Rhabdomyolysis from the Combination of a Statin and Gemfibrozil: An Uncommon But Serious Adverse Reaction

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1 Rhabdomyolysis from the Combination of a Statin and Gemfibrozil: An Uncommon But Serious Adverse Reaction Amy Haavisto Kind, MD; Laura J. Zakowski, MD; Patrick E. McBride, MD ABSTRACT We report a patient with renal insufficiency who developed rhabdomyolysis 1 month after initiating cerivastatin and gemfibrozil for hyperlipidemia. Myopathy caused by HMG-CoA reductase inhibitors (statins) alone is rare, but occurs more frequently when a statin is used with gemfibrozil, a medication that likely has a direct toxic effect on muscles. Predisposing factors to the development of myopathy from the combination include use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism. It has been proposed that alternate-day therapy with a statin and fibrate, spacing of doses in a single day, or use of lower doses of statins may prevent the development of myopathy. Currently, no predictable method to determine who is at risk for myopathy exists, nor is there a reliable screening test. Therefore, patients should be advised to watch for generalized muscle pain or weakness, and if it occurs, stop medications and report symptoms immediately. Doctor Kind is a second year internal medicine resident at Massachusetts General Hospital. She graduated from the University of Wisconsin Medical School in May Doctor Zakowski is assistant professor of medicine at the University of Wisconsin Medical School. She is a general internist practicing in Madison and co-directs Patient, Doctor and Society, a course that teaches first and second year medical students history and physical examination. Doctor McBride is professor of medicine (cardiovascular) and family medicine. He is the director of Preventive Cardiology at the University of Wisconsin Medical School and UW Hospital and Clinics. Address reprint requests to Laura Zakowski, MD, 326 Bradley Memorial, 1300 University Ave; Madison, WI 53706; zakowski@facstaff.wisc.edu.... INTRODUCTION The Third Adult Treatment Panel Guidelines of the National Cholesterol Education Program released in May 2001 (NCEP ATP III) encourage more aggressive treatment of elevated triglycerides and low highdensity lipoprotein (HDL) than previous guidelines, while continuing to emphasize the importance of treating elevated low-density lipoprotein (LDL) levels. 1 Statins lower LDL levels very effectively, while gemfibrozil and other fibrates lower triglycerides and raise HDL more effectively. The combination of the two medications, often useful for patients with a combined hyperlipidemia, increases the risk of myopathy (muscle pain or weakness with an elevated creatine kinase [CPK] of at least 10 times normal) and rhabdomyolysis (rapid and severe muscle breakdown with its associated metabolic effects). CASE PRESENTATION A 51-year-old female with a history of hypertension, hypercholesterolemia, peripheral arterial disease and renal insufficiency (baseline creatinine 1.6) presented to the emergency room with progressive muscle pain, weakness, and lethargy. Initially she noted diffuse arm and leg pain 2 weeks earlier, but attributed her pain to peeling numerous bags of potatoes the previous day. Medications at time of presentation included naproxen, cyclobenzaprine, amlodipine/ benazepril, metoprolol, cerivastatin and gemfibrozil. Her physician had initiated both cerivastatin and gemfibrozil 1 month earlier for treatment of elevated LDL and triglycerides. She denied recent trauma, excessive exercise, infection, seizure, or ethanol use. Physical exam revealed a moderately obese woman who appeared alert, but acutely ill. Vital signs were significant for an elevated systolic blood pressure (170/70). Diffuse tenderness to palpation was noted along her arms and legs with normal strength and sensation. The remainder of the physical exam was unremarkable. Initial laboratory data were remarkable for a potassium of 8.5 mmol/l (normal, ), creatinine of 8.0 mg/dl (normal, ), blood urea nitro- 53

