XARELTO (rivaroxaban) tablet

XARELTO (rivaroxaban) tablet

XARELTO (rivaroxaban) tablet

Rivaroxaban, a factor Xa (FXa) inhibitor, is the active ingredient in XARELTO® Tablets with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89.

Indications and usage

XARELTO is a factor Xa inhibitor indicated:

  • to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation
  • for treatment of deep vein thrombosis (DVT)
  • for treatment of pulmonary embolism (PE)
  • for reduction in the risk of recurrence of DVT or PE
  • for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery 
  • for prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients
  • to reduce the risk of major cardiovascular events in patients with coronary artery disease (CAD)
  • to reduce the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD), including patients after recent lower extremity revascularization due to symptomatic PAD

Mechanism of Action

XARELTO 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.

Contraindications

XARELTO is contraindicated in patients with:

  • active pathological bleeding
  • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions)

Warnings and precautions

Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

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 XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

Advertisement

Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors. Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers

Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing. 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: On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO 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.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and antibeta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Side effects

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

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

Dosage and administration

* Calculate CrCl based on actual weight. 
See CLINICAL PHARMACOLOGY
Patients with CrCl <30 mL/min were not studied, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min)
§ See DOSAGE AND ADMINISTRATION

* 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.

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

* 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.

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 [see Warnings and Precautions (5.2)]. In deciding whether a procedure should be delayed until 24 hours after the last dose of XARELTO, the increased risk of bleeding should be weighed against the urgency of intervention.

Missed Dose

  • For patients receiving 2.5 mg twice daily: if a dose is missed, the patient should take a single 2.5 mg XARELTO dose as recommended at the next scheduled time.
  • For patients receiving 15 mg twice daily: The patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. Two 15 mg tablets may be taken at once.

Drug interactions

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.

Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort)

Anticoagulants and NSAIDs/Aspirin: Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding.

Avoid concurrent use of XARELTO 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.

Use in specific populations

Pregnancy: The limited available data on XARELTO in pregnant women are insufficient to inform a drugassociated risk of adverse developmental outcomes. Use 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

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 XARELTO in this setting.

Lactation: 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 XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Patients with Chronic Kidney Disease not on Dialysis: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment.

Advertisement

Patients with End-Stage Renal Disease on Dialysis: Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF

Hepatic Impairment: In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

Overdosage

Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. 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 XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Advertisement

Leave a Reply

Gafacom
%d bloggers like this: