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and patients should be advised to use the drug only for the treatment of narcolepsy and all other indications should be withdrawn from market authorization, the press release said.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 website.

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 EMA�s recommendations.

US market

Provigil was 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.

Provigil addiction

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 Association.�

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.

Physicians 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 advised.

�Modafinil was 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 therapeutic actions.�

�In addition,� they reported, �a recent imaging study in anesthetized monkeys documented significant occupancy of dopamine transporters by intravenously administered modafinil.�

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 Reference.�

The referenced 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.

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, he warned.

The implications 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 Cephalon.

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.�

�This mechanism 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.

�Dr. Biederman�s misrepresentation of the serious risks posed by this drug, whose target population is children with ADHD, requires reexamination and correction,�they wrote.

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 package insert.�

�However, the 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.�

�Further, the labeling reflects information provided to the FDA at the time of submission of the compound and not necessarily the universe of scientific information available,� he wrote.

�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 said.

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.

However, Biederman 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.