A case of severe rhabdomyolysis caused by an interaction between fusidic acid and simvastatin is described. Fusidic acid significantly reduces the excretion of simvastatin resulting in increased plasma levels thereby increasing the side effect profile. Simvastatin treatment should be temporarily withheld during treatment with fusidic acid.
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Simvastatin is prescribed as the first line treatment for hypercholesterolaemia by many medical practitioners. It was initially marketed by Merck (Hoddesdon, UK) under the trade name Zocor, but is now available generically in most countries following the patent expiry. Statins act by inhibiting 3-hydroxy-3-methylglutarate (HMG)-coenzyme A reductase, the rate-limiting enzyme of the HMG-coenzyme A reductase pathway that is the metabolic pathway responsible for the endogenous production of cholesterol. Side effects include gastrointestinal disturbance and myotoxicity. The spectrum of myotoxicity ranges from mild myopathy to severe rhabdomyolysis.
Simvastatin is metabolised via the cytochrome P3A4 (CYP3A4) enzyme system. It is known that, if given concomitantly with inhibitors of this system, statin concentrations can rise increasing their side effect profile.1,2 Although fusidic acid does not interfere with this pathway it seems to significantly reduce simvastatin secretion, leading to potentially life-threatening side effects. We describe a case of rhabdomyolysis when fusidic acid was taken in concordance with simvastatin. We chose to publish this article in conjunction with the patient in order to improve the quality of patient care and with the hope of reducing patient morbidity.
A 68-year-old man presented to our acute medical team experiencing severe generalised muscle pains. Significant medical background included hypercholestolaemia and hypertension. He had been taking atenolol 50 mg once a day and simvastatin 40 mg once a day since January 2002, his total cholesterol was initially 9.7 mmol/litre, falling to 4.6 mmol/litre on treatment. His liver function tests including aspartate transaminase (AST) and alanine transaminase (ALT) had been normal on treatment, and his creatinine was 109 μmol/litre (normal range 60 to 120).
In April 2008 he sustained a right ankle fracture, which had required external fixation. In early October, 5 months later, the ankle became infected with Staphylococcus aureus, at which time his creatinine was 100 μmol/litre, urea 7.0 mmol/litre and C-reactive protein (CRP) 181 mg/litre (normal range 1 to 10). He was prescribed a course of flucloxacillin 500 mg four times a day and fusidic acid 500 mg three times a day. By the end of October he was experiencing extensive muscles pains and was referred for acute medical assessment. On presentation he was haemodynamically stable, but had tender muscles and urine testing was positive for blood and protein. His admission blood tests showed a creatinine of 152 μmol/litre, urea 15.7 mmol/litre, potassium 4.2 mmol/litre, sodium 140 and creatine kinase 168 351 U/litre (normal 15 to 150), AST 2044 U/litre (5 to 40), ALT 906 U/litre (5 to 40) and hydroxybutyrate dehydrogenase (HBD) 1836 U/litre (normal range 80 to 190). Intravenous fluids and all preadmission medications were continued. The following day on post-take ward rounds we suspected a possible interaction with fusidic acid and simvastatin. The use of modern communication and accessible databases enabled the quick retrieval of a peer-reviewed article: a letter in the Medical Journal of Australia described a similar case.3 Further extensive searches suggested that our patient was possibly only the fifth person in the world to experience this interaction. The fusidic acid and the simvastatin were stopped, and treatment was continued with intravenous fluids. His creatine kinase (CK) peaked on day 2 at 180 000 U/litre, falling to 29 000 U/litre when he was discharged after 7 days. At 3 months later he still had mild muscle pains; his CK was 509 U/litre, creatinine 80 μmol/litre, and ALT and AST levels were normal. His total cholesterol was 7.4 mmol/litre, and he elected to take a fibrate.
Rhabdomyolysis is associated with muscle trauma, muscle disorders, confirmed autoimmune conditions such as myasthaenia gravis and recent viral infections. It can also occur with metabolic abnormalities. Our patient’s clinical presentation indicated medication interaction to be the most likely precipitating cause.
