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Weakness and pain in arms and legs • dark urine • history of vertebral osteomyelitis • Dx?
THE CASE
A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.
Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.
THE DIAGNOSIS
Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).
The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).
Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.1-3
We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.
DISCUSSION
Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.7 There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).11-13
The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.14
Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.15
How our patient’s case differs from previous cases
Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours6 and 32 hours,7 respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.
Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).16
Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.5 Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.17 Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.
Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 111-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.18
Avoiding a drug-drug interaction in your patient
Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 26,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole11 because pravastatin is metabolized by sulfation6 and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.19,20
Among approximately 2700 statin-treated outpatients,4 the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.21
We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.
THE TAKEAWAY
When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).6
Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.22 This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician16 and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.23
The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.
1. Kisakol G, Tunc R, Kaya A. Rhabdomyolysis in a patient with hypothyroidism. Endocr J. 2003;50:221-223.
2. Scott KR, Simmons Z, Boyer PJ. Hypothyroid myopathy with a strikingly elevated serum creatine kinase level. Muscle Nerve. 2002;26:141-144.
3. Barahona MJ, Mauri A, Sucunza N, et al. Hypothyroidism as a cause of rhabdomyolysis. Endocr J. 2002;49:621-623.
4. Rätz Bravo AE, Tchambaz L, Krähenbühl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf. 2005;28:263-275.
5. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658-1669.
6. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med. 2001;111:390-400.
7. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38:111-180.
8. Malhotra B, Dickins M, Alvey C, et al. Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. Br J Clin Pharmacol. 2011;72:263-269.
9. US Food and Drug Administration. Drug development and drug interactions: Table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed February 9, 2017.
10. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005;28:1805-1808.
11. Shaukat A, Benekli M, Vladutiu GD, et al. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother. 2003;37:1032-1035.
12. Hazin R, Abuzetun JY, Suker M, et al. Rhabdomyolysis induced by simvastatin-fluconazole combination. J Natl Med Assoc. 2008;100:444-446.
13. Findling O, Meier N, Sellner J, et al. Clinical reasoning: rhabdomyolysis after combined treatment with simvastatin and fluconazole. Neurology. 2008;71:e34-e37.
14. US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed February 1, 2017.
15. Wolters Kluwer. Lexicomp online. Available at: http://www.wolterskluwercdi.com/lexicomp-online/. Accessed February 9, 2017.
16. Molden E, Skovlund E, Braathen P. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf. 2008;31:587-596.
17. Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. Int J Cardiol. 2014;174:83-89.
18. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-2590.
19. Saito Y. Pitavastatin: an overview. Atheroscler Suppl. 2011;12:271-276.
20. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002;20:303-328.
21. Magni P, Macchi C, Morlotti B, et al. Risk identification and possible countermeasures for muscle adverse effects during statin therapy. Eur J Intern Med. 2015;26:82-88.
22. Ko Y, Malone DC, Skrepnek GH, et al. Prescribers’ knowledge of and sources of information for potential drug-drug interactions: a postal survey of US prescribers. Drug Saf. 2008;31:525-536.
23. Phansalkar S, van der Sijs H, Tucker AD, et al. Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Inform Assoc. 2013;20:489-493.
THE CASE
A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.
Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.
THE DIAGNOSIS
Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).
The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).
Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.1-3
We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.
DISCUSSION
Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.7 There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).11-13
The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.14
Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.15
How our patient’s case differs from previous cases
Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours6 and 32 hours,7 respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.
Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).16
Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.5 Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.17 Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.
Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 111-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.18
Avoiding a drug-drug interaction in your patient
Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 26,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole11 because pravastatin is metabolized by sulfation6 and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.19,20
Among approximately 2700 statin-treated outpatients,4 the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.21
We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.
THE TAKEAWAY
When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).6
Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.22 This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician16 and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.23
The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.
THE CASE
A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.
Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.
THE DIAGNOSIS
Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).
The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).
Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.1-3
We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.
DISCUSSION
Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.7 There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).11-13
The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.14
Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.15
How our patient’s case differs from previous cases
Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours6 and 32 hours,7 respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.
Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).16
Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.5 Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.17 Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.
Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 111-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.18
Avoiding a drug-drug interaction in your patient
Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 26,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole11 because pravastatin is metabolized by sulfation6 and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.19,20
Among approximately 2700 statin-treated outpatients,4 the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.21
We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.
THE TAKEAWAY
When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).6
Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.22 This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician16 and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.23
The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.
