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February 10, 2006

<NYT_HEADLINE type=" " version="1.0">Warning Urged on Stimulants Like Ritalin </NYT_HEADLINE>

<NYT_BYLINE type=" " version="1.0">By GARDINER HARRIS (http://query.nytimes.com/search/query?ppds=bylL&v1=GARDINER HARRIS&fdq=19960101&td=sysdate&sort=newest&ac=GARDINER HARRIS&inline=nyt-per)
</NYT_BYLINE><NYT_TEXT>GAITHERSBURG, Md., Feb. 9 — Stimulants like Ritalin could have dangerous effects on the heart, and federal regulators should require manufacturers to provide written guides to patients and place prominent warnings on drug labels describing these risks, a federal advisory panel voted on Thursday.

The panel's recommendation promises to intensify a long-running debate about whether the medicines are overused. Nearly four million patients take the drugs to treat attention deficit disorder and hyperactivity, and committee members said they wanted to slow explosive growth in the drugs' use.

The committee's action was unexpected. The Food and Drug Administration had convened the panel to help it determine how to research possible heart risks of the drugs. The agency had not asked the committee to address the drugs' labels, and agency officials seemed taken aback by the votes, saying they would not act on the committee's recommendations anytime soon.

"We don't think anything different needs to be done right now," Dr. Thomas Laughren, director of the Division of Psychiatry Products at the agency, said at a hastily arranged news conference after the meeting. "We think the labeling right now is adequate."

The committee voted unanimously to recommend patient guides, and it voted 8 to 7 to suggest that stimulant labels carry the most serious of the agency's drug-risk warnings — a "black box."

"I must say that I have grave concerns about the use of these drugs and grave concerns about the harm they may cause," said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic and a panel member.

The votes came after F.D.A. medical officers described reports of 25 sudden deaths among people taking stimulants — the deaths were mostly children — and a preliminary analysis of millions of health records that suggested stimulants might increase the risks of strokes and serious arrhythmias in children and adults. The reports of sudden deaths never exceeded one in a million for any stimulant drug, although the F.D.A. usually receives reports of only a fraction of drug problems.

The preliminary analysis suggested that the stimulants might increase heart risks more than twofold. Such an increase may not be significant in children, whose heart risks are low, but could cause concern in adults, panel members said.

One of the drugs, Ritalin, has been marketed since 1955, and dozens of studies have shown it to be safe and effective. But no studies have been of sufficient duration or included enough participants to evaluate stimulants' long-term effects on the heart.

But the drugs' soaring popularity and increasing use in adults, panel members said, mean that the F.D.A. should study them more closely and warn patients and doctors about the potential risks to the heart.

Arthur A. Levin, director of the Center for Medical Consumers in New York City and a member of the panel, said that patients assumed that stimulants were safe, but that that confidence was misplaced.

"For us to sit around and talk about it, and for us to not make a very strong warning about the uncertainty of these drugs and their possible risks, would be unethical," Mr. Levin said.

Dr. Thomas R. Fleming, a professor of biostatistics at the University of Washington and a panel member, said stimulants might be far more dangerous to the heart than Vioxx or Bextra, drugs that were withdrawn over the past two years because of their ill effects on the heart.

The committee was composed largely of drug-safety specialists. Next month, the F.D.A. will ask another committee, mostly pediatricians and psychiatrists, to weigh the same issues. Such clinicians tend to focus on drug benefits and oppose warnings that might scare patients.

The vote by the drug-safety panel reflects changing notions about what the drug agency should do in the face of uncertainty. For decades, it generally refused to warn doctors about theoretical medical risks, even when there were strong hints of danger. But the committee said such silence was a mistake, particularly when millions took the drugs.

"Put yourself in our shoes," said Dr. Peter A. Gross of Hackensack University Medical Center in New Jersey and the panel's chairman. "Most of us see our role as protecting the public health. As often happens, the data we would like to see is not clear. In that setting, what we would like to see is a clearer warning."

But top F.D.A. officials said warning patients about theoretical risks might scare many away from needed treatment. "I think it's important not to minimize the benefits of these drugs," Dr. Laughren said.

