June 15th, 2011
NEJM: FDA Officials Explain the New Simvastatin Label
Larry Husten, PHD
In a perspective published in the New England Journal of Medicine, two FDA officials, Amy Egan and Eric Colman, explain in some detail the recent changes made by the FDA regarding simvastatin. They note that in the SEARCH trial, myopathy developed in 52 (0.9%) patients in the 80-mg group compared with only 1 (0.02%) patient in the 20-mg group. There were 22 cases of rhabdomyolysis with the high dose versus no cases with the low dose. Further, patients at high risk usually developed myopathy early in the course of treatment.
In addition, because simvastatin is “particularly prone to drug-drug interactions,” the risk for myopathy is increased in patients taking high-dose simvastatin who are also taking other drugs, including several commonly used cardiovascular drugs such as amiodarone, diltiazem, and amlodipine.
Finally, the FDA authors summarize data from adverse event reports from all the statins, noting that rates of fatal rhabdomyolysis have been higher with simvastatin 80 mg than with atorvastatin 80 mg or rosuvastatin 40 mg.
The following chart provides a summary of the FDA action:
| Key Components of Recent Safety-Labeling Changes for Simvastatin | |
| 1. Use of the 80-mg dose of simvastatin should be restricted to patients who have been taking it for a long time (e.g., 12 months or more) without signs or symptoms of clinically significant toxic effects on muscle.
2. Patients who are currently taking an 80-mg dose of simvastatin without adverse effects but who need to begin taking an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for a drug–drug interaction. 3. Patients in whom the LDL cholesterol goal cannot be achieved with a 40-mg dose of simvastatin should instead be given other appropriate LDL cholesterol–lowering therapy (e.g., a more potent statin that poses a lower risk of myopathy, such as atorvastatin or rosuvastatin). |
|
| Drug Interactions Associated with Increased Risk of Myopathy and Rhabdomyolysis | |
|
Interacting Agents
Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone Gemfibrozil Cyclosporine Danazol |
Prescribing Recommendations
Contraindicated with simvastatin |
|
Amiodarone Verapamil Diltiazem |
Do not exceed 10 mg of simvastatin daily |
|
Amlodipine Ranolazine |
Do not exceed 20 mg of simvastatin daily |
|
Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 qt daily) |
6 Responses to “NEJM: FDA Officials Explain the New Simvastatin Label”
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Once again, the FDA was asleep at the switch. Most lipid experts have known for many years that the 80mg dosage of simvastatin carried a 7-10-fold higher risk of myopathy compared with lower dosages of simvastatin or other statins. In the NEJM commentary, Drs. Egan and Colman state that “Recently, concerns have been raised about a disproportionate increase in the risk of myopathy with high dose simvastatin.” It all depends on what you consider recent. We warned of this risk in an editorial in JAMA in 2004 and the SEARCH Trial confirmed these concerns in 2008. Now, 7 years later, after about 70 deaths due to rhabdomyolysis, FDA has chosen to act. Too little, too late.
HMG COA reductase is not a pathological enzyme . It a vital cell servicing enzyme that maintains integrity of cell membrane.It is not at all surprising it can have dangerous consequence if the dose is exceeded.
Do not ever think simvastatin alone as a culprit .10 years down the line Atorvastatin may be proven a more deadly molecule.
Why do we need so many statins ? why cant drug companies spend their energy in discovering new molecules .
Can we force a ban on creation ( or rather duplication of research)
Plagiarism is considered an offense in every walk of life and why pharma industry is an exception ?. They basically decorate a old drug prefixing few exotic words and loot the public money and many times at the cost of public life too !
please allow me to link a related article in my blog
http://drsvenkatesan.wordpress.com/2010/09/24/regulating-the-regulators/
http://drsvenkatesan.wordpress.com/2008/07/27/journal-club-debates-can-a-aim-of-a-study-be-wrong/
I believe that with the proper monitoring, high dose simvastatin can be safe enough and effective enough to be used in a subset of patients who cannot afford the newer, safer, agents. It is true of all HMG Co A Reductase Inhibitors (statins) that the higher the dose, the greater the risk of myopathy. Simvastatin has more years of use than any of its newer competitors, and this alone should give confidence to the FDA to condone its use at all doses currently available. The FDA seems not to mind leaving the 2,000,000 Americans already on simvastatin 80 mg alone, yet they place a major financial obstacle in front of those who cannot afford the newer agents and do not qualify for benefit programs.
