Weakness and pain in arms and legs • dark urine • history of vertebral osteomyelitis • Dx?

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Case Reports

Weakness and pain in arms and legs • dark urine • history of vertebral osteomyelitis • Dx?

J Fam Pract. 2017 March;66(3):170-173

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References

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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 2^6,7,10,19). 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

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

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.