The Journal of the Arkansas Medical Society Med Journal Feb 2019 Final 2

CASE REPORT Rhabdomyolysis From Atorvastatin and Levofloxacin in an Elderly Patient With Renal Failure Lilianna Hanefeld-Fox, MD; Sai Prasad Desikan, MD; Caston Taylor, PA; Seth Barnes, MD; Raman Desikan, MD White River Health System, Batesville S tatins are increasingly used to ef- fectively lower low-density lipopro- tein cholesterol (LDL) and improve outcomes in coronary heart disease, both in primary prevention of established coronary heart disease and in secondary prevention in established disease. 1,2 However, concerns about muscle toxicity may prompt underutiliza- tion of these effective agents. 3 Rhabdomyolysis is a potentially fatal but rare complication of statin therapy. Risk of statin-induced muscle damage is increased by concomitant administration of drugs that impair the metabolism of statins or other drugs associated with intrinsic myotoxic poten- tial. 4,5 Levofloxacin is widely prescribed for com- munity-acquired respiratory infections; it has pre- dominant renal elimination, and dose reductions are necessary for renal impairment. Levofloxacin has been reported to cause rhabdomyolysis in the elderly, patients on hemodialysis, and post-renal transplantation. 6-8 We report on acute rhabdomy- olysis in an elderly patient with renal impairment from concomitant administration of levofloxacin and atorvastatin. Case Report An 83-year-old white female was admit- ted for increasing weakness and myalgia. Her past medical history was significant for aortic stenosis, coronary artery disease, hypertension, diabetes mellitus type 2, hyperlipidemia, gout, breast cancer, chronic kidney disease, and en- suing normocytic anemia. She had two recent hospitalizations: pneumonia a month prior to this admission and dyspnea with sinus symptoms two weeks before this admission. She was treated with a course of Levofloxacin on both visits. She was switched to Atorvastatin from Simvastatin for coronary artery disease 11 months earlier. She had noticed increasing weakness over a month, necessitating more help with activities of daily liv- ing. She also noticed increasing left upper thigh and hip pain in addition to significant muscular weakness. Left extremity Doppler was unremark- able. Workup revealed rhabdomyolysis with ele- vated myoglobin of 14370 ng/ml, creatine kinase (CK) of 20340 U/L, and creatine kinase, muscle and brain (CK-MB) of 75.5 ng/ml. Transaminases were also elevated with alanine aminotransferase (ALT) of 320 U/L and aspartate aminotransferase (AST) of 742 U/L. Creatinine of 1.3 mg/dl was not significantly elevated from baseline at 1.3 mg/dl and improved during hospitalization. Atorvastatin was held; myoglobin levels and liver enzymes showed progressive improvement. On last evalu- ation four months from onset of rhabdomyolysis, she reported continued improvement of muscle weakness. In addition, myoglobin and creatinine kinase showed continuing reduction, even though values were still above normal at 429 ng/ml and 258 U/L respectively (Figure 1 and 2). Discussion Muscle-related symptoms are well recog- nized, severe adverse effects of statin therapy; the spectrum includes myalgia, myopathy, and rhabdomyolysis. Myopathy, defined by muscle symptoms and CK elevation of 10 fold above up- per limit of normal, occurs in five patients per 100, 000 person years. Rhabdomyolysis, defined by CK elevation above 10,000 IU/L or 10 folds above upper limit of normal with increase in creatinine value, is observed less often (1.6 per 100,000 person years). Less severe manifestations such as myalgia and asymptomatic CK elevation (< 10 fold ULN) are much more common. On average, statin-associated myopathy develops approxi- mately 6.3 months from start of therapy, while rhabdomyolysis is observed much earlier (mean 188 • THE JOURNAL OF THE ARKANSAS MEDICAL SOCIETY time to onset of 9 days). Multiple factors are known to predispose to rhabdomyolysis (fragility, low body mass index, older age, female sex, hy- pothyroidism, hypertension, and polypharmacy). Drug interactions from concomitant medications play a major part in development of rhabdomy- olysis. Statins, especially lovastatin, simvastatin, and atorvastatin are metabolized by CYP3A4 isoform of cytochrome P450. CYP3A4 is inhib- ited by many commonly used drugs (antifungals, macrolides, fusidic acid, cyclosporine, protease inhibitors and calcium channel blockers) making rhabdomyolysis more likely with these agents. Fi- brates, when employed with statin, increase the incidence of rhabdomyolysis. Fibrates have intrin- sic myotoxic potential, causing rhabdomyolysis when employed alone. Fibrates are not known to inhibit CYP3A4. 4,5 Levofloxacin, a commonly employed anti- biotic for respiratory infection, is mainly elimi- nated by kidney and requires dose reduction with renal impairment; acute rhabdomyolysis has been reported in the elderly, patients on he- modialysis, and after renal transplantation. Other fluoroquinolones have also been associated with rhabdomyolysis. 10. Levofloxacin is not known to inhibit cytochromes CYP3A4 or CYP2C8, which are important in metabolism of statins and active metabolites. Levofloxacin is a potent inhibitor of the P-glycoprotein mediated drug efflux system. Levofloxacin is the drug most implicated in causation of rhabdomyolysis in our patient on account of recent exposure. However, she has had multiple exposures to levofloxacin in the set- ting of chronic renal impairment, despite which she did not exhibit symptoms of rhabdomyolysis. Atorvastatin has established myotoxic poten- tial; however, she tolerated Atorvastatin for 11 months without any muscle-related symptoms. VOLUME 115

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