Representatives of Johnson & Johnson, the maker of Concerta, and Shire, the maker of Adderall, two stimulants, said they would work with the drug agency on any label changes.

Dr. Todd Gruber, an executive of Novartis, which makes Ritalin, has said that Novartis has found no evidence that the drug raises the risks of heart problems.

Stimulants are the most widely prescribed medicine for childhood behavioral problems. Data presented at the meeting suggest that about 2.5 million children and 1.5 million adults are taking them. More than 30 million prescriptions for the drugs are written annually.

Several F.D.A. medical officers addressed the committee, and each suggested that the risks could be significant. Dr. Kate Gelperin, a medical officer in the Office of Drug Safety at the agency, began her presentation by telling the committee, "This morning I'm going to tell you a little bit about why the F.D.A. is so worried about these issues."

Dr. Gelperin noted that stimulants had long been known to increase blood pressure (http://topics.nytimes.com/top/news/health/diseasesconditionsandhealthtopics/bloodpressure/index.html?inline=nyt-classifier) and heart rates. Other studies have shown conclusively that increased blood pressure leads directly to increased deaths from heart problems, she said.

Dr. Andrew Mosholder, also a medical officer in the Office of Drug Safety, said he reviewed the chemical structures of stimulants, and he noted that these structures were similar to drugs like ephedrine that had proven heart risks.

Dr. David Graham, another medical officer in the drug safety office, described the agency's preliminary analysis of millions of medical records that suggested an increased risk of strokes and arrhythmias.

"The number of arrhythmia hospitalizations really struck us as surprising," Dr. Graham said. "Arrhythmia is believed to be the pathway for sudden unexplained death."

In an interview after his presentation, Dr. Graham said, "There's smoke. Does that represent a fire? We want to answer that question."

After hearing the presentations, most committee members decided they should do more than simply make suggestions for further research.

"I want to cause people's hands to tremble a little bit before they write that prescription," Dr. Nissen said.

Psychiatrists and psychologists who treat and study attention deficit disorder and hyperactivity were deeply divided over the decision.

"I'm not saying a warning would be baseless, but if we're not careful we're going to engage in a Chicken Little scenario in which we sensationalize what is a very, very low-probability event," said Dr. Russell Barkley, a research professor of psychiatry at the State University of New York Upstate Medical University in Syracuse.

Others said that a black-box warning could prompt families to explore behavioral treatments as an alternative to drugs, which "would be a very good outcome for kids with A.D.H.D. and their families," said William Pelham, director of the Center for Children and Families at the State University of New York at Buffalo.

All agreed that parents of children on stimulants who have pre-existing heart conditions should consult their doctors.

<NYT_AUTHOR_ID>Benedict Carey contributed reporting from New York for this article.

Wow -- sounds like something that could make it harder to get doctors to prescribe Ritalin and related meds. Hope I'm wrong about that.

Scattered

I'm certainly not against warning people of potential risks, and people with heart problems are certainly taking extraordinary risks with stimulants.

What I wonder is why the need for even more labelling? The current labels include warnings and I'm about 95% certain that many people don't read them.

Will adding more warnings ensure people read the warnings? If not, maybe we should be spending our resources trying to educate people on the importance of reading the information that is already there.

I think it's important to warn people too of the risks. I'm also glad they're recommending more research -- it is needed. I just hope it doesn't go to a black box warning, because that pretty much killed Cylert. I think doctors, especial general practioners, are going to be lot more leery for fear of malpractice suites if it gets a black box label. My doctor is no longer prescribing Adderall to patients and I'm afraid he's going to get spooked by methylphenidate as well if that happens. On the other hand, I'd like to see more precautions taken to rule out high risk patients for cardiovascular or stroke complications.

There is always that balance between the risks of taking medication and the risks of not taking it.
Scattered

Thanks for posting on this, Scattered, as I wanted to also, but had too little time to go retrieve the links.

The first news reports I scanned suggested a real split about this, which to me said political motivation was involved. (One quote, perhaps in your article too, spoke about how unusual it was to issue a warning this dire before there were studies confirming it.) To me, it suggests success on behalf of the anti-med factions who have been working hard for years to discredit, discount and scare people about the "horrors" of Rx-dosed stimulants.

