AMIODARONE-SIMVASTATIN INTERACTION

Interaction between amiodarone (marketed as CORDARONE and PACERONE) and simvastatin (marketed as ZOCOR and generics) or simvastatin-combination products (marketed as VYTORIN and SIMCOR)
Amiodarone potentiates the risk for simvastatin-associated rhabdomyolysis
FDA continues to receive reports of rhabdomyolysis in patients given amiodarone in combination with higher doses of simvastatin. Amiodarone is an antiarrhythmic drug indicated to treat certain types of recurrent ventricular arrhythmias. Simvastatin is a 3-hydroxy-methylglutaryl-coenzyme A reductase inhibitor (statin) used to lower cholesterol levels. As with all statins, the risk of rhabdomyolysis is dose-related and increased by high plasma levels of statin. Patients who take amiodarone with simvastatin doses greater than 20 mg daily have an increased risk of rhabdomyolysis. The precise mechanism for this drug interaction is unknown, but stems, in part, from amiodarone's inhibition of the cytochrome P450 3A4 (CYP3A4) enzyme, the same enzyme that metabolizes simvastatin (see Illustration 1). This interaction may result in an increase in the levels of simvastatin in the plasma, potentiating the risk of rhabdomyolysis. Labeling for all of the amiodarone (Cordarone and the generic drug Pacerone)1 and simvastatin-containing products [Zocor2, ezetimibe/simvastatin (Vytorin3) and niacin/simvastatin (Simcor4)] describe this potential risk.
Rhabdomyolysis, a severe form of myopathy, involves injury to and breakdown of skeletal muscles, which in some cases leads to renal failure and death.5 There are multiple etiologies for rhabdomyolysis, including, but not limited to, exposure to certain drugs, including statins.6,7 Healthcare professionals should be aware of the increased risk of rhabdomyolysis when amiodarone is taken concomitantly with doses of simvastatin that exceed 20 mg daily. Prescribers should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone (the maximum recommended simvastatin dose is 80 mg daily).
Illustration 1
Amiodarone-Simvastatin Interaction - Postulated Mechanism
Illustration 1. This illustration depicts a postulated mechanism for the amiodarone-simvastatin interaction, including the subsequent impact of this interaction on skeletal muscle and the kidney. In the first column, amiodarone inhibits the enzyme CYP3A4, limiting simvastatin metabolism (depicted by dashed arrow). By limiting the metabolism of simvastatin, there is an increase in levels of circulating simvastatin in the blood. In the second column, high circulating simvastatin levels may result in myotoxicity in the skeletal muscles (rhabdomyolysis). The rapid breakdown of muscle protein produces excessive levels of myoglobin in the blood. In the third column, myoglobin, now at high circulating levels, reaches the kidneys where it can obstruct renal tubules and lead to acute renal failure. *Amiodarone's direct inhibition of CYP3A4 has been characterized as weak, suggesting that other factors may also contribute to how these two drugs interact.
Both the simvastatin and amiodarone labels were changed in 2002 to reflect the increase in risk for myopathy when amiodarone is taken concurrently with simvastatin.1-4 The simvastatin label (Warnings, Precautions and Dosage and Administration sections) specifically indicates that the dose of simvastatin should not exceed 20 mg daily in patients concomitantly receiving amiodarone, and that the combined use of simvastatin and amiodarone at simvastatin doses higher than 20 mg daily should be avoided unless the clinical benefit is likely to outweigh the increased risk of myopathy. The amiodarone label (Precaution section) notes that there is an increased risk for myopathy/rhabdomyolysis when amiodarone is taken in combination with HMG-CoA reductase inhibitors that are CYP 3A4 substrates, such as simvastatin.
Since this labeling change was made, FDA has received 52 additional U.S. reports of rhabdomyolysis associated with the concurrent use of amiodarone and simvastatin. This article summarizes FDA's analysis of these 52 cases from FDA's Adverse Event Reporting System (AERS) database dating from January 1, 2003 to January 1, 2008.
Reported Cases of Rhabdomyolysis
The 52 cases of rhabdomyolysis reported to AERS involved patients ranging in age from 50 to 88 years (median age was 73). Thirty-seven patients (71%) were male and 10 were female (19%). The sex was not reported for the remaining five patients (10%). In half of the reported rhabdomyolysis cases (26/52), amiodarone was being taken in combination with 80 mg simvastatin. Thirteen patients (25%) were taking amiodarone in combination with 40 mg simvastatin, while four patients (8%) were taking amiodarone with 20 mg simvastatin. One patient (2%) developed rhabdomyolysis when taking amiodarone with 5 mg simvastatin. Eight patients (15%) were taking an unknown dose of simvastatin in combination with amiodarone.
