Rivaroxaban

Generic Name: Rivaroxaban
Brand Names: Xarelto
Drug Class: Direct Oral Anticoagulant (DOAC) – Factor Xa Inhibitor
Formulations: Oral tablets (2.5 mg, 10 mg, 15 mg, 20 mg) and oral suspension (US: 1 mg/mL)
Route of Administration: Oral

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Therapeutic Indications and Clinical Use

Rivaroxaban is a direct factor Xa inhibitor used as an anticoagulant for prevention and treatment of thromboembolic disorders. It is widely used in both venous and arterial thrombosis contexts.

Approved Indications:

1. Venous Thromboembolism (VTE)

   • Treatment of deep vein thrombosis (DVT)

   • Treatment of pulmonary embolism (PE)

   • Prevention of recurrent DVT/PE after initial treatment

   • VTE prophylaxis in patients undergoing hip or knee replacement surgery

2. Atrial Fibrillation (non-valvular)

   • Stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation (AF)

3. Acute Coronary Syndrome (ACS)

   • Prevention of atherothrombotic events in combination with aspirin ± clopidogrel in select patients with ACS with elevated cardiac biomarkers

4. Chronic Coronary Artery Disease (CAD) or Peripheral Artery Disease (PAD)

   • In combination with low-dose aspirin to reduce cardiovascular death, stroke, and MI risk (COMPASS trial)

5. Pediatric use (US/EU-approved):

   • For thromboprophylaxis in children with congenital heart disease or undergoing cardiac surgery (in age- and weight-specific formulations)

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Mechanism of Action

Rivaroxaban is a selective, direct, and reversible inhibitor of Factor Xa, a central enzyme in the coagulation cascade. It inhibits both:

• Free Factor Xa in plasma

• Prothrombinase-bound Factor Xa on activated platelet surfaces

This inhibition prevents conversion of prothrombin to thrombin, thus reducing fibrin clot formation.

Unlike warfarin, rivaroxaban does not inhibit thrombin (Factor IIa) directly, and does not affect platelet aggregation.

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Dosage and Administration

A. Atrial Fibrillation (non-valvular)

• Standard dose: 20 mg once daily with the evening meal

• Renal impairment (CrCl 15–50 mL/min): 15 mg once daily with evening meal

• CrCl <15 mL/min: Not recommended

B. DVT/PE Treatment

• Initial phase: 15 mg twice daily for 21 days

• Maintenance: 20 mg once daily with food

• Extended prophylaxis: 10 mg once daily (after at least 6 months of treatment)

C. VTE Prophylaxis (Hip/Knee Replacement)

• 10 mg once daily, starting 6–10 hours post-op

  • Hip: for 35 days

  • Knee: for 12 days

D. CAD/PAD (COMPASS Regimen)

• 2.5 mg twice daily + aspirin 75–100 mg once daily

E. ACS (with antiplatelet therapy)

• 2.5 mg twice daily + DAPT (aspirin + clopidogrel or ticlopidine)

Pediatric Dosing (based on weight):

• Weight-based dosing; oral suspension or tablets used

• FDA- and EMA-approved for pediatric patients >0.5 years with certain indications

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Pharmacokinetics

• Bioavailability:

  • 10 mg dose: ~80–100% (food-independent)

  • 15–20 mg dose: ~66% (must be taken with food to improve absorption)

• Protein Binding: ~92–95%

• Metabolism: Hepatic (CYP3A4, CYP2J2, hydrolysis)

• Half-Life:

  • 5–9 hours (young)

  • 11–13 hours (elderly)

• Elimination:

  • 66% renal (36% unchanged)

  • 28% fecal via bile

• Peak Concentration: 2–4 hours post-dose

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Contraindications

• Active pathological bleeding

• Severe hypersensitivity to rivaroxaban or its components

• Hepatic disease associated with coagulopathy and bleeding risk

• CrCl <15 mL/min (for most indications)

• Concomitant treatment with other anticoagulants unless transitioning

• Pregnancy (in many indications unless benefits outweigh risks)

• Breastfeeding (excretion in milk not fully known; avoid use)

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Warnings and Precautions

1. Bleeding Risk:

   • Increased with antiplatelets, NSAIDs, SSRIs/SNRIs, and alcohol

   • Monitor for signs of GI, intracranial, or retinal hemorrhage

2. Renal Impairment:

   • Adjust dosing or avoid use in moderate to severe impairment

3. Hepatic Impairment:

   • Avoid use in moderate to severe hepatic dysfunction

4. Spinal/Epidural Hematoma Risk:

   • Especially with spinal puncture or neuraxial anesthesia

5. Premature Discontinuation:

   • Increases risk of thrombotic events

6. Lack of Routine Monitoring:

   • No need for INR, but clinical vigilance is critical

7. Surgery/Procedures:

   • Discontinue ≥24 hours before elective surgery; longer for high-bleed-risk procedures