I do agree that more study is needed. I also agree that the front-line family physician perhaps needs to be a bit more vigilant than is always the case, especially in kids who might have undetected cardiac risk. But that said, geeze, can anyone spell "proportionality"?

Makes me wish we could measure/compare the dopamine hit one gets, say, from an Extra-Large at Starbucks vs. a 20mg dose of Adderall...

If you go to the link:
http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4202B1_05_FDA-Tab05.pdf
You get an FDA document with details on most of the reported deaths. The number and the nature of these incidents is such that I am not worried about these medications.
The FDA is just playing the game of "Cover your *****" with the black box warnings. They've been burned by the recent problems with Baycol and the COX-2 inhibitors and are running scared - especially with meds used by children.
The sad truth is that it will likely hurt people more than it helps. People in the margins will be less likely to get meds.
The politics of health care. special interest groups and tort law.

I've got a copy of the FDA's response to the Canadians w/drawing Adderall at the office.

I've posted on that once before.

In addition to several confounding variables, the rate of deaths were essentially the same as with the normal population.

Personally, I'm glad to have these issues raised, as it needs to be aired.

Hopefully, the resulting discussions can be used to educate the public(including the govt) on ADHD.

When you consider the effects of stimulants, it's no surprise that crdio concerns be raised.

I hope additional warnings don't lead to even less coverage by insurance providers. I think a label like that may scare people (eg parents being less willing to treat it w/ drugs).

I'm taking a neurobiology of addiction course and I just read that with low daily doses of d-isomer amphetamine lead to tolerance for cadio effects, but not subjective feelings of "high" and behavioral effects. It didn't elaborate, but if that's true, doesn't it suggest that there's less cause for worry?

More research is good though... I just hope they do it before they start making labeling changes. My experience with two different MDs has been that they're already cautious. One asked if I had high blood pressure etc and the other asked the same and requested labwork.

The data - thanks Gregster- and case descriptions of the deaths are really a mixed bag. For example, suicides and drownings are included on the amphetamine side, as well as one death due to imipramine overdose. And the numbers are low per prescriptions given (equivalent to a normal expected rate- according to McT)

The committee members state that the data is inconclusive, which it is. Actually, the data is poor and uncontrolled, unfortunately. Why are there so few deaths reported prior to 2000? Is that related to the lower number of prescriptions obtained, or of lack of reporting?

But there is a pattern of cardiovascular-related events which you might expect from stimulants. With Premoline (and acetomiaphen Tylnol) there was an initial pattern of hepatotoxicity which is now undisputed.

Seems like you wouldn't want to give stims to someone with cardiovascular problems, and a physician would want to follow-up on a child's physical reaction to a powerful drug. Cardiovascular conditions are already listed with warnings in the inserts.

As Barb mentioned, someone's not paying attention.


Manufacturers fight hard against black box warnings, a sure indication that the warnings hurt sales and make drugs less available. The branding and marketing of Adderall has been effective due to the renaming and subsequent sanitation of amphetamine as an acceptable drug for ADHD (IMOHO).

But what's in a name?

Well: My GP who is very smart and current, didn't have a clue what Adderall contained. After I told him it contained amphetamine, he immediately examined me for obvious sympathic nervous system changes, blood pressure, heart rate. Then he asked me to hold my arms out straight to see if I was shaking. Not exactly what I was hoping for.

That was early last year.

This year at Kaiser Permanente., all the docs have been informed of the potential hazards of amphetamine-containing compounds. Kaiser has been asked by the FDA to provide data about cardio events and ADHD drugs.

I can't wait to here what my GP says when I next see him. Ha!

The good news is that further research by places like Kaiser, an HMO with tons of longitudinal data on their own patient's health and prescription drug use, will better resolve the true risks.