OUTCOME AND FOLLOW-UP
The case was reported via the Medicines and Healthcare Products Regulatory Agency “yellow card” scheme and discussed with the manufacturer (Merck). The manufacturer reported that fusidic acid competes with simvastatin for excretion in the renal tubules, resulting in raised plasma levels of simvastatin. Rhabdomyolysis is a well recognised side effect of treatment with simvastatin. The manufacturer has altered the text in the package insert and also in the Association of British Pharmaceutical Companies Data Sheet Compendium.
In this case there was good evidence that rhabdomyolysis was caused by the combined prescription of fusidic acid with simvastatin. Rhabdomyolysis is a recognised side effect of simvastatin and is dose dependent. Our patient had tolerated a stable dose for a number of years and therefore simvastatin was unlikely to be solely responsible. An interaction with either its metabolism or excretion was suspected. Simvastatin is metabolised via the CYP3A4 enzyme system. It is well known that, if given concomitantly with inhibitors of this system statin concentrations can rise increasing their side effect profile.4 The CYP3A4 pathway inhibitors include ciclosporin, fibrates, macrolide antibacterials, azole antifungals and antiretrovirals. All have been shown to increase the risk of myotoxicity when prescribed in combination with statins.
Overall, gemofibrozil–statin combinations have been more problematic than other fibrate combinations. Clarithromycin, erythromycin and azithromycin have all demonstrated increased myotoxicity and ketoconazole, itraconazole and fluconazole equally so.
Hyperlipidaemia is common in renal transplant patients who receive immunosuppressant medication such as ciclosporin and prednisolone. The concomitant use of ciclosporin and rosuvastatin are associated with higher rates of myopathy when compared with other statins.
Calcium channel antagonists, are also considered weaker CYP3A4 inhibitors. The predisposition of myopathy with weaker CYP3A4 inhibitors such as diltiazem and verapamil has been reported in the literature over the years, however this has not been exclusively supported.5 Patients assigned to 80 mg simvastatin in the Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine (SEARCH) trial, showed that the use of calcium channel antagonists was linked to an increase in definite or incipient myopathy. Antiretrovirals are CYP3A4 inhibitors and are associated with mitochondrial toxicity. The dual mechanism may further increase the risk of myotoxicity. One study showed that patients receiving ritonavir and saquinavir, had an increased risk about 5-fold for atorvastatin and about 32-fold for simvastatin, but decreased 0.5-fold for pravastatin.6
The risk of myopathy can also be statin dependent. Individual statins are metabolised to differing degrees. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. CYP2C8 is also involved in cerivastatin metabolism.
Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter that may influence their oral bioavailability.7
Cerivastatin was withdrawn because of associated high rates of death from rhabdomyolysis, 25% of which were related to gemfibrozil and cerivastin combination therapy.
The CYP3A4 pathway is important, but other mechanisms may exist. Medications including warfarin, amiodarone, digoxin and thiazolidinediones are also associated with an increased risk of statin myotoxicity when used concomitantly. Fusidic acid is not a CYP3A4 inhibitor, however Merck had reported a potential interaction where fusidic acid competes for secretion.
The manufacturer recognised the seriousness of the interaction and has altered the text in the package insert and also in the Association of British Pharmaceutical Companies Data Sheet Compendium. At present it is not listed in the British National Formulary.
The precise mechanism of statin-induced muscle necrosis is unknown. Muscle fibres that are highly metabolically active tend to be more sensitive in statin-induced muscle necrosis. These muscles have a high number of mitochondria. Mitochondrial mechanisms have been implicated.
The statin accumulation may induce early segmental necrosis with rapid inflammatory cell infiltration and subsequent mitochondrial injury. Mitochondrial degeneration results in myelinoid and vesicular bodies, which accumulate in the subsarcolemmal area leading to progressive muscle fibre disruption. Mitochondrial changes are mevalonate dependent.8 Statins act by inhibiting HMG-coenzyme A reductase, and hence reduces mevalonate.
