On July 22, the
European Medicines Agency recommended restricting the use of modafinil. Doctors
and patients should be advised to use the drug only for the treatment of
narcolepsy and all other indications should be withdrawn from market
authorization, the press release said.
In addition to the
brand name, Provigil, marketed by Cephalon in the US, modafinil is also sold as
Alertec, Modalert, Modavigil, Modiodal, Provake, and Vigil.
A review by the
Agency�s Committee for Medicinal Products for Human Use (CHMP), began in May
2009, because of safety concerns relating to psychiatric disorders, such as
suicidal thoughts, depression, and psychotic episodes, and life threatening
skin reactions, as well as significant off-label use and potential for abuse.
CHMP looked at all
the clinical trial data on modafinil for narcolepsy, obstructive sleep apnoea,
shift-work sleep disorder and idiopathic hypersomnia, and articles from the
published literature. CHMP also reviewed all the side effects reported on
modafinil-containing medicines, and convened a group of experts on clinical
neurosciences to provide advice, according to a Q&A document on EMA�s
On the basis of the
available data, CHMP concluded that the benefits of modafinil only outweighed
the risks in treating narcolepsy and the clinical trials for other disorders
did not provide strong evidence to support use of the drug. For other
indications, CHMP found the data on effectiveness insufficient to outweigh the
risks of skin reactions, psychiatric adverse reactions, and cardiovascular
adverse reactions, such as hypertension and irregular heart beat.
CHMP concluded that
the product information should carry a recommendation saying modafinil should
not be prescribed to children and use of the drug be contraindicated in
patients with uncontrolled moderate-to-severe hypertension and cardiac
arrhythmias. The recommendations were forwarded to the European Commission for
the adoption of a binding decision, the press release said.
Because CHMP noted
in its review that modafinil has often been used for conditions not indicated,
the drug makers were asked to carry out further studies, including a �drug
utilisation study,� to look at why family doctors prescribe the drug, according
to the Q&A. In addition, data on misuse by university students is currently
being collected and will be analyzed once available, the EMA reports.
The Medicines and
Healthcare product Regulatory Agency issued a �stop press� notice in the August
2010 edition of �Drug Safety Update,� reminding healthcare professionals of the
approved for narcolepsy in late 1998, which only affects around 200,000 people
in the US, according to a July 2010 report by Global Industry Analysts.
US sales began in
February 1999. Ten months later, �25 percent of narcolepsy patients in the
country, more than 31,000 people, were taking the drug. It generated $25
million in 1999 sales, and Cephalon�s revenue nearly tripled to $45 million,�
according to an August 1, 2000 report, by Matthew Herper, on Forbes.com.
A November 20, 2002,
New York Times article reported that Cephalon CEO, Frank Baldino, himself, was
taking Provigil, but would not say what condition he used it for. Provigil is
short for �promotes vigilance,� according to the Times.
Use of the drug is �expanding
rapidly, with more than 80 percent of the prescriptions written to treat the
fatigue and sleepiness associated with many other diseases, like depression and
multiple sclerosis, or even just sleepiness caused by no disease at all,� the
article reported in 2002.
At that time,
Baldino denied that the drug was or would be abused. �I don�t think it�s going to
happen, because we�re careful about how we sell it and doctors are careful how
they write prescriptions,� he told the Times.
�He added that the
growing use of the drug for conditions other than narcolepsy is being driven by
physicians, not by Cephalon�s marketing,� the article said.
Less than 11 months
earlier, the FDA had sent a letter warning Cephalon to quit promoting Provigil
for off-label uses. The FDA objected to language indicating the drug could be
used for symptoms such as sleepiness, tiredness, decreased activity, lack of
energy and fatigue. �Provigil is indicated to improve wakefulness in patients
with excessive daytime sleepiness associated with narcolepsy. Provigil is not
approved for use as a daytime stimulant,� the FDA wrote in January 2002.
The letter requested
an immediate end to the dissemination of �all sales aids, journal
advertisements, websites and all other promotional materials and activities for
Provigil that contain the same or similar violations.�
In 2002, Provigil
sold for $5 a pill and some insurers were reluctant to pay that price for
narcolepsy because amphetamines were much cheaper, according to the Times.
The treatment of
excessive sleepiness associated with sleep apnea and shift work sleep disorder
with Provigil were not approved until January 2004. Right before the Summer
Olympics in August 2004, the World Anti-Doping Agency added modafinil to the
list of banned drugs after a runner in the 2003 World Track and Field
Championships tested positive for it.
On March 17, 2009,
Harrisburg, Pennsylvania psychiatrist and addiction specialist, Dr Stefan
Kruszewski, told USA Today that he was currently treating his third case of
Provigil addiction. �I had two doctors back-to-back who were addicted to
modafinil,� he said, �so I became alarmed.� Both were also alcoholics.
