Recent literature reports suggest an increased risk of bleeding in patients with impaired renal function when administered infusion doses of eptifibatide similar to those in patients with normal renal function.
Background
Eptifibatide (Integrilin®, Schering-Plough) reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor and other adhesive ligands to the glycoprotein IIb/IIIa receptors and is currently licensed by HSA for use in unstable angina or non-Q-wave myocardial infarction (UA/NQMI) and for patients who are managed with standard medical therapies and/or with percutaneous coronary intervention (PCI). It is intended for use with aspirin and heparin. Eptifibatide is also indicated as an adjunct to percutaneous transluminal coronary angioplasty for the prevention of abrupt closure of the treated coronary vessel and related acute ischaemic cardiac complications.1
The local recommended dosing regimen for UA/NQMI is an intravenous bolus of 180mcg/kg followed by continuous infusion of 2mcg/kg/min for up to 72 hours. For PCI, an intravenous bolus of 180mcg/kg is administered together with a continuous infusion of 2mcg/kg/min for a maximum of 18 – 24 hours post-PCI. In both cases, a second bolus dose of 180mcg/kg is to follow 10 minutes after the first bolus. Eptifibatide is contraindicated in patients with severe renal impairment or creatinine clearance (CrCl) < 30ml/min.1
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Safety updates
A study on eptifibatide published in 2004 demonstrated that at an infusion rate of 2mcg/kg/min in patients with moderate (30 – 50ml/min) or severe renal impairment (CrCl < 30ml/min), the clearance rate of eptifibatide was about 50% lower and steady-state plasma levels was almost 2-fold higher compared to those with normal renal function. The authors recommended a dose reduction of eptifibatide from 2mcg/kg/min to 1mcg/kg/min in patients with ≤ 50ml/min.2
Another recently published study evaluated the correlates of bleeding event among eptifibatide-treated patients undergoing PCI. The bleeding rates were 2.9% (N=527) in patients with CrCl > 50ml/min and 20% (N=15) in patients with CrCl ≤ 50ml/min who received the standard eptifibatide infusion dose of 2mcg/kg/min, and 0% (N=18) in patients with CrCl ≤ 50ml/min who received a reduced dose of 1mcg/kg/min (p=0.017). The incidence of blood transfusions was also significantly increased in patients with CrCl ≤ 50ml/min on standard eptifibatide infusion dose compared to those who received reduced-dose eptifibatide (26.7% vs 0%; p=0.009).3
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Dosing recommendations in other countries
The package inserts of eptifibatide in the different countries carry varying dosage recommendations for renal impairment. In the US, the approved infusion dose of eptifibatide is 1mcg/kg/min for patients with CrCl < 50ml/min when used for acute coronary syndrome and PCI. However, the dosing of eptifibatide in the UK Summary of Product Characteristics (equivalent of a package insert) recommends 2mcg/kg/min for patients with mild to moderate renal impairment (serum creatinine between 175 – 350 micromol/L) and contraindicates the use in patient with severe renal impairment or CrCl < 30ml/min.
Local situation and action
To date, HSA has not received any local reports of bleeding events associated with eptifibatide. However, in view of the pharmacokinetic handling of eptifibatide in renally impaired patients and available evidence3 of efficacy of the lower dose in these patients, HSA is working with the product licence holder to amend the local package insert of Integrilin® to reflect an infusion dose of 1mcg/kg/min for patients with CrCl between 30 – 50ml/min when used for both acute coronary syndrome and PCI.
References
- Product information Integrilin®, Singapore.
- Clin Ther 2004; 26:290-8.
- J Am Coll Cardiol 2006; 47:2374-9.
