Fibrates adverse effects

Type III hyperlipoproteinemia may be treated with fibrates or niacin. Although fibrates have been suggested as the drugs of choice, niacin is a reasonable alternative because of the lack of data supporting a cardiovascular mortality benefit from fibrates and because of their potentially serious adverse effects. Fish oil supplementation may be an alternative therapy. 

The fibrates are generally well tolerated, with GI distress being the most likely complaint. Other adverse effects include myositis and erectile dysfunction, particularly with clofibrate. There is ongoing concern about the fibrates increasing the risk of gallstones, although the extent of risk is unclear. Because clofibrate was associated with increased mortality in early clinical trials, it should be considered as a second-line drug. 

Rare adverse effects of fibrates include rashes, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and high blood levels of aminotransferases or alkaline phosphatase. A few patients show decreases in white blood count or hematocrit. Both agents potentiate the action of coumarin and indanedione anticoagulants, and doses of these agents should be adjusted. Rhabdomyolysis has occurred rarely. Risk of myopathy increases when fibrates are given with reductase inhibitors. The use of fenofibrate with rosuvastatin appears to minimize this risk. Fibrates should be avoided in patients with hepatic or renal dysfunction. There appears to be a modest increase in the risk of cholesterol gallstones. 

Action HMG-CoA reductase inhibitor Dose 5-40 mg PO daily max 5 mg/d w/cyclosporine, 10 mg/d w/gemfibrozil or CrCl <30 mL/rain (avoid Al-/Mg-based antacids for 2 h after) Caution [X, /-] Contra Active liver Dz, unexplained T LFT Disp Tabs SE Myalgia, constipation, asthenia, abd pain, N, myopathy, rarely rhabdomyolysis Interactions T Effects OF warfarin T risk of myopathy W/ cyclosporine, fibrates, niacin, statins EMS T Effects of warfarin concurrent EtOH use can T risk of liver tox Asian pts have an T risk of adverse effects OD Unlikely to cause life-threatening Sxs... 

The adverse events of the fibrates are essentially the same with all members of the class and are generally mild or absent during short-term treatment. The observed frequency of adverse effects with a micronized formulation of fenofibrate is comparable to that associated with the usual formulation (SEDA-22, 490). 

Non-specific rashes have been reported in patients taking fibrates. With fenofibrate, rashes are reported significantly more often than with placebo (35), and occur in some 0.6% of patients (23). In a double-bhnd trial, the incidence of cutaneous adverse effects was 11% with fenofibrate and less than 1% with placebo they included hives and urticaria (20). In another study, the difference was 6% (36). 

Fibrates should be avoided in gallbladder disease or any form of obstructive jaundice because of the risk of stone formation. The extended therapeutic effect of gemfibrozil, which is due to enterohepatic recycling, may be reduced in obstructive jaundice. Fibrates may have an adverse effect on coagulation if used, the INR/PT should be monitored... 

Statins are well absorbed after administration orally, and are metabolised in the liver. They are well tolerated, the commonest adverse effect being transient, and usually minor abnormality of liver function tests in some 1% of patients. Asymptomatic elevation of muscle enzymes (creatine phos-phokinase, CPK) and myositis (with a generalised muscle discomfort) occur more rarely, but is more frequent when statins are combined with other anti-hyperlidaemic drugs such as fibrates and nicotinic acid patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere with metabolism of some statins, e.g. ciclosporin. 

In patients taking fenofibrate and atorvastatin, increased concentrations of plasma homocysteine were attributed to an action of the fibrates themselves and not indirectly via their lipid-lowering effect (8). Concomitant administration of folic acid, at least in part, offset this adverse effect... 

In order to reduce the risk of myopathy the CSM in the UK have advised that statins should be used with care in patients who are at increased risk of this adverse effect. Among other risk factors, they mention concomitant use with fibrates, such as gemfibrozil , (p.llOO), and with inhibitors of CYP3A4 such as ciclosporin , (p.l097), macrolides ,(p.ll04), azoles , (p.l093), and protease inhibitors , (p.1108). They also recommend that patients should be made aware of the risks of myopathy and rhabdomyolysis, and asked to promptly report muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or dark urine. A 2002 advisory on the use of statins gives some important safety recommendations, which are useful in the context of interactions ... 

There are marked species differences in response to nongenotoxic carcinogens and the data available support the position that human and some animal species such as guinea pigs are nonresponsive to the adverse effects of PPs seen in rodents. Studies with cultured human hepatocytes show that there is no peroxisome proliferation or induction of S-phase in response to PPs. Follow up studies of patients receiving fibrate PP dmg therapy confirm a lack of adverse effects. In addition, there was no increased rate of cancer in workers exposed to DEHP. The lack of response provides clear evidence that humans are... 

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