“While there is a lot of focus on children … the numbers tell me that the magnitude of the excess risk is quite profound in adults.”
A line was thus drawn at FDA’s advisory committee hearing, between those concerned about drug safety—including FDA safety officers—and those concerned with protecting sales of psychostimulants—i.e., prescribed amphetamine—with all of the attendant dangers, in particular cardiovascular and cerebrovascular risks, including strokes and heart attacks.
FDA officials who had convened the meeting in response to recent reports of 25 deaths, had no intent to take action. Their expectation was for the panel to recommend further research which would put the safety issues on hold for several years. Indeed, Dr. Thomas Laughren, director of the Division of Psychiatry Products at the agency, said: “The main purpose of the meeting was to look at study design to review this.”
News reports (below) from Associated Press, New York Times, Los Angeles Times, TIME, noted that FDA officials at the meeting were taken by surprise when the committee “in an unexpected twist” took safety seriously, reasoning that “the evidence of serious risks was so great that a strong new warning — not just more research — was needed.”
TIME reports that cardiologist, Dr. Steven Nissen of the Cleveland Clinic who was among the early warners on the risks of Vioxx, made a motion for a black box warning. He was concerned that the 25 cases might be just the tip of an iceberg. “There’s no mandatory reporting of these cases.”
Dr. Nissen noted that the stimulants in question are known to raise blood pressure and heart rate. “Raising blood pressure of a child or adult continuously over many years worries me,” Nissan told TIME. “There is a linear relationship between increased blood pressure and adverse cardiovascular events.” Nissan further notes that two stimulants that are related to the Ritalin class of drugs—ephedra and phenylpropanolamine (PPA)—have been banned from the market because of cardiovascular risks.”
Another panel member, Dr. Curt Furberg, concurred, stating: it would be “inappropriate, unethical behavior” for the FDA not to disclose to doctors and patients that there was uncertainty about the safety of ADHD drugs.
Most telling to those present was the very aggressive resistance of senior FDA officials in the agency’s Center for Drug Evaluation Development who are essentially watchdogs FOR industry’s interests not watchdogs for public safety—as mandated under the Food Drug and Cosmetics Act. In particular, Dr. Thomas Laughren fought hard and broke protocol when he interjected his opposition against Black Box warnings. (FDA officials are only supposed to offer their views when requested to do so by advisory committee members). Even after the vote, at a hastily arranged news conference, Dr. Laughren said “We don’t think anything different needs to be done right now….We think the labeling right now is adequate.”
But as the news about these drugs’ life-threatening risks hit the air waives, the public was once again left to wonder: can we trust the FDA to protect us from unsafe drugs whose risks are concealed? Why do FDA officials try to sabotage efforts to alert the public about drug safety ?
ADHD is a controversial “condition” whose wide range of “symptoms” can be readily “detected” in just about every one of us. See New York University Dept. of Psychiatry self-test: http://www.med.nyu.edu/psych/psychiatrist/adhd.html
Indeed, the Los Angeles Times reports that as many as 4 million Americans take the medications, and government figures show that about 10% of all 10-year-old boys in the United States get the drugs; about 4% of girls that age use them. “No one is saying that there aren’t children who are desperately dysfunctional and need these drugs,” Nissen said. “But it isn’t 10% of 10-year-olds.”
Until Eli Lilly launched Strattera (2002), ADHD drugs were prescribed only for children. Since then prescriptions for adults shot up 90% and sales for ADHD drugs increased from $759 million in 2000 to $3.1 billion in 2004.
Dr. Thomas Fleming, a biostatistician at the University of Washington, and panel member, suggested that the heart risks of attention deficit drugs might be comparable to those of the painkiller Vioxx and other so-called Cox-2 inhibitors. “While there is a lot of focus on children … the numbers tell me that the magnitude of the excess risk is quite profound in adults.”
Of additional concern—not raised by any of the FDA’s advisory committees:
Since polypharmacy is a widely used wild card in psychiatric practice, and children as well as adults are often prescribed a psychotropic drug cocktail, the risks of psychostimulants need to be examined in context with the other even more toxic psychotropic drugs: antidepressants, and antipsychotics.
The stack of empirical evidence—from clinical trials and practice–about the serious risks linked to these three categories of widely misprescribed drugs measures higher than the height of some of the children / toddlers for whom they are prescribed. Only 1% to 10% of the adverse events are reported to FDA’s MedWatch. Between 1990-2000 the FDA received 186 reports of deaths, but did nothing to warn physicians or parents.
A follow-up Infomail will be from AHRP representatives who testified at the meeting.
Contact: Vera Hassner Sharav
The Los Angeles Times
Warning Urged for ADHD Drugs
An FDA panel cites heart risks in its advisory on Ritalin and similar medications.
By Ricardo Alonso-Zaldivar
February 10, 2006
WASHINGTON — A Food and Drug Administration advisory panel Thursday urged that the strongest possible safety warning be issued for drugs used by millions of children and adults to treat attention deficit hyperactivity disorder, because of emerging concern that they may increase the risks of heart attacks, strokes and sudden death.
The FDA had called the drug safety experts together to help design further research into such risks. But in an unexpected twist, the committee concluded that the evidence of serious risks was so great that a strong new warning — not just more research — was needed.
“This is out-of-control use of drugs that have profound cardiovascular consequences,” said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic and member of the panel. “We have got a potential public health crisis. I think patients and families need to be made aware of these concerns.”
Although ADHD is commonly associated with children, members of the safety panel emphasized that the drugs could pose a greater danger to adults. The FDA has received reports of about 25 deaths linked to the drugs and of a larger number of cases involving serious health consequences, such as heart attacks.
The panel voted, 8 to 7, to call for a “black box” warning on literature distributed with the drugs — which include well-known brands such as Ritalin, Adderall and Concerta. As many as 4 million Americans take the medications, and government figures show that about 10% of all 10-year-old boys in the United States get the drugs; about 4% of girls that age use them. “No one is saying that there aren’t children who are desperately dysfunctional and need these drugs,” Nissen said. “But it isn’t 10% of 10-year-olds.”
The safety experts also voted unanimously to recommend that a brochure be provided to patients and families to inform them in greater detail about the risks and benefits of using the drugs. And it urged the FDA to expedite studies to better understand the drugs’ effects.
Senior FDA officials said that they would study the panel’s recommendations and that they planned to refer the issue to another advisory committee dealing with psychological problems in children. The agency has been criticized in the past as being slow to respond to evidence of health risks associated with medications, including painkillers and antidepressants.
“You don’t want to over-scare people and make them not use an important drug,” said Dr. Robert Temple, a top policy official at the FDA. “But you don’t want people using drugs if they don’t have to.”
Drug makers said Thursday that the attention deficit medications were safe when taken as directed. They noted that some had been in use for more than 50 years. Shire Pharmaceuticals Group, the maker of Adderall, said that it would work with the FDA to make sure patients had the necessary information, but that stronger warnings were not needed. Novartis, which makes Ritalin, said it had reviewed its own data and had not seen any increase in heart risks for patients. The companies suggested there probably were other explanations for the deaths and serious health issues reported to the FDA, such as heart problems that had gone undetected before the patient began taking the medication.
Most of the attention deficit drugs are derived from powerful stimulants, including amphetamines. They are believed to help patients concentrate, though exactly how they work is not clear. But they also raise blood pressure, a major risk factor for heart disease and stroke.
Attention deficit hyperactivity disorder can make it difficult for children to apply themselves in school; adult patients may have trouble with multi-tasking. In the United States, about 2.5 million children and 1.5 million adults are taking medication for the condition. The drugs have been widely prescribed for children since the 1990s, but their use to treat adults is relatively new. Prescriptions written for adults increased by 90% from 2002 to 2005. And the risks for adults may be greater, since high blood pressure and heart conditions are more prevalent among adults. Currently, 10% of those taking ADHD drugs are 50 or older.
FDA officials convened Thursday’s meeting amid concerns about the drugs’ potential health problems. “We wouldn’t be going through this exercise if we didn’t think there was a real possibility of an increase in risk,” said Dr. David Graham, the FDA drug safety investigator who was one of the first to call attention to the heart risks of Vioxx, a leading painkiller withdrawn from the market in 2004. “There’s smoke. Does that represent fire, or not? We want to answer that question.”
The risks appeared to be different for children and adults. Graham and his colleagues undertook a preliminary study using information in the databases of large health insurers and government programs. Their early findings indicated a higher-than-expected number of heart attacks and strokes among adults taking the medications. Among children through age 18, the number of strokes was higher than expected, but the number of heart attacks was lower.
Not all ADHD drugs are the same. Strattera, made by Eli Lilly & Co., is not classified as a stimulant. But several panel members said the warnings should apply to the entire class of drugs, without exception. That might help put a brake on over-prescribing, they said.
Panel member Thomas Fleming, a biostatistician at the University of Washington, suggested that the heart risks of attention deficit drugs might be comparable to those of the painkiller Vioxx and other so-called Cox-2 inhibitors. “While there is a lot of focus on children … the numbers tell me that the magnitude of the excess risk is quite profound in adults,” Fleming said.