Regarding other concomitant medications, 37 patients (71%) were taking medications in addition to amiodarone and simvastatin. These drugs included diuretics (20), beta-blockers (18), angiotensin-converting enzyme inhibitors (16) and insulin (11). Among the concurrent medications taken by these patients, all except for niacin and levofloxacin are either substrates for and/or inhibitors of CYP3A4. These medications included gemfibrozil (9), angiotensin II receptor blockers (3), clarithromycin or levofloxacin (2), protease inhibitors (2), niacin (2), fenofibrate (1), atorvastatin (1), and risperidone (1). The labels of several of these products reflect the risk of rhabdomyolysis when they are used as monotherapy or when administered concurrently with simvastatin.
The mean time interval between the initiation of amiodarone therapy in conjunction with simvastatin (or simvastatin therapy in conjunction with amiodarone) and the onset of rhabdomyolysis was five months (median-2 months). Specifically, 42% of the cases (22) indicated that symptoms of rhabdomyolysis emerged within 2 months of the initiation of concurrent amiodarone-simvastatin therapy. Forty percent of the cases (21) did not report the time interval between the onset of rhabdomyolysis and the initiation of amiodarone-simvastatin therapy.
Ninety-two percent of rhabdomyolysis cases (48) required hospitalization. Twenty-eight percent of the reported cases (15) were considered life-threatening. Ten percent of patients (5) who developed rhabdomyolysis were noted to have become disabled. One death was reported (2%).
Three representative case reports of amiodarone-simvastatin associated rhabdomyolysis are described in Box 1. These cases were selected based on their representation of the demographics and circumstances usually reported with amiodarone/simvastatin-associated rhabdomyolysis. In addition to being reported to AERS, Case 3 has also been published in the scientific literature.8
Box 1
Case 1
A 74-year-old male was hospitalized with ventricular tachycardia. While hospitalized, the patient underwent coronary artery bypass graft surgery and was subsequently started on ezetimibe/simvastatin (10/40 mg daily). At the time of discharge, the patient was also prescribed amiodarone 200 mg (to be taken twice daily), aspirin, ramipril, and metoprolol. Three weeks following his discharge from the hospital, the patient complained of extreme muscle weakness. His creatinine level was "highly elevated". A diagnosis of rhabdomyolysis was made. Ezetimibe/simvastastin was discontinued and the patient recovered.
Case 2A 50-year-old male was hospitalized for coronary artery bypass graft surgery. During his hospitalization, the patient developed atrial fibrillation and was started on amiodarone 400 mg (taken three times daily). The next day, the patient was also started on ezetimibe/simvastatin 10/80 mg daily. Six days following the initiation of simvastatin, the patient experienced progressive leg weakness with a creatine kinase (CK) of 117,400 units/L (for males, normal reference range: 60 to 400 units/L) and a serum creatinine (SCr) of 3.5 mg/dL (normal reference range: <1.5 mg/dL).9 The patient was transferred to the intensive care unit and ezetimibe/simvastatin was discontinued. Three days after the discontinuation of simvastatin, the patient's CK and SCr levels had decreased to 26,700 units/L and 2 mg/dL, respectively.
Case 3
In 2004, a 72-year-old white male was hospitalized complaining of aches and weakness in his thighs. He also noted that his urine was dark for the week prior to his admission. He had a history of diabetes mellitus, hyperlipidemia, hypertension, azotemia, and coronary artery disease. In the summer of 2004, the patient had bypass surgery. Immediately following his bypass surgery, the patient was started on 200 mg amiodarone (taken once daily). One month later, simvastatin (80 mg/day) was prescribed. Other concomitant medications included metformin, enalapril, glimepiride, hydrochlorothiazide and aspirin.
Laboratory testing at the time of the most recent hospital admission indicated a CK level of 19,620 units/L (for males, reference range: 60 to 400 units/L)9 and a SCr of 2.6 mg/dL (normal reference range: <1.5 mg/dL).9 Rhabdomyolysis was suspected and simvastatin was immediately discontinued. Amiodarone was also discontinued four days after discontinuation of simvastatin. Within one day of stopping simvastatin, CK and SCr levels began to fall. Thirteen days after admission to the hospital, CK was 323 units/L and SCr was 1.7 mg/dL.
The concomitant use of amiodarone with simvastatin reduces the dose threshold for simvastatin-associated rhabdomyolysis. The cessation of symptoms (and lowering of laboratory values indicative of rhabdomyolysis) after discontinuation of one or both of these drugs indicates that muscle breakdown can be halted and reversed if identified early. Healthcare professionals should be aware that amiodarone may potentiate the risk for simvastatin-associated rhabdomyolysis. Simvastatin doses greater than 20 mg day daily should be avoided in patients taking or initiating amiodarone therapy. Prescribers should consider use of another statin for patients on amiodarone or initiating amiodarone therapy who require simvastatin doses greater than 20 mg daily to meet their lipid goals