Hyperactivity Disorder - Just What Kids Need - Sparlon - Another ADHD
The pharmaceutical company, Cephalon
Inc, is going through the motions of legitimizing the sale of Sparlon
for the treatment of ADHD even though its active ingredient, modafinil,
has been heavily promoted and sold under the name Provigil, for
off-label treatment of ADHD by Cephalon for years.
Last October, the FDA sent an
"approvable" letter to Cephalon for the pediatric use of Sparlon pending
a March 23, 2006, meeting of the Psychopharmacologic Drugs Advisory
Committee to review the drug’s approval.
Modafinil-based Provigil is
currently only approved for narcolepsy, sleep apnea and shift work sleep
disorder, according to the FDA. However, it is estimated that half of
all Provigil prescriptions are written for off-label use.
"Doctors now prescribe it to treat
everything from attention deficit hyperactivity disorder (ADHD) to
fatigue associated with multiple sclerosis and depression," according to
the November 1, 2004 Business Week Online.
Cephalon gets nearly half of its
$1.2 billion in annual sales from modafinil. Its original patent ran out
in December 2005. However, in a sweetheart deal, Cephalon agreed to pay
4 generic drug makers, including Mylan Laboratories and Teva
Pharmaceutical, over $200 million to postpone marketing generic versions
of the medication until October 2011, GoozNews reported on March 17,
In addition, the Cephalon will get a
6-month extension of that agreement if it wins a pediatric approval for
the drug, according to documents filed with the Securities and Exchange
With Sparlon's application to FDA
approval, Cephalon claimed 3 studies involving more than 600 children
aged 6 to 17, found the drug to be more effective than a placebo.
Which says what? What does it mean
to be more effective than a placebo? The question is, how many trials
did it take to get the drug to win out over a placebo three times?
Each of the Sparlon studies lasted
only 9 weeks and the most common side effects listed were mild insomnia,
headaches and loss of appetite. Sparlon was "generally well-tolerated,"
What does "generally
well-tolerated," mean? Tolerated better than what? A placebo?
One study of 248 patients was
published in December 2005 issue of Pediatrics, and said Sparlon's
effectiveness and safety profile, along with its low potential for
abuse, may offer doctors and parents a new option for children and
adolescents with ADHD.
However, because the study only
lasted 9 weeks, the authors said they did not know if "the initial
benefits will be sustained over longer periods of time," and called for
more research to assess the "longer-term efficacy and safety."
Dr DuBose Ravenel, MD, who will
testify on behalf of the International Center for the Study of
Psychiatry and Psychology at the advisory committee hearing on March 23,
makes the point that although “48% of drug treated subjects at final
follow-up were "much" or "very much" improved clinically, 52% were not.”
“This is a substantially lower
response rate than has been reported for traditional stimulants,” the
Dr Dubose Ravenel is a pediatrician
with 25 years experience in private practice with a heavy emphasis upon
behavioral issues, including diagnosing and managing ADHD.
In addition, he notes, with regard
to potential conflicts of interest, itemized conflicts for each of the
Pediatric study’s authors are numerous.
For instance, “Dr. Biederman
received research support from 10 companies, serves on speakers' bureaus
for 4 companies, and is on advisory boards of 6 companies,” Dr Dubose
“Dr. Kratochvil,” he advises, “has
received research support from, served as a consultant for, and/or
served on speakers' bureaus for 10 pharmaceutical companies.”
Other authors have numerous listed
conflicts as well he notes.
“In light of recent widely
publicized articles showing widespread deceptive practices engaged in by
pharmaceutical companies in designing, selective reporting, and
interpreting studies,” he says, “the large number of pharmaceutical
company ties with the authors of the study do not lend confidence to the
reader even beyond the aforementioned concerns.”
Initial marketing of modafinil, Dr
Dubose Ravenel concludes, “as a drug for treating ADHD reveals
inaccurate and exaggerated claims concerning efficacy, safety, and the
mechanism of action by which the drug works.”
And come to find out, it seems
Sparlon is not so "well-tolerated" after all. Last week the FDA
announced that an analysis provided by Cephalon as part of its response
to the FDA's “approvable” letter found 4 suicidal events, 2 events of
psychosis/mania and 9 aggression events in the double blind clinical
studies of Sparlon, in a summary report for the Pediatric Advisory
In addition, two events of
psychosis/mania and 14 aggression events were seen in open-label studies
of modafinil for ADHD, the FDA said. These rates are compared to 5
aggression events and no suicidal or psychosis/mania events in placebo
patients from the double-blind trials.
