmonary Embolism

Rivaroxaban is indicated for the treatment of pulmonary embolism (PE).

• Reduction Of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Rivaroxaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of Rivaroxaban and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled.

• Reduction In the Risk of Recurrence of Deep Vein Thrombosis And/or Pulmonary Embolism

Rivaroxaban is indicated for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

• Prophylaxis Of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Rivaroxaban is indicated for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

• Reduction Of Risk of Major Cardiovascular Events in Patients with Chronic Coronary Artery Disease (CAD) Or Peripheral Artery Disease (PAD)

Rivaroxaban, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular (CV) death, myocardial infarction (MI), and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).

Pediatric Indication (off-label)

• Thromboprophylaxis after Fontan procedure
• Venous thromboembolism (VTE)
• Prophylaxis against recurrence

Adult Dose

• Venous thromboembolism

Deep vein thrombosis and/or pulmonary embolism treatment

Oral: 15 mg twice daily with food for 21 days followed by 20 mg once daily with food.

Indefinite anticoagulation (reduced intensity dosing for prophylaxis against venous thromboembolism recurrence):

Oral: 10 mg once daily.

Venous thromboembolism prophylaxis

Acutely ill medical patients

Oral: 10 mg once daily for a total duration of 31 to 39 days (including hospitalization and postdischarge). Some experts prefer LMWH as prophylaxis during acute hospitalization and suggest not routinely extending prophylaxis beyond discharge.

Nonmajor orthopedic surgery of lower limb (alternative therapy) (off-label use)

Oral: 10 mg once daily initiated ≥6 to 10 hours after surgery; continue for the duration of immobilization.

Total hip arthroplasty or total knee arthroplasty

Oral: 10 mg once daily initiated ≥6 to 10 hours after surgery or when hemostasis is established.

Peripheral artery disease, stable

Oral: 2.5 mg twice daily; administer in combination with daily low-dose aspirin.

• Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism)

Oral: 20 mg once daily with the evening meal.

Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off-label)

Oral: 15 mg once daily with food; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on the risk for thrombosis and bleeding, and time since percutaneous coronary intervention (PCI). It is recommended to discontinue aspirin 1 to 4 weeks after PCI and continue rivaroxaban and clopidogrel.

• Coronary artery disease:

Acute coronary syndrome (after stabilization with initial management) (off-label)

Oral: 2.5 mg twice daily; administer in combination with low-dose aspirin plus clopidogrel; continue rivaroxaban for ~1 year.

• Coronary artery disease, stable:

Oral: 2.5 mg twice daily; administer in combination with daily low-dose aspirin.

• Heparin-induced thrombocytopenia (off-label use)

HIT with or without thrombosis

Oral: 15 mg twice daily with food for 21 days or until platelet count recovery, whichever is longer, followed by 20 mg once daily with food.

Pediatric Dose

• Thromboprophylaxis after Fontan procedure (off-label use)

Children ≥2 years and Adolescents:

Oral tablet: ≥50 kg: Oral: 10 mg/dose every 24 hours.

• Venous thromboembolism (VTE) (off-label use)

Oral tablet: 30 to 49.9 kg: Oral: 15 mg/dose every 24 hours.

≥50 kg: Oral: 20 mg/dose every 24 hours.

• Prophylaxis against recurrence (off-label use)

Infants, Children, and Adolescents:

Oral tablet: 30 to 49.9 kg: 15 mg/dose every 24 hours.

≥50 kg: Oral: 20 mg/dose every 24 hours.

Rivaroxaban is available in various strengths as 1 mg/mL; 2.5 mg; 15 mg; 20 mg; 10 mg; 15 mg-20 mg.

Rivaroxaban is available in the form of Oral Tablets and Granules for Oral Suspension.

Dosage Adjustment in Kidney Patient

● Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism):

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 15 to 50 mL/minute: 15 mg once daily with the evening meal. Patients with CrCl <30 mL/minute were excluded from clinical trials.

CrCl <15 mL/minute: Avoid use; apixaban or warfarin is preferred. Patients with CrCl <15 mL/minute were excluded from clinical trials; currently, no other clinical data are available to support use in this population.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use. Limited and conflicting data are available.

Peritoneal dialysis: Avoid use.

Postpercutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off-label):

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: 10 mg once daily with food in combination with clopidogrel (preferred P2Y12 inhibitor) is suggested based on the trial design of PIONEER AF-PCI.

CrCl <30 mL/minute: Avoid use. These patients were excluded from the clinical trial for this indication.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid use.

