Massive rhabdomyolysis and life threatening hyperkalaemia in a patient with the combination of cerivastatin and gemfibrozil
Frits Hendriks1,
Jeroen P. Kooman2, and
Frank M. van der Sande2
1 Department of Internal Medicine, Horacio Oduber Ziekenhuis, Aruba and
2 University Hospital Maastricht, Maastricht, The Netherlands
Keywords: myopathy; rhabdomyolysis; hyperkalaemia; cerivastatin
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Introduction
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Myopathy is fairly common in patients receiving statin therapy, especially when administered in combination with other drugs which are concomitantly metabolized through the cytochrome P-450 pathway. Recently, cerivastatin, which is metabolized by a dual hepatic pathway, has been introduced as a lipid lowering agent. This dual metabolic pathway could have the advantage of fewer drug interactions and, therefore, a reduced number of complications [1]. However, it is not well known whether this advantage also holds true for the risk of myopathy due to a combination of cerivastatin and fibrates. In this case report, we describe a patient with life-threatening hyperkalaemia and massive rhabdomyolysis in a patient treated with the combination of cerivastatin and gemfibrozil.
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Case
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A 72-year-old lady was seen at the out-patient clinic of another hospital because of non-insulin dependent diabetes mellitus and hypercholesterolaemia, for which she was treated with 850 mg metformin once daily, 12.5 mg hydrochlorothiazide once daily and 0.2 mg cerivastatin once daily. At that point in time her serum creatinine was 66 µmol/l. Because of the concomitant hyperlipidaemia, 600 mg gemfibrozil was added to her medications. After 3 days, she was admitted to the first-aid unit of our clinic because of chest pain and severe muscle pain, predominantly in the upper legs. At general physical examination no abnormalities were found. Laboratory results showed a serum potassium of 10.3 mmol/l, blood urea nitrogen of 42.3 mmol/l, serum creatinine of 550 µmol/l and a creatine kinase level of 58886 U/l.
The electrocardiogram showed a prolonged PQ-time and severe widening of the QRS segment. The patient was immediately treated with glucose and insulin, and a haemodialysis session was started. Following dialysis, her potassium level decreased to 4.7 mmol/l and her electrocardiographic abnormalities disappeared. The patient remained dialysis dependent for 7 weeks. Thereafter, her renal function gradually improved and stabilized at a level of 190 µmol/l (creatinine clearance 55 ml/min).
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Discussion
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Although this report is not the first to describe rhabdomyolysis in patients treated with both cerivastatin and fibrates, we believe that it is unique in view of the massive and life-threatening hyperkalaemia in combination with oliguric renal failure, for which prolonged dialysis therapy was necessary. Rhabdomyolysis during combined treatment with cerivastatin and fibrates has been described before in three cases [24], whereas in another case this complication was probably provoked by concomitant influenza vaccination [5]. In two of the cases, renal failure resolved with conservative treatment. In the third case, the patient died after a dialysis session, although the exact cause of death was not clear from the report [4]. In these three reports, serum potassium levels were respectively either marginally increased, relatively normal, or not reported.
In our patient, it is not unlikely that the symptoms can be attributed to the concomitant treatment of cerivastatin and gemfibrozil, as she started to experience symptoms shortly after gemfibrozil was added to her drug schedule. Due to its dual metabolic pathway through the cytochrome 3A4 and 2C8-9 isoenzymes, cerivastatin has been suggested to exert fewer drug interactions than other statins, which are solely metabolized through the cytochrome 3A4 isoenzyme [1], possibly with the exception of fluvastatin which is primarily excreted by the kidney. Although gemfibrozil is also metabolized by the cytochrome 3A4 isoenzyme, it is not thought to induce significant inhibition of this enzyme [1, 2]. Nevertheless, the area under the curve for cerivastatin was reported to be increased during concomitant treatment with gemfibrozil (information of the manufacturer) and it has been added by the manufacturer that the combination of cerivastatin and gemfibrozil should be avoided. However, it has also been suggested that rhabdomyolysis observed with the combination of the two drugs is related to additive myopathic effects [1, 7]. Also, the fact that fibrates may impair liver function in isolated cases has been implicated in the origin of rhabdomyolysis in patients receiving combined treatment of statins and fibrates [6].
In conclusion, despite cerivastatin metabolism by two isoenzymes of the cytochrome P-450 systems, in this patient severe rhabdomyolysis occured during combination therapy with fibrates.
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Notes
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Correspondence and offprint requests to: Jeroen Kooman MD PhD, Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Email: JKOO{at}SINT.AZM.NL 
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Received for publication: 2. 7.01
Revision received 27. 7.01.