I have been thinking about the possible mutagenic effects of methylphenidate and it's effect on the developing heart. As you probably know ADD meds can slow growth in children. I believe I have a possible explenation for this. A recent study conducted by el-zein (that is generally called very crappy and unvalid around here) showed damage to genes with ritalin usage. The problem is that cells that sustain gene damage (in some circumstances) cannot divide anymore; become scenescence. This explains the slowed growth (length + weight). Also, if this is true, the development of the heart could also be impaired. I think this could be the cause for possible heart problems on the long run. This kind of damage is undetectable, because the heart has not fully developed and there is no physical damage.

I think it's important to warn people too of the risks. I'm also glad they're recommending more research -- it is needed. I just hope it doesn't go to a black box warning, because that pretty much killed Cylert. I think doctors, especial general practioners, are going to be lot more leery for fear of malpractice suites if it gets a black box label. My doctor is no longer prescribing Adderall to patients and I'm afraid he's going to get spooked by methylphenidate as well if that happens. On the other hand, I'd like to see more precautions taken to rule out high risk patients for cardiovascular or stroke complications.

There is always that balance between the risks of taking medication and the risks of not taking it.
Scattered
This article appeared to be very general. Where are the details about the deaths? Were there comorbids? Other meds? Improper parent dosing of children? Undiagnosed heart problems? Are GP's who have less knowledge and experience treating ADD the one's whose patients have died from stims?

There are more questions, I want all the facts. I dislike scare tactics, yet I want the truth. Adderall was not good for me because of a heart defect. But I have no problems on Concerta and Ritalin. These are such valuable drugs for those of who choose to take them, that to limit them would make it hard for me to be as successful in my career, create many daily difficulties for me if I had to live without meds. All drugs have risks and benefits-unless the risks are so severe-I want the opportunity to make an informed choice.

The problem is that cells that sustain gene damage (in some circumstances) cannot divide anymore; become scenescence. This explains the slowed growth (length + weight).Senescene means old. Please explain your use of this term.

I have been thinking about the possible mutagenic effects of methylphenidate and it's effect on the developing heart. As you probably know ADD meds can slow growth in children. I believe I have a possible explenation for this. A recent study conducted by el-zein (that is generally called very crappy and unvalid around here) showed damage to genes with ritalin usage. The problem is that cells that sustain gene damage (in some circumstances) cannot divide anymore; become scenescence. This explains the slowed growth (length + weight). Also, if this is true, the development of the heart could also be impaired. I think this could be the cause for possible heart problems on the long run. This kind of damage is undetectable, because the heart has not fully developed and there is no physical damage.THERE ARE NO "MUTAGENIC" EFFECTS OF METHYLPHENIDATE

This topic has been well-researched.

The study you refer to does not "show damage". The study has no validity, therefore it shows NOTHING.

The human heart does not "develop" after birth the way the brain does. It simply grows larger like every other organ. The heart should only be large enough to provide circulation for the body it is in; if growth is retarded, it is not selective to the heart.

PLEASE PLEASE PLEASE take a few biology and basic science courses before you present your "theories". And, provide EVIDENCE that actually SUPPORTS your ideas. People need to be given FACTS, not "coffee talk".

Well said Barbyma
I don't think that "Steven d" understands how clinical research is done or how complicated such issues are. His understanding of biology also seems rather limited.
Either that or there is some other agenda he is working towards.
My own theory on the weight/height difference observed in some children taking MPH is that appetite surpression results in these children eating less than their peers, resulting in smaller kids. Studies show that this effect is short term, and that children don't show this long term - they eventually make up this growth difference.

My own theory on the weight/height difference observed in some children taking MPH is that appetite surpression results in these children eating less than their peers, resulting in smaller kids. Studies show that this effect is short term, and that children don't show this long term - they eventually make up this growth difference.Ah, a voice of reason!

I don't really need to see your sources to comment on this, but maybe you could give us a citation or 2 so that steven d can examine them?

Eating less is certainly the most parsimonious explanation, and I know doctors look at weight loss very closely in the newly-treated. But eating habits don't explain all of it. Stimulants tend to increase metabolism, so even children that continue to eat normally, or even eat more, may lose weight.

This is a risk of all stimulants, though. In fact, it's a risk of many other psychoactive meds as well. It's a risk, though, that is small and is greatly outweighed by benefits.

Your point about the temporary nature of the side effect is also important.