1. Kisakol G, Tunc R, Kaya A. Rhabdomyolysis in a patient with hypothyroidism. Endocr J. 2003;50:221-223.
2. Scott KR, Simmons Z, Boyer PJ. Hypothyroid myopathy with a strikingly elevated serum creatine kinase level. Muscle Nerve. 2002;26:141-144.
3. Barahona MJ, Mauri A, Sucunza N, et al. Hypothyroidism as a cause of rhabdomyolysis. Endocr J. 2002;49:621-623.
4. Rätz Bravo AE, Tchambaz L, Krähenbühl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf. 2005;28:263-275.
5. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658-1669.
6. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med. 2001;111:390-400.
7. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38:111-180.
8. Malhotra B, Dickins M, Alvey C, et al. Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. Br J Clin Pharmacol. 2011;72:263-269.
9. US Food and Drug Administration. Drug development and drug interactions: Table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed February 9, 2017.
10. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005;28:1805-1808.
11. Shaukat A, Benekli M, Vladutiu GD, et al. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother. 2003;37:1032-1035.
12. Hazin R, Abuzetun JY, Suker M, et al. Rhabdomyolysis induced by simvastatin-fluconazole combination. J Natl Med Assoc. 2008;100:444-446.
13. Findling O, Meier N, Sellner J, et al. Clinical reasoning: rhabdomyolysis after combined treatment with simvastatin and fluconazole. Neurology. 2008;71:e34-e37.
14. US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed February 1, 2017.
15. Wolters Kluwer. Lexicomp online. Available at: http://www.wolterskluwercdi.com/lexicomp-online/. Accessed February 9, 2017.
16. Molden E, Skovlund E, Braathen P. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf. 2008;31:587-596.
17. Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. Int J Cardiol. 2014;174:83-89.
18. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-2590.
19. Saito Y. Pitavastatin: an overview. Atheroscler Suppl. 2011;12:271-276.
20. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002;20:303-328.
21. Magni P, Macchi C, Morlotti B, et al. Risk identification and possible countermeasures for muscle adverse effects during statin therapy. Eur J Intern Med. 2015;26:82-88.
22. Ko Y, Malone DC, Skrepnek GH, et al. Prescribers’ knowledge of and sources of information for potential drug-drug interactions: a postal survey of US prescribers. Drug Saf. 2008;31:525-536.
23. Phansalkar S, van der Sijs H, Tucker AD, et al. Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Inform Assoc. 2013;20:489-493.
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4. Rätz Bravo AE, Tchambaz L, Krähenbühl-Melcher A, et al. Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy. Drug Saf. 2005;28:263-275.
5. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376:1658-1669.
6. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med. 2001;111:390-400.
7. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet. 2000;38:111-180.
8. Malhotra B, Dickins M, Alvey C, et al. Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects. Br J Clin Pharmacol. 2011;72:263-269.
9. US Food and Drug Administration. Drug development and drug interactions: Table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. Accessed February 9, 2017.
10. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005;28:1805-1808.
11. Shaukat A, Benekli M, Vladutiu GD, et al. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharmacother. 2003;37:1032-1035.
12. Hazin R, Abuzetun JY, Suker M, et al. Rhabdomyolysis induced by simvastatin-fluconazole combination. J Natl Med Assoc. 2008;100:444-446.
13. Findling O, Meier N, Sellner J, et al. Clinical reasoning: rhabdomyolysis after combined treatment with simvastatin and fluconazole. Neurology. 2008;71:e34-e37.
14. US Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. June 8, 2011. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm256581.htm. Accessed February 1, 2017.
15. Wolters Kluwer. Lexicomp online. Available at: http://www.wolterskluwercdi.com/lexicomp-online/. Accessed February 9, 2017.
16. Molden E, Skovlund E, Braathen P. Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors. Drug Saf. 2008;31:587-596.
17. Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. Int J Cardiol. 2014;174:83-89.
18. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-2590.
19. Saito Y. Pitavastatin: an overview. Atheroscler Suppl. 2011;12:271-276.
20. Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002;20:303-328.
21. Magni P, Macchi C, Morlotti B, et al. Risk identification and possible countermeasures for muscle adverse effects during statin therapy. Eur J Intern Med. 2015;26:82-88.
22. Ko Y, Malone DC, Skrepnek GH, et al. Prescribers’ knowledge of and sources of information for potential drug-drug interactions: a postal survey of US prescribers. Drug Saf. 2008;31:525-536.
23. Phansalkar S, van der Sijs H, Tucker AD, et al. Drug-drug interactions that should be non-interruptive in order to reduce alert fatigue in electronic health records. J Am Med Inform Assoc. 2013;20:489-493.
