FDA:Amiodarone potentiates the risk for simvastatin-associated rhabdomyolysis
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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 2
A 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.
Relevant Website
Patient information sheet on amiodarone
References
Amiodarone (Cordarone) product labeling.
Simvastatin (Zocor) product labeling.
Ezetimibe/Simvastatin (Vytorin) product labeling.
Niacin extended-release/Simvastatin (Simcor) product labeling.
Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med.
2007;2:210-18.
Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA.
2003;289(13):1681-90.
The SEARCH Collaborative Group. SLCO1B1 Variants and Statin-Induced
Myopathy -- A Genomewide Study. N Engl J Med. 2008 Jul 23. [Epub ahead
of print]
Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone
interaction resulting in rhabdomyolysis, azotemia, and possible
hepatotoxicity. Ann Pharmacother. 2006;40(4):753-57.
Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the
Massachusetts General Hospital. Weekly clinicopathological exercises.
Laboratory reference values. N Engl J Med. 2004; 351(15):1548-63.
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