As a government regulatory agency, FDA’s fiduciary duty lies with the citizens of the United States. Their first job is to make sure the risk/benefit ratio of meds is of a safe proportion. It does not have to be perfect(nothing is). The second job of FDA is to ensure the medication actually does what it is supposed to do. Simvastatin fits the bill.
With informed discussion in the Patient/Doctor encounter and proper patient monitoring 80 mg simvastatin can be safely used. The choice to use it should be reserved for the patient after consultation with their doctor.
I fear that what will become of this FDA decision is the following: people will stop using simvastatin and take nothing. In CAD a statin is better than no statin. We will see a spike in CVD deaths in a few years.
The same thing happened with SSRI’s in teens and young adults a few years ago. Doctors and patients’ became afraid to use them because of the percieved threats in suicidality. But when you you look at the M&M data the actual suicide rate doubled when the meds were discontinued or not prescribed first line. Things are finally returning to normal. The suicide rates in teens are down because of appropriate treatment.
FDA makes some very interesting snap decisions. A few drugs that were grandfathered in as safe and effective years ago and have proven themselves with the test of time suddenly had to pass FDA muster (l- thyroxine and colchicine are examples). FDA suddenly wants the manufacturers to submit NDA equivalents or face having their low cost, safe, effective drugs taken from the market. The new colchicine costs my patients 100 times what the old formulations cost and only works just as well. FDA collects a substantial fee for these NDA’s and a good number of the people on the FDA board have industry conflicts of interest. This comes off the backs of my gout patients who cannot afford the new formulation and must now suffer because we have already determined colchicine works best for them.
One of my patients with a long list if allergies and osteoarthritis and migraine dropped by last week. I asked her how she was doing? Answer: terrible. Asked her why? Because the only thing that ever gave her pain relief and did not make her sick was propoxyphene. The FDA took it off the market some months back.
When I look at my old Geneva Conventions card it says something about care for the sick and wounded and relief of pain and suffering. It does not say look at statistics and follow the commands of your leaders regarding medical care. This is precisely what FDA is now doing, they sit in a government office and collect fees from manufacturers to follow the statistics and dictate what they believe is safe and effective using data and computers. In fact they should spend some time on the front of the war on illness and see what impact their decisions have on those who matter most, our patients. I am now fielding calls from people who want to know if their simvastatin is safe rather than taking care of the sick. 70 deaths are too many, but so is one death. More people die from aspirin in a month than have ever died from simvastatin. This does not make aspirin a “bad” drug.I would like to know how many have died from myopathy on the newer drugs. In my own experience, the only case of rhabdomyolysis I have ever seen (and required transient dialysis) was with rosuvastatin. This does not make it a “bad” drug either. We need to use common sense here. The nation is in a fiscal crisis, and we are splitting hairs over high dose simvastatin which has a very good risk benefit ratio. People simply cannot afford the newer drugs in many instances. We should not be scaring people away from an “oldie but goodie”. If they desire to live longer and better and cannot afford the new branded drugs they should be offered a choice in their medical care. What is The FDA thinking?
Competing interests pertaining specifically to this post, comment, or both:
My only COI is I am a fellow taxpayer. I also have many patients who cannot afford brand name drugs.
I have never been a fan of Simva 80 mg, but to say that the FDA was “alseep at the switch” is a bit harsh. As a preventive cardiologist and clinical lipidologist I have had the opportunity to speak with many of my primary care colleagues who are confronted by patients unable to afford more potent statins. Simva 80 has been their only means of getting such patients to goal. Yes, it may be that 70 patients have had rhabdo over 7 years, but how many more have had their infarcts averted?
The Higth dose of Simva never was safety. Always we may balance risks /benefices. I think that 40mg/day is endpoint.
Competing interests pertaining specifically to this post, comment, or both:
No conficts.
I never used 80 mg of simva since A to Z was reported. I am skeptical re amlodipine interaction. I have requested more information on this interaction. Short pharmacokinetic studies may not reflect clinical experience (as seen in other trials such as RE-LY). Please let me know if you have a source.
The risk benefit tradeoff between simva 40 and 80 seems quantifiable and may depend on absolute CV risk. Does the 7% further LDL reduction outweigh the rhabdo risk? (Assuming no other possible therapy). Should we assume a linear LDL-MI/CVA relationship or log_linear (where a given percent LDL reduction has the same CV benefit regardless of LDL)?
Competing interests pertaining specifically to this post, comment, or both:
None