Bezafibrate Induced Rhabdomyolysis
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536 Annals of the Rheumatic Diseases 1992; 51: 536-538 CASE REPORTS Ann Rheum Dis: first published as 10.1136/ard.51.4.536 on 1 April 1992. Downloaded from Bezafibrate induced rhabdomyolysis Eduardo Kanterewicz, Raimon Sanmarti, Jaume Riba, Isabel Trias, Josefina Autonell, Joan Brugues Abstract daily) was given with good response. Eight days The case is presented of a 70 year old woman after admission the patient suddenly developed with mild hypercholesterolaemia and hyper- diffuse thoracic and upper limb pain, and tension who was readmitted to hospital six although there were no electrocardiographic months after a previous admission for angina changes a myocardial infarction was suspected. pectoris. The patient was treated with Creatine kinase levels were high (6480 IU/I; MB verapamil, nifedipine, and aspirin, and had fraction 19%, normal value up to 10%) and been receiving bezafibrate (400 mg every 12 AST was 300 IU/l (normal value up to 40). She hours) for the previous 40 days. Twenty four was transferred to the intensive care unit. hours after admission she developed podagra, The next day the patient presented with which was treated with indomethacin (100 mg profound weakness and muscular cramps and daily). Eight days after admission myocardial her limb muscles were painful on examination. infarction was suspected, and the next day she Urine was reddish and reactive strip analysis presented with symptoms of rhabdomyolysis, showed positive haemoglobin with no cells on which was confirmed by laboratory tests. the sediment. Rhabdomyolysis was suspected, Bezafibrate was withdrawn and the patient bezafibrate was discontinued and vigorous became asymptomatic after seven days. It is hydration with urine alkalinisation was started. recommended that doctors should be aware of The diagnosis was confirmed with myoglobin the possibility of patients, especially those blood values of 14-274 ng/ml (normal value up with impaired renal function, developing to 90 ng/ml) and myoglobinuria of 21-316 rhabdomyolysis while being treated with ,ug/24 hours (normal value up to 500 [tg/24 bezafibrate. hours). Creatinine levels reached 238-7 [tmol/l. A right gastrocnemius muscle biopsy sample was taken and showed groups of muscle fibres Bezafibrate, a fibric acid derivative related to with degenerative changes (hyalinisation and clofibrate, is widely prescribed in Europe for fragmentation) and several necrotic fibres were http://ard.bmj.com/ type II and IV hyperlipoproteinaemia.' A few surrounded by a large number of macrophages cases of myopathy, diagnosed as rhabdomyo- (fig); inflammatory infiltrates were not found. lysis24 or myositis' have been reported as side Seven days after bezafibrate withdrawal the effects of its use. This paper describes the patient was asymptomatic and a week later clinical and pathological findings in a 70 year creatine kinase values returned to normal, and old woman with acute rhabdomyolysis after creatinine levels stabilised at about 176-8 [tmol/l. treatment with bezafibrate and a review of the At six months' follow up the patient remained on September 24, 2021 by guest. Protected copyright. literature is presented. well without muscular symptoms. Further investigations, including thyroid function tests, antinuclear antibodies, rheumatoid factor, and Case report antibodies to Jo-I were normal or negative, and Servei de Medicina A 70 year old woman presented in 1980 with creatine kinase levels remained within the Interna (Reumatologia), Hospital General de Vic, mild hypercholesterolaemia and hypertension. normal range. Barcelona, Spain At presentation six months earlier for angina E Kanterewicz pectoris, her serum chemistry results were: R Sanmarti J Brugues creatinine 168-0 [tmol/l, cholesterol 7 9 mmol/l, Discussion Unitat de Cardiologia, triglycerides 5 7 mmol/l, and uric acid 0-46 Compared with other tissues, striated muscu- Hospital General de Vic, mmol/l. Creatine kinase was 29 IU/l (normal lature is usually thought to be tolerant to drug Barcelona, Spain value up to 170). The patient was readmitted induced injuries. Rhabdomyolysis, defined as J Riba with typical angina. There were no abnormalities acute or subacute damage or necrosis of striated Servei d'Anatomia on examination, and serum creatine kinase and musculature with leaking ofmyoglobin, creatine Patol6gica, Hospital General de Vic, serum aspartate aminotransferase (AST) levels kinase and other substances into the plasma is a Barcelona, Spain were within the normal range; the creatinine potentially fatal, although rare event.6 Several I Trias value was 176-8 ,tmol/l. Her angina disappeared drugs have been implicated as causative agents J Autonell completely on treatment with intravenous in this