Letter to the Editor
Rhabdomyolysis and Acute Renal Graft
Impairment in a Patient Treated with
Simvastatin, Tacrolimus, and Fusidic Acid

Peter Kotanko Waltraud Kirisits Falko Skrabal Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Graz, Austria post-transplant the following postoperative is a frequent metabolic disease following re- nal grafting, and atherosclerotic vascular dis- ease represents a major burden to transplant was replaced with fluvastatin (40 mg/day), recipients. There is convincing evidence that was started at a daily dose of 10 mg. Immu- aprednislone was tapered and withdrawn af- long-term immunosuppression with steroids nosuppression consisted of tacrolimus (1– ter 6 months. In January 2001 a soft tissue and calcineurin inhibitors such as cyclospo- 2 mg daily with blood trough levels between infection and osteomyelitis of the third left rine A (CsA) and tacrolimus increase both 6.4 and 13.9 ng/ml), aprednislone 5 mg and toe was treated with fusidic acid (500 mg cholesterol and triglyceride levels [1]. Since function was stable with serum creatinine months after the rhabdomyolysis the patient and diabetes mellitus are particularly prone is well with good graft function (SCr 1.0– to atherosclerotic vascular disease, aggres- mg/dl. Because of persistent hyperlipidemia sive treatment of hyperlipidemia is manda- in October 1999, the simvastatin dose was is unchanged. Hyperlipidemia is currently increased to 20 mg/day (table 1). Ten days Simvastatin, an inhibitor of 3-hydroxy-3- later fusidic acid (500 mg TID) was started because of soft tissue infection and osteo- first report of severe rhabdomyolysis in a ductase, is an efficient drug for the treatment myelitis of the second left toe. Five weeks transplant patient treated with simvastatin of hyperlipidemia. In combination with the later the patient was admitted to the hospital and tacrolimus. There is an intriguing tem- use of CsA simvastatin may increase the risk poral relationship between the increase of gradually 2 weeks earlier. On admission the the simvastatin dose and the onset of signs more frequently used in solid organ trans- and symptoms of rhabdomyolysis (table 1).
aprednislone, felodipine 10 mg, citalopram Simvastatin is a substrate for cytochrome P described in patients treated concomitantly 20 mg, aspirin 100 mg, simvastatin 20 mg, fusidic acid (500 mg TID), and insulin (in- tensified insulin therapy regimen). The SCr sis complicated by acute renal transplant concentration was 3 mg/dl, the creatinine tase inhibitory activity derived from simva- failure. In October 1998, a 51-year-old Cau- clearance was 12 ml/min, the serum creatine statin. The concomitant use of CsA and sim- casian female with insulin-dependent dia- kinase (CK) concentration was 24,000 U/ml vastatin has been shown to increase the risk betes mellitus (IDDM) and dialysis-depen- (normal range: 10–70 U/l). The tacrolimus for myopathy [2]. In contrast, to our knowl- dent renal failure due to diabetic nephropa- trough level 4 days before admission was 9.1 CsA and fluvastatin, a statin metabolized by graft. Due to a hemorrhagic pancreatitis the pancreas graft was removed 4 weeks later.
treatment was started with saline and man- Apart from a cytomegalus infection 5 weeks nitol. Renal transplant function improved tients who experienced rhabdomyolysis after Marschallgasse 12, A–8020 Graz (Austria) Tel. +43 316 7067 2101, Fax +43 316 7067 598, E-Mail [email protected] Table 1. Clinical course and therapeutic regimen in a renal transplant patient suffering from rhabdomyolysis
Tac = Tacrolimus; sim = simvastatin; flu = fluvastatin; fus = fusidic acid.
initiation of simvastatin and fusidic acid may be the lipid-lowering drugs of choice in 4 Dromer C, Vedrenne C, Billey T, Pages M, therapy. Fusidic acid has a time-dependent patients treated with tacrolimus. Whether or Fournie B, Fournie A: Rhabdomyolyse à la activating effect on the CYP450 system [6].
not in our patient the use of fusidic acid pre- simvastatine. A propos d’un cas avec revue dela littérature. Rev Rhum Mal Osteo Articu- Whether or not this pharmacologic property sented an additional risk factor for the devel- is responsible for the observed rhabdomyo- opment of rhabdomyolysis is unclear.
5 Wenisch C, Krause R, Fladerer P, Menjawi I, lysis remains to be determined. One case of Pohanka E: Acute rhabdomyolysis after ator- rhabdomyolysis associated with tacrolimus vastatin and fusidic acid therapy. Am J Med References
was reported [7], but no details of concomi- 6 Reimann G, Barthel B, Rockstroh JK, Spatz D, tant drugs were given. A rise of plasma CK Brockmeyer SH: Effects of fusidic acid on the 1 Jindal RM: Post-transplant hyperlipidaemia.
hepatic cytochrome P450 enzyme system. Int J levels was observed in rats receiving a com- Clin Pharmacol Ther 1999;37:562–566.
bined simvastatin-tacrolimus regimen [8].
2 Gruer PJ, Vega JM, Mercuri MF, Dobrinska 7 Hibi S, Misawa A, Tamai M, Tsunamoto K, Todo S, Sawada T, Imashuku S: Severe rhabdo- chrome P450 3A4 inhibitors and simvastatin.
bined use of tacrolimus and simvastatin in a myolysis associated with tacrolimus. Lancet dose exceeding 10 mg/day may put a patient 3 Jardine A, Holdaas H: Fluvastatin in combina- at an increased risk for rhabdomyolysis. Sta- 8 Yamada H, Kotaki H, Sawada Y, Iga T: Sim- tion with cyclosporine in renal transplant recip- vastatin-tacrolimus and simvastatin-cyclospo- tins not metabolized by the CYP3A4 system ients: A review of clinical and safety experi- rine interactions in rats. Biopharm Drug Dis- ence. J Clin Pharm Ther 1999;24:397–408.

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Department of Experimental and Clinical Pharmacology, College of Pharmacy,University of Minnesota, 7-153 WDH, 308 Harvard Street SE, Minneapolis, MN 55455, USAThe number of reports of drug interactions is so great as to be overwhelmingto most clinicians. On average over the last decade there were 60 papers per yearcited in PubMed with ‘‘drug interaction’’ in the title, and 1420 pape

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