“Some of the children were prescribed anti-psychotics, rather than discontinued from ADHD therapy.”

One of the positive after effects of FDA advisory hearings is the rippling waves elsewhere on the globe: "Documents obtained by The Australian revealed almost 400 adverse reactions had been reported to the Therapeutic Goods Administration (TGA), some involving children as young as three."   Australian Parliamentary Secretary of Health is to meet which Novartis executives to discuss young children suffering strokes and heart attacks from drugs prescribed for ADHD.

From reports in the Pink Sheet (a publication focusing exclusively on FDA issues) following the March 22 Pediatric Advisory Committee meeting devoted to testimony about evidence of ADHD drug induced psychiatric hazards, we learned that committee members were disturbed to learn–from testimony presented by AHRP representatives–that  2.5 million children labeled with ADHD were prescribed antipsychotics in 2002. And from FDA medical officers they learned that children suffered hallucinations from stimulants prescreibed for ADHD:

“The committee heard about reports of children experiencing hallucinations – many of which included tactile and visual delusions involving insects, snakes and worms. Some of the children were prescribed anti-psychotics, rather than discontinued from ADHD therapy.”

Furthermore, though the committee did not vote, panel members comments show they were favorably disposed to some of AHRP recommendations for action. Specifically, they agreed that steps were needed to impact on physician prescribing–to stop prescribing antipsychotics for children made psychotic by psychostimulants.  Panel members agreed to AHRP recommendations (1) to require physicians to provide families with MedGuides,  (2) AND require parental informed consent:  

The Pink Sheet reports:
“Several committee members went further and backed a kind of informed consent document that could be signed by patients or parents.  Committee member Robert Daum (University of Chicago) cited a vaccine informed consent model that creates "a partnership between parents and children and providers." "Those vaccine information sheets have been very successful, parents have to read them and sign them," Daum noted.”
Warnings should communicate specific actions to be taken by a physician if a child on an ADHD drug experiences an episode of psychosis or mania, a number of committee members said.  "We need to communicate to the pediatrician…in the face of those kinds of reactions, that discontinuation of the drug would be a reasonable first step," committee consultant Robert Wade (University of Utah) said.

Psychiatric drug-induced adverse effects were the focus of the meeting, not drug-induced suicide. However, when the risk of suicide was raised, FDA’s Thomas Laughren suggested that “suicidality is common in the pediatric population. "[The Centers for Disease Control] sample 20,000 high school students and they find anywhere from 15% to 20% of normal kids who admit to having suicidal ideas."

That CDC data is clearly at odds with claims made by Dr. David Shaffer and the promoters of TeenScreen. Mass mental screening of America’s school children is being promoted as a suicide prevention strategy. Dr. Shaffer’s rationale for mental screening rests on his (unproven) claim that 90% of adolescents who are suicidal are mentally ill—and (again the unsubstantiated claim) that suicide can be prevented by screening and treating children who screen “positive” for mental illness.

The evidence shows that the treatment being offered for children who screen “positive” for mental health problems is overwhelmingly drugs—the drugs prescribed put children’s lives at risk.

See: AHRP recommendations for the protection of children from life-threatening adverse drug effects at: http://www.ahrp.org/cms/content/view/113/28/


See: AHRP testimonies: joining me were Allen Jones and Ellen Liversidge.
Power point presentations at:
http://ahrp.org/testimonypresentations/FDApediatric0306.ppt
Ellen Liversidge testimony at: http://www.ahrp.org/cms/content/view/113/28/