I just hope it doesn't go to a black box warning, because that pretty much killed Cylert.

Liver damage potential, cost of follow up labs, and the discovery of the more effective less potentially damaging medication for ADD like Concerta and Adderall XR, killed cylert, not the black box. A lot of things have a black box warning hence I agree with Barb on this one most people do not read the warnings any way. Frankly even when you stand there, look them in the eye and give verbal instructions the chances of the people actually following through is less that 50%(ADD or otherwise)!


Your point about the temporary nature of the side effect is also important.


The patient handout and the PDR used to state than appetitie supperssion anlong with other side efects like stomach upset, ect . . .may appear as your body adjust to the medication.If these symptoms become worse or bothersome consult your heath care professional.

I haven't read the PDR discription for Ritalin or Adderall, in a long time but you know come to think of it ritalin already had one about the potietial abuse ( it is a schedule 2 ya know); therefore, this black box has been there at least for the past ten years! Hmmmmm is the biggie deal now would be? :confused:

Perhaps they should look at considering cardiac evaluations for people prior to prescribing. These deaths when compared to other medication deaths are relatively small. I haven't seen the case studies on each child but from what I have read, some had pre-existing (unrecognized until autopsy) structural cardiac abnormalities. Long QT syndrome is another major possible pre-existing cardiac rhythm abnormality that can make a child, or adult for that matter, susceptible to lethal arrhythmias even without being exposed to medication. This won't show up on autopsy and is typically asymptomatic. These can usually be picked with a simple echocardiogram and EKG. Plus it's not necessary to see a cardilogist to have these tests performed. That way you don't have to worry about getting grief from them if they don't know anything about adhd and are biased against stimulants.

Perhaps they should look at considering cardiac evaluations for people prior to prescribing. A good doctor always considers this risk.

Any doc not doing a medical history at the very least (which is a pretty good indicator of risk when it includes family info) shouldn't be allowed to prescribe IMO.



These deaths when compared to other medication deaths are relatively small. This is usually where people get lost. Many think that even one life is too much.

I don't disagree, however, it's important to quantify the risk. Sure, one life is too much, but how many lives are lost when the medication is banned?

I'm willing to bet that the lives lost to accidents and suicides would be greater than those lost to the increased heart problems. This is the bottom line in RISKS vs. BENEFITS.

I don't know the cost of your suggestion, mcguffy, but I wouldn't be surprised if it becomes common to do a more thorough heart screening in the near future.

Doctors will sometimes do a cardiogram prior to prescribing stimulants. I had one done for part of a drug study (a drug for gout) and my doctor took my word that there were no problems. I later had a stress cardiogram done, but that was overkill!
Many heart defects don't show up on such tests however, so there is always some risk. If you are unlucky enough to have one of these defects, it's a ticking time bomb whether you take stimulants or not. The rate of death from stimulants in general (ie. "unexplained" with no overdose, etc) is about the same as the "natural" rate of death (kids do sometimes drop dead for unexplained or undiagnosed problems), so there is no real risk to your heart from stimulants - if you are at risk, it's pre-existing.
Most of this information can be found on the FDA's website - I don't have a link, per se.

If you are unlucky enough to have one of these defects, it's a ticking time bomb whether you take stimulants or not.Wow. EXCELLENT point.

That same logic applies to so many arguments, too. Thanks, Gregster!

I know I'm reviving an old topic, but I'm slightly concerned about the possibility of growth problems. I'm almost sisteen years old and I was wondering if there could be any problems with growth or heart development. This is with taking Adderall or Dextroamphetamine.

I know I'm reviving an old topic, but I'm slightly concerned about the possibility of growth problems. I'm almost sisteen years old and I was wondering if there could be any problems with growth or heart development. This is with taking Adderall or Dextroamphetamine.First, the heart doesn't "develop" after birth other than to grow larger along with the rest of the body. At 16, you don't need to be worried about your heart unless you already have a condition. If you 're concerned about that possibility, you should talk to your doctor.

Regarding growth, all medications come with risks, but the risks of stunted growth due to stimulants is very low. There are readily-available products and foods with greater risks.

Now, the risks with illicit drugs like methamphetamine is another story...