For adults to continue taking ADHD drugs, the benefits of therapy would have to be shown to be substantial, he said. But some panel members said the benefits and risks of the medications for adults had not been extensively studied. Temple, the FDA policy official, said agency officials would discuss internally how to address the problem of the emerging risk for adults.
The committee members suggested several types of studies to look at safety issues for all patients. One option would be to pore through the databases of insurers, as Graham’s preliminary study had done. Another would be to compare heart function in patients taking ADHD medications with that of people who have similar characteristics but don’t take the medicines. Such studies might take two years or more to complete.
The FDA’s database of reports of adverse drug reactions is not thought to be complete enough to base a study on it. Experts estimate that 1% to 10% of serious drug reactions are reported to the agency.
Canada halted sales of Adderall last year after health authorities there received 20 reports of sudden deaths in patients. But the drug was allowed back on the market after statistical studies indicated it was no riskier than other medications. It is not recommended for patients with underlying heart problems, however.
TIME–Getting Hyper About Ritalin
Why an FDA advisory panel suggested strong warnings for Ritalin, freaking out parents and patients—and even doctors
By CLAUDIA WALLIS
Posted Friday, Feb. 10, 2006
Slapping a “black box” warning on a prescription drug is not an action that the Food and Drug Administration takes lightly. So when an FDA advisory committee recommended on Thursday that the agency’s strongest safety warnings be placed on packages of the massively popular drug Ritalin and similar stimulants used to treat Attention Deficit Hyperactivity Disorder (ADHD) and its less frenetic cousin, ADD, the suggestion made national headlines and generally freaked out patients, parents and more than a few doctors.
“Mothers around the country now think they are playing Russian Roulette with their kids,” says psychiatrist Edward Hallowell, author of three popular books on ADHD, including Delivered From Distraction.
The recommendation was made on a close (8 to 7) vote, because of concerns that these drugs may have dangerous effects on the heart. An estimated 2.5 million children and 1.5 million adults currently take these stimulants, which include the popular brands Adderall, Concerta and Metadate.
Oddly enough, the panel wasn’t meant to consider the issue of drug labeling. Instead, it was exploring whether some rare but frightening instances of sudden death occurring in people taking these drugs warranted further study. There have been 25 such cases reported to the FDA in recent years, though it’s uncertain that the drugs caused the deaths. In addition, the panel looked at preliminary data suggesting an increased risk of arrhythmias and strokes associated with these medications. “The main purpose of the meeting was to look at study design to review this,” explained Dr. Thomas Laughren, director of the FDA’s division of psychiatry products.
But the meeting took an unexpected turn when cardiologist Steven Nissen of the Cleveland Clinic made a motion for a black box warning. Dr. Nissen, who was among the early warners on the risks of the now-withdrawn arthritis drug Vioxx, was concerned that the 25 cases might be just the tip of an iceberg. “There’s no mandatory reporting of these cases,” he says. He notes that the stimulants in question are known to raise blood pressure and heart rate. “Raising blood pressure of a child or adult continuously over many years worries me,” Nissan told TIME. “There is a linear relationship between increased blood pressure and adverse cardiovascular events.” Nissan further notes that two stimulants that are related to the Ritalin class of drugs—ephedra and phenylpropanolamine (PPA)—have been banned from the market because of cardiovascular risks.
The panel’s recommendation also reflects a general concern among some members of the medical community that use of ADHD drugs has spun out of control in the U.S. “No where else in the world are 10% of 10 year-old boys diagnosed and treated for ADD,” says FDA panel advisor Curt Furberg, a professor of public health at Wake Forest University, who voted in favor of the warning. “I don’t argue that there are some kids who need that treatment, but it’s probably overused.” Doctors Furberg and Nissan are also concerned about the rising number of adults on these drugs. About 10% are over 50, a group that has a higher rate of cardiovascular problems to begin with. Says Dr. Nissan: “I want the physicians’ hands to tremble a bit when they write a prescription for these drugs.”
FDA clearly wasn’t expecting such a bomb to go off in a routine meeting, but now the agency must deal with the fallout. A black box warning is unlikely. “We don’t feel the risk is well enough established,” said Dr. Laughren. But studies of the cardiovascular effects of these drugs are likely to get underway, and, given how many Americans are already taking them, they are probably long overdue. The FDA will also weigh a unanimous recommendation by the panel to make potential risks to the heart more apparent in the patient guides given out by pharmacies. That topic will doubtless come up for discussion next month when a pediatric advisary panel meets to discuss ADHD drugs.
In the meantime, doctors who prescribe these drugs are left to contend with jittery patients and their parents. “Are we now supposed to do regular EKG’s on every kid on Ritalin?” asks Dr. Gabrielle Carlson, a child psychiatrist at Stony Brook University School of Medicine. “What on earth is the poor consumer to do?”