2 gen of 136 mg/dl (normal, 7-20), and CPK of 22,770 U/L (normal, 0-250). Urine myoglobin was negative. Electrocardiogram exhibited changes consistent with hyperkalemia, including PR lengthening, QRS prolongation and peaked T waves. She was diagnosed with acute renal failure and rhabdomyolysis. This was likely due to the initiation of both a statin and gemfibrozil in the setting of renal insufficiency while taking amlodipine, a medication that causes increased statin levels. In addition to traditional emergent treatment for hyperkalemia, she required 1 course of dialysis for persistent hyperkalemia. Her rhabdomyolysis was treated with intravenous fluids, mannitol, and urine alkalinization. Over the 7 days of her hospitalization, her CPK and creatinine declined gradually, and she was discharged with a creatinine of 2.5. One month later creatinine was back to her baseline at 1.3. DISCUSSION Rhabdomyolysis, a severe myopathy caused by injury of skeletal muscle, results in release of cellular contents into the circulation. Rhabdomyolysis can lead to severe metabolic abnormalities (hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, and hypoalbuminemia), disseminated intravascular coagulation, and acute renal failure. The differential diagnosis of rhabdomyolysis includes massive trauma (crush injuries), hypothermia, hyperpyrexic syndromes, infections, hypoxia, metabolic disorders, immunologic disease (dermatomyositis/polymyositis), and toxins (ethanol, cocaine, PCP, and amphetamines). Statins rarely cause myopathy, but it is more common when patients take medications that inhibit or interfere with cytochrome P450 enzymes. 2 The use of other medications may lead to large increases in the plasma concentrations of statins, since most statins are at least partly metabolized by this cytochrome. Muscle tissue might be sensitive to elevated blood levels of statins, 3 leading to a myopathy in the presence of a competing medication. The list of medications inhibiting this isoenzyme is long and documented in the table. Each medication may have a variable effect on the blood level of the statin. One study showed that itraconazole can cause a 19-fold increase in the serum level of simvastatin. 4 Grapefruit and grapefruit juice are also potent inhibitors of the cytochrome P450-3A4 isoenzyme, thus patients taking statins should limit grapefruit intake. 5 A modest amount of grapefruit ingestion... Table 1. Drugs that inhibit or are metabolized by the cytochrome P450 isoenzymes* Over-the-counter acetominophen Antibiotics clarithromycin erythromycin norfloxacin Antifungals clotrimazole fluconazole itraconazole ketoconazole miconazole Antidepressants fluoxetine fluvoxamine nefazodone imipramine sertraline Food grapefruit Cardiovascular amiodarone amlodipine digoxin diltiazem felodipine isradipine losartan mibefradil nifedipine quinidine verapamil Miscellaneous CNS alprazolam carbamezapine midazolam phenobarbital phenytoin triazolam Protease inhibitors indinavir ritonavir nelfinavir saquinavir Other cimetidine cyclosporine danazole dexamethasone ergotamine ethinyl estradiol omeprazole propoxyphene rifampin sildenafil tacrolimus theophylline zafirlukast * Adapted from Cheitlin MD, Hutter AM, Brindis RG, et al. Circulation 1999;99: (up to 1 quart of juice a day) with statins is not problematic, 7 especially if the grapefruit is ingested in the morning and the statin is taken in the evening. This problem does not apply to other citrus fruits or other foods in general. The potential interaction of each statin with other medications may differ depending on which isoenzyme it is metabolized by, and the degree with which it is metabolized. Lovastatin, simvastatin and atorvastatin are metabolized exclusively through the 3A4 isoenzyme. Cerivastatin is metabolized through both the 3A4 and 2C8 isoenzymes, and fluvastatin is metabolized through the 2C9 isoenzyme. Studies directly comparing toxicities across statins are lacking, but pravastatin should be safest when prescribing other medications affecting liver metabolism, since it is not significantly metabolized through cytochromes. 2 Myopathy can occur with either statin or fibrate monotherapy. One study reported an incidence of 0.08% in patients taking simvastatin 7 and another reported the same percent for lovastatin. 8 In a population-based cohort, the frequency of myopathy in patients taking statins was 1.2 per 10,000 personyears. 9 The fibrate class of drugs, including gemfibrozil can also cause myopathy, but the mechanism 54

