Case Presentation: A 97-year-old male with past medical history of HTN, COPD, CAD post PCI, T2DM, HLD, CVA with no residual deficit, presented to the emergency department (ED) with generalized weakness for one week. The patient had been in his usual state of health until seven days ago when he woke up with symptoms of difficulty walking due to leg weakness and muscle soreness. He denied recent laborious work or extensive exercise. Ten days prior to presentation, he had been prescribed ten days of 200 mg of fluconazole for a persistent groin rash. On exam, vitals were normal. He had bilateral inguinal intertrigo and bilateral lower extremity tenderness to palpation (thighs and calves in particular). His proximal muscle strength in bilateral legs was 3/5. Labs revealed normal cell counts and electrolytes and elevation of AST 493 U/L, ALT 196 U/L, and CK 5966 U/L. Urinalysis was negative except moderate blood but no RBC. Hepatitis panel was negative. A CT head without contrast and CT lumbar spine without contrast showed no acute finding. CT abdomen/pelvis with contrast noted fatty liver. Home medication review showed simvastatin, and with the patient’s recent fluconazole use, he was diagnosed with rhabdomyolysis from statins. It was postulated the fluconazole induced inhibition of CYP3A4 enzyme, which, in turn, increased serum statin levels. Both statin and fluconazole were stopped, and the patient was given intravenous hydration. His symptoms quickly waned with deceasing CK levels. His groin candida rash was treated with nystatin powder and resolved. Ten days later, the patient was back at baseline, walking stably, with normal CK and LFTs, and discharged to follow up with primary care. He was instructed to trial statin again with rosuvastatin as outpatient.
Discussion: 3-Hydroxy-3methyl-glutaryl-CoA (HMA-CoA) reductase inhibitors, commonly known as statins are metabolized in the liver through cytochrome P450 system, primarily CYP3A4. Statins are widely used in patients with CAD and stroke for primary and secondary preventions of atherosclerotic disease. Commonly prescribed statins are atorvastatin, lovastatin, rosuvastatin, and simvastatin. Generally, statins are well tolerated. However, rare events of rhabdomyolysis can occur due to elevated plasma levels of statins when used concurrently with CYP3A4 inhibitors. Antifungal azole derivatives are very potent inhibitors of CYP3A4, which has been shown to cause at least 5-fold increase serum levels in healthy volunteers. Simvastatin is more susceptible to inhibition than atorvastatin and lovastatin. Other potent CYP3A4 inhibitors include erythromycin, clarithromycin, calcium channel blockers, some protease inhibitors and cyclosporine. Recommended prevention of statin induced rhabdomyolysis is to stop statins 2 days before until 2 days after the course of antifungal or antibiotics. As most course of antifungals or antibiotics are short, it is felt that this short absence of medication would not affect long term outcomes related to statin effectiveness.
Conclusions: Statins are some of the most commonly prescribed medications. They are mainly metabolized by the hepatic cytochrome P450 system (mostly CYP3A4). Although they are generally well tolerated, drug-drug interactions with CPY3A4 inhibitors can cause rare rhabdomyolysis and muscles weakness. Physicians should be prudent about reviewing patient medications to prevent morbidities.