Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction

Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction Rhabdomyolysis is a well-documented side effect of statin therapy. This risk is increased with concurrent use of medications that inhibit cytochrome p450-3A4 (CYP3A4), such as macrolide antibiotics. We present the case of a 67-year-old patient who was commenced on clarithromycin on a background of simvastatin therapy, resulting in rhabdomyolysis. This case highlights the need for awareness of common drug interactions associated with statins. It also emphasizes the significance of commencing statins at a lower dose in new patients, and lastly, the importance of early recognition and management of rhabdomyolysis to prevent the development of complications. Grade 4/5) and in shoulder abduction and adduction (MRC INTRODUCTION Grade 4 /5). The past medical history included severe chronic Statins are a group of lipid-lowering medications that act by obstructive pulmonary disease (COPD) and ischaemic heart dis- inhibiting HMG-CoA reductase, an enzyme essential to choles- ease (IHD). terol synthesis. Statin use is becoming increasingly common, Initial investigations revealed a creatine kinase (CK) of with a rise from 18% in 2003/04 to 26% in 2011/12 in the United 62 109 (RI 30–200 U/L), AST 2036 (RI 12–36 U/L), ALT 1145 (RI < States [1]. Given recent recommendations seen in the American 55 U/L), creatinine (Cr) 63 (RI 60–110 umol/L) and potassium 4.4 Heart Association Practice Guidelines, an increasing number of (SI 3.5–5.2 mmol/L). patients are considered eligible to receive statins to reduce car- Of note, the patient had commenced clarithromycin 250 mg diovascular risk [2]. daily 1 month prior to admission following review in the We present a rare case of rhabdomyolysis, complicated by respiratory clinic. This was prescribed on a prophylactic basis significant acute kidney injury (AKI) and hyperkalaemia, in a to reduce the number of COPD exacerbations. Regular medica- patient who was co-prescribed simvastatin and clarithromycin. tion included simvastatin 80 mg daily. A presumptive diagnosis of rhabdomyolysis secondary to simvastatin was made and both medications were ceased. CASE REPORT The patient was hydrated intravenously, however, developed A 67-year-old male presented with a 5-day history of worsening AKI, with the creatinine level deteriorating from 63 umol/L on admission to a peak of 325 umol/L on Day 3 (Fig. 1). This was myalgia and weakness in his shoulders and lower limbs result- ing in reduced mobility. On examination, proximal myopathy complicated by hyperkalaemia (7.4 mmol/L) requiring repeated treatment with insulin/dextrose and calcium resonium. Calcium was noted with weakness in hip flexion and extension (MRC Received: August 18, 2017. Revised: November 21, 2017. Accepted: December 18, 2017 © The Author(s) 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Statin-induced rhabdomyolysis 87 250000 Table 1: Examples of CYP3A4 inhibitors. 200000 Drug Class Examples Antibiotics Clarithromycin, Erythromycin,Telithromycin CK (U/L) Antifungals Clotrimazole, Itraconazole, Fluconazole, Ketoconazole, Voriconazole Protease inhibitors Atazanavir, Darunavir, Lopinavir, Ritonavir, Tipranavir Calcium channel Diltiazem, Verapamil blockers 02468 10 12 Others Amiodarone, Ciclosporin, Ranitidine, Day of admission Sertraline, Tamoxifen Table 2: Causes of rhabdomyolysis 200 � Trauma Cr � Drugs and toxins (umol/L) � Hypo/hyperthermia 100 � Exertional � Infections � Metabolic/mitochondrial myopathies 0 � Electrolyte abnormalities 0 2 4 6 8 10 12 � Endocrine disorders Day of admission � Idiopathic Figure 1: Creatine kinase and creatinine trends. correction is essential in preventing complications, as well as gluconate was administered for cardio-stabilization due to the addressing the precipitating cause. significantly elevated potassium despite no acute changes on One study conducted by the U.S. Food & Drug Administration ECG. The CK continued to rise, reaching a peak level of 223 859 U/L (FDA) in 2002 examining adverse event reporting suggested that on Day 5 of admission (Fig. 1) with transaminases peaking on Day over 50% of cases of statin-induced-rhabdomyolysis were due to 3 with an ALT level of 1667 U/L and AST 3123 U/L. Renal replace- drug interactions [4] with a 2012 study, in a UK primary care ment therapy was considered, however, avoided as the patient population showing that 30% of patients were prescribed a ultimately responded to medical treatment. CYP3A4 inhibitor in conjunction with a CYP3A4-metabolized- The patient’s AKI continued to improve with intravenous statin during the study period of 1 year [5]. fluid therapy and by discharge on Day 11, the creatinine had In this case the patient was prescribed 80mg of simvastatin improved to 106 umol/L (baseline creatinine 63 umol/L) and the daily; a higher dose associated with an increased risk of statin CK had improved to 406 U/L. The patient reported significant myopathy. The U.S. FDA does not recommend initiating new improvement in shoulder and lower limb myalgia and weak- patients on a simvastatin dose of 80 mg, to minimize the risk of ness following physiotherapy and was discharged home after statin-induced-myopathy and rhabdomyolysis [6]. returning to his baseline level of function. Following discharge Clarithromycin is a macrolide antibiotic and a CYP3A4 inhibi- the patient was commenced on long-term prophylactic doxy- tor. It has previously been shown to cause rhabdomyolysis in cycline by his respiratory physician and ezetimibe as an alter- patients taking simvastatin [7]. AKI is a serious complication of native to statin therapy. rhabdomyolysis and a recent case described a patient requiring haemodialysis for statin-induced-rhabdomyolysis after being pre- scribed clarithromycin [8]. Both the FDA and the UK Medicines DISCUSSION and Healthcare Products Regulatory Agency state that simvastatin Rhabdomyolysis is a well-documented side effect of statin ther- is contraindicated in patients taking clarithromycin, erythromycin apy and this risk is greater with concurrent use of drugs that and telithromycin. Fluvastatin, pravastatin and rosuvastatin may inhibit cytochrome p450-3A4 (CYP3A4), examples of which are be considered as alternatives as they are not as extensively meta- shown in Table 1. These agents reduce the metabolism and bolized by CYP3A4 and therefore less likely to result in rhabdo- consequently increase the serum concentration of CYP3A4- myolysis but still require careful monitoring [9]. metabolized statins [3]. Other potential causes of rhabdomyoly- It is estimated that up to 40% of elderly hospital in-patients sis are given in Table 2. experience an adverse drug event and that 10% of emergency Rhabdomyolysis is characterized by the breakdown of skeletal attendances are due to adverse drug events [10]. This case muscle, resulting in the release of sarcoplasmic proteins includ- highlights the need for awareness of important drug interac- ing AST, ALT and CK and electrolytes. It typically presents with tions in an era of increasing polypharmacy and the morbidity myalgia and muscle weakness of the proximal musculature. that can result when these interactions are overlooked. Patients may report dark urine as a result of myoglobinuria. The key laboratory finding is an elevated CK five times above the upper limit of normal (RI 30–200 U/L). Potentially life-threatening ACKNOWLEDGEMENTS complications include AKI, hyperkalaemia, compartment syn- drome and cardiac arrhythmias. Early rehydration and electrolyte We do not wish to make any acknowledgements. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018 88 S. Ezad et al. of Cardiology/American Heart Association Task Force on CONFLICT OF INTEREST STATEMENT Practice Guidelines. Circulation 2014;129:S46–8. No conflicts of interest. 3. Neuvonen PJ, Niemi M, Backman JT. Drug interaction with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81. FUNDING 4. Omar MA, Wilson JP. FDA adverse event reports on statin- There were no sources of funding. associated rhabdomyolysis. Ann Pharmacother 2002;36:288–95. 