Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It prevents stroke in non valvular atrial fibrillation, treats and prevents venous thromboembolism, prevents clots after hip or knee replacement, and at low dose lowers cardiovascular events in stable coronary and peripheral artery disease. The 15 mg and 20 mg doses must be taken with food.

It must not be used with mechanical valves, in moderate to severe rheumatic mitral stenosis, or in antiphospholipid syndrome. In atrial fibrillation with rheumatic heart disease, a large study showed worse outcomes with rivaroxaban than with a vitamin K antagonist. It is available in East Africa at higher cost than warfarin.

Classification. Direct oral anticoagulant; factor Xa inhibitor.

Mechanism. Binds directly and reversibly to the active site of free and clot bound factor Xa and prothrombinase, blocking thrombin generation.

Pharmacodynamics. Peak effect 2 to 4 hours after the oral dose; anticoagulant effect lasts about 12 to 24 hours. Prolongs PT (reagent dependent) and anti Xa assays.

Pharmacokinetics. Oral bioavailability 80 to 100% for the 2.5 and 10 mg doses; 66% for 20 mg on an empty stomach and nearly 100% with food. Half life 5 to 9 hours (11 to 13 hours in older adults). About one third cleared unchanged by the kidneys; two thirds by CYP3A4, CYP2J2 metabolism. A substrate of P-glycoprotein.

Stroke prevention in non valvular atrial fibrillation, adult. 20 mg once daily with the evening meal; 15 mg once daily with the evening meal if creatinine clearance is 15 to 49 mL/min.

Treatment of deep vein thrombosis and pulmonary embolism, adult. 15 mg twice daily with food for 21 days, then 20 mg once daily with food. After 6 months, 10 mg once daily (or 20 mg once daily) for extended prevention.

Prevention of venous thromboembolism after hip or knee replacement, adult. 10 mg once daily starting 6 to 10 hours after surgery, for 5 weeks after hip replacement and 2 weeks after knee replacement.

Coronary artery disease or peripheral artery disease, adult. 2.5 mg twice daily with aspirin 75 to 100 mg daily.

Acute coronary syndrome (after stabilisation), adult. 2.5 mg twice daily with aspirin and clopidogrel or ticagrelor.

Children (where licensed). Weight based dosing for venous thromboembolism (specialist).

Contraindications. Active clinically significant bleeding; hepatic disease with coagulopathy (Child-Pugh B and C); creatinine clearance under 15 mL/min; mechanical heart valves; moderate to severe rheumatic mitral stenosis; triple positive antiphospholipid syndrome; concurrent strong dual inhibitors of CYP3A4 and P-glycoprotein (ketoconazole, itraconazole, ritonavir); pregnancy and breastfeeding; hypersensitivity.

Warnings. Bleeding; reduced absorption of 15 mg and 20 mg doses without food; premature discontinuation raises stroke risk; spinal or epidural haematoma (remove the catheter at least 18 hours after the last dose); accumulation in kidney impairment; low body weight and age over 75 years.

Adverse effects. Bleeding (gastrointestinal, urinary, nose), anaemia, bruising, nausea, raised liver enzymes, rash, dizziness.

Interactions. Strong dual CYP3A4 and P-glycoprotein inhibitors (ketoconazole, itraconazole, ritonavir): avoid. Strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort): avoid (reduced effect). Antiplatelet drugs, non steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, other anticoagulants: bleeding. Clarithromycin and erythromycin: modest rise.

Reversal. Andexanet alfa where available; otherwise prothrombin complex concentrate 25 to 50 units/kg; activated charcoal within 8 hours of ingestion. Haemodialysis does not remove it.

Special groups.

• Pregnancy: contraindicated.

• Breastfeeding: contraindicated.

• Patients of African ancestry: no dose change; check for rheumatic mitral stenosis; warfarin is preferred if present.

• Older adults: no dose change by age alone; adjust for creatinine clearance.

• Kidney impairment: creatinine clearance 15 to 49 mL/min: 15 mg once daily for atrial fibrillation and caution in venous thromboembolism; under 15 mL/min: avoid.

• Liver impairment: Child-Pugh A: caution; B and C: contraindicated.

Formulations. Tablets 2.5, 10, 15, 20 mg; oral suspension in some markets.

Administration. Oral with food for the 15 mg and 20 mg doses (the 2.5 mg and 10 mg doses with or without food). Tablets may be crushed and given in water or apple sauce, and through a nasogastric tube into the stomach with food.

Baseline. Haemoglobin, platelet count, creatinine clearance (Cockcroft Gault), liver function, weight, drug history, pregnancy status, echocardiogram in rheumatic disease.

Monitoring. Creatinine clearance and haemoglobin at least yearly (every 6 months over 75 years or creatinine clearance under 60 mL/min); liver function yearly; adherence at each visit.

Stopping. Stop 24 hours before low bleeding risk surgery and 48 hours before high risk surgery; no bridging. Restart 24 to 72 hours after surgery when bleeding is controlled.

Common prescribing errors.

• Taking 20 mg on an empty stomach.
• Wrong dose after the first 21 days of treatment.
• Using in a mechanical valve or rheumatic mitral stenosis.
• Combining with rifampicin.
• Missing dose reduction in creatinine clearance 15 to 49 mL/min.
• Continuing 15 mg twice daily beyond 21 days.