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Adverse Effects

Common (≥1%):

• Bleeding (epistaxis, hematuria, menorrhagia)

• Anemia

• GI symptoms: dyspepsia, nausea

• Peripheral edema

• Elevated liver enzymes

Less Common/Serious (<1%):

• Intracranial hemorrhage

• GI bleeding requiring transfusion

• Hypersensitivity reactions (rash, pruritus)

• Thrombocytopenia

• Hepatotoxicity (rare but reported)

• Spinal hematoma (procedural risk)

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Drug Interactions

Increased Bleeding Risk:

• Antiplatelet drugs (aspirin, clopidogrel, ticagrelor)

• NSAIDs (e.g., ibuprofen, naproxen)

• SSRIs/SNRIs (e.g., sertraline, venlafaxine)

• Other anticoagulants (e.g., heparin, dabigatran, warfarin)

CYP3A4 and P-gp Interactions:

• Strong CYP3A4 + P-gp inhibitors (↑ rivaroxaban levels):

  • Examples: Ketoconazole, ritonavir, clarithromycin

  • Avoid use

• Strong CYP3A4 inducers (↓ efficacy):

  • Examples: Rifampin, carbamazepine, phenytoin, St. John's Wort

  • Avoid use

Warfarin and Rivaroxaban Transition:

• Stop warfarin and start rivaroxaban when INR <3.0

• If converting to warfarin, overlap until INR is therapeutic

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Monitoring Parameters

• No routine coagulation monitoring needed (unlike warfarin)

• Renal function: Baseline, periodically in elderly or renally impaired

• Hepatic function: If signs of liver dysfunction appear

• Signs of bleeding: hematomas, bruising, melena, hematuria

• CBC and hemoglobin/hematocrit: Periodically

• Adherence assessment: As missed doses compromise efficacy

• Anti-Factor Xa assays: May be used in special circumstances (e.g., overdose, pre-surgery)

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Use in Special Populations

• Elderly: Increased bleeding risk; monitor renal function

• Pregnancy: Avoid unless absolutely necessary

• Breastfeeding: Use not recommended; discontinue drug or breastfeeding

• Children: Approved for some indications with age- and weight-based dosing

• Renal impairment:

  • CrCl 15–50 mL/min: Dose adjustment (depending on indication)

  • CrCl <15 mL/min: Avoid

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Antidote and Reversal

No specific antidote approved solely for rivaroxaban, but:

• Andexanet alfa (Andexxa): Recombinant modified human factor Xa decoy protein; binds and sequesters rivaroxaban

• Prothrombin Complex Concentrates (PCCs): e.g., 4-factor PCC (off-label use for reversal)

• Activated charcoal: If ingestion within 1–2 hours

• Hemodialysis: Ineffective (due to high protein binding)

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Patient Counseling Points

• Take doses with food if ≥15 mg/day (increases absorption)

• Take at the same time daily

• Do not stop medication without medical advice – risk of stroke or thrombosis

• Watch for signs of bleeding (e.g., unusual bruising, blood in stool or urine)

• Inform all healthcare providers, including dentists, about rivaroxaban use

• Avoid NSAIDs and alcohol which may increase bleeding risk

• For missed dose:

  • If taking 15 mg BID: take both doses together if missed once

  • If taking once daily: take as soon as remembered unless next dose is near

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Comparison with Other DOACs

Parameter	Rivaroxaban	Apixaban	Dabigatran	Edoxaban
Dosing (AF)	Once daily	Twice daily	Twice daily	Once daily
Food requirement	With food (15–20)	No	No	No
Renal adjustment	Yes	Yes	Yes	Yes
GI bleeding risk	Moderate-high	Lower	High	Moderate
Antidote availability	Yes (Andexanet)	Yes (Andexanet)	Yes (Idarucizumab)	Yes (off-label)

Storage and Stability

• Store tablets at room temperature (20–25°C)

• Protect from moisture

• Use suspension within manufacturer's specified time after opening

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Availability and Regulatory Status

• Prescription-only medication

• Approved in over 130 countries

• Brand Name: Xarelto (by Bayer and Janssen)

• Listed on the WHO Model List of Essential Medicines