5. Bakhai A, Rigney U, Hollis S, Emmas C. Co-administration ETHICAL APPROVAL of statins with cytochrome P450 3A4 inhibitors in a UK pri- mary care population. Pharmacoepidemiol Drug Saf 2012;21: No ethics approval is required. 485–93. 6. U.S. Food & Drug Administration (FDA). FDA Drug Safety CONSENT Communication: New Restrictions, Contraindications, and Dose Limitations of Zocor (simvastatin) to Reduce the Risk of Muscle We have not identified any direct or indirect potential patient Injury. Additional Information for Healthcare Professionals. identifiers in our case report. The patient has provided their 2011. https://www.fda.gov/Drugs/DrugSafety/ucm256581. informed consent for the publication of this case report. htm (November 2016, date last accessed). 7. Wagner J, Suessmair C, Pfister HW. Rhabdomyolysis caused GUARANTORS by co-medication with simvastatin and clarithromycin. J Neurol 2009;256:1182–83. Saad Ezad, Nicholas Collins. 8. Hill F, McCloskey S, Sheerin N. From a fish tank injury to hos- pital haemodialysis: the seriousconsequencesofdruginter- REFERENCES actions. BMJ Case Rep 2015;2015. doi:10.1136/bcr-2015-209961. 1. Gu Q, Paulrose-Ram R, Burt VL, Kit BK. Prescription 9. Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin cholesterol-lowering medication use in adults aged 40 and over: United States 2003–2012. NCHS Data Brief 2014;177:1–8. Pharmacokinet 2002;41:343–70. 10. Hohl CM, Dankoff J, Colacone A, Afilalo M, et al. Polypharmacy, 2. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the adverse drug-related events, and potential adverse drug inter- actions in elderly patients presenting to an emergency depart- treatment of blood cholesterol to reduce atherosclerotic car- diovascular risk in adults: a report of the American College ment. Ann Emerg Med 2001;38:666–71. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

Statin-induced rhabdomyolysis: a complication of a commonly overlooked drug interaction

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Abstract

Rhabdomyolysis is a well-documented side effect of statin therapy. This risk is increased with concurrent use of medications that inhibit cytochrome p450-3A4 (CYP3A4), such as macrolide antibiotics. We present the case of a 67-year-old patient who was commenced on clarithromycin on a background of simvastatin therapy, resulting in rhabdomyolysis. This case highlights the need for awareness of common drug interactions associated with statins. It also emphasizes the significance of commencing statins at a lower dose in new patients, and lastly, the importance of early recognition and management of rhabdomyolysis to prevent the development of complications. Grade 4/5) and in shoulder abduction and adduction (MRC INTRODUCTION Grade 4 /5). The past medical history included severe chronic Statins are a group of lipid-lowering medications that act by obstructive pulmonary disease (COPD) and ischaemic heart dis- inhibiting HMG-CoA reductase, an enzyme essential to choles- ease (IHD). terol synthesis. Statin use is becoming increasingly common, Initial investigations revealed a creatine kinase (CK) of with a rise from 18% in 2003/04 to 26% in 2011/12 in the United 62 109 (RI 30–200 U/L), AST 2036 (RI 12–36 U/L), ALT 1145 (RI < States [1]. Given recent recommendations seen in the American 55 U/L), creatinine (Cr) 63 (RI 60–110 umol/L) and potassium 4.4 Heart Association Practice Guidelines, an increasing number of (SI 3.5–5.2 mmol/L). patients are considered eligible to receive statins to reduce car- Of note, the patient had commenced clarithromycin 250 mg diovascular risk [2]. daily 1 month prior to admission following review in the We present a rare case of rhabdomyolysis, complicated by respiratory clinic. This was prescribed on a prophylactic basis significant acute kidney injury (AKI) and hyperkalaemia, in a to reduce the number of COPD exacerbations. Regular medica- patient who was co-prescribed simvastatin and clarithromycin. tion included simvastatin 80 mg daily. A