She and other psychiatrists point out that unlike Vioxx, Ritalin is a drug with a 50 year history. Says Dr. Hallowell, “I have never had a patient suffer a lethal side effect nor anything close to it. I have had to discontinue the medication, perhaps once out of every 10 times I prescribe it, due to side effects,” which include weight loss, insomnia, tics and twitches, and personality changes. “These meds are far from perfect,” says Hallowell, “but they are the best medication option we have and are very safe when used correctly.”
Those who disagree and want a strong warning may not get their black box, but they’ve accomplished their goal of alerting patients to possible risks. Last week’s flurry of headlines took care of that.
THE NEW YORK TIMES
February 10, 2006 p. A-1
Warning Urged on Stimulants Like Ritalin
By GARDINER HARRIS
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 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.
Benedict Carey contributed reporting from New York for this article.
Copyright 2006The New York Times Company
Feds Recommend Warnings on ADHD Drugs
By ANDREW BRIDGES,
Federal science advisers voted narrowly Thursday to recommend the most serious type of warning labels for Ritalin and other stimulants that are used to treat attention deficit hyperactivity disorder.
The 8-7 vote, with one abstention, by the Food and Drug Administration committee was to recommend adding “black box” safety warnings to ADHD drugs. Doctors prescribe the increasingly popular drugs to about 2 million children and 1 million adults a month.The FDA isn’t required to follow the recommendations of its advisory committees but typically does.
The federal agency originally had asked the scientific panel to consider ways of studying the drugs, which include amphetamines, such as Adderall, and methylphenidates, sold as Ritalin, Concerta, Methylin and Metadate.
The agency’s own data suggested a link between the drugs and an increased risk of sudden death and serious cardiovascular problems, including heart attacks.
The panel quickly turned to a debate on whether it should consider new warnings for the drugs rather than simply discuss the need for more studies.
Panel member Dr. Curt Furberg said it would be “inappropriate, unethical behavior” for the FDA not to disclose to doctors and patients that there was uncertainty about the safety of ADHD drugs.
Dr. Steve Nissen told his colleagues they should push for the black box warning on the drugs’ packages.
The drugs already bear warnings related to the possible risk they could pose to patients with heart defects, the FDA’s Dr. Gerald DalPan said. “We feel this warning is appropriate given our current knowledge of these drugs,” he said prior to the votes.
The balloting on warning labels followed an earlier 15-0 vote to recommend that the FDA require that the drugs include a medication guide for patients and parents.
A federal health official said Thursday that there was a strong possibility the drugs may be linked to the deaths of 25 people. “There’s smoke. Does that represent a fire?” asked Dr. David Graham of the Food and Drug Administration.
The deaths occurred between 1999 and 2003, according to an FDA report. Nineteen of them involved children. The report also detailed 54 cases of serious cardiovascular problems, including heart attack, stroke, hypertension, palpitations and arrhythmia, in adults and children being treated with ADHD drugs. Some of these patients had pre-existing heart conditions or hypertension.
The FDA said it has tallied an additional 26 deaths between 1969 and 2003 in ADHD patients involving death by suicide, intentional overdose, drowning, heat stroke and from underlying disease.
The FDA’s Drug Safety and Risk Management advisory committee was reviewing different ways to study whether the deaths were linked to use of the drugs. The few studies that have looked at longer-term use of ADHD drugs provide little information on those risks, the FDA said.
Analysis of the reports of death and injury suggests a possible link between the drugs and cardiovascular problems, the FDA’s Dr. Kate Gelperin told the panel. But the link is not conclusive, nor is it clear whether there is an increased incidence of death or serious injury, she said. That, Gelperin said, “is really a question we’d like to have answered.”
An FDA review found fewer than one death or serious injury per 1 million ADHD drug prescriptions filled, with one exception: 1.79 cases per million of nonfatal cardiovascular or cerebrovascular problems in adults treated with amphetamines.
Sales of ADHD drugs increased to $3.1 billion in 2004, from $759 million in 2000, according to IMS Health, a pharmaceutical information and consulting firm. That stepped up use could spell increased risk. “Because adults have a higher risk of heart disease and stroke to begin with, any increase in risk caused by these drugs could affect a large number of people,” Graham said.
The FDA’s Canadian equivalent, Health Canada, briefly pulled the ADHD drug Adderall XR from the market last year. A Canadian panel eventually concluded there was inadequate evidence of increased harm from the drug. The FDA reached a similar conclusion at the time.
Adderall is made by Shire Pharmaceuticals and Ritalin is made by Novartis Pharmaceuticals Corp. Various other companies make generic versions of Ritalin as well.
Copyright © 2006 The Associated Press. All rights reserved.
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