3 ... is unknown. 10 It has been proposed that gemfibrozil may have a direct toxic effect on the muscles, 11 similar to the myositis described by a related fibrate, clofibrate. 12 Fibrates are excreted by the kidney, and the risk of myopathy increases in patients with renal insufficiency. 2 The degree of increase in this risk is not known. In the same population-based cohort reported above, the frequency of myopathy from fibrates was 6.6 per 10,000 person-years. 9 Often, statin therapy alone only partially treats the lipid abnormality in patients with combined dyslipidemias. If a patient does not have adequate triglyceride control when already on an agent to lower LDL, the choices include niacin, fish oil capsules or fibrates (gemfibrozil or fenofibrate). A number of studies examining the efficacy and safety of a statin and gemfibrozil used together demonstrate that this combination approach is more effective than monotherapy at reducing lipid levels and, for the most part, is quite safe. 13,14 The risk of myopathy with combination statin and gemfibrozil therapy ranges from 0.4% up to 5.0% of patients taking the medication over the course of a study, the latter with lovastatin. 13,15 The frequency of this occurrence has not been reported for cerivastatin, but is higher than the other statin-gemfibrozil combinations. 1 In one study, myalgias without CK elevation were found to be the most common reason for discontinuation of combination therapy, occurring in 2% of subjects. 13 The other medications that can be used with statins to treat elevated triglycerides have not been as well-studied as gemfibrozil. The incidence of myositis from the combination of a statin and fenofibrate is not currently well-documented, but a study evaluating the combination of fluvastatin and fenofibrate documented no significant increase in CPK levels. 16 Two prospective studies showed no increase in adverse effects when a statin and niacin were used together. 17,18 There are no reported cases of myopathy occurring from the combination of a statin and fish oil. 19 Several case studies of gemfibrozil-statin related rhabdomyolysis have been reported in the medical literature. This life-threatening complication has been reported with lovastatin, simvastatin, cerivastatin, and atorvastatin. 3,20-22 If CPK measurements were obtained prior to the reported episodes, these were normal, suggesting that screening CPK levels may be of low utility. Predisposing factors to development of myopathy when the combination is used has not been well-studied. Published reports suggest that hypothyroidism, 23 diuretic therapy, 11 high doses of statins, and renal insufficiency 10 are important factors. In one case dehydration and pancreatitis was thought to be the cause. 22 Because of a higher incidence of myopathy when combined with gemfibrozil, cerivastatin was withdrawn from the market. Lovastatin also has a relatively high incidence of myopathy when combined with gemfibrozil, and it should be used with caution. It is likely lovastatin use will increase, since it will soon be available in generic form. The gemfibrozil label itself states that the benefit of combination therapy with a statin and gemfibrozil does not outweigh the risks of severe myopathy, rhabdomyolysis and acute renal failure. 24 The combination of a statin and gemfibrozil is often needed, however, for severe combined dyslipidemias, and this has been approved by the new NCEP ATP III guidelines. 1 To avoid complications with use of a statin and gemfibrozil, administration of simvastatin on alternate days with fenofibrate has been effective in lowering lipid levels with very few side effects. 25 Administration of a fibrate in the morning and a statin in the evening may also be a safe alternative 10,19 because both medications have a short half-life, and one would be mostly cleared from the circulation before the administration of the other. Others have advocated prescribing lower doses of statins with fibrates to minimize complications. 2 Temporarily discontinuing lipid-lowering therapy may be a useful preventive strategy if a condition occurs that places a patient at increased risk of myopathy, such as major surgery, severe infection, hypotension, severe metabolic, electrolyte, or endocrine disorders or major trauma. 3 The University of Wisconsin Preventive Cardiology clinic uses the following treatment algorithm: 1) If a patient has very high triglyceride levels (>300 mg/dl) with a modest LDL elevation, niacin or gemfibrozil is used to lower the triglycerides to the target level. Because fenofibrate is more expensive than gemfibrozil, it is used only if patients have difficulty with either niacin or gemfibrozil. If the LDL is not lowered sufficiently with this treatment, then a low-dose statin is added. 2) If the patient has very high triglyceride levels (>300 mg/dl) with a high LDL, a statin is used first to lower the LDL to target level, then either gemfibrozil or niacin is added. The patient is carefully instructed in either case to alert the clinic if muscle pain develops. CK levels are not monitored routinely, but one 55

