Fondaparinux

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa through antithrombin. It prevents and treats venous thromboembolism and acute coronary syndromes, and it has a very low rate of heparin induced thrombocytopenia, so it is used when that complication occurs or is feared. It has a long half life, accumulates in kidney impairment, and has no specific antidote. It is limited in East Africa because of cost.

Classification. Synthetic factor Xa inhibitor (indirect, antithrombin mediated); pentasaccharide.

Mechanism. Binds antithrombin, increasing its inhibition of factor Xa about 300 fold. It does not inhibit thrombin and does not bind platelet factor 4.

Pharmacodynamics. Peak anti Xa activity 2 hours after subcutaneous injection; steady state in 3 to 4 days. Does not prolong aPTT or INR meaningfully.

Pharmacokinetics. Subcutaneous bioavailability 100%. Half life 17 to 21 hours (longer in kidney impairment). About 77% excreted unchanged in urine within 72 hours. Protein bound to antithrombin only.

Prevention of venous thromboembolism, adult. 2.5 mg SC once daily, first dose 6 hours after surgery (or 6 to 8 hours); continue for 5 to 9 days (up to 24 to 32 days after hip fracture surgery).

Treatment of deep vein thrombosis and pulmonary embolism, adult. Once daily SC by weight: under 50 kg, 5 mg; 50 to 100 kg, 7.5 mg; over 100 kg, 10 mg. Continue for at least 5 days and until the INR is 2.0 or more for 24 hours when warfarin is used.

Unstable angina and non ST elevation myocardial infarction, adult. 2.5 mg SC once daily for up to 8 days or until discharge.

ST elevation myocardial infarction, adult. First dose 2.5 mg IV, then 2.5 mg SC once daily for up to 8 days. Not used as the only anticoagulant in primary percutaneous coronary intervention (catheter thrombosis); add unfractionated heparin.

Heparin induced thrombocytopenia (specialist, off label). Treatment dose by weight: under 50 kg, 5 mg; 50 to 100 kg, 7.5 mg; over 100 kg, 10 mg once daily.

Children. Not established.

Contraindications. Creatinine clearance under 20 mL/min; active major bleeding; acute bacterial endocarditis; body weight under 50 kg for prevention; hypersensitivity.

Warnings. Bleeding without an antidote (use recombinant factor VIIa or prothrombin complex concentrate in life threatening bleeding); spinal or epidural haematoma; accumulation in kidney impairment; older age raises bleeding risk. Prevention dose of 1.5 mg daily in creatinine clearance 20 to 50 mL/min (some labels).

Adverse effects. Bleeding, anaemia, injection site reaction, raised liver enzymes, thrombocytopenia (rare), nausea.

Interactions. Aspirin, antiplatelet drugs, non steroidal anti-inflammatory drugs, warfarin, thrombolytics, direct oral anticoagulants: bleeding. No known drug interactions with cytochrome P450.

Special groups.

• Pregnancy: use only when heparin allergy or heparin induced thrombocytopenia exists; limited data.

• Breastfeeding: small amounts in milk; avoid or monitor.

• Patients of African ancestry: no dose change.

• Older adults: use with care; check creatinine clearance.

• Kidney impairment: creatinine clearance 20 to 50 mL/min: reduce prevention dose to 1.5 mg daily (and use caution in treatment); under 20 mL/min: contraindicated.

• Liver impairment: no adjustment in mild to moderate disease; use with care in severe disease.

Formulations. Prefilled syringes 2.5, 5, 7.5, 10 mg.

Administration. Deep SC injection into the abdomen; alternate sides; do not expel the air bubble.

Baseline. Platelet count, haemoglobin, creatinine clearance, weight, liver function.

Monitoring. Haemoglobin and platelet count at baseline and at 1 week; creatinine every 3 months in long courses; anti Xa (calibrated for fondaparinux) in kidney impairment or obesity.

Stopping. Stop after the planned course; effect wears off over 3 to 4 days.

Common prescribing errors. Giving it with creatinine clearance under 20 mL/min; using the prevention dose in a treatment indication; using it alone for primary percutaneous coronary intervention; giving to patients under 50 kg for prevention; omitting weight bands.