• Coronary artery disease

Acute coronary syndrome (after stabilization with initial management) (off-label):

CrCl ≥ 30 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: Avoid use; these patients were excluded from the clinical trial for this indication.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid use.

Coronary artery disease, stable:

CrCl ≥15 mL/minute: No dosage adjustment necessary; use with caution in severe impairment.

CrCl <15 mL/minute: Avoid use; patients with eGFR <15 mL/minute were excluded from the clinical trial for this indication; currently, no other clinical data are available to support use in this population. The manufacturer provides conflicting recommendations for US and Canadian labeling.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid use.

● Peripheral artery disease, stable:

CrCl ≥15 mL/minute: No dosage adjustment necessary; use with caution in severe impairment.

CrCl <15 mL/minute: Avoid use; patients with eGFR <15 mL/minute were excluded from the clinical trial for this indication; currently, no other clinical data are available to support use in this population.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid use.

● Superficial vein thrombosis, acute symptomatic (off-label use):

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl <30 mL/minute: Avoid use; Patients with CrCl <30 mL/minute were excluded from clinical trials; no other clinical data are available to support use in this population.

• Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism treatment OR heparin-induced thrombocytopenia:

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl 15 to <30 mL/minute: Avoid use. Patients with CrCl <30 mL/minute were excluded from clinical trials; no other clinical data are available to support use in this population.

CrCl <15 mL/minute: Avoid use.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid use.

Indefinite anticoagulation (reduced intensity dosing against venous thromboembolism recurrence) OR venous thromboembolism prophylaxis for acutely ill medical patients, nonmajor orthopedic surgery of lower limb, total hip arthroplasty or total knee arthroplasty:

CrCl ≥30 mL/minute: No dosage adjustment is necessary.

CrCl 15 to <30 mL/minute: Avoid use. Patients with CrCl <30 mL/minute were excluded from clinical trials; no other clinical data are available to support use in this population.

CrCl <15 mL/minute: Avoid use.

Hemodialysis, intermittent (thrice weekly): Not dialyzable: Avoid use.

Peritoneal dialysis: Avoid the use

Dosage Adjustment in Hepatic impairment Patient

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer’s labeling. Limited data indicate pharmacokinetics and pharmacodynamic response were similar to healthy subjects.

Moderate to severe impairment (Child-Pugh class B or C) and any hepatic disease associated with coagulopathy: Avoid use.

Avoid herbs and supplements with anticoagulant/antiplatelet activity (e.g. garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba). Avoid St. John's Wort. Co-administration will decrease levels of this medication.

Rivaroxaban is contraindicated in patients with

● Active pathological bleeding.

● Severe hypersensitivity reaction to Rivaroxaban (e.g., anaphylactic reactions)

• Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including Rivaroxaban, 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 to warfarin in clinical trials in atrial fibrillation patients. If Rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

• Risk of Bleeding

Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe Rivaroxaban 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 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, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of drugs that are combined with P-GP and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

• Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An epidural catheter should not be removed earlier than 18 hours after the last administration of Rivaroxaban. The next Rivaroxaban dose is not to be administered earlier than 6 hours after the removal of the catheter. If a traumatic puncture occurs, the administration of Rivaroxaban is to be delayed for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

• Use in Patients with Renal Impairment

Nonvalvular Atrial Fibrillation

Avoid the use of Rivaroxaban in patients with CrCl< 15 mL/min since drug exposure is increased. Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue Rivaroxaban in patients who develop acute renal failure while on Rivaroxaban.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

Avoid the use of Rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Avoids the use of Rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on Rivaroxaban should discontinue the treatment.

• Use in Patients with Hepatic Impairment

No clinical data are available for patients with severe hepatic impairment. Avoid the use of Rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased.

• Use with P-GP and Strong CYP3A4 Inhibitors or Inducers

Avoid concomitant use of Rivaroxaban with combined P-GP and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan). Avoid concomitant use of Rivaroxaban with drugs that are combined with P-GP and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

• Risk of Pregnancy-Related Hemorrhage

In pregnant women, Rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. Rivaroxaban dosing in pregnancy has not been studied. The anticoagulant effect of Rivaroxaban cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

• Patients with Prosthetic Heart Valves

The safety and efficacy of Rivaroxaban have not been studied in patients with prosthetic heart valves. Therefore, the use of Rivaroxaban is not recommended in these patients.

• Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy

Initiation of Rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue Rivaroxaban, considering the importance of the drug to the mother.

Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth. Direct acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended.

