European Heart Journal Advance Access originally published online on August 25, 2005
European Heart Journal 2005 26(21):2344-2345; doi:10.1093/eurheartj/ehi466
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Ezetimibe coadministered with fenofibrate: some safety questions: reply
Point Medical
Dijon, France
E-mail address: mfarnier{at}ipac.fr
Merck Research Laboratory
RY34-A216
Rahway, NJ 07065
USA
We thank Dr Borja for interest in our work1 and this letter allows us to expand on the criteria related to creatine kinase (CK) elevations used in our study. First, it is important to state that there were no measured CK elevations more than 10 times upper limit of normal (ULN), no reports of myopathy, and that the incidence of myalgia was low and similar among all four treatment groups (3.1% for placebo, 1.6% for ezetimibe 10 mg/d, 1.1% for fenofibrate 160 mg/d, and 1.6% for fenofibrate 160 mg/d plus ezetimibe 10 mg/d) over 12 weeks.1 Additionally, there were no measured elevations in CK more than five times ULN with or without symptoms with any treatment (one patient in the fenofibrate plus ezetimibe group had one measured CK level between three and five times ULN). The CK criteria used in the current protocol for retesting and discontinuing patients are the same as those used in all lipid lowering protocols over the past several years by Merck & Co., Inc. and Merck–Schering Plough Pharmaceutical. Although the criteria developed by the ACC/AHA/NHLBI2 appear reasonable, the CK criteria used in the current protocol have been used extensively during the development of lovastatin, simvastatin, ezetimibe, and ezetimibe/simvastatin.
Word counts imposed by the journal allow us only to summarize the details for all procedures used in this study. Subsequently, we describe in detail the procedures for monitoring and handling elevations in CK used in our study. According to the protocol, the central laboratory will notify an investigational site if CK is more than five times ULN, and the site will then contact the patient for a retest within 3 days of the first blood draw. At the follow-up visit, a patient's history will be evaluated: for potential drug interaction with known inhibitors or substrates of CYP3A4; for any recent unusual and/or strenuous exercise, trauma, or intramuscular injections prior to blood draw; and to rule out myocardial ischaemia. As per the protocol, all patients with elevated CK levels will be followed until resolution. The following criteria for CK elevations were used in this study:
- Patients with persistent (two consecutive) CK elevations five-fold or more WITH muscle symptoms were discontinued.
- Patients with persistent CK elevations more than 10-fold WITH or WITHOUT muscle symptoms were discontinued.
- Patients with a persistent CK elevation five-fold or more and less than 10-fold WITHOUT muscle symptoms may at the discretion of the investigator and with patient monitoring, remain on study drug until a repeat CK is obtained.
- Patients with a single CK elevation 10-fold or more WITH muscle symptoms interrupted study drug and had a follow-up CK within 3 days.
- Patients with a single CK elevation 10-fold or more WITHOUT muscle symptoms may at the discretion of the investigator and with patient monitoring, remain on study drug until a repeat CK is obtained.
References
- Farnier M, Freeman M, Macdonnell G, Perevozskaya I, Davies M, Mitchel Y, Gumbiner B. Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J 2005;26:897–905.
[Abstract/Free Full Text] - Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567–572.
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