FDA Advisory Committee: discontinuation of the drug would be a reasonable first

April 12, 2006

FDA Advisory Committee: " discontinuation of the drug would be a

reasonable first step "

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

http://www.ahrp.org/cms/ <http://www.ahrp.org/cms/>

FYI

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. "

" 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, "

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 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 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 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.

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 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

212-595-8974

veracare@... <mailto:veracare@...>

~~~~~~~~~~~~~~

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 (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, " 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, "

added.

Office of Medical Policy Director 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 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 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 Wade (University of Utah)

said.

Pediatric Health Organization Representative 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 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 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 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, " 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

(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, "

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 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 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 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 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 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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April 12, 2006