presumptive diagnosis of rhabdomyolysis secondary to simvastatin was made and both medications were ceased. CASE REPORT The patient was hydrated intravenously, however, developed A 67-year-old male presented with a 5-day history of worsening AKI, with the creatinine level deteriorating from 63 umol/L on admission to a peak of 325 umol/L on Day 3 (Fig. 1). This was myalgia and weakness in his shoulders and lower limbs result- ing in reduced mobility. On examination, proximal myopathy complicated by hyperkalaemia (7.4 mmol/L) requiring repeated treatment with insulin/dextrose and calcium resonium. Calcium was noted with weakness in hip flexion and extension (MRC Received: August 18, 2017. Revised: November 21, 2017. Accepted: December 18, 2017 © The Author(s) 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Statin-induced rhabdomyolysis 87 250000 Table 1: Examples of CYP3A4 inhibitors. 200000 Drug Class Examples Antibiotics Clarithromycin, Erythromycin,Telithromycin CK (U/L) Antifungals Clotrimazole, Itraconazole, Fluconazole, Ketoconazole, Voriconazole Protease inhibitors Atazanavir, Darunavir, Lopinavir, Ritonavir, Tipranavir Calcium channel Diltiazem, Verapamil blockers 02468 10 12 Others Amiodarone, Ciclosporin, Ranitidine, Day of admission Sertraline, Tamoxifen Table 2: Causes of rhabdomyolysis 200 � Trauma Cr � Drugs and toxins (umol/L) � Hypo/hyperthermia 100 � Exertional � Infections � Metabolic/mitochondrial myopathies 0 � Electrolyte abnormalities 0 2 4 6 8 10 12 � Endocrine disorders Day of admission � Idiopathic Figure 1: Creatine kinase and creatinine trends. correction is essential in preventing complications, as well as gluconate was administered for cardio-stabilization due to the addressing the precipitating cause. significantly elevated potassium despite no acute changes on One study conducted by the U.S. Food & Drug Administration ECG. The CK continued to rise, reaching a peak level of 223 859 U/L (FDA) in 2002 examining adverse event reporting suggested that on Day 5 of admission (Fig. 1) with transaminases peaking on Day over 50% of cases of statin-induced-rhabdomyolysis were due to 3 with an ALT level of 1667 U/L and AST 3123 U/L. Renal replace- drug interactions [4] with a 2012 study, in a UK primary care ment therapy was considered, however, avoided as the patient population showing that 30% of patients were prescribed a ultimately responded to medical treatment. CYP3A4 inhibitor in conjunction with a CYP3A4-metabolized- The patient’s AKI continued to improve with intravenous statin during the study period of 1 year [5]. fluid therapy and by discharge on Day 11, the creatinine had In this case the patient was prescribed 80mg of simvastatin improved to 106 umol/L (baseline creatinine 63 umol/L) and the daily; a higher dose associated with an increased risk of statin CK had improved to 406 U/L. The patient reported significant myopathy. The U.S. FDA does not recommend initiating new improvement in shoulder and lower limb myalgia and weak- patients on a simvastatin dose of 80 mg, to minimize the risk of ness following physiotherapy and was discharged home after statin-induced-myopathy and rhabdomyolysis [6]. returning to his baseline level of function. Following discharge Clarithromycin is a macrolide antibiotic and a CYP3A4 inhibi- the patient was commenced on long-term prophylactic doxy- tor. It has previously been shown to cause rhabdomyolysis in cycline by his respiratory physician and ezetimibe as an alter- patients taking simvastatin [7]. AKI is a serious complication of native to statin therapy. rhabdomyolysis and a recent case described a patient requiring haemodialysis for statin-induced-rhabdomyolysis after being pre- scribed clarithromycin [8]. Both the FDA and the UK Medicines DISCUSSION and Healthcare Products Regulatory Agency state that simvastatin Rhabdomyolysis is a well-documented side effect of statin ther- is contraindicated in patients taking clarithromycin, erythromycin apy and this risk is greater with concurrent use of drugs that and