Contact: Vera Hassner Sharav
veracare@ahrp.org <mailto:veracare@ahrp.org>  
~~~~~~~~~~~~~~  
PinkSheet
March 27, 2006
Volume 68  |  Number  013  |  page 3
  ADHD Drug Warnings In New Highlights Section Replaces Need For Black Box
 
The ability to highlight warnings under FDA new labeling rule may obviate the need for a "black box" warning against risks associated with attention deficit/hyperactivity disorder drugs, FDA’s Pediatric [sic Oncology] Advisory Committee suggested March 22.
"From an information perspective, I think it’s less important you put [risk information] in a black box, when you can now frame it much more appropriately where it ought to be in terms of the contraindications or the precautions and warnings" in the Highlights section described by FDA’s

Physician’s Labeling Rule, Committee Chairman Robert Nelson (Children’s Hospital of Philadelphia) said at a post-meeting FDA press briefing.
The Highlights of Prescribing Information section, one of the key labeling changes instituted by FDA’s February Physician Labeling Rule, is a concise presentation of prescribing information, including safety risks, to be presented in the first half-page of labeling.

The committee convened March 22 to review potential cardiovascular and psychiatric adverse events, including psychosis/mania, aggression and suicidality, associated with the use of ADHD therapies such as Lilly’s Strattera (atomoxetine) and Cephalon’s pending Sparlon (modafinil), in addition to traditional amphetamine (Shire’s Adderall) and methylphenidate products (J&J’s Concerta and Novartis’ Ritalin).
"Part of the motivation at times for a black box is to get it up front….Now the Highlights are up front," Nelson explained. "It’s a highlight of the entire label." When a black box is included in the Highlights section it becomes "sort of a mini black box," Nelson added.

Office of Medical Policy Director Robert Temple noted at the FDA press briefing that while not all companies with ADHD drugs are required to update their labeling when the new rule takes effect, he hoped that they would do so .

Overall the committee felt that the psychiatric and cardiovascular risks with ADHD drugs do not rise to the level of a black box warning.
FDA’s Drug Safety & Risk Management Advisory Committee suggested a black box for cardiovascular risks with ADHD drugs at its Feb. 9 meeting.

 The drug safety committee also recommended a medication guide for ADHD drugs, a suggestion echoed by the pediatric oncology subcommittee.  A MedGuide was recommended to enhance communication of risks and concerns with ADHD drugs between the physician and patient or parent of a child.  "The problem has been a failure to communicate," committee consultant Daniel Pine (National Institute of Mental Health) asserted. "There is a need for patients and parents to sit down with physicians."

Temple explained the circumstances that merit a MedGuide as "something so troublesome that people need to understand this before they even use the drug or that there’s something that, if they knew about, they could track and follow to avoid future troubles. Would you say that threshold has passed?"  "Speaking from the psychiatric perspective," Pine said. "I think that threshold has been passed."

Several committee members went further and backed a kind of informed consent document that could be signed by patients or parents.  Committee member Robert Daum (University of Chicago) cited a vaccine informed consent model that creates "a partnership between parents and children and providers." "Those vaccine information sheets have been very successful, parents have to read them and sign them," Daum noted.

The committee emphasized that any MedGuide or informed consent document should mention alternative therapies. A MedGuide for ADHD drugs should also include information on FDA’s MedWatch to inform patients "that there is a place to let the government know about bad stuff that happens," committee member Judith O’Fallon (Mayo Clinic) said.

Warnings should communicate specific actions to be taken by a physician if a child on an ADHD drug experiences an episode of psychosis or mania, a number of committee members said.  "We need to communicate to the pediatrician…in the face of those kinds of reactions, that discontinuation of the drug would be a reasonable first step," committee consultant Robert Wade (University of Utah) said.

Pediatric Health Organization Representative Richard Gorman said that dictating practice "sounds like a great suggestion, whether in a MedGuide or even perhaps in the labeling."

The committee heard about reports of children experiencing hallucinations – many of which included tactile and visual delusions involving insects, snakes and worms. Some of the children were prescribed anti-psychotics, rather than discontinued from ADHD therapy.

An analysis of post-marketing adverse event reports of psychosis/mania submitted to MedWatch between January 2000 and June 2005 found that 58% of amphetamine cases, 33% of atomoxetine reports and 48% of methylphenidate events resulted in a positive de-challenge, a discontinuation of therapy with a resolution of the psychotic episode.

"That thing I’m worried about…where the MedGuide would help, where it might even warrant a black box, if this is common, where somebody hallucinates and then gets put on an anti-psychotic drug. That would really be something worth making sure it doesn’t happen," committee member Thomas Newman (University of California) said.

Current labeling for approved ADHD therapies does not clearly address the risk of drug-induced signs of psychosis/mania or state that patients who develop such symptoms should discontinue drug therapy.

The MedWatch review found that 3% of amphetamine, 3% of methylphenidate and 9% of modafinil cases resulted in a positive re-challenge, suggesting a causal effect between ADHD drugs and psychotic reactions.  "Psychosis is not an event that occurs really very commonly in this population," FDA Psychiatry Products Division Director Thomas Laughren noted. "It’s not like aggression or suicidality where those events are very common in this population, psychosis is not."

While committee members felt comfortable discussing possible hallucinations with ADHD drugs, some members appeared disturbed by the use of the general term "psychosis" to describe such events. "We are throwing [around] the term ‘psychosis’ very loosely," committee psychiatric consultant Jorge Armenteros (Coral Gables, Fla.) said. "If labeling talks about psychosis and we’re ascertaining psychosis and mania, I think that’s a dangerous ground to walk." Armenteros is a new member of FDA’s Psychopharmacologic Drugs Advisory Committee.

While the committee thought that that hallucinations fall outside the realm of normal child behavior, adverse reports of aggression can be harder to interpret due to that fact that "aggressive behavior is part of the phenomenology of the condition of which psychosis is not," Nelson said.

"There is quite a big difference with the aggression," Pine noted. "There is actually quite a rich database that looks at the effect of psychostimulants on aggression. There’s pretty good evidence that there are less increases of aggression."

Committee consultant Benedetto Vitiello (National Institute of Health) noted that aggression should be seen as a contraindication only if the child does not previously exhibit aggressive behavior. "We don’t want to give the message that aggression is a reason to refrain from using medication," he said.

Of the events reported to MedWatch, 89% of amphetamine, 81% of atomoxetine and 91% of methylphenidate cases occurred in children with no prior history of aggression.
Due to the prevalence of heightened aggression in many ADHD patients, the committee was hesitant to advise discontinuation of drug use if the condition occurs.

"What I hear is that you’d be a little lighter weight on this because you’re not sure, but you’d like to remind people that [aggression] is a possibility," Temple summarized. "This is obviously a weaker signal."

The committee also expressed lesser concern about the risk of suicidality and cardiovascular adverse events with ADHD drugs in children. The committee recommended some precautions and said the risks should be viewed as a class effect (see 5 following story).
Contents copyrighted © F-D-C Reports, Inc. 2006; protected by U.S. Copyright Law.
  ~~~~~~~~~~~~~

