Fibrates: What Have We Learned in the Past 40 Years?

James M. Backes, Pharm.D.; Cheryl A. Gibson, Ph.D.; Janelle F. Ruisinger, Pharm.D.; Patrick M. Moriarty, M.D.

Disclosures

Pharmacotherapy. 2007;27(3):412-424. 

In This Article

Drug Interactions

A key difference among fibrates is the potential for drug interactions ( Table 2 ).[25,26,27,28,29,30,31,32,33,34,35,36,37,38,39] Pharmaco-kinetic studies indicate gemfibrozil significantly increases peak plasma concentration and mean area under the concentration-time curve of all statins except fluvastatin.[40,41] This interaction occurs secondary to gemfibrozil inhibiting metabolism through glucuronidation or by preventing biliary excretion of the statin,[25,39] which results in higher overall statin concen-trations and suggests a greater potential for muscle toxicity. Moreover, reports from the United States Food and Drug Administration from January 1998-March 2002 showed that the combined use of gemfibrozil and a statin resulted in 590 cases of rhabdomyolysis compared with 16 cases with fenofibrate and statin therapy.[42] Most of the cases with both gemfibrozil (533 cases) and fenofibrate (14 cases) also involved cerivastatin. This indicates an approximate 20-fold increase with the gemfibrozil-statin regimen compared with the fenofibrate-statin regimen, when considering the number of prescriptions dispensed during that time frame. The major limitation regarding these values is that they represent reported event rates rather than the actual incidence rates. Nevertheless, these data strongly suggest a greater rate of rhabdomyolysis with cerivastatin, as well as with the combined use of statin therapy with gemfibrozil.

One group of authors evaluated the incidence of "hospitalized rhabdomyolysis" among patients in a managed care organization who received lipid-altering agents.[43] The authors reported that the average incidence of rhabdomyolysis per 10,000 person-years for monotherapy with a fibrate was 2.82, compared with 0.44 for those receiving a statin (atorvastatin, pravastatin, or simvastatin). When evaluating combination therapy, the incidence rose to 5.98 when a fibrate was prescribed with atorvastatin, pravastatin, or simvastatin and 1035 with the cerivastatin-fibrate combination. Note that the ratio of rhabdomyolysis cases:person-years for gemfibrozil was 7:10,614 compared with 1:3434 for fenofibrate.

Although the use of a statin-fibrate regimen has inherent risk, precautions can be taken to reduce the likelihood of myopathy and rhabdomyolysis.[32,44] One such approach is limiting the statin dosage. The manufacturers of simvastatin and rosuvastatin suggest not exceeding 10 mg/day when the drug is adminis-tered with gemfibrozil.[45,46] For lovastatin, daily doses should not exceed 20 mg when given with a fibrate.[47] Monitoring creatine kinase concen-trations may also help identify individuals with myositis.[32] Most patients experiencing muscle soreness and weakness have normal creatine kinase concentrations. However, obtaining a baseline creatine kinase concentration is helpful to better assess later values obtained when patients report muscle complaints.

Finally, an essential tool to prevent rhabdomy-olysis is patient education. This is especially important for patients at greater risk for developing severe muscle symptoms such as the elderly, patients receiving a combination of a fibrate and statin, or those receiving higher dosages of lipid-altering agents.[32,43] Although the occurrence of severe muscle damage is rare, each patient receiving a fibrate or statin should be counseled on reporting any unexplainable muscle soreness and weakness. According to the authors of the above-mentioned study,[43] symptoms of rhabdomyolysis began an average of 7 days before hospitalization, indicating the presence of a time period in which the lipid-altering agents could be discontinued to potentially avoid the onset of rhabdomyolysis.

Fibrates are also involved in other drug interactions. Although gemfibrozil has no effect on the cytochrome P450 (CYP) 3A4 isoenzyme, the agent does inhibit CYP2C9 and CYP2C8.[25,41] Inhibition of these isoenzymes results in gemfibrozil increasing plasma concentrations of commonly prescribed agents such as repaglinide, pioglitazone, rosiglitazone, and the sulfonylureas. Conversely, fenofibrate does not appear to significantly inhibit the major CYP isoenzymes or hinder statin metabolism.[25] Fibrates displace warfarin from albumin-binding sites, thereby enhancing the hypoprothrombinemic effects.[27] A reduction in the warfarin dosage with frequent monitoring of prothrombin time or international normalized ratio is suggested to prevent bleeding complications.

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