telithromycin. Fluvastatin, pravastatin and rosuvastatin may inhibit cytochrome p450-3A4 (CYP3A4), examples of which are be considered as alternatives as they are not as extensively meta- shown in Table 1. These agents reduce the metabolism and bolized by CYP3A4 and therefore less likely to result in rhabdo- consequently increase the serum concentration of CYP3A4- myolysis but still require careful monitoring [9]. metabolized statins [3]. Other potential causes of rhabdomyoly- It is estimated that up to 40% of elderly hospital in-patients sis are given in Table 2. experience an adverse drug event and that 10% of emergency Rhabdomyolysis is characterized by the breakdown of skeletal attendances are due to adverse drug events [10]. This case muscle, resulting in the release of sarcoplasmic proteins includ- highlights the need for awareness of important drug interac- ing AST, ALT and CK and electrolytes. It typically presents with tions in an era of increasing polypharmacy and the morbidity myalgia and muscle weakness of the proximal musculature. that can result when these interactions are overlooked. Patients may report dark urine as a result of myoglobinuria. The key laboratory finding is an elevated CK five times above the upper limit of normal (RI 30–200 U/L). Potentially life-threatening ACKNOWLEDGEMENTS complications include AKI, hyperkalaemia, compartment syn- drome and cardiac arrhythmias. Early rehydration and electrolyte We do not wish to make any acknowledgements. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018 88 S. Ezad et al. of Cardiology/American Heart Association Task Force on CONFLICT OF INTEREST STATEMENT Practice Guidelines. Circulation 2014;129:S46–8. No conflicts of interest. 3. Neuvonen PJ, Niemi M, Backman JT. Drug interaction with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81. FUNDING 4. Omar MA, Wilson JP. FDA adverse event reports on statin- There were no sources of funding. associated rhabdomyolysis. Ann Pharmacother 2002;36:288–95. 5. Bakhai A, Rigney U, Hollis S, Emmas C. Co-administration ETHICAL APPROVAL of statins with cytochrome P450 3A4 inhibitors in a UK pri- mary care population. Pharmacoepidemiol Drug Saf 2012;21: No ethics approval is required. 485–93. 6. U.S. Food & Drug Administration (FDA). FDA Drug Safety CONSENT Communication: New Restrictions, Contraindications, and Dose Limitations of Zocor (simvastatin) to Reduce the Risk of Muscle We have not identified any direct or indirect potential patient Injury. Additional Information for Healthcare Professionals. identifiers in our case report. The patient has provided their 2011. https://www.fda.gov/Drugs/DrugSafety/ucm256581. informed consent for the publication of this case report. htm (November 2016, date last accessed). 7. Wagner J, Suessmair C, Pfister HW. Rhabdomyolysis caused GUARANTORS by co-medication with simvastatin and clarithromycin. J Neurol 2009;256:1182–83. Saad Ezad, Nicholas Collins. 8. Hill F, McCloskey S, Sheerin N. From a fish tank injury to hos- pital haemodialysis: the seriousconsequencesofdruginter- REFERENCES actions. BMJ Case Rep 2015;2015. doi:10.1136/bcr-2015-209961. 1. Gu Q, Paulrose-Ram R, Burt VL, Kit BK. Prescription 9. Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin cholesterol-lowering medication use in adults aged 40 and over: United States 2003–2012. NCHS Data Brief 2014;177:1–8. Pharmacokinet 2002;41:343–70. 10. Hohl CM, Dankoff J, Colacone A, Afilalo M, et al. Polypharmacy, 2. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the adverse drug-related events, and potential adverse drug inter- actions in elderly patients presenting to an emergency depart- treatment of blood cholesterol to reduce atherosclerotic car- diovascular risk in adults: a report of the American College ment. Ann Emerg Med 2001;38:666–71. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/3/omx104/4935134 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Oxford Medical Case ReportsOxford University Press

Published: Mar 1, 2018

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