CAN RIFAXIMIN TRIGGER RHABDOMYOLYSIS DESPITE LONG TERM USE OF ATORVASTATIN?

Case Presentation: A 72 y/o African American male with PMHx of HTN, IDDM, CAD, ESLD 2/2 Hepatitis C in remission with portal hypertension and hepatocellular carcinoma s/p radioembolization presented after a fall at home. He had generalized weakness for 3 weeks with worsening over last 3 days. His ROS significant for diarrhea from lactulose and anorexia. Rifaximin was added 2 months prior to his medication regimen. On Atorvastatin for >10 years. Other medications are Lactulose, Lasix, Aldactone, Propranolol, NPH insulin and Gabapentin. He had normal vital signs and was A&O x3. PE significant for Trace leg edema, flexor-extensor weakness of bilateral hips 4/5 and asterixis. Initial labs notable for lactate 4.1 mmol/L, ammonia 130µmol/L, AST 1024 U/L, ALT 313 U/L (baseline AST 44 U/L and the ALT 27 U/L), ALP 173 U/L, INR 1.3(baseline), total bilirubin 2.7 mg/dL ( baseline 1.7 mg/dL), BUN 47 mg/dL & Cr 2.9 mg/dL (baseline BUN 24 mg/dL, Cr 1.4 mg/dL) high sensitivity troponin 2473 ng/L,. EKG concerning for anteroseptal infarct. US abdomen: liver cirrhosis, minimal ascites, decreased size of right hepatic mass, no biliary tree dilatation. On admission thought to be dehydrated with hypotensive event from diarrhea/poor PO intake causing the clinical picture of weakness, AKI, Elevated LFTs, lactate and troponins given medications above. IV fluids given. He had MSSA in urine cultures and antibiotics given. Was not in sepsis. Cardiologist determined he had a type II NSTEMI event. On workup for unexplained LFT elevation and weakness: CK was 16236 U/L. At this point statin induced rhabdomyolysis was the main diagnosis. Atorvastatin stopped and was aggressively hydrated. His LFTs, RFTs and weakness improved over 5 days.

Discussion: Statins are used in management of HLD and metabolized by CYP-450 (Atorvastatin by CYP3A4). Statin induced myopathies are commonly reported. Clinical trial definition of statin induced rhabdomyolysis is elevation of CK >10 times upper limit with acute renal failure [1]. The incidence of rhabdomyolysis is rare and reported in 2 cohort studies as 3.4 per 100,000 person-years [2]. We present a person on Atorvastatin 40 mg/day for >10 years duration with a delayed rhabdomyolysis which corrected rapidly off of Atorvastatin. On literature, we identified 1 similar case of a 73 y/o female taking simvastatin >9 years [3]. While looking for other temporal causes, his most recent medication change was addition of Rifaximin. Rifaximin does not inhibit CY3A4P. But shown to be a metabolic substrate for this enzyme in-vitro studies. We did find a prior RCT describing increased incidence of Myopathies with use of high dose Simvastatin and Rifaximin concomitantly [4]. This raises concerns whether Rifaximin contributed to our patient’s rhabdomyolysis. The diagnosis was delayed given the fact with increased use of hsTroponin, we do not readily get CK results during ER evaluation.

Conclusions: Our case highlights a late presentation of statin induced myopathy & rhabdomyolysis occurred after a decade of Statin use precipitated after initiation of Rifaximin. Statin induced myopathy usually involves proximal muscles and symmetric and happens in 0.1% of patients treated with statin. Rhabdomyolysis should be suspected in cases of unexplained elevated LFTs, BUN, creatinine, and hsTroponin. The risk for adverse muscle events increased by drugs that inhibit the cytochrome P-450 system. With increasing use of high sensitivity troponin assays: CK/CK-MB needs to be ordered separately. We question Rifaximin can induce statin myopathy.