The onset of muscle necrosis appears to be treatment duration dependent. It has been reported to occur after 10 days of treatment.8 This may explain the time interval in clinical presentation and the commencement of fusidic acid. Our patient’s creatine kinase peaked on day 2 of presentation and following active treatment fell substantially over the following 7 days. At 3 months later creatine kinase was still mildly elevated and he continued to experience mild muscle pains despite simvastatin cessation. Creatine kinase levels rise after 12 h of the initial damage, remain elevated for 1–3 days and then fall gradually. Treating with intravenous fluids preserves renal function and stopping the suspected medication can prevent further muscle damage and hence further release of creatine kinase. The case reported in the Medical Journal of Australia showed a similar pattern with prompt recovery of renal function but a gradual decline in creatine kinase. Variable persistent symptoms can occur in up to 68% of patients. One hypothesis is that the persistent muscle effects may be associated with respiratory exchange ratios.9 Statins elevate the respiratory exchange ratio. Patients who have been symptomatic on statins show continued off-statin elevated respiratory exchange ratios.
Further research stills needs to undertaken. The clinical presentation led us to suspect a possible interaction, however could it have been prevented earlier? The doctor who prescribed the initial prescription for fusidic acid and the pharmacist who dispensed the prescription were in positions to have identified a potential interaction. Practical methods to reduce potential interactions include developing interlinked prescribing systems to identify potential drug interactions, increasing awareness of interactions by encouraging up to date clear documentation in medication leaflets and resources such as the British National Formulary, and by encouraging reporting of drug interactions. Medical professionals should display caution when prescribing in high-risk patients. Patients at high risk of statin therapy side effects include those over 70 years old, patients with a history of liver disease, patients with known alcohol excess, patients with a history of myopathy including myopathy related to prior statin and fibrate therapy, and patients with untreated hypothyroidism.
The decision to discontinue or reduce a statin if myotoxicity occurs following the commencement of a new drug is dependent on a number of factors, including the duration of new medication, the clinical indication and potential alternatives and the perceived benefit of the statin.
If the duration of concomitant therapy is for a defined time the statin could be discontinued and given again when symptoms settle, alternatively if a prolonged duration is expected consideration of statin dose reduction or alternative lipid-lowering treatment should be made.
The adverse event rates from statins are very uncommon and the benefit–risk ratio is extremely high. Statins are very effective at reducing the incidence of myocardial infarction, stroke and other manifestations of vascular disease. Among the studies, the Heart Protection Study was the largest. It showed a 12% reduction in total death rate, a 17% reduction in vascular death rate, a 4% reduction in coronary heart disease events, a 27% reduction in all strokes and a 16% reduction in non-coronary revascularisations.10 Statins are used for primary and secondary cardiovascular prevention and doctors actively increase doses to meet recommended lipid-lowering targets.
If patients develop muscle effects arising on statins they do not uniformly resolve fully following statin discontinuation. How do we target future lipid-lowering therapy in patients where such a serious drug interaction has taken place? Patients do not need to be considered as absolutely statin intolerant. Alternative dosing options and the use of alternative statins are useful strategies.
Alternate day dosing has been trialled with rosuvastatin. Rosuvatatin has a longer half life (19 h) with high potency.11 Therapeutic lifestyle changes are critical to achieving maximal risk reduction. This remains difficult to implement but emphasis on a cardioprotective diet and physical activity is important. Non-statin lipid-lowering drugs (alone or in combination) do not have the established benefit of statins but do have potential benefit in secondary prevention. Niacin and fibrate (clofibrate, gemofibrozil, bezafibrate and fenofibrate) and ion exchange resins (colestipol, cholestyramine) offer alternative potentials.
In conclusion, the development of myopathy is induced by a complex interaction between drug, disease, genetics and concomitant therapy. The mechanism by which statins cause myopathy is not completely understood, however association seems to be dose dependent and the risk is increased when statins are prescribed in combination with agents that are myotoxic. The combination of fusidic acid and simvastatin has been demonstrated to increase the risk of rhabdomyolysis. Fusidic acid is used for treatment of staphylococcal infections.
Doctors and pharmacists should be aware of this interaction. Simvastatin treatment should be stopped temporarily during fusidic acid treatment.
Simvastatin should be stopped when fusidic acid is prescribed due to potential drug interactions.
Yellow card reporting to the Medicines and Healthcare Products Regulatory Agency is an important method to highlight clinical interactions.
The use of modern communication methods and databases enables quick retrieval of peer-reviewed articles that can assist in resolving difficult clinical cases.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.
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