syndrome.7 Since the first description in Correspondence to: Dr E Kanterewicz, nitrates. The patient received verapamil 120 mg 1968 of clofibrate acute muscular syndrome,8 Servei de Medicina every 12 hours, nifedipine 20 mg daily, and this lipid lowering drug has been associated Interna (Reumatologia), Hospital General de Vic, aspirin 200 mg daily. She had also been with rhabdomyolysis.9 '0 In the review by Rush C/Francesc Pla 1, receiving bezafibrate (400 mg every 12 hours) et al "l in 1986, 78 cases of clofibrate myopathy 08500 Vic, Barcelona, Spain. for the previous 40 days. were quoted and data available from half of Accepted for publication Twenty four hours after readmission she these showed that toxicity developed after three 6 August 1991 developed podagra and indomethacin (100 mg to 370 days of treatment, 43 of 64 patients had Bezafibrate induced rhabdomyolysis 537 muscle enzymes are known to occur with bezafibrate'4 and other fibric acid compounds. 5 Almost all patients had some degree of Ann Rheum Dis: first published as 10.1136/ard.51.4.536 on 1 April 1992. Downloaded from decreased renal function before the introduction of bezafibrate. With discontinuation of the drug recovery usually occurred, although a transient but considerable renal injury sometimes requiring haemodialysis was observed. Histo- pathological features of bezafibrate myopathy are described in only one patient and these confirm the presence of necrotic material along with phagocytosis without evidence of active inflammation, as in our patient. In a patient with rhabdomyolysis induced by lovastatin, a lipid lowering drug which is not related to the fibric acid derivatives, the histology was described as 'consistent with polymyositis'.'6 These workers suggest that the cellular infiltrate was due to mononuclear elements being present to remove tissue debris. We feel that these histological findings are not sufficient to diagnose polymyositis.7 in the absence of inflammatory infiltrates. We also maintain that ....- the lack of adequate definition in patients with Section ofmuscle biopsy specimen showing a degeneratedfibre surrounded by macophagic cells drug induced rhabdomyolysis may lead to (haematoxylin and eosin stain). conflicting situations with respect to treatment and prognosis. It is interesting to note that lovastatin induced muscle pain, 32 of 45 had weakness, and all rhabdomyolysis has been described in association patients had increased muscle enzymes. Most of with other drugs such as gemfibrozil,'6 cyclo- the patients had some degree of previous renal sporin,'8 and erythromycin.'9 Our patient disease and this was considered to predispose to developed acute rhabdomyolysis just after the toxicity. Muscle biopsy findings showed introduction of indomethacin; this drug has not atrophy, fragmentation, hyalinisation, vacuoli- been involved in drug induced rhabdomyolysis, sation, deranged mitochondria, and phagocytosis but it is known that indomethacin can lead to an by macrophages. Inflammatory infiltrates were impairment of renal function in older patients not seen. and in this way it may predispose patients to Bezafibrate is a second generation fibric acid bezafibrate toxicity. http://ard.bmj.com/ derivative (chemically related to clofibrate) that The actual mechanism of this toxic effect by is being increasingly prescribed in Europe. 12 To bezafibrate is far from clear; the drug is rapidly our knowledge, only eight cases of bezafibrate absorbed after a dose by mouth, is highly induced myopathy, classified as rhabdomyo- protein bound, and is largely excreted unchanged lysis2' myositis,5 or necrotising myopathy,13 in urine; therefore a dose reduction is recom- have been reported. The table gives the main mended in patients with impaired renal features of these cases. function.' Our patient was receiving a larger on September 24, 2021 by guest. Protected copyright. The whole clinical spectrum includes patients dose than normally advised (400 mg daily or less with painful proximal and distal limb muscles, in case of renal failure), but from other reports weakness, and increased serum muscle enzymes it seems that even with adjusted doses, the including aldolase and lactate dehydrogenase. A concentrations of bezafibrate in blood were high predominance of lactate dehydrogenase iso- enough to be toxic.4 5 Several cases of clofibrate enzyme 1 in a patient with bezafibrate induced induced rhabdomyolysis have, however, been rhabdomyolysis has been reported.5 Notably, as described in patients with previously normal in case 4, patients may present increased renal function' and hence a direct toxic effect of creatine kinase values and deterioration of renal these drugs, not related to accumulation, might function as the only signs of bezafibrate toxicity. be another aetiological possibility.