THE PINK SHEET
March 27, 2006
Volume 68  |  Number  013  |  page 5
  Suicidality Risk With ADHD Drugs Should Be Treated As Class Effect – Committee.
.
The risk of suicidality in children receiving drugs to treat attention deficit/hyperactivity disorder should be viewed as a class effect, FDA’s Pediatric Advisory Committee recommended March 22.

"They are chemically similar," committee Chairman Robert Nelson (Children’s Hospital of Philadelphia) said. "It would be hard to justify different labeling for the different drugs." Lilly’s Strattera (atomoxetine) is currently the only ADHD drug to carry a black box warning concerning the risk of suicidal ideation in pediatric patients (1"The Pink Sheet" Oct. 3, 2005, p. 8). Other ADHD drugs such as methylphenidate (J&J’s Concerta and Novartis’ Ritalin) and amphetamine (Shire’s Adderall and Adderall XR) products do not carry the warning.

At the committee’s June 2005 meeting, the group was reluctant to recommend labeling changes for Concerta and methylphenidate products for fear that a warning about suicidality would be interpreted as causality.

 In the interim, the warning was added to Strattera and more data on suicidal events have been collected from companies at FDA’s request. The committee discussed the class effect in the context of data showing different rates of suicidal behavior for the various ADHD drugs. The different rates, committee members suggested, could be due to the large differences in patient exposures and the sizes of the databases analyzed.

"There is more patient care exposures in [atomoxetine] product development than there is the entire sum of the other stimulants," Nelson noted. "Whether that’s just simply what’s being seen because it’s a richer database or because there are differences or not…that’s a different set of questions."