The same day,
Bloomberg ran the headline, �Narcolepsy Pill Used as Smart Drug May Be
Addictive,� in reporting a study, by researchers at the National Institute on
Drug Abuse, that found Provigil �effects the same brain chemicals as stimulants
like Ritalin and amphetamines.�
�PET or positron
emission tomography scans of the brain activity in 10 healthy volunteers who
took the drug showed it boosted the level of dopamine circulating in the part of
the brain involved in pleasure, reward and addiction,� Bloomberg wrote, in
summarizing the study published in the �Journal of the American Medical
The increase of
dopamine seen with the medicine is �the signature for drugs that have the potential
for producing addiction,� Nora Volkow, the lead author and director of the
National Institute on Drug Abuse, told Bloomberg.
prescribing Provigil should �be alert to the possibility that it could produce
addiction,� she said. Consumers also should be aware the drug �may have more
abuse potential than originally believed.�
Volkow wanted to add
questions about the Provigil to the Institute�s annual survey of high school
drug use, she told Bloomberg.
The study noted that
Provigil was being used off-label by people who want to boost their mental
ability. �Modafinil is increasingly being diverted for nonmedical use by
healthy individuals with the expectation that it will improve cognitive
performance,� the authors wrote in the March 18, 2009 Journal.
�The growing use of
modafinil in clinical medicine and as a cognitive enhancing agent and the
uncertainties surrounding the mechanisms underlying its pharmacological effects
highlight the need to better understand its mechanisms of action,� they
developed with an expectation that a medication could have a nondopaminergic
target for its wake-promoting effects,� they said. �However, the current
findings in humans, along with preclinical studies documenting the
indispensable role of dopamine in the wake-promoting effects of modafinil,
support modafinil�s dopamine-enhancing effects as a mechanism for its
�In addition,� they
reported, �a recent imaging study in anesthetized monkeys documented
significant occupancy of dopamine transporters by intravenously administered
They also pointed
out that �modafinil was shown to be self-administered in monkeys previously
trained to self-administer cocaine.�
But the potential
for abuse is not the only reason why healthy people should not take modafinil
or other so-called �smart drugs,� Volkow told USA Today. They can have serious
adverse effects, such as brief psychotic episodes, she said, and there is
little evidence they improve cognition. Modafinil also significantly increased
heart rate and systolic blood pressure, the study found.
In the paper, the
authors pointed out that there had been previous �debate surrounding its
potential for abuse,� and cited two examples. The first, was a March
2006 Letter to the Editor, of the American Journal of Psychiatry, from Dr Kruszewski, in response to an August
2005 paper in the Journal, by Dr Charles O�Brien, that claimed modafinil may decrease cocaine use in some cocaine users and
specifically stated: �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, O�Brien referenced two studies by his own research
group. In his letter, Kruszewski wrote that, �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
article may demonstrate that modafinil can, in some cases, blunt cocaine
euphoria, he said. �However, it does not say anything about modafinil�s
intrinsic ability to produce euphoria (or not).�
In fact, 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,� he wrote.
The PDR also states
that �modafinil is reinforcing, as evidenced by its self-administration in
monkeys previously trained to self-administer cocaine,� Kruszewski noted.
He pointed out that
the comment on the lack of euphorigenic effects was also contradicted by the
FDA in a January 14, 2002, warning letter sent to Paul Kirsch, the senior
director of regulatory affairs at Cephalon, which specifically reiterates the
drug�s package insert addressing the modafinil�s euphorigenic effects and its
potential for abuse.
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,
loomed even larger, he said, because Cephalon had submitted a �reformulated�
modafinil to the FDA under a new name for the treatment of children and
adolescents with attention deficit hyperactivity disorder.
The second example of the debate, was a June 2007 Letter to
the Editor, of the Journal of Clinical Psychiatry, from Dr Kruszewski and Dr Steven Klotz, in response
to an article published in an August 2006 supplement to the Journal titled,
�New Developments in the Treatment of Attention-Deficit/ Hyperactivity
Disorder,� by Dr Joseph Biederman,
Chief of Pediatric Psychopharmacology at Massachusetts General Hospital and
Professor of Psychiatry at Harvard Medical School.
The supplement was underwritten by an educational grant from
In his article,
Biederman stated: �The pharmacologic profile and structure of modafinil are
notably different from those of stimulants and other agents used to treat ADHD,
and modafinil may reduce the core symptoms of ADHD via the same mechanism by
which it improves wakefulness -- selective activation of the cortex without
generalized effects on the central nervous system.�
results in reduced abuse potential and less likelihood of jitteriness, anxiety,
or excess locomotor activity than traditional stimulants,� he claimed.
Their concern with
Biederman�s commentary was that �it appears to seriously misrepresent
modafinil�s neuropharmacologic characteristics, contradicting the science-based
evaluation of the data by the U.S. FDA and DEA,� Kruszewski and Klotz wrote.
