FDA Drug Safety Communication: Ongoing safety review of high-dose
Zocor (simvastatin) and increased risk of muscle injury
[3-19-2010] Based on review of data from a
large clinical trial and data from other sources, the U.S. Food and Drug
Administration (FDA) is informing the public about an increased risk of muscle
injury in patients taking the highest approved dose of the cholesterol-lowering
medication, Zocor* (simvastatin) 80 mg, compared to patients taking lower doses
of simvastatin and possibly other drugs in the "statin" class.
The clinical trial data being reviewed is from the Study
of the Effectiveness of Additional
Reductions in Cholesterol
and Homocysteine (SEARCH) trial. The agency is
also reviewing data from other clinical trials, observational studies, adverse
event reports, and data on prescription use of simvastatin to better understand
the relationship between high-dose simvastatin use and muscle injury (see Data
Summary below).
The muscle injury, also called myopathy, is a known side effect with all
statin medications. Patients with myopathy generally have muscle pain,
tenderness or weakness, and an elevation of a muscle enzyme in the blood (creatine
kinase). The higher the dose of statin used, the greater the risk of developing
myopathy. The risk of myopathy is also increased when simvastatin, especially at
the higher doses, is used with certain drugs (see Simvastatin Dose Limitations
below).
The most serious form of myopathy is called rhabdomyolysis. It occurs when a
protein (myoglobin) is released as muscle fibers break down. Myoglobin can
damage the kidneys. Patients with rhabdomyolysis may have dark or red urine and
fatigue, in addition to their muscle symptoms. Damage to the kidneys from
rhabdomyolysis can be so severe that patients may develop kidney failure, which
can be fatal.
Known risk factors for developing rhabdomyolysis include age (> 65 years),
low thyroid hormone levels (hypothyroidism), and poor kidney function. Myopathy
and rhabdomyolysis are listed as possible side effects in the simvastatin and
other statin drug labels.
Healthcare professionals should:
 | Understand that rhabdomyolysis is a rare adverse event
reported with all statins. |
| Be aware of the potential increased risk of muscle injury with
the 80 mg dose of simvastatin compared to lower doses of simvastatin and
possibly other statin drugs. |
| Follow the recommendations in the simvastatin label regarding
drugs that may increase the risk for muscle injury when used with
simvastatin (see Simvastatin Dose Limitations below). |
Patients should:
| Not stop taking simvastatin unless told to by their healthcare
professional. |
| Talk to their healthcare professional about any questions they
have about the use of simvastatin. |
| Call their healthcare professional if they experience any of
the following: muscle pain, tenderness or weakness, urine that is dark or
red-colored, or unexplained tiredness. |
This communication is in keeping with FDA's commitment to inform the public
about its ongoing safety review of drugs. The agency will update the public as
soon as this review is complete.
*Simvastatin is sold as a single-ingredient generic medication and as the
brand-name, Zocor. It is also sold in combination with ezetimibe as Vytorin; and
niacin as Simcor.
Patients currently using 80 mg simvastatin should:
| Know that rhabdomyolysis is a rare side effect reported with
all statin medications. |
| Not stop taking simvastatin unless told to by their healthcare
professional. |
| Review their medical history and current medications with
their healthcare professional to determine if they should continue using
simvastatin. |
| Talk to their healthcare professional about any questions or
concerns they have about simvastatin. |
| Call their healthcare professional if they have muscle pain,
tenderness or weakness, dark or red colored urine, or unexplained tiredness. |
| Report any side effects with simvastatin to FDA's MedWatch
program using the information at the bottom of the page in the "Contact
Us" box. |
FDA recommends that healthcare professionals should:
| Understand that rhabdomyolysis is a rare adverse event
reported with all statins. |
| Be aware of the potential increased risk of muscle injury with
the 80 mg dose of simvastatin compared to lower doses of simvastatin and
possibly other statin drugs. |
| Review patients' medical history and medications to determine
if simvastatin is clinically appropriate. |
| Discuss with patients the benefits and risks, including the
risk of myopathy and rhabdomyolysis, of simvastatin therapy. |
| Be aware of potential drug-drug interactions with simvastatin. |
| Report any adverse events associated with the use of
simvastatin to FDA's MedWatch program using the information in the
"Contact Us" box at the bottom of the page. |
FDA's review of the SEARCH trial is part of the agency's continuing effort to
evaluate the risk of muscle injury with simvastatin; this review includes
evaluating data from clinical trials, observational studies, and adverse event
reports, as well as data on prescription use of simvastatin.
The SEARCH trial evaluated over 6.7 years the number of major cardiovascular
events (heart attack, revascularization, and cardiovascular death) in 6031
patients taking 80 mg of simvastatin compared to 6033 patients taking 20 mg of
simvastatin. All patients in the study had previously had a heart attack.
Preliminary SEARCH trial results revealed that more patients in the
simvastatin 80 mg group developed myopathy compared to patients in the
simvastatin 20 mg group (52 [0.9%] cases compared to 1 case [0.02%]). Further,
FDA's preliminary analyses of the primary data suggest that 11 (0.2%) of the
patients in the simvastatin 80 mg group developed rhabdomyolysis compared to no
patients in the simvastatin 20 mg group.
In 2008, the agency alerted the public about an increased risk of developing
rhabdomyolysis when doses greater than 20 mg of simvastatin are given with
amiodarone. The agency also included information about this drug interaction in
its Summer 2008 issue of the FDA
Drug Safety Newsletter and in its November 2008 Patient
Safety News broadcast.
In March 2010, FDA approved a labeling revision for simvastatin based on
interim results from an ongoing clinical trial – the Heart Protection Study 2
(HPS2). The revised label states that patients of Chinese descent should not
receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing
products. Further, the revised label recommends caution when such patients are
treated with simvastatin 40 mg or less in combination with cholesterol-modifying
doses of niacin-containing products. The interim HPS2 results showed that the
incidence of myopathy was higher in patients of Chinese descent (0.43%) compared
with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus
cholesterol-modifying doses (≥1 g/day) of a niacin-containing product. It
is not known if the increased risk for myopathy observed in these patients
applies to other patients of Asian descent.
Moreover, FDA has requested that the sponsor of simvastatin change the
product labeling to instruct healthcare professionals to avoid prescribing
simvastatin doses greater than 40 mg daily when patients are taking the
medication diltiazem, due to an increased risk for myopathy.
A 2010 review of prescription drug use data conducted by FDA found that,
despite dose limitations and drug-drug interaction precautions included in the
simvastatin drug label, patients are continuing to be prescribed higher doses of
simvastatin with other medications that are known to increase the risk for
rhabdomyolysis (see Simvastatin Dose Limitations below).
It is important for healthcare professionals to consider the potential risks
and known benefits of simvastatin compared to other cholesterol-lowering
therapies when deciding to use simvastatin. Healthcare professionals should also
carefully review patients' medications for potential drug-drug interactions
before prescribing or dispensing simvastatin.
This communication is in keeping with FDA's commitment to inform the public
about its ongoing safety review of drugs. The agency will update the public as
soon as this review is complete.
These limitations apply to ALL patients taking simvastatin.
Do not use simvastatin with these
medications:
| Itraconazole |
| Ketoconazole |
| Erythromycin |
| Clarithromycin |
| Telithromycin |
| HIV protease inhibitors |
| Nefazodone |
Do not use more than 10mg of simvastatin
with these medications:
| Gemfibrozil |
| Cyclosporine |
| Danazol |
Do not use more than 20mg of simvastatin
with these medications:
| Amiodarone |
| Verapamil |
Do not use more than 40mg of simvastatin
with this medication:
| Diltiazem |
| 