Randomized double-blind pediatric clinical trials of atomoxetine were considerably larger and/or longer than those of other ADHD therapies; 525 person-years of exposure were recorded in Strattera clinical trials versus 26 and 64 person-years for Ritalin and Adderall XR. Patient-years of exposure for Cephalon’s Sparlon (modafinil) was listed as 75 years.

FDA’s review of the data suggests that the frequency of suicidal events is higher with modafinil and atomoxetine. Double-blind pediatric trials yielded 5.3 reports of suicidal events per 100 patient-years for modafinil and 1.5 events per 100 patient-years for atomoxetine, respectively, none of which were completed suicides. No events were reported with oral or transdermal methylphenidates in the clinical trials. The rate for Adderall XR was 1.6 events per 100 patient-years.

One of the reasons for recommending that drugs with different mechanisms of action be treated similarly with regard to suicidality risk was the committee’s fear that patients would be switched from one ADHD medication to another with equal risk of suicidality.  "If we single out one class and put a label on that one and change the labeling…people shift to the other class. There’s just that there’s less data with that class," committee member Thomas Newman (University of California) said.

FDA, however, expressed discomfort at treating suicidality as a class adverse effect. "We’re not seeing signals other than the atomoxetine and that’s already labeled, and we’re sort of seeing signals for modafinil," Psychiatry Products Division Director Thomas Laughren said. "I’m not comfortable extrapolating findings from two programs to the other programs."

Laughren went on to note that suicidality is common in the pediatric population. "[The Centers for Disease Control] sample 20,000 high school students and they find anywhere from 15% to 20% of normal kids who admit to having suicidal ideas."
Office of Medical Policy Director Robert Temple summarized the debate by stating "fair isn’t the issue, right is the issue."

While the committee felt that the risk of suicidality is probably similar across the ADHD drug class, the committee was more concerned about episodes of psychosis, especially hallucinations, and possible aggression reported with the drugs. The committee recommended labeled warnings and a MedGuide to communicate the risks to physicians and parents (see 3preceding story).

Contents copyrighted © F-D-C Reports, Inc. 2006; protected by U.S. Copyright Law.
 
 
 http://theaustralian.com.au <http://theaustralian.com.au/>  
The AUSTRALIAN    
Drug chiefs called in after children suffer strokes
Clara Pirani and Patricia Karvelas
28 March 2006

AN urgent investigation has been launched into claims drugs used to treat attention deficit hyperactivity disorder could be killing children.

Parliamentary Secretary for Health Christopher Pyne will also meet pharmaceutical company executives this week to discuss whether such drugs should carry stronger warnings.

Mr Pyne yesterday said he had requested an urgent meeting with Novartis Australia, in response to a report in The Australian that children as young as five had suffered strokes, heart attacks, hallucinations and convulsions after taking ADHD medication.

Documents obtained by The Australian revealed almost 400 adverse reactions had been reported to the Therapeutic Goods Administration, some involving children as young as three.

"I’ve asked the people of Novartis, who are the makers of Ritalin, to come and see me this week and explain why Ritalin shouldn’t have a black box applied to it," Mr Pyne said.

Black box warnings signify that a drug may cause dangerous side-effects. They are the strongest warnings that can be issued by drug regulators.

"The problem is that doctors are inappropriately prescribing Ritalin because they think it’s the wonder drug for children with ADHD," Mr Pyne said.

"I’m very concerned about this. Parents are entitled to expect the Government to protect them from those kind of (drugs) that lead to the deaths of their children. I have spoken to the head of the TGA and directed him to fast-track an investigation of the use of Ritalin, including speeding up discussions with the FDA in the United States, who are also investigating."

A spokeswoman for TGA said there was no conclusive evidence ADHD was linked to sudden death or cardiovascular episodes. However, data obtained by The Australian showed the TGA’s reports lacked detailed information about the side-effects experienced by dozens of children. Many of the reports failed to note the patient’s age.

In more than 60 cases the TGA did not conduct any follow-up investigation to find out whether individuals recovered from the side-effects.

    
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