Amiodarone and Atorvastatin: Interaction Details

a) In a review of adverse events reported to the US Food and Drug Administration (FDA) adverse events (AE) reporting database for simvastatin, atorvastatin, and pravastatin, muscle toxicity cases were reported with coadministration of atorvastatin and amiodarone. The review analysis included AE reports that affected major organ systems (MOS) such as muscle (myopathy, myalgia, rhabdomyolysis, elevated CPK, myolysis); liver (abnormal liver function tests); pancreas (pancreatitis); and bone marrow (pancytopenia, leukopenia, thrombocytopenia). Rates of MOS reports involving concurrent use of amiodarone with atorvastatin and simvastatin were 0.7% (n=29/3,767) and 1% (n=36/3,651), respectively (p=not significant). Among pravastatin-associated MOS reports, 0.4% of reports involved concurrent amiodarone use (p less than 0.05, compared to simvastatin). The majority of AEs reported with concurrent amiodarone and statin use involved muscle toxicity and occurred in older male patients (mean age 76 years) who were on multiple other medications. Muscle toxicity occurred in 76% and 77% of MOS reports involving concurrent use of amiodarone with atorvastatin (n=29) or simvastatin (n=36), respectively, with no statistically significant differences between the 2 statins. No significant differences were noted with concomitant usage of other cardiovascular medications and incidence of AEs reported among the 3 statins. While this review was limited by its retrospective nature and discrepancies between FDA reporting rates and actual reporting rates, it may be important to monitor for muscle-related complaints in patients taking concomitant amiodarone and statins, such as simvastatin and atorvastatin, particularly in elderly patients on several other concomitant medications. Use of a statin that is not metabolized by CYP3A4 may be preferred in such situations ¹.

b) Rhabdomyolysis, accompanied by renal failure and possible hepatotoxicity, developed in a 72-year-old man after simvastatin 80 milligrams/day (mg/day), a HMG-CoA reductase inhibitor metabolized by CYP3A4 similar to atorvastatin, was added to an established regimen of amiodarone 200 mg/day which was initiated after a coronary artery bypass. The patient had a history of diabetes, hypertension, hyperlipidemia, and mild azotemia and had previously taken pravastatin 20 to 40 mg/day and fluvastatin 40 to 80 mg/day without any adverse effects. Approximately 1 month after initiation of simvastatin, the patient developed symptoms of thigh weakness, achiness, and dark urine. Laboratory analysis showed an elevated CK level of 19,620 units/liter (U/L) (reference range 60-224 U/L), AST level of 912 U/L (30-60 U/L), ALT level of 748 U/L (30-60 U/L), and highly elevated serum and urine myoglobin levels. In addition, serum creatinine level (2.6 mg/dL or 230 mcmol/L) and BUN (50 mg/dL or 18 mmol/L) were also elevated and the 24-hour urine protein level was 549 mg. Both simvastatin and amiodarone were immediately discontinued and the patient was hydrated with forced alkaline diuresis. After 13 days, hepatic enzyme levels dropped significantly and 3 months later, ALT, AST, and CK levels were 49, 32, and 640 U/L, respectively. Inhibition of CYP 3A4-mediated simvastatin metabolism by amiodarone was proposed as a possible mechanism for this interaction ².

c) Rhabdomyolysis developed in a 63-year-old man after amiodarone (1 gram/day for 10 days, followed by 200 milligrams (mg)/day)) was added to an established treatment regimen that included simvastatin 40 mg daily, a HMG-CoA reductase inhibitor metabolized by CYP3A4 similar to atorvastatin. Approximately 11 days after beginning amiodarone therapy, the patient showed signs of rapid exertional exhaustion, followed 5 days later by complaints of diffuse muscle pain and generalized weakness. Laboratory analysis revealed a creatine phosphokinase (CK) serum concentration of 18,852 units/liter (U/L) accompanied by an aspartate aminotransferase and lactic dehydrogenase serum concentrations of 438 U/L and 807 U/L, respectively. Despite the discontinuation of simvastatin, serum CK concentration continued to rise, reaching a peak of 40,392 U/L 3 days later. Amiodarone and phenprocoumon were both stopped and pravastatin 20 mg daily was substituted for simvastatin, after which the patient's CK serum concentration declined to within normal limits and the patient showed a slow improvement in muscle strength. The case study authors assign to the proposed interaction a Naranjo causal probability relationship of 'probable'³.