�Dr. Biederman may
have misrepresented modafinil�s pharmacologic (stimulant) properties and
minimized modafinil�s abuse potential -- as described in the authoritative
FDA-approved product label,� they told the editor.
misrepresentation of the serious risks posed by this drug, whose target
population is children with ADHD, requires reexamination and correction,�they
In conclusion, they
correctly pointed out that if Cephalon �ere to directly mischaracterize
modafinil�s pharmacocharacteristics -- as Dr. Biederman has -- they could be
prosecuted under federal law.�
In a June 2007 reply letter, Biederman wrote, the �background research to support the
claims of Drs. Kruszewski and Klotz begins and ends with the manufacturer�s
manufacturer�s package insert is neither a standard of care nor the most
comprehensive and up-to-date review of the preclinical or clinical science
about a molecule,� he said. �Were
that so, new knowledge or findings would never be able to be conveyed to the
field until the company or the U.S. Food and Drug Administration (FDA)
determined to alter the manufacturer�s package insert.�
labeling reflects information provided to the FDA at the time of submission of
the compound and not necessarily the universe of scientific information available,�
�The letter by Drs.
Kruszewski and Klotz seriously misrepresents the facts, shows ignorance about
the neuropharmacologic characteristics of modafinil, and demonstrates a failure
to understand the clinical significance of alternative treatments for ADHD,�
the hubristic Biederman told the Editor.
�As an independent
clinician-researcher and not the agent of the manufacturer, I am compelled to
base my teaching on all the information and knowledge available to me,� he
However, an investigation,
the very next year, by the US Senate Finance Committee, led by Iowa Republican
Senator, Charles Grassley, found Biederman to be far from independent from
Cephalon. For instance, when disclosing plans for a study sponsored by Cephalon
in 2001, Biederman claimed he had no financial relationship with the sponsor.
But seven years later, in March 2008, Grassley found Cephalon had paid him
$13,000 in 2001.
Again in 2005, when
Biederman began another trial, sponsored by Cephalon, to run from September
2005 to September 2006, he disclosed no financial relationship with the firm.
But in March 2008, Grassley learned that Cephalon had paid him $11,000 for
honoraria in 2005, and an additional $24,750 in 2006.
In fact, all total,
Biederman had earned about $1.6 million from drug companies between 2000 and
2007, but failed to report about $1.4 million on forms filed with Harvard.
In disclosures at
the end of his reply letter, Biederman listed 14 drug companies, including
Cephalon. In December 2008, Mass General announced that Biederman would no
longer be participating in several drug company funded trials and would limit
his speaking and consulting activities, pending the outcome of an inquiry of
his potential conflict of interests and disclosure obligations.
As mentioned by
Kruszewski in his letters to the editor, Cephalon had applied for approval of
modafinil (in a larger dose formulation called Sparlon), to treat children and
adolescents with ADHD, in December 2004.
was out giving talks promoting off-label use with kids long before it came up
for approval. On May 26, 2005, in Doctors Guide Dispatch, Bruce Sylvester
reported on a May 24th presentation titled, �Modafinil Pediatric Formulation
Has Early and Sustained Effect in ADHD,� given by Biederman at the annual
meeting of the �American Psychiatric Association,� on a study funded by
Cephalon and led by Biederman, which claimed Sparlon was effective for children
aged 6 to 17 with ADHD.
�This study not only
shows that this medication is effective and rapid in onset for the treatment of
pediatric ADHD,� Biederman said in the presentation. �It also gives the clear
signal that here we have a medication that can be used by physicians to treat
ADHD in children who cannot tolerate amphetamine salts or for whom the
clinician simply prefers not to use amphetamine salts.�
Another study, in
the December 2005, �Pediatrics� journal, with lead investigator Biederman, said
Sparlon�s effectiveness and safety profile, along with its low potential for
abuse, may offer doctors and parents a new option for children with ADHD. At
that time, Biederman�s disclosures showed he received research funding from ten
drug companies, served on the speaker�s bureau of four, and sat on advisory
boards of six.
In applying for FDA
approval, Cephalon submitted three trials of Sparlon on less than 700 children.
According to a report by FDA reviewer Andrew Mosholder, �two kids experienced
psychotic or manic episodes; four kids considered suicide; and nine kids
engaged in serious �aggression events� in the modafinil trials,� Merrill
Goozner reported in GoozNews on March 20, 2006.
�That was the
equivalent of 20 negative reactions for every 100 patients who take the drug
for a year,� Goozner said. �Only Adderall and a skin patch had a worse record.�
In the end, an FDA
Advisory Committee determined that Sparlon was not safe enough to be marketed
to kids, by a vote of 12 to 1, in March 2006, and in August 2006, Cephalon
reported that the FDA had rejected the drug for children and the company
decided to end development of Sparlon.
Part II will be published tomorrow.
Evelyn Pringle is an
investigative journalist focused on exposing corruption in government and