4 is obtained if there is a history supporting development of myopathy. CONCLUSION We recommend that all health care providers prescribing statins recognize that this class of medication has numerous drug-drug interactions. When statins are combined with gemfibrozil, there is an increased risk of myopathy or rhabdomyolysis. Caution is especially indicated for patients with associated conditions including renal insufficiency that place them at increased risk. Theoretically, the risk of myopathy with combination therapy may vary by compound within the statin class, but more studies are needed to assess the actual risk of each compound. If combination therapy is needed, patients should closely monitor and report muscle pain or weakness, and clinicians should have a low threshold to obtain CPK levels in symptomatic patients. Clinicians should also consider discontinuing statins or gemfibrozil temporarily when patients are at increased risk of myopathy, or when an interacting medication is needed for a short period of time. REFERENCES 1. National Cholesterol Education Panel Adult Treatment Panel III. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285: Knopp RH. Drug treatment of lipid disorders. New Eng J Med. 1999;341: Pierce L, Wysowski D, Gross T. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA. 1990;264: Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther. 1998;63: Micromedex. Copyright MICROMEDEX Thomson Healthcare MICROMEDEX(R) Healthcare Series Vol Physicians Desk Reference. Montvale NJ, Medical Economics Company, Inc., 2002, page Boccuzzi S, Bocanegra T, Walker J. Long-term safety and efficacy profile of simvastatin. Am J Card. 1991;68: Dujovne CA, Chremos AN, Pool JL, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. IV. Additional perspectives on the tolerability of lovastatin. Am J Med. 1991:91(Suppl 1B): Gaist D, Rodriguez LAG, Huerta C, et al. Lipid-lowering drugs and the risk of myopathy: a population-based followup study. Epidemiology. 2001;12: Shepherd J. Fibrates and statins in the treatment of hyperlipidemia: an appraisal of their efficacy and safety. Euro Heart J. 1995;16: Guyton JR, Dujovne CA, Illingworth DR. Dual metabolism of cerivastatin-clarifications. Am J Card. 1999;84: Sekowski I, Samuel P. Clofibrate-induced acute muscular syndrome. Am J Cardiol. 1972;30: Murdock D, Murdock A, Murdock R, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J. 1999;138: Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Card. 1997;80: Tolbert JA. Reply (letter). N Engl J Med. 1988;318: Farnier A, Dejager S. Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. French Fluvastatin Study Group. Am J Cardio. 2000;85: Stein EA, Davidson MH, Dujovne CA, et al. The efficacy and tolerability of low dose simvastatin and niacin, alone and in combination, in patients with combined hyperlipidemia: a prospective trial. J Cardiovasc Pharmacol Ther. 1996;1: Kashyap ML, McGovern ME, Berra K, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol. 2002;89: Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug Safety. 1998;19: Tal A, Rajeshawari M, Isley W. Rhabdomyolysis associated with simvastatin-gemfibrozil therapy. Southern Med J. 1997;90: Pogson G, Kindred L, Carper B. Rhabdomyolysis and renal failure associated with cerivastatin-gemfibrozil combination therapy. Am J Card. 1999;83: Duell PB, Connor WE, Illingworth DR: Rhabdomyolysis after taking atorvastatin with gemfibrozil. Am J Cardiol. 1998;81: Ahmad S. Lovastatin-induced myopathy in a hypothyroid patient. J Fam Pract. 1995;41: Physicians Desk Reference. Montvale NJ, Medical Economics Company, Inc., 2002, page Kayikcioglu M, Ozerkan F, Soydan I. Effectiveness and safety of alternate-day simvastatin and fenofibrate on mixed hyperlipidemia. Am J Card. 1999;83:

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