Avoid herbs and supplements with anticoagulant/antiplatelet activity (e.g. garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba). Avoid St. John's Wort. Co-administration will decrease levels of this medication.

• Common Adverse effects

Heavy menstrual bleeding, Gastroenteritis, vomiting, hemorrhage, Cough, Syncope, Pruritus, skin blister, skin rash, wound secretion, abdominal pain, gastrointestinal hemorrhage, increased serum transaminases, anxiety, depression, dizziness, fatigue, insomnia, back pain, limb pain, muscle spasm, hemophthalmos, surgical bleeding, intracranial hemorrhage.

• Rare Adverse effects

Cardiac tamponade, hemopericardium, hypersensitivity angiitis, thrombosis (with premature discontinuation), Bullous pemphigoid, Stevens-Johnson syndrome, adrenal hemorrhage, cholestasis, abnormal uterine bleeding, agranulocytosis, pulmonary hemorrhage, retroperitoneal hemorrhage, spinal hematoma, splenic rupture, thrombocytopenia, vitreous hemorrhage, hepatic failure, hepatic injury, hepatitis, jaundice, anaphylactic shock, anaphylaxis, angioedema, hypersensitivity reaction, cerebral hemorrhage, epidural intracranial hemorrhage, hemiparesis, bronchiectasis.

• Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, erythromycin and fluconazole), increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. The increases in exposure ranged from 30% to 160%. Significant increases in rivaroxaban exposure may increase bleeding risk. When data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors. Avoid concomitant administration of Rivaroxaban with combined P-gp and strong CYP3A4 inhibitors.

• Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems

Results from drug interaction studies and population PK analyses from clinical studies indicate coadministration of Rivaroxaban with a combined P-gp and strong CYP3A4 inducer (e.g., rifampicin, phenytoin) decreased rivaroxaban exposure by up to 50%. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy. Avoid concomitant use of Rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

• Anticoagulants and NSAIDs/Aspirin

Single doses of enoxaparin and Rivaroxaban given concomitantly resulted in an additive effect on anti-factor Xa activity. Single doses of warfarin and Rivaroxaban resulted in an additive effect on factor Xa (FXa) inhibition and PT. Concomitant aspirin use has been identified as an independent risk factor for major bleeding in efficacy trials. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with Rivaroxaban. Coadministration of the platelet aggregation inhibitor clopidogrel and Rivaroxaban resulted in an increase in bleeding time for some subjects. 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.

• Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

Results from a pharmacokinetic trial with erythromycin indicated that patients with renal impairment coadministered Rivaroxaban with drugs classified as combined P-gp and moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, dronedarone, and erythromycin) have increased exposure compared with patients with normal renal function and no inhibitor use. Significant increases in rivaroxaban exposure may increase bleeding risk. While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)] . Rivaroxaban should not be used in patients with CrCl 15 to 80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors unless the potential benefit justifies the potential risk.

The common side effects of Rivaroxaban include the following

• Common

Muscle spasm, pain in arms or legs, vomiting, stomach pain, cough, rash.

• Rare

Bloody, black, or tarry stools, pink or brown urine, coughing up or vomiting blood or material that looks like coffee grounds, frequent nosebleeds, bleeding from your gums, heavy menstrual bleeding, weakness, tiredness, headache, dizziness or fainting, blurred vision, pain in arm or leg, rash, itching, difficulty breathing or swallowing, hives, pain or swelling at wound sites.

• Pregnancy

Pregnancy Category C

There are no adequate or well-controlled studies of Rivaroxaban in pregnant women, and dosing for pregnant women has not been established. Use Rivaroxaban with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of Rivaroxaban cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations but increased post-implantation pregnancy loss occurred in rabbits. Rivaroxaban should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. 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. This dose corresponds to about 14 times the human exposure of unbound drug.

• Nursing Mothers

It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue Rivaroxaban, considering the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Of the total number of patients in the RECORD 1-3 clinical studies evaluating Rivaroxaban, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of Rivaroxaban in the elderly (65 years or older) was like that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

• Overdose of Rivaroxaban may lead to hemorrhage. Discontinue Rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of Rivaroxaban overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.

Pharmacodynamic

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 unique 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.

Pharmacokinetics

• Absorption

The absolute bioavailability of rivaroxaban is dose dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. Rivaroxaban 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of Rivaroxaban with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). Rivaroxaban 15 mg and 20 mg tablets should be taken with food. The maximum concentrations (Cmax) 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. Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax 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 Cmax 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 Cmax was 18% lower.

• Distribution

Plasma 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 [ 14C]-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

Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a [14C]-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). 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.

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