“There were more events in all
categories among modafinil treatment patients compared to placebo, but
the exposure to modafinil was greater,” the FDA said.
“It will be noted, however, that the
frequency of these events during double-blind treatment was higher than
during open-label treatment,” the FDA said.
The FDA summary also pointed out
that “two additional probable cases of aggression during double-blind
treatment, in study 207”, were found by the agency's Psychiatry Products
A March 3, 2006, memorandum to
various FDA’s divisions on drug safety, from FDA official Andrew
Mosholder, noted that psychosis/mania events occurred during
double-blind treatment with every ADHD drug studied except Adderall XR.
“With respect to psychosis and mania
events,” the memorandum wrote, “although the numbers of such events with
drug treatment were small, the complete absence of such events with
placebo treatment was notable.”
The memorandum also noted that
suicidal events were found to be more frequent with modafinil treatment
than with placebo.
At a hearing last month on February
9, 2006, Dr Mosholder, told the FDA's Drug Safety Advisory Committee
that modafinil, marketed as Provigil, is a stimulant. He said “modafinil
is a different type of stimulant, marketed for excessive sleepiness
associated with various sleep disorders.”
“It too may have some cardiovascular
effects,” Dr Mosholder told the panel. “There was a finding that use of
antihypertensives during the clinical trials was more frequent than on
placebo, which suggests that there are some cardiovascular effects there
Promoters of modafinil contend it
can be useful in the treatment of cocaine addiction. In the August 2005,
American Journal of Psychiatry, Charles O’Brien, MD, PhD, claims
modafinil, the active ingredient in Sparlon, may decrease cocaine use in
some cocaine users and specifically states:
“The medication has not been
reported to produce euphoria, and there has been no indication of
excessive use or abuse in clinical trials" As the scientific basis for
his comments, Dr O’Brien references his own group’s work
According to Psychiatrist, Dr Stefan
P Kruszewski, MD, "the author’s statement does not appear to be
supported by his referenced work, nor is it supported by information
widely available in the 2004 edition of the Physicians’ Desk Reference.”
The referenced article, Dr
Kruszewski says, may demonstrate that modafinil can, in some cases,
blunt cocaine euphoria. However, it does not say anything about
modafinil’s intrinsic ability to produce euphoria (or not), he says.
"Separately," Dr Kruszewski advises
in the March 2006, American Journal of Psychiatry, "the 2004 PDR raises
specific concerns about modafinil, saying that it can produce
"psychoactive and euphoric effects, alterations in mood, perception,
thinking and feelings typical of other CNS stimulants."
"The PDR also states that "modafinil
is reinforcing, as evidenced by its self-administration in monkeys
previously trained to self-administer cocaine," he adds.
In addition, says Dr Kruszewski, the
comment about the lack of euphorigenic effects is contradicted by the
FDA in a January 14, 2002, warning letter sent to Paul Kirsch, the
senior director of regulatory affairs at Cephalon, that specifically
reiterates the drug's package insert addressing the modafinil's
euphorigenic effects and its potential for abuse.
That the euphorigenic side effects
or abuse potential may be minimized has current treatment implications
because modafinil is increasingly promoted for fatigue and excessive
sleepiness unrelated to narcolepsy as well as for cocaine abuse, Dr
Kruszewski says in the Journal.
Sparlon's approval is set to be
reviewed by the Psychopharmacologic Drugs Advisory Committee on March
Last month, Allen Jones, testifying
as a representative of the Alliance for Human Research Protection, told
the advisory panel: "Most of you have had past or current relationships
with the drug industry.”
As it turns out, conflicts of
interest exist on this month’s advisory panel as well. Wayne Goodman,
the chairman of the Psychopharmacologic Drugs Advisory Committee that
will consider Sparlon's approval heads the psychiatry department at the
University of Florida, which receives hundreds of thousands of dollars a
year in research grants from 2 of Cephalon's competitors in the field of
Another member of the Committee,
Andrew Leon of Cornell University, disclosed he owns less than $25,000
in stock in a Cephalon competitor, according to GoozNews on March 18,
The Pediatric Advisory Committee is
meeting on March 22, 2006, the day before the Sparlon hearing, to focus
on neuropsychiatric adverse event reports and clinical trial data from
approved ADHD medications, and will also receive an update on
cardiovascular adverse events possibly related to ADHD medications,
according to the FDA web site.
By Evelyn Pringle
Evelyn Pringle is a columnist for Independent Media TV and an
investigative journalist focused on exposing corruption in government.
Books on ADHD
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